We are catching up on the backlog of drug repurposing patent commentaries; here we present five applications published in September and early October 2013.
At H.M. Pharma Consultancy we are building a database covering peer review and patent literature on drug repurposing, a tool that is strictly internal at the moment but will become increasingly useful as the content grows. Much on this blog deals with drug repurposing patent applications in near-real time.
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Modafinil for Cocaine Dependence
In April 2012 the development and marketing history of the non-amphetamine psychostimulant, modafinilwas reviewedon this blog – a chronology that eventually became the most-accessed post. Originally developed for narcolepsy, modafinil branched out to less pathological forms of daytime sleepiness, and was repurposed for attention deficit-hyperactivity disorder. A drug interaction study of modafinil and cocaine that was reported ten years ago (Drug Alcohol Depend. 2003; 70(1):29-37, here) had shown blunting of cocaine euphoria. Two years later a double-blind, placebo-controlled, 8-week Phase II study reported success (Neuropsychopharmacology 2005; 30(1):205-11, here). How can WO/2013/128088(Debregeas Pharma [FR]; Sept. 6, 2013) now claim modafinil as novel and inventive for the treatment of cocaine addiction? Because the claims are for the (S) form, allowing lower doses (from 50 to 100 mg/day, as opposed to 200-400 mg in the above trials). There is also a formulation with fast pharmacokinetics. The overall aim is to achieve a very rapid onset of action within 15 to 30 minutes to reduce the window of craving and allow the subject to resist the addictive compulsion.
An Anti-Allergic for COPD
Rupatadine, a long-acting histamine H1 receptor and platelet-activating factor receptor (PAF) antagonist, was developed by the Spanish company Uriach and has been marketed since 2003 (as Rupafin® in several European countries, and as Rupanex® in India) for urticaria and allergic rhinitis (Expert Rev Clin Immunol. 2011; 7(1):15-20, here). The additional PAF antagonism, which is not present in antihistaminics such as cetirizine, is the reason why it makes sense if WO/2013/131324(Beijing Weifeng Yimin Biotechnology [CN]; Sept. 12, 2013)claims rupatadine for chronic obstructive pulmonary disease: Increased PAF production in the airways of smokers enhances inflammatory cell recruitment and exacerbates inflammation (Am J Physiol Lung Cell Mol Physiol. 2012; 302(1):L47-55, here). The same PAF antagonism makes rupatadine a candidate for treating pulmonary fibrosis (PLoS One 2013; 8(7):e68631, here), a related condition with a subtly different pathogenesis. Data from animal models of smoke-induced COPD and TLR4-deficient mice with emphysema are presented. Note that researchers from Nanjing University have reported a protective effect of rupatadine against acute lung injury induced by oleic acid in rabbits (Yao Xue Xue Bao. 2007; 42(3):252-6, here).
A Somatostatin Analog for Broad Uses
Novartis markets Signifor® (pasireotide) for adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. It is only the second drug to be approved for this condition in the United States and Europe. The company’s application WO/2013/131879(Novartis [CH]; Sept. 12, 2013) names hypertonia, obesity, depression, stress and/or alcoholism as new uses for the cyclic peptide. This is a scientifically and commercially obvious move to open several incomparably larger markets to Signifor: in Cushing’s disease (a rare neuroendocrine disorder that affects only a few tens of thousand patients worldwide), a tumor in the pituitary gland generates ACTH, which spurs excess production of cortisol by the adrenal glands, which in the long run causes hyperglycemia, treatment-resistant hypertension, depression and anxiety. Novartis bases its claims on data from the PASPORT-CUSHINGS Phase III study. – Corcept Therapeutics’ Korlym®, the first drug approved for Cushing’s, could in principle also be useful in other causes of pathological hypercortisolemia; but its agent is mifepristone, bound to have many more caveats in broad settings than pasireotide – especially in women of childbearing age. Corcept is investigating it for psychotic depression and weight gain caused by antipsychotics. – A Phase II clinical study investigating pasireotide in polycystic kidney disease (NCT01670110) is currently enrolling patients.
An Anti-Fibrotic for Acne
Pirfenidoneinhibits collagen synthesis, down-regulates profibrotic cytokines, and decreases fibroblast proliferation. Its path towards the pharmacy shelves as the first-ever drug for idiopathic pulmonary fibrosis (as Intermune’s Esbriet®) was tortous, and is not yet complete. First approved in Japan (where Shionog had developed it as Pirespa®) in October 2008, its international Phase III program returned data that were marginally convincing. The EMA approved it in March 2011 and granted it orphan market exclusivity lasting until 2021. The FDA however demanded another Phase III study, which completed enrollment in January 2013. – And here comes WO/2013/147577(Cell Therapy & Tech [MX]; October 3, 2013), with an interesting new application: If pirfenidone can prevent lung fibrosis, and if it can ameliorate keloids(wound contractions caused by collagen proliferation; Arch Dermatol Res. 2012; 304(3):217-22, here), it should be able to prevent atrophic acne scars. The inventors mixed it into a semi-solid topical composition with modified diallyl disulphide oxide (M-DDO) as an antimicrobial, and treated 70 patients with moderate to severe acne for one month. – Just on the sidelines: as Esbriet, one patient-year of pirfenidone therapy costs around $21,000 (€15,000)…
A Motor Disorder Drug and a Muscle Relaxant for Menopausal Symptoms
When pharmaceutical companies sought ways to go beyond L-dopa in the treatment of Parkinson’s disease, they backtracked and developed non-ergot “clean” dopamine D2-like receptor agonists. One of them was ropinirole, which GlaxoSmithKline marketed mostly as ReQuip® (but as Adartrel® in France and Switzerland, and Repreve® in Australia). GSK’s use patent for restless leg syndrome (US 2003/153612), and subsequent approval extensions, were successful elements of the drug’s life cycle management. Occasional clinical studies investigated ropinirole for depression and epilepsy; Santen Pharmaceutical formalized a “quantum leap” repurposing idea by claiming ropinirole for retinal diseases in WO 2008/140052, but that did not result in clinical development. What WO/2013/134080(Individual [US]; Sept. 12, 2013) claims is something else again: hot flashes during menopause (based on the dopaminergic feedback loop that controls the hypothalamic gonadotrophic hormone, GnRH). With the anti-spastic, centrally acting alpha2-adrenergic receptor agonist tizanidine(Zanaflex®, Sirdalud®, and generics) added, the muscle cramps are also addressed. Both drugs should be synergistic for the treatment of menopausal sleep problems: tizanidine has sedating action, and dopamine receptor agonists come with a black-box warning for daytime sleepiness and narcolepsy.