The H.M. Pharma Consultancy Blog

Drug Repurposing Patent Blog, Issue #2

2012-02-13T10:02:00.000+01:00

Todaywe highlight four PCT documents published between January 12 andFebruary 2, 2012: cancer drug candidates for neglected tropicaldiseases; ifetroban, a THX2 receptor blocker, for hepaticencephalopathy; the oral antidiabetic, glibeclamide for peripheraland CNS ischemia and injury; and losartan for psoriasis.

ForwardThe Patentome!

mTOR/PI3KInhibitors for Trypanosomatid Diseases

NVP-BEZ-235

TheWHO estimates that every year over 22 million people are infectedwith Trypanosomabrucei, T. cruzi,and Leishmaniasp. For African trypanosomiasis (sleeping sickness) there are fourdrugs available, most of them old and all with severe side effects:suramin (used since the 1920s) and pentamidine, introduced in the1940s; melarsoprol (one of the very few arsenic-containing drugsstill in use), and eflornithine, an irreversible ornithinedecarboxylase inhibitor. For visceral leishmaniasis and Chagasdisease the situation is comparable. - And now there might be acommon alternative for all of these: WO/2012/006619(Northeastern Univ. [US]; Jan. 12, 2012)demonstrates that T.bruceiand L.majorpossess enzymes from the mammalian targets of rapamycin (mTOR) classthat are essential for their cell growth and virulence. In addition,trypanosomatid genomes encode at least 12 proteins belonging to thephosphoinositide-3-kinase (PI3K) protein superfamily, some of whichare unique to parasites. Eli Lilly's LY294002(a morpholine derivative of quercetin), Wyeth's WYE-354,and most of all Novartis' imidazo[4,5-c]quinoline NVP-BEZ-235(see structure; first claimed in WO/2006/122806and now in Phase II for various solid tumors) are dualmTOR/PI3Kinhibitors that werefound to be highly effective. - Thispatent document has a July 2010 priority date, and a peer-reviewcompanion paper published in PLoSNeglected Tropical Diseasesin August 2011 (PDF).

Ifetrobanfor Hepatic Encephalopathy

Ifetroban(BMS 180291-02) is an injectable thromboxane A2 receptor antagonistcreated by Bristol-Myers Squibb which migrated to VanderbiltUniversity and then to Cumberland Pharmaceuticals, Inc. which in 2011started clinical studies for hepaticencephalopathy as a complication of the hepatorenal syndrome(pressrelease). The new application seems plausible (but alsonon-trivial) considering that the literature on this drug almostexclusively concerns endothelial dysfunction in the context ofgeneral cardiovascular conditions. The rationale is that high levelsof liver-derived isoprostanes mediate microvascular constriction andpermeability via thromboxane receptor activation, and that anantagonist will normalize cerebral blood flow. A Phase II study(NCT01436500)is currently recruiting patients, and is scheduled for completion inOctober 2015. WO/2012/009545(Cumberland Emerging Technologies [US], Jan.19, 2012)is the IP document covering this new indication.

GlibenclamideInfusion for Ischemic Attacks and CNS Injury

Glyburide(glibenclamideoutside the U.S. and Canada) is an old sulfonylurea-class oralantidiabetic drug. In WO/2012/012347(Remedy Pharmaceuticals [US]; January 26, 2012)the formulations are intravenous infusions (development code RP-1127)for emergency use in stroke, traumatic brain or spinal cord injury,myocardial infarction, hemorrhagic shock, and acute ventriculararrhythmia. Phase II studies are recruiting patients for the twofirst-mentioned indications (NCT01454154for TBI and GAMES-PILOTfor stroke). An earlier Phase I study has been concluded, from whichthe patent document discloses pharmacokinetics data. The staged 0.4mg/day dose regimen according to the invention builds glibenclamideplasma concentrations of 4-5 ng/ml within 15 hours. This dose had avery minor effect on blood glucose levels; it was more pronouncedwith the 3.0 mg/day dose but still without hypoglycemia, which wouldbe damaging in ischemic conditions. The inventors believe thatglibenclamide levels of approx. 25 ng/ml should be targeted. - It iswell known that the sulfonylurea receptor 1 (SUR1) plays a key rolein various forms of CNS injury (see here).Specifically, glibenclamide has been shown to reduce hippocampalinjury and to preserve spatial learning in a model of traumatic braininjury (see here).The potential effects of anti-diabetic medications on myocardialischemia-reperfusion injury have recently been discussed (see here),and its has been demonstrated that exenatide (also a K(ATP) channelopener) prevents endothelial dysfunction in a human model ofperipheral ischemia-reperfusion injury (see here).

Losartanfor Psoriasis

WO/2012/013990(indiv. inventors [GR]; Feb. 2, 2012) is one of those patentapplications that make you scratch your head. Titled "Medicationfor curing the disease of psoriasis," it has exactly three pages(two if you don't count the front page), gives no data and cites noliterature. It simply states that losartan potassium (100 mg/dayp.o.) was given to 21 hypertensive psoriasis patients, and that 20"noted immediate regression, almost after the first week of themedication treatment. Whithin a period of 90 days, all the symptomsof the disease of psoriasis were disappeared." (sic) - That would benotable indeed because what little linkage can be found in theliterature points exactly to the opposite: angiotensin receptor IIantagonists can induce psoriasis (see hereand here).Any further details from the Greek inventors (who have not publishedin PubMed-listed journals) would be much appreciated. Indeed,learning about finding related to these claims would be a goodapplication of life science crowdsourcing. If you have something toadd, please use the blog comment section or our contact (below).

H.M.Pharma Consultancy is a leader in knowledge extraction from drugrepurposing patent documents, and gives strategic advice todevelopers looking for repurposing opportunities. Find out more atwww.hmpharmacon.comor contact us at office@hmpharmacon.com.

Why we Need a Medical Patentome Array

2012-02-10T09:57:00.000+01:00

Patent databases are proliferating. There is not a single IP document published by the major offices (and an increasing number of smaller ones) that you could not download – free of charge because patent law demands distribution of information in exchange for granting exclusivity. In addition to all the usual Boolean searches for inventors, assignees and IPC categorization codes, the public databases maintained by the U.S., European and PCT offices allow you to search the full text. Google Patents offers bitmap scans of U.S. patents back to the late 18th century and has put everything granted by the USPTO since 1976 through a optical character recognition (OCR) process; the European ESPACENET has been doing the same using other resources.

Then there are dozens of vendors who provide added value services on a subscription basis. In most cases these are more or less ingenious applications of semantic search technologies which have been evolving like mad since the millennium. SureChem offers automatically extracted chemical information. Entire meta-services, such as Intellogist, exist solely to keep track of this scenery and to comment on the products' features.

And yet all such services do not nearly make full use of the scientific and technical information in IP documents in the way and to the extent medical researchers need it. This is because all patent databases are designed around the needs of intellectual property professionals – and these specialists have needs that are very different from the desires of those who want to treat patent documents the same way as peer review papers, namely as a source of scientific and technical information.

Working off OCRed paper documents has severe technical limitations. Look at how chemical names are rendered and no chemistry software will make sense of it -- no OCR software has dictionaries or correction algorithms for chemistry. Go back to the 1980s and you have typewritten patents; the OCR output that is so error-riddled even for normal text that you barely get an idea of the content. You have chemical formulas drawn with stencils or even by hand, and reaction schemes that combine all of this. A good example for the gibberish that results can be seen here. Mind you, all that is for English documents. Imagine the patent is, lets say, in French and you feed the OCR output into Google Translate, as the PCT's PatentScope database offers to do...

But now imagine for a moment that all IP documents relevant to a particular well-defined medical field have been identified and collated. Imagine the buried, distorted and implicit information contained therein captured in fully corrected fashion, chemistry and pharmacology extracted, annotated, tagged and hyperlinked within the database as well as to outside sources of scientific literature and chemistry. Now let all the cutting-edge semantic and chemistry software work on that. Imagine the prior art granularity such a “patentome” would provide. Imagine how many questions it could answer!

But hasn't IBM done such a thing for millions of patents last year (as reported e.g. here)? Well, what Big Blue did with its Strategic IP Insight Platform simply was what it does best: applying its hardware superiority to Big Data. The output is actually quite interesting, and will be useful to anybody who seeks the emulation of an entry-level patent analyst with no particular specialization. Its impressive only in the way IBM boasted that their SyNAPSE project had developed a “cognitive chip” that allowed them to simulate a cat brain by 2009, with the simulation of a macaque brain now within immediate reach. That type of PR came perilously close to a scam (and not a few cognition scientists say it was one), but of course the media picked up on it.

Don't get me wrong, one day we will have artificial intelligence systems that will accomplish all this -- and more if they actually achieve semi-sentience (which I guess won't happen until about 2025). Even then these machines will need to train on material that has been compiled and value-enhanced by human experts.

Until then we need true, high-granularity patentomes with perfect data quality for well-defined but overlapping areas of the medical sciences. With its THIRDSPACE project H.M. Pharma Consultancy has developed a plan how this could be accomplished through qualified crowdsourcing, and we are progressing towards the exemplary patentome of ocular pharmacology and biotechnology. That will ultimately allow perfect navigation of the ophthalmology patent space, with interconnections to the outside online universe. Stay tuned while we work on it!

The Happy Toils of a Consultancy With Drug Development Ambitions

2012-02-01T10:10:00.000+01:00

Ah, what a month January has been! The power of networking and collaboration is making itself felt. Our business development path until midyear has been mapped, as far as such planning can go. No guarantees of course - there are no such things if you are working in the truly independent line. To paraphrase Clausewitz' pun on battles, no business plan survives contact with reality as long as you are treading unknown ground.

You will have noticed that this blog has been given a new design -- simpler, fewer gadgets, easier to read, and with all the options to switch between views accessible from the menu. The color scheme is now better aligned with that of our Twitter site - and of course with that of our website.

But that was a matter of minutes. Other things have been making more demands on our time and creativity. Transitioning our general patent reviews to the soon-to-be-launched journal, Pharmaceutical Patent Analyst has required some tweaking of our formatting to meet the standards of the Future Science Group. But thats good, such things force us to reconsider well-trodden paths. In addition, refocusing the more informal patent highlights on this blog exclusively on IP documents that touch on drug repurposing has tickled our creative thinking in more than one way.

Off-Target Drug Repurposing

If you are looking for openings in this field each such published patent application speaks of a missed opportunity: "Hey, I might have had this idea myself!" - Never mind that; the intersection of unmet need space in medicine and the unexploited pharmacological potential of known compounds will not be exhausted for many years to come. As you might remember from some of my earlier ramblings here, we believe intelligent prior art search in our own focused databases and exhaustive text analysis - in conjunction with know-how in drug development - to provide as a distinctive edge in drawing up concepts for drug repurposing. The figure illustrates one potential embodiment of this strategy.

We have formalized several concrete project proposals for redeveloping drugs or drug candidates - some discontinued, some not -, and these have already attracted enough attention to be tested by interested parties. If, when and how we can move forward with any of these depends [A] on the outcome of the experiments (to be awaited), [B] on the tenacity of our development partners (beyond doubt of course), and [C] on the degree of external funding that can be racked up this year or in early 2013 -- provided that the science can be made to work. Expressions of interest to that effect are of course invited.

The HMPC Drug Repurposing Patent Blog Issue #1

2012-01-23T16:47:00.000+01:00

Here is our first post focusing on international patent applications that concern themselves with some new applications for known or discontinued drugs. In this pilot issue we highlight documents published between December 29, 2011 and January 12, 2012.
H.M. Pharma Consultancy is a leader in knowledge extraction from drug repurposing patent documents, and gives strategic advice to developers looking for repurposing opportunities. Find out more at www.hmpharmacon.com. or contact us at office@hmpharmacon.com.

An ACAT-1 Inhibitor for Diabetes

Kowa Co. Ltd. is developing K-604, a competitive inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase-1, as an oral drug candidate for atherosclerosis (see here); a Phase II clinical study (NCT00851500) was completed in August 2011. The hypocholesterolemic mechanism is clear enough, but a direct antidiabetic action - with lowering of plasma glucose and insulin resistance, as claimed in WO 2011161964 (Kowa [JP]; Dec. 29, 2011) - is much more difficult to envisage. One lead to follow could be the fact that the old sulfonylurea antidiabetic, glibenclamide is also an ACAT inhibitor (see here). However, the chemical structure of K-604, which is N-[2,4-bis(methylsulfanyl)pyridin-3-yl]-2-(4-{2-[(6-methyl-1H-1,3-benzodiazol-2-yl)sulfanyl]ethyl)piperazin-1-yl)acetamide, is quite different.

Fragile X Mental Retardation Protein and Metastasis

Quite soon, Fragile X syndrome, the most common geneticall determined form of mental retardation, could become be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up (see here). And now, WO 2012/001178 (University Leuven [BE]; Jan. 5, 2012) tells us that the faulty Fmr1 gene product (deficient in its capability as an RNA-binding protein involved in multiple steps of neuronal RNA metabolism) may help prevent or reduce metastasis. The inventors stop short of claiming that inhibitors of group 1 metabotropic glutamate receptors (in particular, of mGluR5 as in the case of AFQ056, also under development for levodopa-induced dyskinesias) which are under investigation for Fragile X syndrome could be reporposed for metastasis -- after all, the mechanisms could be very different. However, claim 14 is for "an FMR1 inhibitor for use in the treatment and/or prevention of metastasis," and that's what counts in patenting.

Propofol for Influenza

WO 2012/004768 (Individual inventor [FR]; Jan. 12, 2012) is our definite favorite in this issue. For who would have expected this injectable anesthesia agent (2,6-diisopropylphenol; marketed as Diprivan by AstraZeneca, and as generic products) to protect against enveloped viruses? In specifically pathogen-free 10-day old chicken embryos protection against influenza A virus was observed at propofol doses between 32 µg and 625 µg per egg; the highest dose resulting in survival of all embryos. The peer-review literature does not seem to contain any data that might suggest such an effect. Note that hepatitis C virus can apparently survive in commercial preparations of propofol for extended periods; see here.

Etanercept for Fibromyalgia

Etanercept (Amgen's and Pfizer's Enbrel® for rheumatoid arthritis) is a recombinant fusion protein that captures tumor necrosis factor alpha. Of course TNFα, a proinflammatory cytokine, has been strongly implicated in fibromyalgia for many years (see e.g., here); but in WO 2012/004966 (Axis Inc. [JP]; January 12, 2012) the inventors claim to see room for getting etanercept patented for this application. In 2009 a paper from Lyon Hospital has stated the association between rheumatoid arthritis and fibromyalgia to be "fortuitous," and Chinese researchers found short-term use of etanercept (<3 months) to be without significant effect in fibromyalgia syndrome (see here).

Drug Repurposing Patent Highlights Feature in 2012

2012-01-16T08:57:00.000+01:00

In March 2012, the Future Science Group will launch a paper and online subscription journal, the Pharmaceutical Patent Analyst (PPA; ISSN 2046-8954). It will highlight and review patents of relevance to pharmaceutical science across all therapeutic areas, from small molecules to biologics. We are happy that H.M. Pharma Consultancy has been given the opportunity to establish a presence on PPA's international editorial board, and to contribute content during the new journal's formative first year. We congratulate the Future Science Group, which also publishes the journals Future Medicinal Chemistry, Clinical Investigation and Therapeutic Delivery, for its decision to join the pharmaceutical patent analysis publishing market. With Informa's Expert Opinion on Therapeutic Patents and Bentham's “Recent Patents on...” array of journals, this field is already well established and the New Kid On The Block will face some challenges – which can be mastered, provided that a distinctive and appealing profile is developed.

Under our current agreement we will publish 10-15 patent commentaries in each issue of PPA until January 2013. They will be much in the way of those you have become accustomed to on this blog but with significantly extended and deepened analysis.

However, this does not mean that we will abandon our monthly Patent Highlights. They will continue with a tighter focus as Drug Repurposing Patent Highlights, and instead of accumulating everything from the past month they will now be published under a news-driven schedule. These new Highlights will be shorter than before but will be published whenever a few remarkable IP documents claiming potential new applications for known drugs or drug candidates – under development, discontinued or marketed – cross our desks. That could mean two or even three such Highlights per month if ingenious people and diligent reviewers at the patent offices generate a swelling stream of such documents. But during slow times we will not bother you with trivialities, and then these posts might be five or six weeks apart.

These adaptive changes underscore our belief that finding new uses for known compounds holds tremendous potential which is only beginning to be tapped. Collaborative non-profit efforts are already successfully using this approach to make inroads towards new treatments for some of the so-called “neglected diseases,” such as malaria. For clever startup pharma enterprises with tight budgets but a lot of brainpower and out-of-the-box thinking, drug repurposing can be the Golden Way. In case you have forgotten, we have established a LinkedIn discussion group, “Drug repurposing - reprofiling – repositioning,” which currently has 286 members and will always accept more. And we are considering more plans.

Patent Highlights for December 2011

2011-12-30T14:49:00.002+01:00

Right before the New Year rockets are launched, we once again present and discuss some interesting life science patent disclosures. See you again in 2012!

PLEASE CITE AS : Mucke HAM. Patent Highlights for December 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/12/patent-highlights-for-december-2011.html) on December 30, 2011. Contact us at office @hmpharmacon .com .

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Screening for Calcification Modulators

In Greek mythology Klotho, the youngest of the three Moirae who guide the mortals' fate, was responsible for spinning and maintaining the thread of human life which her sister Lachesis had measured out. Quite appropriately, a signalling protein associated with premature aging (see here), tumor suppression, and epigenetic modifications has been assigned this name. Klotho is a transmembrane protein that acts as a cofactor for fibroblast growth factor 23 ( FGF23), but it also exists as a soluble circulating form which appears to protect against renal disease, hyperphosphataemia, increased oxidative stress, endothelial dysfunction, and diffuse vascular calcification. It is also intimately associated with accretion processes in bone metabolism and with atherosclerosis. WO 2011/158655 (Hiroshima Univ. [JP]; Dec. 22, 2011) presents screening methods for compounds that modulate the formation of soluble Klotho-containing complexes with FGF-23 and the FGF receptor. See WO 2011/071783 and WO 2011/068893 for Amgen's recent patenting on this subject.

