Once again, the past month has seen so many published international applications related to drug repurposing that we have to split or report in twain. Here are four examples from the first half of April.
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Laropiprant to Rise From the Ashes?
Niacin(nicotinic acid) has been used for decades to treat dyslipidemia, and it remains the most effective marketed agent for increasing levels of high-density lipoprotein. Its major drawback is that cholesterol-lowering doses produce facial flushing because the synthesis of the vasodilator prostaglandin D2 is stimulated. Merck & Co. combined niacin with laropiprant(J Med Chem. 2007; 50(4): 794-806, here), a selective prostaglandin D2 receptor-1 antagonist, to counteract this undesirable effect and got the combination approved in 70 countries (including Europe but not the U.S.) as Tredaptive®, Pelzont®, and Trevaclyn®,. The drug was discontinued in early 2013 after the huge Phase III HPS2-THRIVEstudy had revealed an increased risk of blood and lymphatic disorders, gastrointestinal problems and infections but no therapeutic benefit over statins. Whether this was attributable to niacin, laropiprant, or some synergy between these agents remains unresolved. Laropiprant alone did not provide benefit in asthma and allergic rhinitis (J Allergy Clin Immunol. 2009; 124(5): 942-8, here). WO/2014/049300 (Galderma [FR]; April 3, 2014) makes another attempt that is more aligned with facial flushing: topical preparations for rosacea. The company’s concurrently published applications WO/2014/049295 through ’99 claim combinations with doxycycline, metronidazole, oxymetzazoline, ivermectin and brimonidine for the same purpose.
Unexpected Perspectives for a Rare Inherited Disorder
The extremely rare autosomal recessive neurodegenerative disorder Wolfram Syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), is caused by mutations in the WFS1 gene which encodes wolframin, an endoplasmic reticulum membrane protein (Clin Genet. 2011; 79(2): 103-17, here). The proposed mechanism is ER stress-induced damage to neuronal and hormone-producing cells (Orphanet J Rare Dis. 2013; 8: 64, here). The inventors have found that increased levels of p21 (CIP1/WAF1) can prevent apoptosis and reverses the cell cycle disturbance in wolframin-depleted neuronal cells, and that it has a protective interaction with the V1A subunit of ATPase (Hum Mol Genet. 2013; 22(2): 203-17, here). Going beyond this peer review companion paper, they tested a number of compounds known to increase expression and/or functional activity of p21 for their effects on cell death in neuronal cells, and obtained positive in vitro results with the NSAID flurbiprofen, the cardioprotectant dexrasoxane(Pfizer’s Zinecard®; Novartis’ Cardioxane®), and rapamycin(Pfizer’s Rapamune ®). The results can be found in WO/2014/049366 (Univ. Birmingham [UK]; April 3, 2014).
Selegiline for a Very Visible Cancer Therapy Side Effect
The monoamine oxidase inhibitor, (-)deprenyl(selegiline) has a long history of development and use in depression and Parkinson’s disease; several additional applications have been proposed, many of them based on its neuroprotective effects. Now WO/2014/056070 (Brandon Univ. [CA]; April 17, 2014) claims selegiline and related MAO inhibitors, such as rasagiline(Teva’s Azilect®) for hair loss caused by chemotherapy. Data from the mouse cyclophosphamide-induced alopecia model, which produces p53-dependent follicular cell apoptosis, shows that the approach works. – The literature has good evidence that the anti-apoptotic effect of selegiline has nothing to do with MAO inhibition but is conferred by a metabolite, desmethyldeprenyl, probably acting through a glyceraldehyde-3-phosphate dehydrogenase mediated signaling cascade (Proc Natl Acad Sci USA. 2006; 103(10): 3887-9, here).
From Male-Only to Female-Only
Degarelix(Ferring’s Firmagon®; Astella’s Gonax®; an injectable gonadotropin-releasing hormone receptor antagonist) is approved for prostate cancer. WO/2014/053223 (Individuals [IT]; April 10, 2014) makes the leap from men to women, claiming it for the treatment of endometriosis and endometriotic ovarian cysts. (Note that this is paradoxical to a degree because GnRH agonists are used in women who require assisted reproduction because of endometriosis.) The applicants had disclosed, at the 2012 ASRM 68th Annual Meeting, that the monthly administration of 80 mg degarelix for a period of three months resulted in reduction of pain and recurrence in women with severe endometriosis. Similar findings have been reported for elagolix(Reprod Sci. 2014; 21(3): 363-71, here), which is being developed by Abbott and Neurocrine Pharmaceuticals; and Takeda has relugolix(TAK-385) further up in the pipeline.