Is it just us, or are you too seeing more papers, and hearing more talk, about drug repurposing recently? For sure there are more international patent applications with this focus being published this summer, which is why we are pushing out another issue of or reviews barely a week after the last one.
In five out of the six cases we present, it is the original developer who is claiming distinct new uses for one of its own in-development novel compounds; especially GlaxoSmithKline seems to be good at this earliest-occasion originator repurposing. Diversification of potential uses is a good economic driver, and repurposing is not only for failed candidates or generics.
If you take our routine updates on drug repurposing patent applications as an indication of proficiency in this expanding field (as we definitely hope you will), please recommend this blog and contact us for any consulting requirements you may have. Our corporate website will give you more information on what H.M. Pharma Consultancy does beyond drug repurposing.
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The Long Story of an Alzheimer Drug Branches Out
Ladostigil(TV3326) was designed at the University of Jerusalem as an Alzheimer drug, to combine the neuroprotective effects of rasagiline(a selective inhibitor of monoamine oxidase-B)with the cholinesterase inhibitory activity of carbamates (J Neural Transm Suppl.2000; (60):157-69, PMID: 11205137).The drug candidate, which is developed by Avraham Pharmaceuticals (Yavneh, Israel), has completed a Phase II clinical trial in mild-to-moderate Alzheimer’s (NCT01354691). An ongoing 3-year prospective Phase II trial (NCT01429623) is investigating whether ladostigil can delay the progression of mild cognitive impairment to Alzheimer’s. Now, in WO/2013/118126(Yissum R&D [IL]; Aug. 15, 2013), the university’s intellectual property arm is claiming additional uses in inflammatory conditions, including septic shock, myocardial ischemia, Crohn’s disease, and diabetes;all apparently unrelated to the compound’s known pharmacological actions. The animal data, which used rivastigmine as a control (because cholinesterase inhibitors can have anti-inflammatory action outside the brain; see e.g., Bull Exp Biol Med.2012; 152(5):600-2, PMID: 22803143) are quite convincing. A part of this work relating to neuroprotection against lipopolysaccharide has been published in J Neuroimmune Pharmacol.2012; 7(2):488-98 (PMID: 22454040).
Inhibiting Phosphodiesterase IV in Huntington’s Disease
WO/2013/117693(GlaxoSmithKline [GB]; Aug. 15, 2013) claims a PDE-4 inhibitor identifiable as GSK356278(Org. Process Res. Dev. 2010; 14 (5): 1153–1161; here), a pyrazolo[3,4-b]pyridine originally disclosed in WO/2004/056823(as Example 98) for inflammatory and/or allergic diseases, and then again in GSK’s WO/2011/107394as an anxiolytic, for Huntington’s disease. Given the established efficacy of the PDE-4 inhibitor rolipramin a rodent model of this incurable neurological condition (Neurobiol Dis. 2008; 30(3):375-87, PMID: 18424161 and Neurobiol Dis. 2012; 46(1):225-3, PMID: 22311347), inventiveness might not be high but novelty appears to be present. GSK has completed NCT01602900, a Phase I open-label PET imaging study in healthy men, to investigate single oral doses of GSK356278; 11C-(R)-rolipram was used as a comparator.
From Late-Stage Tumors to Idiopathic Pulmonary Fibrosis
In a variety of tumor settings oncogenicity is promoted by dysregulated phosphoinositide-3 kinase (PI3K) signaling resulting from either p110 mutation, over-expression, or alternatively by reduced functionality of the regulatory phosphatases. It is also likely that such aberrant signalling may play a critical role in both initiation and progression of fibroblast functions in idiopathic pulmonary fibrosis (IPF). So it is no surprise to see WO/2013/117503(GlaxoSmithKline [GB]; Aug. 15, 2013) now making additional claims for its PI3K inhibitor GSK2126458, a highly selective and potent inhibitor of the PI3K subunits p110α through δ, mTORC1 and mTORC2 with picomolar Ki values (ACS Med. Chem. Lett. 2010, 1(1), 39-43; here) which is being investigated for ovarian cancer (Clin Cancer Res2012; 18:A44; here). GSK has NCT01725139, a double-blind Phase I proof-of-mechanism study in IPF, already recruiting patients. NCT01248858, another Phase I study investigating GSK2126458 in patients with advanced solid tumors in combination with the oral MEK inhibitor trametinib, is also ongoing.
A Da-Capo for Laquinimod in Crohn’s Disease
In WO/2013/116657(Teva Pharmaceutical Industries [IL]; Aug. 8, 2013) claims are made for laquinimod(a derivative of roquinimex, an immunomodulatory drug investigated for multiple sclerosis in the 1980s) as a second-line therapy for patients with non-fibrostenotic Crohn’s disease who had not undergone surgery. If this sounds like a narrow indication, this is because Teva had already made broad Crohn’s disease claims for this immunomodulator in WO/2011/014255, a patent application which covered the company’s Phase IIa clinical trial (NCT00737932) for this indication. CONCERTO (NCT01707992), another Phase III trial for relapsing-remitting MS (the primary indication), is enrolling patients; two studies for lupusarthritis and nephritis (NCT01085084and NCT01085097) have been completed.
Donepezil for Fibromyalgia: It Just Keeps Coming, And Coming…
It had to happen of course: In spite of several failed clinical trials with cholinesterase inhibitors in fibromyalgia(see e.g., Arthritis Rheum. 2008; 58(2):612-22, PMID: 18240245 for pyridostigmine, and JAMA 2004; 292(10):1195-204, PMID: 15353532 for galantamine), somebody had to try again and make similar repurposing claims for donepezil, the commercially most successful of the cholinesterase inhibitors that are approved for symptomatic tretament of Alzheimer’s dementia. In WO/2013/115083(Shin Nippon Biomedical Labs [JP]; Aug. 8, 2013) the animal data seem more supportive of the compound’s use as a pure analgesic, but one could go along with that given the characteristics of fibromyalgia as an incompletely defined condition with a strong component of diffuse pain. More, and very distinct, trouble in terms of novelty lurks in the claims for “functional pain syndromes”made by the Eisai (the original developer of donepezil) in WO/2000/015205.Also see WO/2009/139470(Axis, Inc., JP) with fibromyalgia claims for the muscarinic receptor agonist, pilocarpine– another cholinergic agent.
Repurposing a Biotech Drug Candidate: rHA-Infestin-4 for Multiple Sclerosis
There is solidevidence that Factor XII (Hagemann factor) is not only involved in thrombus formation during ischemic stroke, but is also involved in the inflammatory processes that go along with it (Ann N Y Acad Sci. 2010; 1207:149-54; PMID: 20955438 and JACC Cardiovasc Imaging2012; 5(11):1127-38; PMID: 23153913), through the formation of bradykinin via the kinin-kallikrein system. Yet other roles of FXII are in chemotaxis, aggregation, and degranulation of neutrophils, a fact that has long been known (Blood1986; 67(6):1731-7; here). It can also enhance monocyte production of the proinflammatory cytokine IL-1, and is involved in the complement system. Given all this pre-existing knowledgeit is surprisingthat WO/2013/113774(CSL Behring [DE]; Aug. 8, 2013)should be the first claim for FXIIa inhibitors in multiple sclerosis, which matches all these features perfectly. The inhibitors include CSL Behring’s recombinant human albumin/infestin-4 hybrid (Circulation2010; 121:1510-17, here), based on a Kazal-type serine protease inhibitor from the gut of the bug Triatoma infestans, that is under development for stroke. See also the company’s WO/2013/014092claiming inhibitory anti-Factor XII/XIIa monoclonal antibodies for neurological inflammatory diseases in general.