Natural Compounds for MS and Pancreatic Cancer

Iridoids are bitter-tasting secondary plant metabolites, derived from isoprene and frequently glycosylated. They serve primarily as a defense against herbivores and insects, or against infection by microorganisms. There is also considerable medical value: iridoids from Valeriana species have recently been reported as having neuroprotective effects (see here); many others are known as anti-inflammatory constituents of plant extracts. WO 2011/153678 (Xuanwu Hospital [CN]; Dec. 15, 2011) combines these activities to suggest compositions containing morroniside and loganin (the actives in the traditional Chinese medicine Liu Wei Di Huang Wan, used i.a. for postmenopausal osteoporosis; paper here) for the treatment of multiple sclerosis. The neuroprotective potential of morroniside has been reported three years ago (see here).

In WO 2011/151831 (Carmel-Haifa Univ. Economic Coop. [IL]; Dec. 8, 2011) inventors have found cytotoxic components in new strains (CBS 126585 and HAI-1302) of Cyathus striatus , known as the bird's nest fungus. While most bioactive substances isolated from mushrooms are high-molecular-weight polysaccharides, the inventors have shown that ethyl acetate extracts obtained from mycelium or its culture medium contains small molecules (not identified in the application) that are toxic to the human pancreatic cancer cell lines HPAF-II and PL45. Cell cycle analysis, DNA fragmentation assays, caspase activation, and TUNEL staining support the claims.

News on Noble Gases in Medicine

The time when noble gases were believed to be incapable of chemical reactions is long past. Although xenon, krypton and argon are chemically inert under most circumstances, all have anesthetic and neuroprotective properties (see this review). This applies especially to xenon, which has the best lipid solubility, and can exert anti-excitatory activity by blocking NMDA receptors (but not N-type voltage-gated calcium channels or GABA-A receptors) at normobaric conditions. Given this pharmacology it is not very surprising that it could prevent relapses in addicted patients, as WO 2011/151551 (L'Air Liquide [FR]; Dec. 8, 2011) claims. Xenon inhalation worked in a rat model of stimulus-induced relapse into alcohol consumption, a paradigm which is regarded as highly relevant in human alcoholism.

A companion application, WO 2011/154630 (L'Air Liquide [FR]; Dec. 15, 2011) claims inhaled krypton for peripheral organ failure. There are no animal data; instead, extensive in vitro experiments using the U2OS osteosarcoma cell line are presented, showing reduced apoptosis under conditions that promote ischemia-reperfusion injury. L'Air Liquide, the leading supplier of medical gases, has dominated this exquisite field of patenting for many years.

Four Pieces of News on Vaccines

Active immunotherapies can be relied on to make their mark in international patenting each and every month. WO 2011/149389 (individual inventors [RU]; Dec. 1 2011) deals with autologous dendritic cell vaccines for hepatitis C virus; the patient's antigen-presenting cells are isolated, loaded with fragments of recombinant HCV core or NS3 protein (e.g., by electroporation), and re-infused. In a case study, a patient was treated with 1.5 ml of composition comprising 10⁶ autologous dendritic cells 10 μg of a 192 amino acid NS3 protein fragment) and 10⁷ activated lymphocytes. After the first course of therapy consisted of 5 rounds, the virus titre was decreased to from 10 ⁶-10⁷ virus particles/ml 400 ME/ml.

WO 2011/150249 (Selecta Biosciences [US]; Dec. 1, 2011) deals with multivalent vaccines where the individual immunization antigens are immobilized on distinct sets of synthetic nanocarriers. This can enable vaccine properties previously thought impossible. As an example, vaccines for Streptococcus pneumonia ( US 6,132,723 to Alberta Research Council and WO 2008/143709 to Wyeth) contain multiple polysaccharide-coupled antigens. Since the attachment chemistry conditions are not the same for all of them, coupling methods that would attach all of the surface antigens to a single population of nanocarriers in a single coupling environment would be undesirable. Another example of multivalent vaccines that could benefit from this embodiment of the invention comprise vaccines against Neisseria meningitides which is polysaccharide-based and multivalent, being directed at serogroups A and C (bivalent) or groups A, C, W135 and Y (tetravalent). Agonists for toll-like receptors 7 and 8, such as those disclosed in US 6,696,076, can also be attached to the carriers to act as adiuvants. Preferred adjuvants comprise imiquimod and resiquimod.

The leading cause of bacterial gastrointestinal disease worldwide is Campylobacter jenuni. Such infections are more frequent than those caused by Salmonella sp. or E. coli 0157:H7, which receive much more publicity. WO 2011/156619 (Univ. Arkansas [US]; Dec. 15, 2011) presents DNA vaccines that that include immunostimulatory polypeptide such as CD154 (CD40 ligand) or HMGB1 (high mobility group box 1) and are claimed to elicit mucosal, humoral, and cell-mediated immune responses against multiple serovars. Efficacy studies in broiler chicken and turkey poults are presented.

Reverse vaccinology, where a synthetic antigen is designed which structurally mimics an epitope of the target to be neutralized, must build on a good knowledge of the carbohydrate moieties that define this epitope and are a necessary component for antibody binding. WO 2011/156690 (Brandeis Univ. [US; Dec. 15, 2011) presents a method of directed evolution of carbohydrate-oligonucleotide conjugates by attaching carbohydrates to a library of DNA backbones and performing iterative aptamer selection with a monoclonal antibody that binds to the target. The mAb 2G12, which recognizes an epitope of the HIV envelope protein gp120, is used as an example.

NAGLU For Sanflippo

The type-III mucopolysaccharidoses (MPS-III; sometimes called the Sanflippo syndromes) are autosomal recessive deficiencies in brain enzymes that degrade gylcosaminoglycans. In MPS-IIIB the deficiency is in alpha-N-acetylglucosaminidase, expressed from the NAGLU gene. The most severe symptom is the progressive loss of cognitive ability, which results not only to the accumulation of heparan sulfate in neurons, but also the subsequent elevation of gangliosides. WO 2011/163652 (Shire Human Genetic Therapies [US]; Dec. 29, 2011) presents an enzyme replacement therapy consisting of an intrathecally delivered fusion protein consisting of the Naglu protein and a terminal lysosomal targeting moiety, such as insulin-like growth factor II (IGF-II) or Kif. Injection of Naglu-IGFII into Sanfilippo B mutant mice demonstrated extensive distribution well beyond the meninges, and reversal of lysosomal storage was achieved in the cerebral cortex as well as in the subcortical regions. For a recent paper on AAV vector-mediated gene therapy for MPS-IIIB see here.

A European Union Without the UK - and its Life Science Companies?

2011-12-09T18:58:00.002+01:00

During today's latest summit to save the Euro monetary union (and for once, it was a decisive summit!) , the United Kingdom has taken clear steps towards detaching itself even more from European collaboration and integration. That might serve to bolster the financial sector in London's City, but if Mr. Cameron's "bulldog fight" will really serve the country's overall best interests in the longer term is anybody's guess. Twenty-six against one is never going to be a very promising perspective.

One thing is for sure: the UK will remain outside the fiscal and political union that will eventually emerge on the Old Continent. There are already those who say that the UK joined the European Union only (with several opt-out clauses and exceptions from EU rules) to do what Great Britain has been doing for centuries - playing the continental powers against each other for its own benefit. There are also those who say that the UK is becoming more and more of a U.S. overseas territory anyway, and has merely taken one more step on this way. Whatever truth there might be in such attitudes, the UK political class is evidently viewing the dynamic German-French axis with deep suspicion - like some Fourth Reich emerging, as has been explicitly claimed here.

And what does this mean for Europe's pharmaceutical industry? GlaxoSmithKline - the single top-ten player with roots in the UK - is of course a globalized company, more a distributed state than a corporation; Shire, though in a much smaller league, is at least as much American as it is British, and highly internationalized all the same. Current events will have minimal impact on such companies; they have sufficient maneuvering mass to adjust and adapt.

What will happen to those small research-driven startup companies in the UK that have to a good part relied on European Union funding is a different matter entirely. Today and perhaps also during 2012, they won't feel much impact. But how these companies will fare when the apply for new funding in, lets say, the 8th Framework Programme... thats something I would not dare to predict at this point.

In H.M. Pharma Consultancy's recently published Protein Engineering Report we have shown that antibody engineering is one of the few fields of advanced therapeutics R&D where Europe plays in the same league as the United States; the small and extremely innovative European biotech companies that specialize here are almost all either German, or from the United Kingdom. How will the balance shift during the years to come?

It won't be a matter of "the continental powers taking revenge"; it will simply be a matter of the UK no longer being more than a very peripheral player in the community, by the country's own free choice. In a crisis-driven Europe that will now make a more determined stand to become economically and fiscally united - if only to avoid becoming an irrelevancy as Asia rises - the UK has chosen the place on the doorstep. Last week's government announcement of a £180 million U.K. biotech fund (see here) might not be a coincidence; it might be direly needed two or three years from now.

Patent Highlights for November 2011

2011-11-27T09:26:00.001+01:00

Greetings to our followers! Here are eight international patent applications from the life sciences published in October 2011, plus two that have the October 27 date but came online only in November after our last issue of these Patent Highlights was published. This review has new drugs for malaria, tuberculosis and viral infections; personalized therapy for Fragile X syndrome; a progranulin antibody for liver cancer; known drugs repurposed for mountain sickness, hyperlipidemia, tinnitus and ovulation induction; and a drug delivery implant for the inflamed knee joint.

PLEASE CITE AS: Mucke HAM. Patent Highlights for November 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/11/patent-highlights-for-november-2011.html) on November 27, 2011. Contact us at office @hmpharmacon .com.

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Oxoisoaporphines for Malaria, 4-Thioureido-iminomethylpyridinium for Tuberculosis

After a lull of decades, malaria drugs are becoming a hot topic now - economic development of countries where the disease is endemic, its re-emergence in major markets, and increased tourism to the tropics are making this happen. WO 2011/131816 (Univ. Santiago de Compostela [ES]; Oct. 27, 2011). The patent seems to be an outgrowth of computational biology efforts (see also here) using drug-protein interactions documented in DrugBank. The orally bioavailable 5-methoxy-6-oxoisoaporphine is highly active and selective in combating the first phases of liver infection by P. falciparum. - Tuberculosis, another re-emerging threat, is the objective of WO 2011/132114 (Pharmasyntez [RU]; Oct. 27, 2011). Very similar compounds to the one claimed here (see figure) have been described as cholinergic nerve gas antidotes (see here).

A Companion Diagnostic for A Fragile X Syndrome Drug Candidate

Novartis' AFQ056 (mavoglurant) is a mGluR5 antagonist under clinical investigation for levodopa-induced dyskinesia in Parkinson's disease, but also for Fragile X syndrome which is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. (Details for ongoing Phase II/III study here). In a pilot study, mavoglurant improved 7 patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA, but not 18 patients with partial promoter methylation, compared to placebo ); WO 2011/137206 (Novartis [CH]; Nov. 3, 2011) takes care of the intellectual property side of these findings (published here) by claiming levels FMR1 mRNA transcript, FMR1 protein levels, or methylation of an FMR1 gene region as biomarkers for drug responsiveness.

Destabilizing Viral Capsids for Antiviral Activity

CMPD-A

The HIV-1 capsid shell is composed of about 250 assembled mature capsid protein hexamers and 12 pentamers. WO 2011/139637 (Philadelphia Health & Education [US]; Nov. 10, 2011) uses this as the point of attack against HIV but also other viruses. 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid (CMPD-E, I-XW-053) showed IC50 valued between 51 and 94 µM for 4 HIV-1 strains from subtypes A, B and C. 4,4'-(5,5'-(dibenzo[b,d]furan-2,8-diyl)bis(4-phenyl-1H-imidazole-5}2-diyl))dibenzoic acid (CMPD-A; see figure) had an IC50 of 33 μΜ against HIV-1 but is even more effective against Dengue virus strains (IC50 = 2-8 µM) and respiratory syncytial virus (IC50 = 10.2 µM). Docking sites to the N-terminal domains of the viral capsid proteins and mechanisms for destabilization are proposed.

A New Attack Angle for Hepatic Cancer

A decade ago granulin-epithelin precursor (GEP, also progranulin, acrogranin, or PC-derived growth factor) was identified as a high molecular weight secreted mitogen, and later as a potential therapeutic target for hepatocellular carcinoma where it is overexpressed (see here). Its expression in liver cancer stem cells is associated with chemoresistance and reduced survival times. Suppression of GEP can enhance the apoptotic effect of chemotherapy because it also regulates the ATP-dependent binding cassette (ABC) drug efflux transporter family that play a role in chemoresistance, such as ABCB5 and ABCF1. Targeting GEP with RNA interference has been proposed, but monoclonal antibodies have also been described for some time. WO 2011/140828 (Hong Kong Univ. [CN]; Nov. 17, 2011) claims and characterizes such an antibody, alone and in combination with doxorubicin chemotherapy.

Hydroxymethylfurfural for Mountain Sickness

Alleviating the symptoms of altitudinal hypoxia in healthy persons might not be the most pressing concern of drug development; but there is no FDA approved drug that lowers the P50 value of hemoglobin (and thus increases its affinity for oxygen) in normal subjects. Mountaineers and people dispatched to high places for professional reasons are a market that could be addressed with relative ease - easier than the market for sickle-cell disease for which such drugs are normally investigated, for example by the company that now got WO 2011/146471 (AesRx [US]; Nov. 24, 2011) published. The preferred compound is 5-methoxy-2-furfural (5-HMF) or a prodrug thereof. This compound is present in heat-processed diary products such as coffee and caramel products, sometimes at a concentration above 6 g/kg - but the effective dose is 3-5 grams, so you would have to consume a lot of these products to not need the drug if you ascend to 3,000 meters and above.

More From the Drug Repurposing Cabinet

There are more examples that claim new uses for known drugs. WO 2011/144545 (Unilever [NL]; Nov. 24, 2011) claims theobromine for dyslipidemia - indeed, cocoa powder and dark chocolate, which contain theobromine, are known for this effect. In WO 2011/145062 (Link Research [PA/MC]; Nov. 24, 2011) it is the prototypical opiate receptor antagonist naltrexone, claimed here as being useful to treat tinnitus - a condition which is among the most difficult ones to address pharmacologically. This has a clear rationale, as the current model for tinnitus involves has dynorphins - endogenous opiates - enhancing the action of glutamate on sensorineuronal hair cells in the cochlea (see here). The main purpose of WO 2011/143752 (Univ. Saskatchewan [CA]; Nov. 24, 2011) claiming aromatase inhibitors such as letrozol for timing ovulation in an animal or synchronizing it in a herd, is a human-to veterinary transmigration - perhaps nobody has thought of using this application of anticancer agents (which is a new but established practice in in vitro fertilization; see here) in domesticated animals before.

An Artificial Bursa for Drug Delivery

WO 2011/139594 (Medtronic [US]; Nov. 10, 2011) offers a solution for the numerous (primarily degenerative and/or inflammatory) disorders which affect the normal workings of the knee. Advancing a concept that Medtronic and other medical device manufacturers have proposed before, the inventors propose inserting a flexible polymeric drug delivery device (preferred volume, 0.75 - 1.5 ml) through the synovial joint and anchoring it within the joint capsule so that it does not substantially interfere with movement of the joint. This achieves high local drug concentrations while avoiding excess systemic burden.

Vaccines - Preceding Drugs Then, Revolutionizing Therapy Now

2011-11-01T17:30:00.002+01:00

Vaccines - Preceding Drugs Then, Revolutionizing Therapy Now

Our recent Protein Engineering Report (see here) has been very well received, and now Cambridge Healthtech Institute has published another report from our "Beyond Small Molecule" series. This time the subject is vaccines, and it looks like this piece is really hitting a nerve; the interest has been tremendous. You can access information on our new piece at the Insight Pharma Reports website:

Presentation

Table of Contents

Executive Summary

...and of course you can order here, too!

Vaccines go back a very long way; the first crude preparations were around many decades before the first tentative steps towards standardized drugs were taken. Reasonably effective prevention of specific infectious diseases with vaccines was possible at times when medical science had no idea how the human immune system worked, and even before the concept of microbial infectious agents was more than dimply perceived. There was opposition against mass vaccination then, and there is opposition now.

Besides being firmly associated with prevention of infection, vaccines have also become weapons for elimination of infectious diseases. If smallpox has been wiped from the face of the earth, if polio has been driven to the brink of eradication, and if childhood diseases such as measles or meningitis are being kept in check, it is because of vaccines and vaccination programs.

Even so, vaccines are available for only some two dozen infectious diseases. Two chronic infections with deadly viruses, HIV and hepatitis C disease, can be managed but not prevented. Parasitic diseases such as Malaria still defy vaccination; tropical viruses (such as West Nile virus) continue their march northwards into the temperate zones, and new viruses can emerge any time. (Remember the SARS epidemic of 2003? Until then coronaviruses had been known mostly to veterinarians.) And then of course, influenza: on top of the seasonal epidemics, the next true pandemic (the Big One - not the fizzling "bird flu") is long overdue. Man-made threats, such as biowarfare agents, are in a totally separate class.

No wonder that infection-preventing vaccines - and new insights and technologies to design, produce and administer them - take up a large part of our 100+ page report. Every aspect mentioned above (and much more) gets attention. Modern vaccines make use of genetics, protein engineering, cell culture production, and nanotech-enabled delivery. They can target specific elements of the human immune system preferentially, and oral or transdermal delivery routes are taking shape for those vaccines that still need to be injected. Vaccines currently under development are efforts that call on many life science disciplines.

