Finding new uses for known drugs and drug candidates is gaining momentum, and has been on the rise for the past 12-18 months — this is clearly to be seen in the output of international Patent Convention Treaty documents that are published every week. There is no patent code or other easy modality to identify patent applications that concern drug repurposing, you must look at every single document that does not clearly claim new chemical entities or new formulations. This (and of course, applying the appropriate interest filters) is what we are doing in this blog post series as a service for our readers. We hope that this assists in engaging the gears of your creative thoughts. Greetings from H.M. Pharma Consultancy; please contact us at office@hmpharmacon.com if you need advice of any kind in your drug repurposing project.
An Industrial Solvent for Osteoporosis
Some things you have to read twice if you aren’t an expert in the field. This certainly applies to WO/2012/101173 (Universität Zürich [CH]; August 2, 2012) which claims N-methyl-2-pyrrolidone(NMP, CAS No. 872-50-4), a solvent widely used in large-scale organic chemistry, as an osteoporosis agent. Well, for those who are in the bone metabolism field this does not come out of the blue: In Tissue Eng Part A 2009; 15(10):2955-63 (here) an enhancing effect on bone regeneration had been described, based on increased activity of bone morphogenetic protein (BMP) in osteoblasts and preosteoblastic cells. In fact, the present invention is based on the results of a clinical trial on 10 patients where a NMP-releasing guided bone regeneration membrane was investigated for jawbone healing after the removal of wisdom teeth. An increase in new bone density had been expected, and was found; but the histological results also showed an increase in old bone density (from 3.78 ± 2.68 arbitrary units without NMP to 9.48±2.97 with the NMP releasing membrane, indicating that NMP inhibited the degradation of the old bone and pointing to an inhibiting effect on osteoclast activity. Further investigations demonstrated that NMP attenuates bone resorption by disrupting actin ring formation and decreasing MMP-9 activity. – This is the patent companion to the peer review paper that appeared in J Biol Chem. 2011; 286(27):24458-66 (PubMed).
Fampridine Repurposed On-Target, Again?
A simple compound, 4-aminopyridinewhich had originally been used as a bird poison (Ann Neurol. 2010; 68(1):A8-9; here) has already been successfully repurposed once, for multiple sclerosis: as a potassium channel inhibitor, it blocks the axonal channels that become exposed through the demyelinating process, helping the motor signals to pass through areas of damage and allowing MS patients to walk somewhat better. The FDA approved Accorda Therapeutics’ Fampyra(TM), a 10 mg SR tablet now distributed by Biogen-Idec, in January 2010. Seeking related uses in neurology, the company has generated WO/2012/103471(Acorda Therapeutics [US]; August 2, 2012) claiming such potassium channel blockers for cerebral palsy. Extensive sensorimotor recovery data obtained in rat models are presented, as is a clinical study protocol intending to treat cerebral palsy patients of the spastic, ataxic, athetoid/dyskinetic, and hypotonic type. Clinicaltrials.gov shows almost a dozen ongoing or planned studieswith 4-aminopyridine in various non-MS neurological disorders, but at this time (late August 2012) the list does not include cerebral palsy. We admit we haven’t looked, but without doubt there are patent applications for all of these. – For a summary of aminopyridines in neurological therapy see Clin Neuropharmacol. 2012; 35(4):191-200 (PubMed).
Masitinib for Severe Asthma
As Kinavet(TM) and Masivet(TM), masitinib is approved to treat mast cell tumors in dogs — and of course mast cells are pivotal in asthma. “Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics” — this paper was published three years ago (Allergy 2009; 64(8):1194-201; PubMed); so what might have moved the distributor (outside the U.S.) to file the priority document for WO/2012/104402(AB Science [FR]; August 9, 2012) only in February 2011, citing this exact clinical study? Indeed the examiner at the European patent office cited this paper with a “big fat X” and apparently did not even think it necessary to search beyond that blatant prior art obviousness. Of course this delayed filing does not make the new application less interesting in any way.
MMP Inhibitors for Tuberculosis
There is a large body of published research on the role of matrix metalloproteinases (MMPs) in tuberculosis (TB) (PubMed search) — MMP-1 seems to be the collagenase causing tissue destruction; but somehow the investigations always seem to just narrowly avoid investigating known MMP inhibitors as TB treatments. WO/2012/112945(Columbia Univ. [US]; August 23, 2012) has used doxycycline (an FDA-approved MMP inhibitor used to treat periodontal disease) and a novel murine model of TB which expresses MMP-1 only in lung macrophages (mice do not have a functional ortholog of MMP-1) to demonstrate a functional role for MMP-1 driving extracellular matrix remodeling in TB in the absence of necrosis. Roche’s MMP-1 inhibitor cipemastat(discontinued in 2000 for failing Phase II arthritis trials) but also ilomastat(discontinued as a candidate for treating corneal ulcers, now in repurposed development by Arriva Pharmaceuticals for respiratory tract inflammation), batimastat (discontinued 10 years ago by British Biotech), Pfizer’s prinomastat(failed lung cancer clinical trials), minocycline, and less well known MMP inhibitors such as RO 31-9790 and FN-439 are also claimed as suitable. The companion peer review paper for this patent application is Am J Respir Crit Care Med. 2012; 185(9):989-97 (PubMed).