Slow time in drug repurposing on all fronts; but we did manage to identify a few patent applications that were published during the üast few weeks. – Enjoy and peruse… And remember that H.M. Pharma Consultancy can assist you with all projects related to drug repurpoising.
Tarenflurbil: Alzheimer’s Disease (failed) →Dermatitis
In contrast to its (S)-isomer (R)-flurbiprofen (tarenflurbil; (R)-2-(2-fluoro-4-phenylphenyl)propionic acid; Flurizan™) does not inhibit cyclooxygenases and/or prostaglandin synthesis. But it does inhibit gamma secretase, and it has a good side effect profile in man (IDrugs 2007; 10(2): 121-33, here). A few years ago it failed as Myriad Genetics’ Phase III clinical candidate for the treatment of Alzheimer’s disease, in the largest and longest such trial ever conducted up to that time. The failure was ascribed to low potency and brain penetration (J Alzheimers Dis. 2009; 17(4): 757-60, here). Now, WO/2013/026772(University of Dresden [DE]; Feb. 28, 2013) has found a new use: skin diseases. In mouse models of IgE-mediated or dinitrofluorebenzene – induced dermatitis, scratching behavior and inflammation were reduced. The drug also worked in the zymosan-induced non-allergic dermatitis model where itching does not play a significant role. – These findings are particularly remarkable because cases of contact dermatitis have been reported with flurbiprofen (Contact Dermatitis 2000; 42(3): 167-8, here). There is no immediate suggestion for a potential mechanism in dermatology. – Note that a Phase II clinical trial investigating tarenflurbil for delaying the recurrence of localized prostate cancer (NCT00045123) has never been formally closed.
Maraviroc: HIV Infection (marketed) →Pulmonary Hypertension
Last year Pfizer sponsored a clinical study (NCT00948753) showing that its anti-HIV drug Selzentry™(maraviroc) – a CCR5 antagonist – might have potential in preventing Graft versus Host Disease in patients undergoing bone marrow transplantation (also see N Engl J Med 2012; 367:135-145; here). But CCR5 also affects intimal monocyte infiltration and neointimal growth (Thromb Haemost. 2007; 97(5): 730-7, here), a key event in the development ofpulmonary arterial hypertension (and a reason for PAH as a complication of HIV infection). WO/2013/024022(INSERM [FR]; Feb. 21, 2013) has made the connection, and claims maraviroc (and most other CCR5 antagonists known from the literature) for PAH. To assess the inhibitory effects of maraviroc on development of hypoxia-induced PAH, the inventors used CCR5 knock-in mice in which the murine CCR5 gene was replaced by the human homolog. Maraviroc (200 mg/kg/day) protected KICCR5 mice, but not wild-type mice, as shown by a reduction of right ventricular systolic pressure, Fulton index, percentage of muscularized vessels, and proliferative cells detected by ki67immuno staining.
Beta-Inferferon: Multiple Sclerosis (marketed) →Alopecia
The lengths to which some middle-aged men will go to delay natural hair loss (or to hide it) can be traced through mankinds’s history, but WO/2013/023961(Tigo [DE]; Feb. 21, 2013) tops it by claiming beta-interferons – top-priced products of pharmaceutical biotechnology and a mainstay of multiple sclerosis therapy – for a hair loss condition that is cosmetically awkward but certainly not dangerous: alopecia areata. And just as with MS, baldness therapy with IFN beta-1b (intradermally at daily doses of 4.5-30 μg per 10 cm2 of treated scalp area) needs to be permanent: the regimen resulted in hair loss being completely stopped, but it resumed 1 week after the last dose. – Regardless of the cause of hair loss, this will never be eligible for reimbursement.
Avasimibe: Dyslipidemia (failed) →Niemann Pick Disease
Acyl coenzyme A:cholesterol acyltransferase (ACAT) is an intracellular integral membrane enzyme that catalyzes the formation of cholesteryl esters from cholesterol and long chain fatty acids. In the late 1990s this protein was considered a target for lipid lowering and prevention of atherosclerosis. Parke Davis’ avasimibe(CI-1011) reached Phase III in the early 2000s but was discontinued. Researchers kept looking for other, less obvious uses where modulating the cholesterol pathway could be useful, such as Alzheimer’s disease (FASEB J. 2009; 23(11):3819-28, here). In WO/2013/016315 (Dartmouth College [US]; Jan. 31, 2013) another such opportunity is pointed out — Niemann-Pick disease. The choice is quite obvious in retrospect because the NP-C mutation affects a broad spectrum of metabolic responses related to the processing of exogenously derived cholesterol (Biochim Biophys Acta 1991; 1096(4): 319-27, here). Avasimibe was administered to suckling or freshly weaned Niemann-Pick mice in sesame oil by daily subcutaneous injection or by oral gavage in methylcellulose for up to 7 days; ganglioside accumulation and foam cell formation in organs as well as brain sterol composition were determined.