Exciting as all this may be, vaccines have grown beyond infectious disease prevention into areas of therapy -- not simple passive immune therapy or personalized cell therapy, but standardized off-the shelve therapies that engage the immune systems of patients with established disease. Such a disease could be HIV or HCV infection - especially with those viral subtypes that do not respond well to chemotherapies -, but also autoimmune diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis or type 1 diabetes where the immune system itself is the problem.

And the disease could also be cancer. A large part of the tumor establishment process hinges on the ability of tumors to induce immune tolerance: although they continue to express the telltale marker proteins that distinguish them from healthy tissue, the patients' immune system cannot properly attack them. Carefully designed tumor vaccines can break this immune tolerance, and trigger responses that are specifically directed against the tumor's cells. Such vaccines would not replace chemotherapy, but they could serve to eliminate minimal residual disease and prevent relapse after successful primary therapy. Because this is such a hot topic, we have given cancer vaccines a chapter of their own, separate from the discussion of therapeutic vaccines. Our four-part expert online survey, analysis of which is part of the report, attracted hundreds of participants in its cancer vaccine section.

This is probably the "hottest" market report H.M. Pharma Consultancy has ever written. Two other recent reports - on protein engineering (published July 2011) and advanced delivery technologies (January 2011) - are perfect up-to-date companions.

Patent Highlights for October 2011

2011-10-28T10:37:00.000+02:00

In the aftermath of a fire that occurred at the WIPO offices on October 27, the patent documents that had been due on this day were not entered into the public WIPO database until early November. We will cover any remarkable life science documents that were to to be published in this batch in out next monthly review. - Even for the October 6-20 period we can present a selection of 9 PCT publications from the U.S., UK, Spain and France that stand out from the crowd. At least three - tetrathiomolybdate for hypothermia induction, valproate as an antiviral, and simvastatin for drug addiction - directly concern drug repurposing. Others discuss methionine aminopeptidase inhibitors for weight reduction; gamma-D-glutamyl-L-tryptophan for radiation-induced mucositis; engineered antibody constructs for Chikungunya virus infection; beta-2 microglobulin for autoimmune diseases; small molecules for spinal muscular atrophy, an orphan disease; and dopaminergic neurons from human plripotent stem cells to treat Parkinson's disease.

PLEASE CITE AS: Mucke HAM. Patent Highlights for October 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/10/patent-highlights-for-october-2011.html) on October 28, 2011. Contact us at office @hmpharmacon .com.

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A Copper Chelator Repurposed for Hypothermia Induction

Tetrathiomolybdate has one established therapeutic use (in Wilson's disease) and several proposed ones, all of which are based on its ability to scavenge copper. WO 2011/121354 (Magnus Intellectual Property [UK]; Oct. 6, 2011) discloses a new application: reducing the body core temperature, a standard intervention in emergencies involving severe shock (e.g., from hypoxemia, haemorrhage or infection), trauma (brain injury), or potential post-ischemic reperfusion injury (including elective vascular and cardiac surgery surgery involving interruption and re-institution of blood flow). Intravenous infusion of tetrathiomolybdate into awake rats at at 10 and 20 mg/kg reduced oxygen consumption and CO2 production without sedation; in anesthetized rats a fall in core temperature was induced. The hyperthermic response to endotoxin was abolished at 20 mg/kg -- an effect that might be related to the abrogation of lipopolysaccharide-induced inflammatory responses by tetrathiomolybdate (see here). However, that would not readily explain why endotoxemic animals also developed hypothermia.

Valproic Acid Against Enveloped Viruses

Many applications other than those for seizure disorders have been reported for the antiepileptic valproate, but WO 2011/121162 (CSIC [SP]; Oct. 6, 2011) offers a surprising activity beyond neurology: antiviral action against flaviviruses, especially emerging mosquito-transmitted viruses. Propagation of the neurotrophic West Nile virus strain NY-99, and also of Usutu virus, in Vero cells was inhibited at 50 mM. In infected mice, mortality rates were reduced from 75% to 17-25% by i.p. injection. The document does not speculate on the mechanisms involved.

Protein Processing Inhibitors for Obesity

The methionine aminopeptidases (MetAP1 and 2) are required for mammalian cell proliferation (review). MetAP2 is involved in the regulation of post-translational processing (by cleaving the N-terminal methionine residue of newly synthesized proteins) and protein synthesis (by protecting the subunit of eukaryotic initiation factor-2 from phosphorylation). Small molecule inhibitors such as the 3,5-bis(benzylidene)-4-piperidone derivative NC2213 have been proposed as treatments for cancers which overexpress the enzyme. WO 2011/127304 Zafgen [US]; Oct. 13, 2011) claims irreversible MetAP2 inhibitors, e.g. fumaligin derivatives, for --- weight reduction in obesity, at doses that do not substantially modulate angiogenesis. Based on data from mice (1 mg/kg daily for 250 days while on a high-fat diet), the inventors believe that fat oxidation and lipolysis are stimulated by enhancing the level and function of thioredoxin and/or overriding the inhibitory effects of hyperinsulinemia and/or of high fat diet induced NADPH oxidase activity.

An Unnatural Dipeptide to Prevent Mucositis

In many cancer therapies, especially those that involve radiation, oral mucositis is a dose-limiting side effect that severely interferes with quality of life. Most preventive measures merely attempt to coat and stabilize the buccal mucosa with gel films. Gamma-D-glutamyl-L-tryptophan (SCV-07) stands out because it is a complex immune modulator. Response is not complete but can be predicted on the basis of gene signatures (see here). WO 2011/126853 (SciClone [US]; Oct. 13, 2011) is an omnibus document that summarizes the preclinical development of SCV-07 and a Phase II study in head and neck cancer patients -- so far perhaps the best review on this interesting molecule from Russia which had originally been investigated for the treatment of tuberculosis (see here).

Antibody Constructs for Chikungunya Infection

There is no vaccine and no specific treatment available for Chikungunya fever, an epidemic disease caused by an arbovirus transmitted by Aedes mosquitoes. In WO 2011/124635 (Humalys [FR]; October 13, 2011), antibody engineering has been set to work on two original mAbs (8B10F8 and 5F10F175E2) to create neutralizing recombinant protein constructs (rec8B10F8 and rec5F10F175E2) that bind to the E1 or E2 surface glycoproteins of Chikungunya virus A226 and A226V strains with picomolar Kd values. The constructs are Fv fragments, the minimum dimer of one heavy- and one light-chain variable domain that constitutes a complete antigen-recognition and -binding site. Obviously, the entire battery of today's protein engineering technologies (reviewed e.g. in our recent report) can be set loose to modify these basic constructs and to adapt them to desired criteria. Gene sequences and extensive in vitro and cell culture data are provided.

Beta2 Microglubulin as an Immunomodulatory Drug

WO 2011/125029 (Beta Innov [FR]; Oct. 13, 2011) presents the ubiquitous serum and cerebrospoinal fluid protein beta2-microglobulin (β2m) as an active ingredient for the treatment of autoimmune diseases. This is less surprising than it might seem at first sight: β2m is a constituent of the Class I major histocompatibility complex; knockout mice do not develop CD8 lymphocytes and have correspondingly impaired immune responses. The 99 aminoacid protein - which is not glycosylated and hardly immunugenic by itself - has actually been used as a vaccine adjuvant. The inventors have found decreased relative concentrations of β2m (compared to healthy controls) with respect to MHC I heavy chain proteins in four patients suffering from Hashimoto's thyroiditis with primary Sjogren's syndrome and/or celiac disease, or multiple sclerosis. They believe that this is cause, not effect, and that restoration of the molar ratio (calculated on the basis of the total lymphocyte protein) to values below 2 and approaching 1 (the ratio seen in controls) should be therapeutic. Administration of β2m-loaded cholesterol/sphingomyelin liposomes is proposed (and extensive data on such liposomes are presented), as is gene therapy.

New Hope for Spinal Muscular Atrophy

Substituted thiazol-2-yl-piperidines and -piperazines increase production of SMN2, the isoform of survival motor neuron protein that is expressed from a centromeric copy, and this should improve disease serverity in spinal muscular atrophy: this is the message from WO 2011/130515 (U.S. Dept. of Health and Univ. of Massachusetts [US]; Oct. 20, 2011). Molecules featuring desirable potency below 150 nM in a luciferase reporter assay were examined to evaluate the effect on the human SMN protein expression using fibroblasts from SMA patients. A compound identified as 8m (not readily identifiable among the many specifically claimed molecules) at 37 nM increased the SMN protein level by 2-3 fold, and produced a more than 2 fold of increase of the number of SMN positive foci in the nucleus. The SMN protein level decreased with increasing drug concentration, matching the bell-shaped curve observed in the reporter assay. Two other compounds (see figure) were also investigated in great detail.

Human Dopaminergic Neurons From Pluripotent Stem Cells

Many years ago the first trials with human fetal mesencephalic tissue implants in patients suffering from Parkinson's disease stirred up a huge ethical row. Much has been learned since then and attempts to generate dopaminergic replacement neurons from stem cells of various sources have become a hot field of neurodegeneration research (see this review). WO 2011/130675 (McLean Hospital [US]; Oct. 20, 2011) claims methods to differentiate dopaminergic SN-A9 substantia nigra neurons or ventral tegmental area (VTA-A10) neurons not only from human embryonic stem cells but also from induced pluripotent stem cells, which are ethically uncritical and could be patient-isogenic to reduce the risk of immune rejection. This is achieved by exposing the stem cells to retinoic acid, human sonic hedgehog (SHH) protein, and FGF8A protein, optionally also with a WNT1 protein, in an inert biological suspension matrix and artificial cerebrospinal fluid. Although isolated non-neural cell types may remain in these cultures, purified populations of SN-A9/VTA-A10 neurons are obtained using flow cytometry. - This patent application, which documents research partially funded by the Udall Parkinson's Disease Center of Excellence, contains an impressive amount of in vitro data.

An (n+1)th Use for Statins

If you believe that you know all about the many activities of statins that have been reported beyond inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibition (the activity responsible for serum cholesterol reduction), look here: WO 2011/128810 (CNRS [FR]; Oct. 20, 2011) tells us that chronic administration of simvastatin (1 mg/kg i.p.) to cocaine-dependent rats reduced cocaine self-administration and the craving reaction precipitated by withdrawal. There was a comparable effect in a model of nicotine dependence. The peer review literature holds very little (if anything) on this subject; lovastatin did not influence cocaine clearance from serum (see here), but in 1998 Chongquing Medical University had claimed a lovastatin transdermal system for smoking cessation in CN 1186659.

Starting a Drug Development Company Now... Are You Serious?

2011-10-23T17:09:00.002+02:00

Last week I talked to the CEO of a small, innovative startup pharma development company; he had some interesting facts to relate. Specifically, he told me about the latest one-to-one meeting series he had.

It is always the same time-honored thing with such events: you pay a lump sum, in return for a guarantee that the organizer will broker X time slots for private talks with potential customers or investors; with each one you probably have ten minutes to make your pitch. Normally this is a pretty one-sided business: you strive to make yourself unforgettable; your counterpart will decide, by coming back to you (or not), whether you really stand out.

Not so with the meeting series. The CEO was looking for additional venture capital, and several VCs who agreed to see him had actually expressed considerable interest in this small startup. After the third meeting this afternoon, it was clear to him that he didn't need to make a pitch. What he needed to do was ask, "Do you have any liquid funds you could invest?" and in most cases the answer would be a no, we can't, not at this time. Which ended these meetings, after a few polite exchanges, even before the allocated time slot was over.

What an interesting reversion! Apparently there are sufficient VCs with life science portfolios remaining (many have folded) who would probably love to invest in startups that pass their scrutiny. But they cannot, not now. Their portfolios have suffered severely during the past three years, when IPOs and other exits that looked like good bets in early 2008 ceased to be an option. Even if the incubator companies survived, the VCs are now facing a locked-in investment. And in the present environment they simply can't raise more capital for life science investments. So they turn to Web 2.0 companies where products are more immediately understandable and exit horizons are much shorter. The Atlantic magazine ran a story on this a month ago.

But for companies that were started on a good idea, a patent application, and a bit of kickoff funding, and are now unable to raise the follow-up funding that they would desperately need, this does not change a thing. Several of our customers are facing this situation. One of them, a German developer with a cancer drug candidate and good Phase II data, will close its books by year's end because three years' effort to find funding for a Phase III program, or a strategic investor, were in vain. A promising Spanish customer who seemed poised for takeoff a year ago has to lie low until the investment winds change again. A U.S. distributor of an intelligent medical device who wants to develop the European market with us has asked for more time because.... well, you get it.

And this tell us what? That the situation is dire for most existing life science startups? Obviously so. And does it also tell us that starting a new one now would be nothing less than crazy? Here is where it gets interesting: an increasing number of observers, us at H.M. Pharma Consultancy included, do not necessarily think so. During the life science industry's passing through this long Valley of Tears, a huge desire for renewed vigor has been building: pharma has been looking for promising new business models for years. The year 2012 will bring a hair-trigger environment: just a few macroeconomic things need to turn out right, and money will flow back to the VCs. Matthew Geller, president of healthcare investment bank Geller Biopharm, put it succinctly in a recent BioWorld Perspectives blog post (see here): “If things do turn, they would turn on a dime. The market is bipolar.”

It has often been said that great fortunes are made based on decisions made in deep crisis. It will be the same this time. Those who gear up now might be much better off than those who started a few years ago.

More Patent Coverage News - Our Services are Set to Grow

2011-09-27T12:45:00.002+02:00

Our monthly life science patent commentaries have quickly achieved top ranks in the access statistics for our blog. They have also not gone unnoticed elsewhere in the science publishing environment. I am happy to tell that starting with 2012, even more detailed pharma patent analyses will be published in a to-be- launched specialist journal (details to follow later). But don't worry, this doesn't mean that the monthly reviews here will stop. And they will always be free to access.

We will even throw in a little bit more. Following up on user suggestions, H.M. Pharma Consultancy will compile annual e-book editions based on our monthly patent commentaries. These will be freely accessible in PDF and EPUB file formats at our website.

For the moment, please stay tuned for our continuing monthly postings. Here are a few selected highlights for the upcoming September 2011 issue, to be published next weekend:

# Outside the Mainstream: Carbon monoxide, Rhenium, Boron, and Ferrocenyl Flavonoids
# A Drug Repurposing Candidate for Vision Problems in Albinos
# An Anti-Amyloid Nasal Spray
# Androgens and Their Receptors in Fabry Disease
# Naked Gene Delivery "Out of the Box"

Patent Highlights for August 2011

2011-08-29T14:19:00.002+02:00

The International Patent Office has not been idle during this summer, and neither were we. Once again, ten international patent applications are brought to the fore: for childhood epilepsy, obesity, cancer, muscle wasting, Parkinson's and Alzheimer's disease, and for laser-triggered ocular drug delivery.

PLEASE CITE AS : Mucke HAM. Patent Highlights for August 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/08/patent-highlights-for-August-2011.html) on August 29, 2011. Contact us at office @hmpharmacon .com .

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Genetic Diagnosis for Dravet Syndrome

Infants with a mutation in the SCN1A (neuronal sodium channel α1 subunit, Na _v 1.1) gene can develop Dravet syndrome, a rare and difficult to control form of fever-triggered epilepsy during their first year of life that is sometimes misdiagnosed as vaccine encephalopathy (see here). This condition - a hereditary channelopathy - can later develop into a malignant myoclonal childhood epilepsy. Building on their discovery that altered Ca _v 2.1 calcium channel function is another component of the condition (see here), Japanese researchers now claim a gene diagnostic method for the high-precision assessment of the potential for the development of Dravet syndrome based on these two channel α1 subunit mutations in WO2011/093393 (Okayama Univ. [JP]; Aug. 8, 2011) . The international search report cites Bionomics' WO2006/133508 (which claims SCN1A as a target), but only as a Category A document that defines the state of the art. For a recent review, see here.

Inhibiting Obesity, The Cellular Way: Two Inventions From Korea

Scopolin

Many attempts towards anorectic drugs have been tried and have failed, sometimes in spectacular ways that made attorneys rich years after the drugs had been withdrawn from the market. But what if you could prevent adipogenesis by blocking the differentiation of preadipocytes into adipocytes? There is a significant body of peer review and patent literature on the subject, but no drug exploiting this mechanism has entered advanced clinical trials. InWO2011/093664 (Sungkyunkwan Univ. [KR]; Aug. 4, 2011), (1S,2S, 3S,4S)-5-aminocyclopentane-1,2,3,4-tetraol is claimed to accomplish just that. Looking closer, this aminocyclitol would seem to be a mannostatin - a compound that inhibits alpha-mannosidase, an enzyme that can interfere with the carbohydrate moities that are involved in the binding of insulin to its cellular receptor. - The same pathway is proposed inWO2011/102577 (Yonsei Univ. [KR]; Aug. 25, 2011)which proposes to target uncoupling protein genes ( UCP1 and UCP3; involved in thermogenesis) with scopolin, an anti-inflammatory hydroxycoumarin glucoside fron cassava roots.

A Terpenoid Antiparkinsonian from Herbal Lore

3-Methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol is the core compound claimed in WO2011/093742 (Tomsk Pharma Combinate [RU]; Aug. 4, 2011) as an agent to treat Parkinson's disease. In less formal chemical terms, this molecule is 1-p-menthen-2-ol-3-one or 2-hydroxypiperitone, also known as diosphenol, bucco camphor or buchu camphor, a component from the volatile aromatic oil from Agathosma (Barosma) betulina. In the mouse MPTP Parkinson model, 20 mg/kg had activity comparable to that of L-dopa. Diosphenol is synthetically accessible from alpha-pinen. There is no indication of the possible mechanism in Parkinson's disease. Buchu oil has been recommended for urinary tract infections, prostatitis, gout and as a stomach tonic, but little of this has been scientifically corroborated (see here).

Phytotoxins for Alzheimer's

Yessotoxins, polycyclic ethers from marine dinoflagellates, can induce apoptosis in a variety of cell types, including transformed ones (see here), but its mode of action has not been established. In WO2011/095668 (Univ. Santiago de Compostela [SP]; Aug. 11, 2011) show that yessotoxin derivatives might be useful in Alzheimer's disease: in neocortical neuron cultures from triple-transgenic mice, beta-amyloid expression and tau hyperphosphorylation was reduced. This finding has no precedence in the peer review literature currently accessible through PubMed. Yessotoxins being huge molecules, they cannot be more than interesting leads. In WO2005/012543, the university had claimed analysis methods for yessotoxins in fish, and stated them to be phosphodieseterase inhibitors.

A TWEAK to Muscle Wasting

Astronauts on extended space missions and bedridden patients - as well as many cancer patients - share a common predicament: muscle degeneration. WO2011/097500 (Louisville Univ. [US]; August 11, 2011) approaches the problem by looking at the interaction between T umor necrosis factor-like WEAK inducer of Apoptosis ( TWEAK , a multifunctional cytokine) and its receptor, FGF-inducible 14-kDa protein ( Fn14 ). It is known that circulating TWEAK levels are differentially upregulated in patients with dilated cardiomyopathy compared with other forms of heart disease and normal control subjects (see here ), but actions of the TWEAK/Fn14 pathway on skeletal muscle have not yet been described. Using TWEAK transgenic and knockout mice strains, the inventors show that modulation of this interaction can promote or decrease slow to fast-type fiber switching, that TWEAK enhances inflammation in regenerating muscle, and that its pharmacological inhibition inhibits starvation-induced muscle loss in mice. Animals were also studied under free-running exercise conditions. Also see WO2010/085648 and WO2010/088534 claiming methods for reducing radiation damage to tissue and for pancreatic tissie regeneration, respectively - the last of several disclosures from Biogen-IDEC that deal with TWEAK. Genentech, Amgen, and Axaron Biosciences are other companies that have made their mark in TWEAK patenting.

Alpha-Methyltryptophan for Cancer

A few weeks ago researchers working at Bristol University (see here) advanced the concept of indoleamine 2,3-dioxygenase (IDO), an enzyme in the tryptophan-kynurenine pathway which is induced by proinflammatory cytokines, as a link between inflammation, cancer and depression. (In fact there are at least two isozymes, IDO1 and IDO2.) Also in July 2011 a paper from Amgen identified an selective IDO-1 inhibitor (see here). WO2011/100295 (Medical College of Georgia [US]; Aug. 18, 2011) now adds alpha-methyl-tryptophan, apparently a substrate analog similar to those discussed in Med. Chem Res 1996; 343-352, to this still-short list. Because IDO contributes to the induction of peripheral immune tolerance (see here), the focus of this application is on cancer therapy. Mouse xenograft studies were performed with two estrogen receptor-positive breast cancer cell lines (ZR75.1 and MCF7) and one ER-negative breast cancer cell line (MB231). Alpha-methyltryptophan in drinking water (2 mg/ml) reduced growth of ZR75.1 cells but did not effect the growth of MCF7 cells (in the presence of estrogen administration) and MB231 cells. Plasma concentration of alpha-methyltryptophan in mice after two weeks of administration in drinking water was 8.5 ± 0.5 μΜ.

A New Tool to Treat Hereditary Kidney Cancers

The anthracyclin mithramycin binds to GC-rich DNA and can globally displace specificity protein-1 ( Sp1) family transcription factors which play an essential role in controlling the gene expression of proteins that promote oncogenesis (see here). Its use in combination cytotoxic regimens to treat pancreatic tumors and melanomas has been recently described in the literature. WO2011/101677 (Myrovlytis Technology Ventures [GB]; Aug. 25, 2011) adds another still-deadly cancer - renal clear cell carcinoma, especially those cases that are associated with Von Hippel-Lindau disease or Birt-Hogg-Dubé syndrome which are characterized by loss-of-function mutations in the VHL or folliculin genes. The peer review companion paper from the University of Birmingham is in the January issue of Molecular Cancer Therapy (see here).

A Candidate Compound for Alzheimer's

Pfizer's 5-HT4 partial agonist

WO2011/101774 (Pfizer [US]; Aug. 25, 2011) is a patent application of a type that has become rare in pharmacology: a single compound, the serotonin 5-HT4 receptor partial agonist (R)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2 H-pyran-4-ol, is claimed for the treatment of neurodegenerative diseases, in particular Alzheimer's. An impressive amount of chemical and synthesis information is provided.

A Laser-Activated Drug Delivery Device

WO2011/097634 (On Demand Therapeutics [US]; Aug. 11, 2011) presents an implantable drug delivery device that uses multiple reservoir elements to sequentially release doses when irradiated. Its outer shell consists of osmotically impermable material that can be easily destructed by laser radiation, exposing the inner shell which has low permeability for the drug it contains. Although laser radiation of appropriate sequences can penetrate several millimeters of living human peripheral tissue without being excessively absorbed, this invention is intended for the only organ where light absorption is not a problem at all - the eye. Intravitreal implants and laser treatments are extensively established therapeutic options for the posterior parts of the eye.

Join Me On Google+

2011-08-23T17:25:00.004+02:00

Hermann Mucke,
H.M. Pharma Consultancy's CEO

I would like to invite you to follow me on the new social web service, Google plus. It might look (and sometimes, also feel) like Facebook, and it is still in beta; but it works well already, and you can already see what makes it different from Facebook. G+ is built around Circles to which you can post, and your posts are restricted to these Circles from the very beginning - which means that you can compartmentalize your communications completely between these groups of people.

H.M. Pharma Consultancy never put up a Facebook page - this environment would make no sense for us. Google+ is different. if you add me to one of your G+ circles you will find me sharing news there that are different from those I put on this blog, on Twitter (where we are hmpharmacon), or on LinkedIn.

Here is the invitation link:

https://plus.google.com/_/notifications/ngemlink?path=%2F%3Fgpinv%3DbDZFyLnYGVI%3AWG96WMVa4PM

Hope to see you on Google+ soon. And remember, we are not only on this blog and on social media - the less variable content, including the downloads, are on the H.M. Pharma Consultancy website at http://www.hmpharmacon.com .

Our LinkedIn Drug Repurposing Discussion Group - Taking Stock

2011-08-08T09:12:00.002+02:00

Eight months into the existence of "Drug Repurposing - Reprofiling - Repositioning," a little bit of analysis would seem to be in order. An active online community has formed, and its still growing -- of course not as much as it did initially, but we still run an average of 15-20 new members per month. January and May 2011 were strongest so far, with 43 and 32 people joining.

Membership is at 232, which is not much as LinkedIn science and technology groups go nowadays: Systems Biology has over 3,000 members, and even Hyperspectral Imaging has more than 1,600. But then, our group has been around only since December 2010. In any case what counts is the professional quality of the people here - and that they are using this group for discussing matters related to the subject.... which they do: 25 of our members started a total of 62 threads and 16 more participated in the ensuing discussion. Of these 62 initial postings, 48 evolved into discussions (meaning that they drew at least one comment). In other words, 18% of our members had active involvement at least once. This is a high percentage for such a group, where you can expect at least 90% lurkers. I am satisfied that my idea of founding this group has taken so much hold.

To put this in relation, look at what The Linus Group, a marketing consulting firm focused on creating demand for scientific products and services, found out when they recently analyzed community dynamics of LinkedIn scientific discussion groups. The table published there summarizes posting profiles, showing that each of the groups listed there had less than one percent of users making multiple posts during the past two months, and that the fraction of those who respond to group posts by either commenting or clicking "Like" is in the single-digit percentage range for all groups. At least 90 percent of all group members made no contribution at all during the past two months. In large groups, this figure was be more like 99%, which corresponds to what is known about online communities. You can't compare these figures with ours directly because Linus had looked only at the two most recent months (instead of 8, as we did here). Also, each group was larger than ours. But there is no doubt that our group compares well in terms of activity parameters.

People doing bioinformatics, or with a background in it, are the single largest segment - nothing has changed here - but very few take part in our group's discussions. Are they only looking for ideas here, and discuss the specifics in the focused bioinformatics groups, of which LinkedIn has several? Perhaps. There are clear limits to what can be discussed in such a group; in the end, most of us have intellectual property interests to consider in one way or the other. Even so, I believe there is much potential which we have hardly addressed: applications of cheminformatics, drug reformulation issues, and patenting are subjects that are rarely raised in our discussions. Lets make this group even more interdisciplinary! - And then of course, there is the small matter of financing drug repurposing efforts, in times where investors scramble to buy gold and Swiss Francs, and budgets are cut...

Protein Engineering - Where Biotechs Play With Building Blocks

2011-08-05T16:27:00.002+02:00

H.M. Pharma Consultancy is happy to announce the launch of its newest technology and market report, again published and marketed by our longtime partners, Insight Pharma Reports:

"Engineering Next-Generation Therapeutic Proteins: Trends and Markets to 2020"

Table of contents and ordering details here

Read the Insight Pharma Reports press release here.

The pharmaceutical industry's current dilemma has only two (comparatively) immediate solutions: find an ingenious way to repurpose small molecule drugs for new therapeutic uses; or design biological drugs to fit your purpose. There's been much on drug repurposing on this blog. Now, a slight change of focus: biotech, second wave.

In the 1980s, pharmaceutical biotechnology was all the craze: everything from cancer to multiple sclerosis, not to mention AIDS, would be cured by these wonderful recombinant proteins and antibodies. Investors were eager to board ship as long as the biotechs that popped up in the United States (there was not much going on elsewhere) were young, and their shares cheap. What resulted is now known as the classical hype cycle: by the late 1990s biotech was about as "out" as it had been "in" at the time of overblown expectations. Sure, a few of the hopefuls had made it: Amgen, Genentech, Biogen, and a few others in the second line. But everything else was disappointment: large and delicate proteins, workable but too expensive to be used for anything but life-threatening conditions; monoclonal antibodies that were moderately effective because they had a short half life, and were too large to penetrate tissue properly.

And now biotech is back -- roaring. And its quite different from what we became used to.

Today developers pick out high-affinity antibodies using sophisticated panning techniques, they look at the gene segments that code for the complementarity-determining regions (the parts that bind to the respective antigen), they chop off everything that is not needed for binding, link up several copies of these DNA sequences, optimize the codon usage for the recombinant expression system they intend to use; they produce the engineered protein chains and get them to fold correctly. The result is an artificial biodrug that can bind not two molecules of the same antigen (as a natural antibody would), but several; or it could bind different antigens at the same time - with unheard-of affinity and avidity. Want another type of biological activity thrown in? It can be done - fusion proteins can combine several domains. At the same time these constructs are much smaller than an antibody, much more stable, and behave much more like drugs.

And it is no longer only the United States where the ground is fertile. Companies from Germany, a country that once was so scared of biotech that you had to hand in a dozen forms before you were allowed to grow a transformed E. coli in a lab flask, now excel in protein engineering innovations. The United Kingdom, France, and Spain are doing fine too. China... well, in most cases we won't really know whats going on in many of their their labs there until they are ready to show it -- much as with their other high-tech programs. And what the Chinese do show us proves that they are every bit as good in protein engineering as they are elsewhere. The world is changing; keep up with it!

Patent Highlights for July 2011

2011-07-29T10:21:00.003+02:00

This month's reviewed patents are rife with claims indicating drug repurposing opportunities: the antidiabetic glibenclamide for cerebral malaria; various prenyltransferase inhibitors for hepatitis delta infection; and the antidepressant amitryptiline for lung cancer. There are plenty new compounds as well: carbolines for hearing loss and tinnitus,STEP inhibitors for cognitive disturbances esp. in schizophrenia, compounds for synucleinopathies, and parstatin for neovascular eye dseases.

PLEASE CITE AS : Mucke HAM. Patent Highlights for July 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/07/patent-highlights-for-july-2011.html) on July 29, 2011. Contact us at office @hmpharmacon .com .

Beta-Carbolines for Sensorineural Ear Conditions

While pharmacology has always paid attention to the eyes, the auditory system has been neglected in comparison: antibiotics left aside, there are very few drugs being developed for medical conditions that involve hearing and inner ear diseases. In WO 2011/079841 (Individual [DE]; July 7, 2011) there are claims for treating conditions involving the acoustic nerve (tinnitus, acoustic trauma, and Meniere's disease) with 9-alkyl-beta-carbolines. The common mechanism is neuroprotection. Presented data show the activation of expression of neurotrophic factors, including BDNF and NGF as well as the expression of dopamine D1 receptors, specifically in dopaminergic neurons from rat organ of Corti. Additional data from human SH-SY5Y neuroblastoma cells demonstrate differentiating effects and neurite outgrowth enhancement; expression of the transcription factor CREB was induced up to tenfold. This was strongest and most dose dependent with 9-fluoroethyl-beta-carboline and 6-methoxy-9-methyl-beta-carbolin. The inventor has recently published on restorative effects of 9-methyl-beta-carboline in Parkinson's disease (see here).

One STEP at a Time for Schizophrenia and Cognition

A number of protein tyrosine phosphatases specifically expressed within the brain have been identified, including STEP (for STriatal- Enriched tyrosine Phosphatase, also known as PTPN5). STEP dephosphorylates at least four groups of proteins: the mitogen- activated protein kinases (MAPKs), the tyrosine kinase Fyn, the NR2B subunit of the NMDA receptor complex and GluR2 in AMPA receptors. STEP inhibition might mediate some beneficial effects of antipsychotic drugs, and probably also the activation of the ERK pathway in the CNS which can trigger neurotrophic pathways that are important in cognitive functioning. On no less than 768 pages, and under the less than descriptive title "Therapeutic compounds and related metods of use," WO 2011/082337 (Galeana [US] and Otsuka Pharmaceuticals [JP]; July 7, 2011) claim STEP inhibitors that include (pyridin-3-yl)(quinazoline-4-yl)-N-acetamides and (pyridin-3-yl)(quinazoline-6-yl)phenols. Semiquantitative IC50 values for STEP inhibition (or, interestingly, activation), but no biological data, are provided for hundreds of compounds.

A (Not-So) New Target for Cerebral Malaria

The ion channel SUR1/TRPM4 (also known as the sulfonylurea receptor-1 regulated non-selective cation calcium- ATP channel) was first identified in native reactive astrocytes and later at least in neurons and capillary endothelial cells after stroke or traumatic brain or spinal cord injury where it has a role in the pathogenesis of blood-brain barrier breakdown and development of brain edema. (see WO 2003/079987 and the papers here and here.) These are also symptoms of cerebral malaria, and therefor the inventors listed in WO 2011/084514 (University of Baltimore [US]; July 14, 2011) figured that blocking SUR1/TRPM4 could be beneficial in this condition too. Presented data show that this channel is significantly upregulated in a murine model of Plasmodium berghei infection, in the same manner as in rodent models of cerebral ischemia. This was also demonstrated in histological brain samples from human cerebral malaria fatalities. The sulfonylurea drug glibenclamide, known to target this ion channel as part of its antidiabetic action, is proposed as being useful here. This is in line with recent reports concerning the neuroprotective and cognition-preserving action of glibenclamide in traumatic brain injury (see here).

Synuclein Oligomerization Blockers

NPT200-5

Synuclein, the common factor in primary dementia (Alzheimer's, Lewy body disease, multiple system atrophy) and Parkinson's disease, can adopt complex structures with two-alpha helixes at the N-terminus and a movable C-terminus tail. WO 2011/084642 (Neuropore Therapies [US]; July 14, 2011) focuses on compounds that block this formation of toxic oligomers instead of fibril formation. In a transgenic mouse model, the lead compound NPT200-5 (see figure) completely blocked synuclein aggregation early and late in the oligomerization process at 5 μΜ, with an ED50 of 0.1 μΜ. When the B103 neuronal cell line was infected with a lentivirus expressing synuclein, there was a 50-60% reduction in the levels of aggregates (but also the monomers) in the various fractions.

Parstatin, An Ocular Angiogenesis Inhibitor and Cardioprotectant

This anti-angiogenetic 41-amino acid peptide, which thrombin cleaves from the the proteinase-activated receptor 1 (PAR1) and is its putative signal peptide, did not appear in the peer-reviewed literature until 2009 (see here). The present patent application, WO 2011/087491 (Johns Hopkins University [US]; July 21, 2011) which names the original discoverers from the Greek University of Patras as inventors, is largely a companion document to two papers published in March and November 2010 (see here and here) that describes the utility of angiostatin in ocular neovascularization and inflammation, as well as cardioprotective effects in myocardial ischemia which seem to be mediated through the PI3K/Akt pathway; NO-related mechanisms were excluded by specific experiments. The difference is that the patent identifies partial hydrophobic sequences (esp. aminoacids 1-26) as being suitable for the treatment of corneal neovascularization, wet age-related macular degeneration, diabetic retinopathy, and cardiac reperfusion injury.

Prenyltransferase Inhibitors To Treat Hepatitis Delta

Farnesyl:protein transferase (FTase) inhibitors, which block farnesylation and geranylgeranylation of proteins, are known for their potential as anticancer agents. The large antigen of hepatitis delta virus ( HDV) contains a so-called CXXX box, a structural motif consisting of a cysteine residue at the C-terminal tetrapeptide of a protein that is a potential farnesylation site. In WO 2011/088126 (Eiger Biopharmaceuticals [US]; July 21, 2011) this is exploited for using a range of structurally diverse FTase inhibitors as HDV inhibitors. Almost predictably for those who follow this field, Merck's lonafarnib (in Phase II trials for breast cancer and progeria) and AstraZeneca's AZD3409 (discontinued in 2006) and are among the claimed compounds, but several others (e.g., L-744,832 and RPR-130401, to name only a few examples) are also included. HDV needs hepatitis B virus to propagate and greatly exacerbates HBV infection. AZD3409 was tested in Huh7 cells transfected with a combination of plasmids coding for HDV large antigen and Hepatitis B surface antigen, where it abolished HDV particle production in a dose-dependent manner (EC50 = 0.12 µM), without significant inhibiting HBV replication.

A Tricyclic Antidepressant for Lung Cancer
Amitryptiline is one of the most effective antidepressants ever marketed, and it is only for the side effects of this particular structural drug class that it has largely fallen out of favor. It has already been repurposed once, as a transdermal gel to treat neuropathic pain especially if it coexists with depression. WO/2011/089289 (University of Sevilla [ES]; July 28, 2011) suggests another use: non-small cell lung cancer. While there have been some reports on the cyctotoxic properties of amitryptiline in the 1990s, the mechanism was never properly elucidated. The present inventors suggest that the action is through oxidative stress: a study of the activity of respiratory chain complexes in the NSCLC cell line H460 showed a significant decrease in the activity of the mitochondrial complexes I and III after treatment with 50 μΜ amitryptiline, which did not occur in the presence of antioxidants. In these assays amitryptiline induced more apoptosis than camptothecin, doxorubicin, or methotrexate.

Drug Repurposing: Pulling The Tiger's Tail

2011-07-17T15:13:00.005+02:00

The world of the pharmaceutical industry is a world of science, manufacturing, and doing studies. It also is a world of patents. A good part of H. M. Pharma Consultancy's business is rooted just in this fact: we help small and/or virtual companies with their strategic patenting, we draft patent applications, we try to find gaps in intellectual property and we try to avoid them. With new molecules, this is a boundless field.

And then, there is drug repurposing which we increasingly believe to be a viable alternative strategy in small molecule development. Here we identify known compounds, take a hard look at their (demonstrated and/or potential) pharmacological properties, and think up new medical uses. In many cases these would involve different doses and/or different routes of administration.

Now you can safely assume that whatever compound you pick - approved drugs, late-stage clinical candidates, discontinued drugs - they will be covered by at least one patent, for the simple reason that no developer in his right mind would have made any public disclosure without having at least filed a patent application. Your scrutiny of these documents will have to match you scientific considerations in intensity and thoroughness.

You might well find that your repurposing idea has been mentioned there, at least to some degree. Thats for another simple reason: once you know a compound's pharmacological activity it is easy to extract whatever medical condition has been reported to show some response to this activity. Listing these conditions as potential uses effectively costs nothing. We have seen cases where entire sections had been copies from the ICD or DSM classifications.

In earlier times developers might have got patents issued with such broad claims -- but not today. All major patent offices now insist on (non-prophetic) examples and biological data that support concrete claims. So the originators' strategy became narrower: never mind even making a formal claim. Simply mentioning compound X in the context of condition Y might throw a stick into the gears of a subsequent developer by preempting novelty and/or inventive content. Well, even this doesn't really work anymore today; there are countless examples from infringement proceedings showing that patent courts will not consider the mere contemplation of potential uses that are based on indiscriminate combinations of lists as being preemptive.

But in any case, by filing a second use patent application you will pull the originator's tail once it is published. It might be a tiger's tail. Of course this doesn't mean you shouldn't do it. What needs to be considered in advance is your strategy: do you want to risk a fight? Or would you rather approach the compound's originator pragmatically, and suggest a cooperation? Or would you rather avoid all that by focusing on compounds that are so old that all patents have expired? (Don't laugh. Unexploited opportunities of this type abound, with sufficiently unconventional thinking.) We have helped many of our customers in that respect.

So if you have a drug repurposing idea, consider... And DO IT.

Patent Highlights for June 2011

2011-07-01T14:16:00.003+02:00

YES! -- Did it again. Here are 9 international applications for life science patents, published in June 2011, that we find remarkable. Vision loss, cardiomyocyte regeneration, hepatic encephalopathy, and new targets for Alzheimer's disease, influenza, and cancer are our subjects for this month. As always, we link chemical compounds to ChemSpider, genes and peer review literature to the respective NCBI resources, and patents to ESPACENET.

PLEASE CITE AS : Mucke HAM. Patent Highlights for June 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/07/patent-highlights-for-june-2011.html) on July 1, 2011. Contact us at office @hmpharmacon .com .

Three Novel Approaches to Ocular Diseases

Retinal vascular disorders (diabetic retinopathy and choroidal neovascularization as a complication of age-related macular degeneration) are the major causes for visual impairment in industrialized countries. Instead of photodynamic therapy or depletion of vascular endothelial growth factor, WO 2011/065968 (Scripps Research Institute [US]; June 3, 2011) proposes to use monocyte chemoattractant compounds, such as MCP-1 or fractalkine ( CX3CL1). The inventors demonstrated that new cells found in the retina after intravitreal chemokine injection were largely recruited from the circulation, and expressed the macrophage-microglia markers isolectin and CD11b, but not the lymphocyte markers CD3e or CD19. CX3CL1 or MIP-1 both resulted in significantly enhanced repair in a mouse model of ischemic retinopathy.

Glaucoma, also a significant reason for loss of eyesight, is commonly treated using eyedrops that reduce the increased intraocular pressure that accompanies most forms of the disease - but there are additional neurotoxic factors attacking the optic nerve head. WO 2011/075462 (Alcon Research [US]; June 23, 2011) modulates expression of the gene encoding serum amyloid A protein (SAA; a marker of inflammatory disease activity), or the interaction of SAA with its receptor. Most preferably, the agent will be fenofibrate, Wy-14643, (4-chloro-6-(2,3-xylidino)-2-pryrimidinylthiol)-acetic acid, ciprofibrate, 2-bromohexadecanoic acid, bezafibrate, ciglitizone, bafilomycin, concanamycin, or pseudolaric acid B.

Cataract and presbyopia are common age-related problems of the ocular lens that are not usually addressed pharmacologically; but the REDWING ocular module of our THIRDSPACE patent knowledgebase shows a constant trickle of such patent applications. The most recent example, WO 2011/075430 (University of Massachusetts [US]; June 23, 2011) is innovative: instead of the usual antioxidants or advanced glycation endproduct inhibitors it proposes electrostatic interaction inhibitors (simple salts or ionic solutions of organic compounds) to prevent the formation of betaL-crystallin aggregates as well as to deaggregate already formed aggregates. Effects on the kinetics of cyrstallin aggregation were extensively studied in vitro, in both water and PBS, but there are no data on intact lenses or animal data.

Differentiating Cardiac Stem Cells Into Cardiomyocytes

"A totally novel approach to stimulate in vivo resident cardiac stem cells and to commit them into the cardiac lineage" is claimed in WO 2011/067317 (Cardio3 Biosciences [BE]; June 9, 2011) . The approach consists of exposing the progenitor cells to cocktails of least two stem cells-stimulating-agents, preferably elected from the group consisting of TGF-1, BMP-4, FGF-2, IGF-1 , Activin-A (from the the TGF-β superfamily), Cardiotrophin 1 (a cardiac hypertrophic factor from the interleukin-6 cytokine family), and Merck's Cardiogenol C which is 2-(4-methoxyanilino)-4-(1-hydroxyethylamino)pyrimidine. Microspheres or nanospheres are the preferred vehicles to be injected into the cardiac tissue. Experiments in a porcine model of acute myocardial infarction showed a pronounced reduction in infarct size. Immunostaining for c-kit was used to demonstrate that the regenerated myocardial structures originated from resident cardiac stem cells.

ARF6, A New Potential Target For Alzheimer's Disease

ADP-ribosylation factor 6 ( ARF6) is a small GTPase that regulates the trafficking of endosomal membrane, and was not previously implicated in the pathogenesis of Alzheimer's disease. In WO 2011/067420 (University of Leuwen [BE]; June 9, 2011) the inventors demonstrate that blocking beta-secretase (BACE1) in ARF6-positive cell vacuoles prevents processing of amyloid precursor protein (APP), significantly reducing the formation of beta-amyloid. BACE1 enter the cells via a clathrin-independent ARF6-mediated pathway before reaching the Rab5-positive endosome, whereas APP is internalized via a clathrin-dependent pathway. An imaging-based screening assay in mouse embryonic fibroblasts is described but apparently only as a prophetic example.

Peroxiredoxin-1 Is A TLR4 Ligand

WO 2011/071992 (Health Research [US]; June 16, 2011) is based on the discovery that peroxiredoxin 1 (coded by PRDX1) is a ligand for Toll-like receptor 4 ( TLR4), and that inhibition of its interaction with TLR4 (primarily by interfering antibodies and peptides) can be exploited for inhibition of tumor angiogenesis. Reduction of peroxiredoxin-1 levels by expression of interfering RNAs results in inhibition of prostate tumor growth in two murine tumor models of prostate cancer. As it seems this is purely through a loss of VEGF expression within the tumor microenvironment; tumor cell growth in vitro or cell survival in vivo were not modified. The ability of peroxiredoxin-1 to bind to TLR4 is dependent upon it chaperone activity. A huge amount of biological data is provided. This is the companion patent document to Cancer Res. 2011 ; 1;71(5):1637-46 (see here) which focuses on prostate cancer. Also see Health Research's WO 2011/071988 of the same date claiming peroxiredoxin-1 as a vaccine adiuvant.

Macroporous Ferrogels As Drug and Cell Carriers

Ferrogels consist of magnetic micro- or nanoparticles that are confined in an elastic polymer network. Under a non-uniform magnetic field, particles will respond to the external force gradient and move to induce elongation, contraction, or bending of the gels with short response time. WO 2011/075516 (Harvard University [US]; June 23, 2011) exploits this to trigger the release of an active agent contained in the pores of the gel by altering porosity, pore size and connectivity, swelling agent concentration, and/or specific volume using an external magnetic field. The examples include the release of small molecules, plasmid DNA, and living cells. One hour after the implantation of ferrogels with enclosed murine mesenchymal stem cells into the back region of female nude mice, animals were exposed to 120 cycles of an external magnetic field by simply approaching and retracting a magnet against the skin of the mouse; fluorescent markers revealed burst release of stem cells into the surrounding tissue. A lot of literature exists on this "smart biomaterial" approach, - e.g., PNAS 2011;108(1):67-72, here and Phys Rev E Stat Nonlin Soft Matter Phys . 2009; 79(4 Pt 1): 040801, here - and patenting is competitive.

A New Approach To Influenza

WO 2011/070369 (Respivert [GB]; June 30, 2011) claims a new target in influenza virus infection: HCK, a little-studied hemopoietic cell kinase from the Src B family that has been described as being involved in linking activation of the IgG-Fc receptor to the respiratory burst in neutrophils and macrophages ( Eur. J Cell Biol 2008; 87:527-42; here). In addition to many in vitro and in vivo data for this and related HCK inhibitors, the efficacy of N -(4-((4-(3-(3- tert -butyl-1-p-tolyl-1 H -pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide to inhibit influenza virus (H3N1 Memphis 71 strain) viral load in vivo in the mouse lung was investigated, and found to be reduced from 46.6 +/- 16.6 to 8.1 +/- 1.9 million pfu/g lung tissue. The HCK-related pathways would have be be investigated more closely before this could be developed into a drug, but the lead is exciting.

A Glutaminase Inhibitor For Hepatic Encephalopathy
Progressive liver failure will cause delirious conditions which are initially reversible, but ultimately hepatic coma will develop if neurotoxic compounds (in particular, ammonia) that are produced in the intestines are no longer effectively removed from the circulation before they reach the brain. (See the review in Expert Opin Pharmacother. 2010; 11(8):1317-27 by one of the inventors) . An intestinal enzyme, GAP ( glutaminase activated by phosphate) plays a central role by producing glutamate and ammonium. WO 2011/076967 (University of Sevilla et al. [ES]; June 30, 2011) claims N-phenyl-N'-(3-methyl-2-butenyl)thiourea as a suitable partial and non-competitive GAP inhibitor. This is a known compound ( CAS-RN: 104 741-27-7) and was described in Gazzetta Chimica Italiana 1960; 90:919-40. In rats with portocaval shunts, the cognitive impairment was improved in a Y-maze after doses that showed GAP inhibition in post-mortem isolated enterocytes and astrocyte mitochondria.

THIRDSPACE and the Discontinued Drug Database: A Marriage for Drug Repurposing

2011-06-15T16:59:00.002+02:00

Those among our colleagues, observers, and competitors who routinely follow this blog or our tweets at @hmpharmacon will probably wonder why we are not posting much concerning our THIRDSPACE patent knowledge management project. Well, the reason is that we are working hard on two fronts. One is acquiring, indexing and annotating the textual and chemical data for the ocular pharmacology pilot module: we are rapidly narrowing a gap around the millennium, and we are preparing to extract chemistry information. The second reason is strategic - we are evaluating concepts for the integration of THIRDSPACE and the Discontinued Drug Database project.

We at H.M. Pharma Consultancy believe that a fresh look at drug repurposing strategies is badly needed. While algorithm-based and structure-driven theoretical considerations have resulted in some interesting leads, especially in neglected fields of medicine (e.g., see here, by Sean Ekins and the good people at Collaborative Chemistry) there are now already too many companies trying variations of the same concepts.

As I have pointed out here on June 1, 2011 we intend to use the most up-to-date data dredging and analysis capabilities to mine open source data, and then apply expert-based pharmacological knowledge and - yes, heresy! - good old intuition to arrive at new leads. The decisive difference is that we acquire open data from sources that remain largely unexploited. THIRDSPACE is only one element in these efforts - but it is an important one because whatever patent database vendors may tell you they are not opening up patent information in a way that can be directly used in generating drug repurposing leads. Now we are about to integrate another component, our Discontinued Drug Database (D3) which this blog has discussed here. There are hundreds of potential leads to be found among these abandoned molecules - which could be approved drugs but also clinical candidates that have fallen on the wayside: after all, Phase II is the Great Eliminator in drug development.

The D3 project is in its early stages, but this means that we can steer it towards integration with THIRDSPACE without having to care much about legacy formats. We see both sources to go under the same XML-based umbrella sooner or later. Meanwhile we chop away at what is still missing, and we refine these tools for internal use. Stay tuned for news!

Looking At Drug Repurposing From Another Angle

2011-06-01T08:49:00.002+02:00

For decades the pharmaceutical industry has flourished on the discovery of new small molecule drugs. A paradigm change is now under way: as the best-selling drugs from the trailing end of this long-sustained wave of innovation loose their patent protection, they are not replaced to any extent that could be called sufficient – not economically, certainly not in terms of meeting of unmet medical need, not even in terms of chemical creativity. The much cited "patent cliff" is not the reason that the industry has reached this tipping-point; its a symptom. Small molecule drug discovery has degenerated into thrashing around for new molecules that can still be patented, and at the same time show some benefit (however incremental) over what is already known. If large pharma companies spend so much more on marketing and litigation than on drug discovery and development, this is symptomatic too.

Enter drug repurposing. People are now taking hard, bioinformatics-driven looks at well-selling drugs that are late in their life cycle -- might they do something entirely unexpected? A sensible idea, and it has become a business model for dozens of small companies already.

We at H.M. Pharma Consultancy believe that certain other data sources are largely neglected in these repurposing efforts. So we are developing models where cutting-edge mining, extraction and assembly of all publicly available data come together: drug side effects, contextual information in the peer review and patent literature, and so on -- all come together. In essence, its comprehensive open-source intelligence.

Isn't somebody doing this already? Sure, its happening, at regulatory authorities such as the FDA and the EMEA. But their focus is on safety, and therefor defensive. Its also happening at large pharma companies, but mostly to build line extensions for their own drugs -- also an essentially defensive angle. Our model is designed to take the offensive. Also, it does not focus on top-selling drugs -- more likely, the opposite. The Failed Drug Database and our ThirdSpace application-focused patent database modules are designed for these datamining efforts. What we need now is partners, and financing.

If you believe that viable answers to pharmaceutical productivity can be found in creative, machine-assisted excavation of information that "is already somewhere out there," though buried in published information that has never been properly analyzed from the perspective of alternate medical uses, please contact us at office@hmpharmacon.com -- we have some interesting concepts.

Patent Highlights for May 2011

2011-05-29T14:30:00.003+02:00

Here are 9 remarkable international applications for life science patents that were published during the past month: wound hemostasis, metabolic syndrome, artificial glands and lymph nodes, malaria vaccines, oral coagulation factors for hemophila, brain cancer magnetotherapy, proliferative vitroretinopathy and rational methods for identifying regenerative tissue therapies are the focus areas.

PLEASE CITE AS : Mucke HAM. Patent Highlights for May 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/05/patent-highlights-for-may-2011.html) on May 29, 2011. Contact us at office @hmpharmacon .com .

Gallium Nitrate for Open Wounds

In a niche of medicine that tends to attract little attention today, work is being done on simple anorganic salts that have pharmacological activity beyond any potential role as trace elements. Gallium trinitrate is one such case (see e.g., Pharmacol Rev. 1998; 50(4): 665-82 [ PubMed ] and Int J Environ Res Public Health 2010; 7(5): 2337-61 [ PubMed ]); antiinflammatory activity and inhibition of bone resorption have been demonstrated. A formulation of Ga(NO₃)₃ (Genta, Inc.'s Ganite®) is FDA-approved as an i.v. infusion for the treatment of cancer related hypercalcemia . The ability of gallium nitrate to enhance the later stages of the wound healing process was disclosed in a series of patents by Bockman et. al., including US patents 5,556,645, 5,686,1 16, and 6,165,514, and 6,287,606. US patent application 2007/0155273 proposes a wound bandage incorporating solid gallium nitrate. So how could anybody claim such a use as new, as in WO 2011/051924 (Individual [IL]; May 5, 2011) ? The point is the use of solutions, applied directly to bleeding open wounds, for hemostasis. For the companion paper, see here . The inventor has founded Adjuvant Medical Solutions, an Israeli company offering personalized treatment for cancer and other chronic diseases.

Protein Engineering for Hyperlipidemia

Who might need antagonists of proprotein convertase subtilisin-kexin type 9? People with hypercholesterolemia could, especially if they also suffer from diabetes. PCSK9 lowers the amount of hepatic LDLR protein and thus compromises the liver's ability to remove LDL cholesterol from the circulation. It is one of the rare new pharmacological targets that have actually brought new compounds into clinical trials (see two ahead-of print abstracts here and here ) and might be helpful in metabolic syndrome, especially with an hereditary background. It has also been been ascribed a role in the differentiation of hepatic and neuronal cells. WO 2011/053783 (Merck Sharpe & Dohme [US], May 5, 2011) defines its claims as extending to antibodies and engineered protein constructs that compete for binding to PCSK9 with one of two antibodies, AX132 and AX213. Results from computational docking studies and epitope mapping by hydrogen-deuterium exchange mass spectrometry (DXMS).

Artificial Glands - And Toolboxes For Synthetic Biology

Implantable reservoirs or micro-volume cell-based bioreactors that secrete biologically active reaction products, optionally in response to parameters of their biological environment, constitute a special subsegment of medicine where biotechnology and medical devices meet to open new therapy options. WO 2011/056390 (Individual [US], May 12, 2011) combines the concept of laminar flow in microchannels with tropism and taxis, wherein living cells direct their movements to the surface of a droplet, bubble, gel, or combination thereof straddling the intersection of the two adjoining liquids in the laminar flow, stimulating their self-assembly into a continuous anisotropic membrane. Taxis may be driven by magnetic or electric fields, or laser light. This method has direct implications on the development of molecular and synthetic biology toolsets for redesigning or de novo engineering of biological signaling networks.

A Malaria Transmission-Blocking Vaccine

The complex life cycle of the Plasmodium parasite (see here ), which passes through the sporozoite, merozoite and gametocyte stage in man and then passes a series of stages in the mosquito midgut to produce sporozoites again, defied attempts at developing a preventive vaccine for malaria for decades. Only a single such vaccine (GlaxoSmithKline's RTS,S ) has been developed, but it confers only 38-54% protection and does not block transmission. WO 2011/056877 (George Washington University [US]; May 12, 2011) aims at achieving this by preventing the development of malarial parasites within the mosquito. This could be a valuable component in a "cocktail" vaccine that would target different life stages of the parasite by separate vaccine components. The vaccine contains a fragment of the Anopheline midgut specific membrane-bound alanyl aminopeptidase, a putative ligand for P. falciparum and P. vivax ookinetes. which has already been proposed as an antimalarial drug target ( Trends Biochem Sci. 2010 Jan;35(1):53-61 [ PubMed ]. The 135 amino acid N-terminal fragment is highly immunogenic in rabbits, and achieved virtually complete development blockade in field isolates of both Plasmodium species in two completely divergent Anopheles vectors. The antigen was identified using Merck Research Laboratories' Epitope Identification Suite, which also suggests in silico that the fragment would readily adsorb to aluminum hydroxide gel adjuvant, and would have very little cross-reactivity in humans.

Coagulation Factor Expression in Plants And Oral Tolerance

One of the most significant problems with chronic administration of recombinant therapeutic proteins, especially in hemophilia patients, is the development of neutralizing antibodies. At present this can be limited but never avoided. In addition, acute severe and type I hypersensitive allergic reactions have been reported for treatment of hemophilia A and B, lysosomal storage disorders such as Pompe and Fabry disease. Oral delivery of coagulation factors has long been discussed as a potential approach to tolerance induction in hemophilia but remains elusive. WO 2011/057243 (Univ. of Florida [US]; May 12, 2011) seeks an alternative approach, expressing coagulation factors in transgenic chloroplasts and inducing tolerance by oral administration of compositions comprising chloroplasts containing the expressed factors. Human coagulation factor IX was produced in lettuce as a cholera toxin beta fusion protein to ensure stability of the transgenic protein in the chloroplast. An additional nontoxic B subunit introduces high-affinity binding to the oligosaccharide domain of ganglioside GM1 (a lipid-based membrane receptor), thereby tethering the protein to the plasma membrane of host cells of the intestinal epithelium upon release from the plant cells in the ileum. The peer review companion paper is PNAS 2010; 107(15): 7101-6 [ PubMed ].

Nanoparticles And Magnetic Fields For Glioblastoma

Along with carcinoma of the pancreas and advanced small lung cell carcinoma, glioblastoma multiforme (primary brain cancer) is the solid tumor with the most dismal long-term prognosis. Glioblastoma is never completely resectable, tends to be radioresistant, and sheds cells into the surrounding healthy brain tissue. WO 2011/058018 (University of Hamburg [DE]; May 19, 2011) tries a new approach: magnetic nanoparticles that are the size of a protein (5-50 nm) or a virus (20-450 nm) and feature a core of iron or gadolinoium oxides covered by an adsorbed hydrophilic coating are applied directly to the tumor, whose cells internalize the particles. A static external magnetic field is then applied to concentrate freely moving malignant cells to a location where they are accessible to hyperthermia treatment or surgical removal. In related approaches, see Nanotechnology 2010; 21(45): 455102 [ PubMed ] from Toyo University, and J Neurooncol. 2011; 103(2): 317-24 [ PubMed ] from the German Armed Forces medical services.

A Combinatorial Approach to Tissue Regeneration

WO 2011/060298 (Tengion [US]; May 19, 2011) claims what can be best described as algorithmic discovery of multi-component cell therapies in vivo. The actual method is to complicated to be discussed here in any detail, but the patent application describes it in detail and gives examples, e.g. for chronic kidney disease where the list of core input elements comprises proximal and distal tubular cells, collecting duct cells, erythropoietin-producing cells, glomerular cells, and vascular cells. Hyaluronic acid, synthetic candidate biomaterials, and various forms of collagen serve as additional inputs. In vivo experiments were conducted to compare the effects of the above cell, cell/cell combinations, and cell/biomaterials in stimulating a regenerative outcome when introduced intra-renally, after disease onset in a terminal model of CKD. See also Tengion's WO 2010/056328 claiming the isolated renal cell types.

On The Way To Articifial Lymph Nodes?

Cancer vaccines based on dendritic cells are limited by the minimal motility of these cells from subcutaneous or intradermal injection sites to locally draining lymph nodes. WO 2011/062909 (Moffitt Cancer Center [US]; May 26, 2011) claims bioengineered dendritic cells that can be loaded with tumor antigens or other antigens associated with disease. These engineered dendritic cells create the functional equivalent of lymph nodes at the site of their injection. How? They additionally express at least two chemokines to attract CD4+/CD8+ T cells, natural killer cells, and B cells. In some embodiments, these chemokines are CCL-21, CX3CL-1, and CXCL-13. Very extensive in vivo data show that this approach works, inter alia with a melanoma cell model. Staining for CD3 indicated that T-cells were recruited to follicle-like structures near the injection site, as desired. See Adv Immunol. 2010; 105: 131-57 [ PubMed ] for a review on artificial lymphoid tissue engineering.

Pharmacotherapy For Proliferative Vitroretinopathy

Retinal detachment can be caused directly by ocular trauma, or it can result from the traction of trauma-induced fibrous structures in the vitreous body that pull the retina from the retinal pigment epithelium; extreme myopia is a rarer cause. In either case, proliferative vitroretineopathy and contraction of pathological pre-retinal membranes are relatively rare but severe complications. Treatment is usually by replacing the vitreous body with a heavy silicon oil or a sulfur hexafluoride gas bubble. WO 2011/063161 (University of California [US]; May 26, 2011) might offer a pharmacological alternative, treatment with inhibitors of epithelial membrane protein-2 (EMP-2, a tetraspanin ). The results support a role for EMP-2 in facilitating the activation of the signalling complex consisting of focal adhesion kinase (FAK) and steroid receptor coactivator (Src) leading to collagen contraction. The companion paper is Curr Eye Res. 2011; 36(6): 546-52 [ PubMed ], building on work described in Invest Ophthalmol Vis Sci. 2009; 50(1): 462-9 [ PubMed ].

Drug Repurposing and Patents: Our Most-Favored Content

2011-05-18T16:50:00.002+02:00

You may have noticed that this blog now lists the three posts that have been most frequently accessed during the past 30 days. There is a quite satisfactory month-over month growth in overall visitors to this blog, and so I thought it might also be of interest to summarize some additional access statistics that span the past two years, from May 2009 to today.

The post that generated most all-time interest was the one announcing the launch of the drug repurposing discussion group on LinkedIn -- and this one leads by a large margin. Ranks 2 to 4 are taken by the life science patent highlights of December 2010, January 2011, and March 2011, respectively. On rank 5 is the July 2010 post that announced the publication of our Drug Repositioning Report and the cooperation with Coleman Research Group for telephone consulting assignments. Also popular: " The Winds Of Change" for drug discovery, and the August 2010 post on our practice of employing Open Source Intelligence to satisfy our customers. All these items continue to accrue hits.

Traffic statistics show LinkedIn to be the leading referring site to our blog (not very surprising, since we promote most new posts there), followed by Google which gives us a backgound of hits coming from keyword searches. Referrals from Twitter (we are @hmpharmacon there; please follow) have remained infinitesimal, although our steadily increasing quality followership there receives promotions for every blog post as well. Geographically, the majority of visitors to our blog hails from the United States - as was of course expected; but if you accrete all visitors from European Union countries the EU comes in as a not-too-distant second. Recently we are seeing more and more hits from Asia - India, Russia, Korea, even Ukraine and Iran. Canada and Australia do not seem to have noticed us yet.

Most visitors (84%) use some version of MS Windows; Apple's Macs register only at 8%, but yes, some are coming to us even through there iPhones. Slight surprise: only slightly more then half use Internet Explorer; more than a quarter use Firefox. Other browsers register only on a minimal level.

We will continue to supply you with information on things that resonate... that are, as the saying goes, "hot." Don't forget, H.M. Pharma Consultancy believes that the hottest insights can be gained from what has already been reported but sank like a stone because its relevant context is not (yet) accessible to search engines, and therefore not consistently found and exploited. There is a universe of knowledge languishing out there; lets go and make use of it.

Patent Highlights for April 2011

2011-05-02T08:26:00.004+02:00

Today we present 11 new international patent applications from four focus fields: influenza vaccines (2), complement activation (2), addiction (3), and rare central nervous system diseases (4). As usual, all of these are not quite the run-of-the-mill type patent documents.

PLEASE CITE AS : Mucke HAM. Patent Highlights for April 2011. Published online on the H.M. Pharma Consultancy Blog (URL:http://hmpharmacon.blogspot.com/2011/05/patent-highlights-for-april-2011.html) on May 2, 2011. Contact us at office @ hmpharmacon .com .

Influenza Vaccines

WO 2011/040811 (Mucosis [NL]; April 7, 2011) attempts to improve on adjuvants for pernasal administration of live attenuated influenza virus vaccines by co-formulating the antigens with peptidoglycan microparticles obtained from the cell walls of Gram-positive bacteria or intracellular parasites. WO 02/101026 (Applied Nanosystems [NL]) is referenced for a method to obtain such particles which are "ghosts," deprived of intact surface proteins and intracellular content. The thick peptidoglycan cell wall however remains intact, and provides structural rigidity to the bacterial shaped peptidoglycan spheres of about 1 μm diameter. They skew the immune response towards Th1, while many of the current nasal adjuvants like chitosan, ISCOMS , or lipids, induce a mixed Th1/Th2 type response. A pure Th1 response is considered to be superior because it helps by inducing secretion of IFN-γ. The enhancement of the systemic serum antibody response towards intranasal hemagglutinin (5 μg H1N1 A/Beijing) was assessed in an intranasal mouse model, and was found to work best when 0.1 mg peptidoglycan particles were added to 67 μg hemagglutinin-specific IgG per ml. With this combination both the magnitude and the kinetics of the intranasal vaccine were equivalent to a standard intramusclular injection vaccine.

WO 2011/043584 (Helix [KR]; April 14, 2011) advances the concept of an edible influenza vaccine. Hemagglutinin proteins of the H5N1 "avian flu" virus are expressed in transgenic plants in a highly efficient manner, and with antigenic properties caused by near-correct glycosylation during retention in the endoplasmic reticulum. IA vaccine made from this antigen is protective in animal models of influenza infection (see figure on the right). The plant transformation vector has a cellulose-binding domain inserted therein to separate the expressed proteins. This competes directly with work done by Medicago, Inc. (Quebec City, Canada) as claimed in WO 2010/148511; see Plant Biotechnol J . 2010; 8(5): 607-19 [ PubMed]) and PLoS One 2010; 5(12): e15559 [ PubMed]

Addressing Complement Activation in Disseminated Coagulopathy and SLE

The complement system provides an immediately available immune mechanism to initiate and amplify the inflammatory response to microbial infection; however, if it runs out of control it contributes to the pathogenesis of inflammatory conditions. One of these, disseminated intravascular coagulation, is addressed by WO 2011/047346 (Omeros [US]; April 21, 2011) . The lever is inactivation of mannan-binding lectin-associated serine protease type 2 ( MASP-2, a key enzyme in the non-classical lectin pathway of complement activation), reducing the generation of both anaphylatoxins C3a and C5a. Extensive biological data are provided, based on the localized Shwartzman reaction and various inhibitors of MASP-2 in wildtype and knockout mice.

WO 2011/047337 (Exagen Diagnostics [US]; April 21, 2011) comes from a Houston, Tex. company that has published two peer review papers on biomarker discovery as well as 10 international patent applications. Now their attention has turned to methods for the diagnosis and monitoring of systemic lupus. None of the individual markers that are employed - antinuclear and anti-dsDNA antibodies, ECR1 (erythrocyte complement receptor type 1), or complement cleavage products EC4d, BC4d and PC4d (C4d bound to erythrocytes, lymphocytes, and platelets, resp.) - are new in the context of SLE, but combining them into a set of complex biomarkers that are amenable to microarray testing and bioinformatic analyses probably is. Applying a two-tier algorithm to blood samples from SLE patients (with Tier-1 negative subjects re-tested in Tier 2), a sensitivity of 72% and a specificity of 92% were achieved.

Unconventional Approaches to Substance Abuse

Problem drinking need not meet the entire set of clinical criteria that are required to diagnose alcohol addiction, but it exerts all its harmful medical and social effects. In WO 2011/038451 (Sydney Univ. [AU]; April 7, 2011) the inventors found that male and female P rats (a strain bred for alcohol preference over water in a free-choice drinking model) reduced their alcohol consumption significantly following administration of a single acute dose of oxytocin, and that alcohol-naive animals given repeated doses of oxytocin reduced both their absolute alcohol intake and relative preference. Importantly, water consumption was not affected, indicating that oxytocin is selective in reducing alcohol consumption relative to water. As the inventors confirm with a dedicated experiment, this might be due to the anxiolytic activity of oxytocin. An extensive clinical study plan in persons habitually engaged in harmful drinking practices is disclosed. Although the literature has implicated oxytocin and other peptide hormones in addictive disorders recently, this particular application should be new. For background, see Addict Biol. 2011; 16(2): 199-201 here .

Botulinum toxins have been claimed (and used) for applications almost beyond count, from facelifting to writer's cramp to intestinal complaints. WO 2011/041483 (ToxCure [US]; April 7, 2011) adds another twist which seems crude but might conceivably work (provided the subject is willing to take some risk): the neurotoxin is applied locally to the mouth, nose or fingers of the addicted person, in a dose that alters sensory perception sufficiently to break the pattern of sensations associated with the initiation or maintenance of substance addiction-related behaviors. A list of case studies concerning smokers with a quitting wish is presented.

WO 2011/050158 (Columbia Univ. [US]; April 28, 2011) would at first sight seem to be another one of the many vaccination approaches to cocaine abuse that have been patented over the past decades. However, in the approach presented here the cocain carriers (necessary because cocaine is not immunogenic by itself) are "self" proteins, such as human plasma proteins -- i.e., only the conjugate is immunogenic in man. Relapsing into cocaine use after vaccination would effectively trigger an automatic booster inoculation. Cocaine challenge experiments revealed no stimulatory effects in vaccinated mice at ED100, while 100% of the control group was affected at the same dose. None of the immunized mice succumbed to cocaine overdose at either LD50 or LD100, compared to 4 and 9 deaths at each respective dose for the control group.

Rare CNS Diseases Attract Attention
The best-known choreatic syndrome that can be traced to polyglutamate repeat expansion is Huntington's disease, but the wider framework includes form of spinocerebellar ataxia, spinobulbar muscular atrophy , and dentatorubral-pallidoluysian atrophy. Using three Drosophila models of dominant spinocerebellar ataxias (SCA1, SCA3 and SCA7), WO 2011/042872 (Paris University [FR]; April 14, 2011) identifies the gene DNApol-alpha50 , the ortholog of human PRIM1 (encoding DNA primase) as a major contributor: reducing its expression level by RNA interference can remove much of the toxic effects of pathological proteins in the models. Protection against ocular neurodegeneration was observed in a Drosophila model expressing pathologically truncated human Huntingtin. The SCA3 model identifies several other players in the replication of DNA that may modulate pathology: MCM2 , dup/CLTE ("chromatin licensing and DNA replication factor 1), DNApol-alpha73 / POLA2 (encoding the B subunit of DNA polymerase alpha) and timeout / TIMELESS , grp/ CHKB, which takes us to ATR (Ataxia Telangiectasia and Rads-related), all of which are required for DNA replication; HUWE1 , an inhibitor of DNA replication, has a protective effect in SCA3 pathology.

WO 2011/047301 (Medtronic [US]; April 21, 2011) describes a new gene therapy vector for treating Huntingtons diasease with brain-derived neurotrophic factor (BDNF). The inventors used the bacterial artificial chromosome (BAC) transgenic mouse model and showed that intrastratial injection of the vector construct reduces the huntingtin aggregates in the cerebral cortex and hippocampus. Locomotion, anxiety and cognitive parameters also improved. Importantly, the vector carries a genetic tag that allows its functional termination (by application of a "killer" nucleic acid) in case the gene therapy has to be aborted.

Rasagiline (N-propargyl-1-(R)-aminoindan), an irreversible monoaminooxidase B inhibitor marketed for Parkinson's disease by Teva and Lundbeck, is also useful in progressive supranuclear palsy (PSP): this is the essence of WO 2011/042812 (Teva [IL/US]; April 14, 2011) . A clinical study in 17 PSP patients is described; 10 received rasagiline (1 mg/day) over the complete observation time of 12 months. Three were discontinued because of drug-related side effects. A reduction in falls was seen and depression was alleviated although prior antidepressant therapies were discontinued (to be expected, given that MAO-B inhibitors have antidepressant action). Indicators also suggested a slowing of dysphagia progression.

Type II mucopolysaccharidosis, also known as Hunter's syndrome, is an inherited metabolic disease caused by a defect in the enzyme iduronate 2-sulfatase (IDS), which degrades mucopolysaccharides. In WO 2011/044542 (Armagen [US]; April 14, 2011) protein engineering was used to fuse IDS to an antibody that binds to the extracellular domain of the human insulin receptor, so that the construct may penetrate the blood-brain barrier. Cell culture studies show that the construct is taken up by Type II MPS/Hunter fibroblasts and normal human fibroblasts.

Cloud File Storage and Client Confidentiality

2011-04-28T15:02:00.002+02:00

Cloud computing is helping H. M. Pharma Consultancy. Its also taking a slight toll on our resources because we keep getting questions whether the client-confidential data we keep or generate really are, well, secure?

Recently the no-hassles file backup and synchronization service Dropbox modified its terms of use, and a discussion erupted that went all emotional and bitter. Much of it revolved around the fact that, in the course of legal proceding ("including but not limited to, a subpoena") Dropbox would have to hand over customer files to the party demanding it, including the (U.S.) government.

Well, that's a totally moot point. Not that I trust my dear competitors, opponents, or - least of all - any government; its a fact of life that governments all across the globe steal from their citizens, coerce them, and they also spy on them. (Of course, its all within the legal framework governments create for themselves, so the politically correct terms are: taxation, leadership, and watchful awareness.) But then, adult individuals with full command of their mental faculties have to be aware of that; and for businesses with confidential data it should be the Primary Directive (as in Star Trek) anyway -- oneline, offline, wherever.

This is what I posted today in the discussion thread on the Dropbox blog:

Well, I haven't had time to read all 105 comments and maybe something like this has been said before, but here is my position - not only with respect to Dropbox, but to any cloud storage service: If you want to be reasonably sure that your data are not accessed by governments or service employees, don't upload them anywhere without state-of-the-art encryption. If you want to be as sure as you can get in a world of hackers, don't upload anything anywhere. IMHO, cloud storage of any flavor is for uncritical files. Thats it, period. -HM

At H.M. Pharma Consultancy we upload client-confidential data only after local encryption, using systems and keys that are either restricted to our office machines (with primary passwords not stored on any machine), or they shared with our customers through some offline method. And then of course there are things that will never go on an external server now matter how. In this way we do cloud file storage and exchange, and we love it!

Patents And Peer-Review Papers: How Do The Universes Overlap?

2011-04-19T15:25:00.003+02:00

Readers of this blog will know that H. M. Pharma Consultancy has always been an adamant advocate of using patents not only as strategic tools but also as an invaluable source of technical and scientific information. In the engineering and information technology there would be no need to stress this, but in medicine and the life sciences the“ Patents-Ugh!” attitude remains strong.

Our little enterprise is certainly not the only one working towards a change of attitude here, but turning the tables is a slow process. Large segments of the bioscience community remain biased against intellectual property documents, to a good part because the legalistic and repetitive semantics of patents brushes scientists against the grain. Sometimes it is merely the unwillingness to search different databases, and using the different search methods which they require, that form an entry hurdle. There is also a frequently encountered opinion concerning information about new biomedical developments being published in peer review journals. In the simplest version this opinion has it that “everything worthwhile learning about will be published in journals anyway.”

Well, you can always argue what is or is not worthwhile reading, but H.M. Pharma Consultancy wanted to know the simple facts: In a given set of medical patents, how many have peer-reviewed companion papers? Are these published before or after the corresponding patent applications are published?

And here is the surprise: a search or the scientific literature shows that very few systematic investigations of this matter have been published that can claim any sort of scientific validity. General search engines return tons of opinion but hardly any facts. So I set out and did my own research, for three fields of cardiovascular medicine: atherosclerosis, hypertonia, and aneurysm. The result has just been published in Vascular Health and Risk Management. Its an Open Access paper which you can download here, and the high point is this: If an international patent application has a peer review companion, this paper is likely to reach the community earlier than the patent document; but only a minority of patents ever get a companion paper that you could find in PubMed.

In other words, ignoring patents will seriously impair the completeness of the information that you are using for your research.

Mucke HAM. Relating patenting and peer-review publications: an extended perspective on the vascular health and risk management literature. Vasc Health Risk Manag 2011:7 265–272

DOI 10.2147/VHRM.S14454 - PubMed entry forthcoming

Patent Highlights for March 2011

2011-04-04T08:47:00.003+02:00

Starting with this fourth edition of our monthly life science patent highlights, we link patent identifiers to the new version of Espacenet at http://t1.espacenet.com/. To facilitate navigation with the commentaries, title patents and their base data now carry a yellow marker .

PLEASE CITE AS : Mucke HAM. Patent Highlights for March 2011. Published online on the H.M. Pharma Consultancy Blog (http://hmpharmacon.blogspot.com) on April 4, 2011. Contact us at office @hmpharmacon .com .

Elevated Procalcitonin - A Bad Sign

Like C-reactive protein, procalcitonin is a serum biomarker for systemic inflammation. Initial findings had focused on sepsis and bacterial infection ( J Clin Microbiol . 2010;48(7):2325-9; PubMed), but more recently it has been found that its concentrations can be elevated to the upper limit of normal in several conditions that are not primarily infectious in nature, including coronary artery disease and acute coronary syndromes. In WO 2011/023813 (Brahms [DE]; March 3, 2011) procalcitonin levels have been prospectively investigated as risk markers for adverse medical events (including death from any cause, excluding exogenous trauma) in 5,313 apparently healthy persons (mean age, 47.3 +/- 12 yr., normal blood pressure). It was found that elevated procalcitonin serum levels confer increased risk for cardiac and cerebrovascular events, cardiovascular mortality, cancer mortality, and overall mortality. Gender-specific effects were noted; men tended to have higher baseline levels than women. Optimal cut-off values are disclosed for various disease classes, including diabetes. This biomarker has attracted attention from many sides and for many purposes, including the Chinese military investigating mortality in heat stroke patients ( Emerg Med J 2011; PubMed)

Environmentally Friendly Alkaloid Extraction

Plant tissue remains the prime source for many of the chemically more complicated alkaloids with medical uses. For some, semisynthetic approaches are used; for others, extracted and synthetic material compete. A prime example for the last-mentioned case is galantamine, a cholinesterase inhibitor and nicotinic reptor modulator which used to be available only from limited agricultural sources in Bulgaria and Turkey for about $30,000 per kilogram until a fully synthetic version brought down the price to a fraction. Meanwhile, many new vendors (especially from China) have entered the market, but their processes are based either on toxic halogenated hydrocarbons or use supercritical carbon dioxide, which is environmentally friendly but energy-intense. WO 2011/026637 (Extranthis [DE]; March 10, 2011) demonstrates that extraction of galantamine, but also other alkaloids of medical utility, can be achieved at ambient or slightly elevated temperatures using virtually any industrial-quality plant oil, including rapeseed and sunflower oil. The oil can be used several times, and ultimately it can be combusted together with the plant material residues to generate much more heat than the limited amount that the process requires.

Earthworms For Drug Safety Tests

For scientific and ethical reasons, the Draize paradigm that tests drug and cosmetics candidates for their eye and skin irritation potential has been controversial for decades. Today's routine versions are mild compared to what had been done to the experimental rabbits in the 1940s to 1960s, but alternatives that use non-vertebrates would be more than welcome. WO 2011/026841 (ViewPoint [FR]; March 10, 2011) claims just that: the company, which develops high-throughput motion analysis for behavioral testing, uses garden-variety earthworms in a simple container, a video camera, and PC software for motility analysis. Irritants produce hyperactivity. As with all alternatives to drug safety testing in animals, utility of this paradigm would hinge on whether regulatory authorities would accept it as valid, even if full validation can be proven.

Sequencing By Opposing Forces

WO 2011/028296 (Caerus Molecular Diagnostics [US]; March 10, 2011) might well contain another step towards the "$1,000 genome." Millikan Sequencing, a label-free technology, represents a " sequence by synthesis " approach, which involves detection of the identity of each nucleotide immediately after its incorporation into a growing strand of DNA in a polymerase reaction. In this invention, opposing electrical, hydrodynamic and entropic forces are used to measure the increased charge as nucleotides are added to DNA templates attached to a tethered bead. Using analyzers such as those from 454 Life Sciences it can be multiplexed millionfold, allowing very fast sequence reading.

Growing Nerves In Vitro

Neurogenic cytokines can make neurites sprout, but that is not all there is to consider if you want to regenerate nerves; conduits are required that mimic the natural biological milieu. These must provide contact guidance and - especially if they are supposed to traverse long defects - they must be semi-permeable to allow access of nutrients. At the same time, these sheaths need to maximize the concentrations of neurotrophic agents and minimize inflammatory, molecule infiltration. Silicone tubing, bovine collagen and biodegradable materials have been used; each type has its drawbacks. WO 2011/028814 (Cleveland Clinic Foundation [US]; March 10, 2011) continues work disclosed in WO 2009/124170 by using naturally occurring epineural tubes that already express all neurotrophic and angiogenic factors (and optionally, bone marrow stromal cells). Details for isogenic and allogenic rat stromal cell-epineural conduits, which take about 14 days to grow prior to implantation, are presented. Maximal sensory recovery was achieved in all of 4 rats at week 5. Motor recovery as measured by toe-spread was robust with 3 out of 4 animals receiving a score of 2 by week 6. The principle of the technique has been known for years (see e.g., Ann Plast Surg. 2002;48(4):392-400 PubMed), and the question of its patentability should be interesting.

Galectin-3 As Biomarker In Cardiac Resynchronization Therapy

That galectin-3 (a multifunctional beta-galactoside-binding protein) may be a useful biomarker for decompensated heart failure has been reported before ( Curr Heart Fail Rep. 2010; 7(1):1-8 PubMed). But WO/2011/031493 (BG Medicine [US]; March 17, 2011) claims that measuring its serum levels can identify those heart failure patients who are better candidates for cardiac resynchronization therapy. Apparently the inventors analyzed samples from a long-concluded clinical study ( N Engl J Med. 2005; 352(15): 1539-49 PubMed) in which patients were randomized to optimized pharmacological therapy alone or combined with pacemaker implantation (InSync® III, Medtronic) in an open-label manner. Out of the 10 patients with the greatest reduction in galectin-3 levels between baseline and 3 months post-baseline, 6 (60%) died or were hospitalized for heart failure within 18 months. In contrast, of the other patients with a serum galectin-3 value at baseline and at 3 months after baseline and available information on adverse outcome, 81% (128 out of 159) suffered the adverse outcome of death or hospitalization for heart failure at 18 months. Baseline galectin-3 in the group of patients who did not receive CRT was not significantly associated with adverse outcome.

An Engineered Anti-Amyloid Antibody For Alzheimer's

Blocking the active site of beta-secretase is a popular route of attack against amyloid plaques in Alzheimer's disease; however, this is associated with side effects. WO 2011/031720 (Arizona State University [US]; March 17, 2011) presents a bispecific nanobody with dual activity. It blocks beta-secretase not by binding to the enzyme's active site, but rather by binding to its substrate, amyloid precursor protein (APP), which allows the β-secretase enzyme to carry out other beneficial proteolytic functions. The nanobody's other moiety has been engineered to cleave the α-secretase site of beta amyloid or APP, where targeted α-secretase activity permanently precludes Αβ formation. The nanobody is an engineered single chain antibody that is based on a recombinant antibody light chain, mk18, originally raised by immunization against vasoactive intestinal peptide. See the patent application's companion paper, Biotechnol Prog . 2009; 25(4):1054-63 here.

Cancer Drug Delivery Liposomes Activated By sPLA2: Another Try

Constructing liposomes that encapsulate antiproliferative drugs and have a membrane that can be lysed by the elevated levels of secretory phospholipase A2 in cancerous tissue is not a new idea (see e.g. Curr Drug Deliv . 2005;2(4):353-62 PubMed). There is potential synergy: the products of sPLA2-mediated hydrolysis, a lysolipid and a fatty acid, should permeabilize the cancer cell membranes and increase cellular uptake of the drug cargo released from the liposomes. But elevated sPLA2 levels might occur elsewhere in the body too. In WO 2011/032563 (Bio-Bedst [DK]; March 24, 2011) the inventors tried to narrow the trigger range for sPLA2-mediated lysis by adding a polymer (3-6% mol/mol) that is conjugated to the head group of phospatidyl ethanolamine (which introduces an anionic charge), or to ceramide. In a Phase I dose escalation trial of cisplatin encapsulated in sPLA2 hydrolysable liposomes in patients with advanced or refractory tumors, the maximum tolerated dose was above 80 mg per 3-week treatment cycle, which was surprising in view of the MTD predicted from animal experiments. A superior safety and tolerability profile was noted compared to free cisplatin formulations in terms of nausea, diarrhea, vomiting, anemia, neuropathy, nephrotoxicity and ototoxicity. The preparation does not require hydration (in contrast to free cisplatin), and can can be administered on an outpatient basis.

Kinase Inhibitors For Down Syndrome

WO 2011/037962 (Neuronascent [US]; March 31, 2011) targets DYRK1A (dual-specificity tyrosine-Y phosphorylation regulated kinase 1A), a homolog of the Drosophila mnb (minibrain) gene, which is localized in the Down syndrome critical region of chromosome 21. Along with acetylcholinesterase, this kinase is considered to be a strong candidate gene for cognitive defects associated with this disorder because it inhibits neurogenesis during postnatal brain development, especially in the hippocampus ( J Neurochem . 2010; 115(3):574-84; PubMed). NNI-351 (see figure) is the parent compound of the Dyrk1a inhibitors that are presented here; the biological examples that are given are entirely prophetic. NNI-351 or its blood-brain barrier penetrating analogs will be administered to Ts65Dn mice (which produce Dyrk1a protein at the gene dosage found in human Down syndrome, and exhibit many of its behavioral features) at 0.1-1.0 µM i.p., starting at 7-9 weeks of age and continuing daily until four months of age. Brains will be flash frozen in liquid nitrogen and analyzed for hippocampal neurogenesis.

A Neurotoxin For Osteoporosis

Years ago, before it began its diversification, Allergan, Inc. used to have only two main lines of business: ocular pharmacology, and a preparation of botulism neurotoxin A which marketed as BOTOX(TM) and has multiple uses, from spastic syndroms to foot sweating and cosmetics. In WO 2011/038015 (Allergan [US]; March 31, 2011) the company claims an appealing new application for the neurotoxin: osteoporosis; and the toxin is not injected but ingested (an established practice for the treatment of gastrointestinal spasticity). The rationale is inhibition of the production of gut-derived serotonin (GDS), which has a role in bone formation ( Curr Opin Pharmacol. 2011 Feb 12; PubMed ); long-term administration of selective serotonin re-uptake inhibitors, which increases GDS formation, can cause loss in cortical bone mass. The priority date of this application is from September 2009, a safe half-year earlier than the paper from Columbia University ( Nat Med . 2010;16(3):308-1; PubMed ) reporting the same findings. However, Allergan presents only two anecdotal single-case studies in support of its claims.

From Archaeology To Drug Development: Do Our Archives Already Have The Answer?

2011-03-23T17:17:00.003+01:00

In early March I spent a week on Tenerife - doing a bit of enthnopharmacology research, relaxing a bit once and a while. (Easy to do if you have only slow wireless internet access) A note in a local newspaper caught my eye: reports of prehistoric aboriginal habitation in a ravine where archeologists had been working for eight months, digging and (good practice!) milking the locals for useful facts. But it was not this field work that had yielded the exciting part of the news. The best finds were made in the archives of the local archeological museum: a series of extensive but unpublished manuscripts on these exact cave sites, written by the museum's director decades ago and resting in forgotten paper files until his modern colleagues wanted to check on some minor background facts. It seems as if a good part of their research had been preempted, but it had passed from knowledge even though it was the inheritance of the same institution that had commissioned the present dig. Now the "new" insights are hailed as a breakthrough in the prehistory of the Canary Islands. (See here)

Want an example closer to pharmacology? Easy. Two days ago there came the news that Jeffrey Bada, a chemist at the Scripps Institution of Oceanography in California and a former student of Stanley Miller (who in 1953, together with Harold Urey, had performed the famous electrical discharge experiment that demonstrated how the building blocks of life might have been created on primordial Earth) had made an equally belated discovery. Bada had retrieved a dusty cardboard box with samples from Miller's 1958 second series of experiments where sulfide had been added to the "primordial soup." The samples contained, among other interesting compounds, sulfur-containing aminoacids. (See here.) Big deal? Yes, because until now it had been believed that these modified Miller-Urey experiments had generated neither methionine nor cysteine, and that therefore the "lightning-in-primordial-soup" hypothesis had a hole in it. It hadn't, but we didn't know it because until 2011 nobody had bothered to take a second look at decade-old samples.

Looking back and seeing what has already been done can yield invaluable information, and not only from unpublished manuscripts or forgotten biochemical samples. It is frequently forgotten (or conveniently pushed aside) that we are constantly loosing scientific data that have never been properly mined, and will be beyond retrieval if we don't do something about it. Example? Everybody is talking about how global warming makes the polar caps shrink, but how old are our oldest satellite images showing what the extent of the icecaps was before that discussion started - lets say, in the mid-1960s? The early Nimbus satellites were in polar orbits at that time, but only their low-resolution data had been processed. The raw data were recorded and deep-archived on magnetic tape that has physically and magnetically decayed since then, and for which drives are no longer available. It took an almost unprecedented effort ("almost" because NASA had done something similar for the Lunar Orbiter images before) to rescue and mine these data. Since 2010 we know how exactly the Arctic and Antarctic icecaps looked like from orbit in 1966, in multispectral high-resolution as originally recorded. (See here) But much other early satellite data has been irretrievably lost to bit rot or - believe it or not - because NASA engineers had to reuse the stored media, taped over the old high-res-data, and kept only low-resolution versions.

Sadly, our attitude towards old pharmacological data is not too different. Everybody wants to push ahead, and wants "to go where nobody had been before." We generate petabytes of new data in our Bio-IT efforts, and current technology allows us not only to store but also to mine them. But there seems to be little glory in archival work which concerns itself with what has already been done (and even documented) decades ago.

There is hope. As the dug discovery pipelines dry up and pharma companies are increasingly desperate to discover what could become their major cash generators a decade from now, the concept of drug repurposing is on the rise. In a nutshell, you look at known compounds (marketed or discontinued from development) and investigate, with the entire battery of cutting-edge wetlab and silicon tools, what unknown potentials these molecules may carry beyond what they had originally been developed for. That's true knowledge discovery for you, and the good news is that it is (relatively) cheap compared to ab initio discovery strategies. I'm somewhat proud of having argued this approach since the mid-1990s.

This blog has discussed issues related to drug repurposing several times before, but here is a summary:

* H.M. Pharma Consultancy's Pharma's market and technology intelligence report,
" Drug Repositioning: Extracting Added Value from Prior R&D Investments " (July 2010):

* Here you can register for membership in our Drug Reurposing- Repositioning discussion group on LinkedIn (you need to be a LinkedIn member):

And the blog notice on the group's foundation is here.

H.M. Pharma Consultancy has amassed expertise in drug repositioning during the past decade, and we would be pleased to serve you.

Please contact us at office@hmpharmacon.com , or call at +43 664 101 0121 (Central European Time = GMT+1 hr.)

Carrying On With Pharma During Mayhem In Japan

2011-03-15T17:32:00.002+01:00

In Japan, there are already thousands confirmed dead in the aftermath of what will go down in history as the Great Sendai Quake. Many more thousands are still unaccounted for, hundreds of thousands have been displaced. There are not even estimates yet as to the trillions in direct property damage, and as for the Japanese economy...

Against this background there is astounding news, and actually I read it twice before I could quite believe it: Yesterday Astellas Pharma Inc., one of Japan's major pharma companies, has submitted a Japanese marketing application for a new drug -- bixalomer, a phosphate binder for use in dialysis patients. ( Asahi Simbun article)

IMHO, nothing illustrates the Japanese mentality better than this action. This people will not be daunted by the most devastating earthquake in recorded history. After having lost a war, being nuked twice within a few days, Japan surrendered but carried straight on to become (for a relatively brief period) the world's second-largest economy. Japan will also survive what happened on March 11 (and whatever might come from the aftermath at the nuclear power plants).

Japan is also the world's second largest pharma market and although its companies have been severely hit, none has taken a deadly blow. Japanese subsidiaries of U.S. and European companies also seem to have things under control, in spite of severe damage and some loss of life among their staff ( pharmalive.com article). There is no information yet concerning development-related data lost in the mayhem - data that could have saved lives and prevented suffering later - and we will probably never learn about this. But Japan's pharmaceutical and biotech industry will also carry on. You can see this even now. Bravo Astellas!

Patent Highlights for February 2011

2011-02-25T13:21:00.002+01:00

This third issue of our monthly Life Science Patent Highlights. As always, the most recent documents might become available at the European Patent Office only a few days after this analysis goes online.

PLEASE CITE AS: Mucke HAM. Patent Highlights for January. Published online in the H.M. Pharma Consultancy Blog (http://hmpharmacon.blogspot.com) on February 26, 2011. Contact us at office @hmpharmacon .com .

An Insight Into Bitterness

With a limited repertoire of about 30 taste receptor genes, humans can detect thousands of different bitter-tasting compounds. This promiscuity results from a survival-promoting evolutionary mechanism that allows humans to recognize toxic compounds with chemical structures as widely diverse as those of e.g. cycloheximide, various alkaloids, and cyanide -- all of which have an highly aversive bitter taste. For the pharmaceutical industry this has turned into a legacy; many drugs have a very bitter taste that requires addition of masking agents in high concentrations if they are to be fomulated as oral solutions or buccal presentations. It would be much more reasonable to use specific receptor blockers. WO 2011/012298 (German Institute for Nutrition Research [DE]; Feb. 3, 2011) focuses on a particular receptor known as TAS2R49, and describes methods for identifying agonists that are structurally related to the anti-asthma agent cromolyn or the antiemetic muscarinic antagonist diphenidol by their interactions with expressed subunit polypeptides. These compounds are then modified to become antagonists. Obviously such compounds could also make bitter-tasting foodstuff more palatable -- but unless they are already known and "generally recognized as safe" (GRAS), they could hardly be legally used for such purposes. The institute has two related international patent applications, WO 2010/099983 and WO 2008/128730.

A Lotion To Detect Emerging Pressure Sores

Decubitus ulcers, also known as pressure sores or bed sores , are the bane of bed-ridden patients and persons restricted to wheelchairs. Once developed, decubitus lesions can take months to heal. Dark-skinned people are at particular risk because the earliest stages of decubitus are not visible even to nurses trained in skin assessment.WO 2011/014552(Individual inventor [US]; Feb. 3, 2011) offers an ingenious solution: a thermochromic lotion (based on liquid crystals, microparticles or leuco dyes) is applied to the skin areas that make contact with surfaces, and the result is read by visual comparison with a color chart. This allows decubitus to be diagnosed in Stage I (blanchable erythema from reactive hyperemia), when its progression is easily preventable by massage, skin care and a turning schedule for the patient. There might be additional uses in the diagnosis of hypothermia for detection and grading of frostbite, in the treatment of chemical burn victims where the total area of exposure may be unknown or undetectable to the eye, and in the diagnosis of radiation injuries to skin.

Dashurin, A New Biomarker For Renal Injury

Although serial measurement of serum creatinine is an accepted method of detecting and diagnosing acute kidney injury, this marker can take two days or more for serum creatinine to rise to values that are considered diagnostic for injury and prognostic for the development of acute renal failure. Urine biomarkers which are closer to real-time processes would be needed. But what is dashurin? WO 2011/017614 (University of Vienna [AT]; Feb. 10, 2011) is the only document in the entire PCT database that mentions this name. PubMed returns exactly one paper, Biochim Biophys Acta. 2010; 1800(4): 430-8 (see here ) which names two of the inventors as authors. The patent document gives sequence information for an open reading frame of 945 bp coding for 314 amino acids of a protein (the first 28 aa are a signal protein) which is expressed in glomeruli. Antibodies and immonoassays for dashurin are presented.

A Protein To Activate Gamma Secretase

WO 2011/016861 (Intra-Cellular Therapies, Inc. [US]; Feb. 10, 2011 ), the companion patent application to a Nature paper from Rockefeller University (see here ) which was published last September, deals with a novel γ-secretase activating protein (gSAP) that selectively modulates Aβ production. This happens through a mechanism involving its interactions with both γ-secretase and its substrate, amyloid precursor protein C-terminal fragment (APP- CTF). gSAP does not interact with Notch, which makes it a potentially attractive target for the treatment of Alzheimer's disease. Interference with this interaction between gSAP and APP- CTF appears to be the mechanism by which the cancer drug imatinib(Novartis' Gleevec) achieves its amyloid-beta-lowering effect. N-(6-methyl-5- (4-phenylpyrimidin-2-ylamino)pyridin-3-yl)-4-((1 -methylpiperidin-4-yl)methyl)benzamide significantly lowers Aβ at concentrations of <500 nM. Also claimed is a method of identifying persons at risk of developing Alzheimer's disease based on single nucleotide polymorphisms of gSAP. Intra-Cellular Therapies banks on the work of 85-year old Paul Greengard, Rockefeller University's Vincent Astor Professor at the Laboratory of Molecular and Cellular Neuroscience and the winner of the 2000 Nobel Prize for Medcine, who heads the company's scientific advisory board.

Nucleic Acid Therapy For Ebola Infection

Filoviridae such as Ebola and Marburg viruses cause only a few hundred reported deaths worldwide each year and as such they are hardly among the most pressing global infectious disease agents. However, especially Ebola has characteristics that could make it suitable as a biological weapon -- and once biodefense is involved there is enough research funding to make development of countermeasures a viable proposition for the pharmceutical industry. A case in point is WO 2011/020023 (Alnylam Pharmaceuticals [US]; Feb. 17, 2011) which describes lipid formulations of double-strand RNAs that are 19-24 nucleotides long, have one strand that is complementary to an Ebola virus gene (e.g., the L gene) and inhibit its expression of by at least 40%. The dsRNA can be administered at doses of 0.03-3.0 mg/kg. Data from mice and guinea pig models with formulations based on N,N-dimethyl-2,3- dioleyloxy)propylamine (DODMA) and liposomes are presented. This application seems to stem from the Alnylam Biodefense Initiative for which the company won two NIH contracts for a total of more than $63 million in 2006 and 2007; this proceeds under the umbrella of the U.S. Defense Threat Reduction Agency’s Transformational Medical Technologies Initiative ( TMTI). For RNAi approaches to the Ebola L gene see J Infect Dis 2006; 193(12): 1650-7, here.

CNS Drug Delivery Through The Ear

The U.S. Food and Drug Administration recognizes more than 100 routes of drug delivery, and the first on the alphabetical list is the auricular route. However, WO 2011/019954 (Individual inventor [US]; Feb. 17, 2011) is not directed to otic infections or inner ear problems such as tinnitus - it aims at the delivery of brain-targeted drugs, formulated as solid lipid nanoparticles, to the cerebrospinal fluid via the perilymphatic compartment. This should be possible because the cochlear aqueduct connects the inner ear and the subarachnoidal space. Wearable thermoelectric dispensing systems with electronic control are claimed which look very much like a typical behind-the-ear hearing aid. A conduit is implanted in the tympanic membrane and configured to convey fluid from the ear canal to the round window membrane. The application focus is on the treatment of intractable cancer pain with opioids; however, eating disorders and obesity are also exemplified. For a related 2007 paper in Acta Pharm Sinica , see here. Given the absence of supporting biological data in the application it is difficult to judge if this route could be as effective as intracisternal delivery. The inventor has no papers listed in PubMed but is namend on 14 international patent applications, most of which deal with aerosolizing devices and are assigned to Aerogen, Inc., a company he had founded in 1991.

Agmatine Promotes Stem Cell Efficacy and Survival

Agmatine (1-amino-4-guanidinobutane) has many roles: it is an is an endogenous neuromodulator with affinity to alpha(2)-adrenergic, imidazoline and NMDA receptors, and it inhibits nitric oxide synthases. WO 2011/019124 (Yonsei University [KR]; Feb. 17, 2011) now teaches that agmatine not only promotes the differentiation and colonization of transplanted neuronal stem cells, but also their post-transplant functional survival (see figure). Considering that the protection of retinal ganglion cells by agmatine had been claimed (also be Korean inventors) in WO 2008/123684, this does not come entirely as a surprise. However, no such action on stem cell survival seems to have been reported so far. For more remotely related claims for agmatine see WO 2001/095897 (seizures) and WO/1999/008669 (neuropathic pain)

Insect Models for Pharmacokinetics and Blood-Brain Barrier Penetration Testing

WO 2011/018446 and WO 2011/018450 (Entomopharm [DK]; Feb. 17, 2011) outline the interesting business concept of this Copenhagen company, which was established in 2009: to use insect systems for drug discovery screening. For PK studies, a locust or cockroaches are administered test compounds and subsequently hemolymph is obtained for analysis by puncturing the ventral membrane between the head and the thorax.Locusta migratoriahad been used to develop and validate the model. An ex vivo approach was chosen for BBB penetration testing: the dorsal part of the insect head is dissected to expose the brain, eyes, antennas, and nerve associations. The brain is exposed to the test compound solution while still in its cuticle shell, and then homogenized for assaying. A large number of examples show that typical CNS active compounds such as mianserin, caffeine, trazodone, buspirone, and propranolol permeate the grasshopper BBB to a much larger extent than peripheral acting drugs such as colchicine and atenolol. This type of testing could save large numbers of rodents in the drug discovery stage, and would be the ideal second stage to cell culture-based high-content screening.

Antidotes for Botulism Toxins

WO 2011/022721 (Microbiotix [US]; Feb. 24, 2011) is another application related to bioterrorism countermeasures. In the case of Botulinum neurotoxins (two-chain polypeptides with a heavy chain joined to a zinc-dependent endopeptidase light chain which impairs neuronal exocytosis through proteolysis of essential components of neurotransmission) , their development essentially focuses on preventive vaccines and passive immunotherapy with "despeciated" F(ab)2 antibody tragments. Here comes what, especially could be a very viable alternative to these biotech products which are less than ideal under conditions of public mass emergency or combat: simple organic compounds that inhibit the toxin's proteaolytic activity, and work particularly well for serotype A. Data are presented for 5-chloro-7-((pyridin-2-ylamino)(thiophen-3-yl)methyl)quinolin-8-ol (MSL-151862), 2-(lH-benzo[d]imidazol-2-yl)-3-(3-iodo-4-methoxyphenyl)acrylonitrile (MSL-145815), and (E)-3-( [2,2'-bithiophen] -5-yl)-2-(1H-benzo[d] imidazol-2-yl)acrylonitrile (MBX 1553). IC50 values are mainly in the 10.75 µM range.

New Report on Advanced Drug Delivery Technologies Published

2011-02-08T09:43:00.003+01:00

Insight Pharma Reports has published the latest of our technology and market assessment reports: Advanced Drug Delivery Technologies: Enabling Drug Reformulations and Administration Routes. A detailed description of its contents can be found here.

As I have stated several times on this blog (last time, here), the classical concept of pharmaceutical innovation - as measured by drug approvals based on new chemical entities - is broken. According to the Centre for Medicines Research International, the average for the combined success rate at Phase III and submission has fallen to ~50% in recent years. The "biotech revolution" has not happened in the way it had been foretold since the late1980s, when you could read forecasts in industry publications such as SCRIP stating that more than half of all pharma sales would come from biologicals in 2000.

The simple take-home message is that we need to make better use of what we already have. One option is drug repurposing, for which I have founded a steadily growing discussion group on Linked In (which you can join here). The second one is developing new formulations for known drugs. Of course these approaches are intimately connected: intelligent new formulation technologies, especially those driven by nanotechnology and medical devices, can enable repurposing of known drugs in ways that would not have been possible otherwise.

Our newest report discusses how drug delivery can overcome the blood brain barrier and how drugs can be effectively delivered to tumors while minimizing systemic exposure to cytotoxic drugs. Then the report turns to non-injection delivery modalities for peptides, proteins, and antibodies, and to the role that alternative formulations will play in the emerging field of follow-on biologicals ("biogenerics"). We then explore the role of alternative delivery in drug lifecycle management. It is shown that development of a follow-up new chemical entity is already an economically unattractive proposition, as opposed to reformulation or repurposing. Case studies demonstrate how cleverly applied technologies can reinvigorate drugs that have lost patent protection or have not fully exploited their potential.

The report concludes with as showcase of dozens of reformulation companies and their development pipelines, and with an outlook to what we call the “Preprogrammed Rise of Alternative Drug Delivery”—an unavoidable development driven by the fact that lifecycle management and recouping of value from existing resources will continue to rule the pharmaceutical industry’s business throughout the 2010s.

Going, Going, Gone: Big Pharma Continues to Abandon R&D

2011-02-03T10:33:00.002+01:00

Pfizer's announcement of its plans to shut down its Sandwich (Kent, UK) facility - which since its establishment in 1954 had developed into a hub of corporate life science R&D in Europe - continues to provoke outcries of all sorts.

What seems to get lost in the hue and cry about 2,400 researchers and their supporting staff facing layoff (or, in a few selected cases, offers for relocation to the United States) during the next two years is what else Pfizer said in its press release: “ Driving this decline [i.e., the R&D expense cut in the range of $1-2 billion] is the planned reduction in the number of disease areas the company will focus on ... as well as a realigned R&D footprint."

In other words, what we have seen happening for years is now spelled out, is being "given a face" ... a development that is accelerating. Big Pharma, which has been in-licensing or buying the great majority of the drug candidates it eventually brought to the market, is increasingly doing what makes most sense to the MBA-displaying Controllers: pull out of research. Instead, concentrate even more on what we can do best by leveraging our greatest asset (capital), namely late-stage development and marketing (most especially, marketing). Keep the investors, who provide us with said capital assets, happy by "realigning the R&D footprint." (As every Controller knows, R&D is a constant drain on resources, and these mad scientists, well...) Wall Street analysts have already reacted with enthusiam, or so I hear.

Of course this strategy doesn't stop here. Pull out of Europe, where you need to complete a dozen forms before you can even work with recombinant E. coli in your lab; go back to the U.S. instead. Specifically, pull out of the United Kingdom where you can't do preclinical research unless you can find employees who enjoy the thrill of being shot at by animal rights activists. The world is large and globalized; lets go to China where you don't get every construction project delayed for years under the pretense of an "Environmental Compatibility Evaluation," with protesting mobs in front of your gates regardless of what you say and do. Makes sense, doesn't it?

IMHO, in the end everybody in the game will get what is being paid for. Big Pharma will get more of its current image of a commodities marketing organization. Investors will maybe stop selling Big Pharma stock for a while until they shift their assets regardless, to cash in on more promising targets. Europe gets its slow life and deepening slumber, and full insurance against the harshness of life for everybody. The U.S. gets its sense of decline assuaged for a moment, and at one spot. China gets a step closer to ... everything it wants to be eventually.

And small, agile and risk-taking drug discoverers and early-stage developers might get their chance too. As we have said before in this blog, drug repurposing and intelligent reformulation will be a big part of that. However, if a truly new chemical entity actually makes it from the lab bench to the market, it will likely have been discovered and initially characterized by a small outfit where business-focused science rules. H.M. Pharma Consultancy exists to help such outfits.