August tends to be a somewhat less busy time in terms of patent office output. So we have only three international applications to report this time: INT-131, a PPAR modulator, for multiple sclerosis; ultra-low dose naltrexone for many disorders with neuropsychiatric context; and thalidomide for aging diseases.
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A PPARγ Modulator for MS
INT131(formerly Amgen’s AMG131, which originated at Tularik), a potent and selective non-thiazolidinedione, peroxisome proliferator-activated receptor-γ modulator (J Mol Biol. 2009; 386(5): 1301-11; here), has produced good data for the treatment of type 2 diabetes — steeply dose-dependent reductions in HbA1c, equivalent to 45 mg pioglitazone (Actos®) but with less fluid accumulation and weight gain (Diabetes Care2014; 37(7): 1918-23, here). In WO/2014/120538(InteKrin Therapeutics [US]; Aug. 7, 2014) the new licensee company says that the compound is also good for treating multiple sclerosis. Actually, InteKrin’s sole mission is “to bring INT131 to [MS] patients and their physicians”. It is known that PPARγ agonists modulate signaling molecules and pathways, including MMP-9, MAP kinases, and Wnt signaling; all of which makes them candidates for neuroprotection (Drug News Perspect. 2010; 23(4): 241-56; here). Elevated expression of PPARγ has been observed in the cerebrospinal fluid of MS patients (Neurosci Lett. 2013; 554: 131-4, here).
Ultra-Low-Dose Naltrexone Does Many Things
The scientific literature is awash with reports of the opiod receptor antagonist, naltrexonebeing useful not only to reduce craving in opioid or alcohol addiction, but also in impulse control disorders and obesity; there is little if any mention of major depression. Twenty years ago a trial in patients with Parkinson’s disease showed that naltrexone 100 mg/day did not help their motor impairment, or L-dopa induced tardive dyskinesia (Mov Disord. 1994; 9(4): 437-40, here). In WO/2014/120936(PharmoRx Therapeutics [US]; Aug. 7, 2014) makes claims for naltrexone for treating treatment-refractory and breakthrough depression, Parkinson’s disease and Restless Leg Syndrome, bipolar disorder, attention deficit disorder, and obesity – for human doses of naltrexone as low as 1 mg bid, frequently in combination with the respective standard drugs. (The oral doses of Alkermes’ Vivitrol®in alcohol or opiate dependence are 50 -100 mg/day; Takeda/Orexigen’s Contrave®, FDA-approved for obesity a few days ago, is naltrexone 32 mg + bupropion 360 mg in sustained release.) – Scientists at the City University of New York and Pain Therapeutics, Inc. have shown years before the priority date that naloxoneand naltrexone, at very low doses, prevent µ-opioid receptors from switching their morphine-induced coupling from Gi/o to Gs by binding to a pentapeptide binding site on filamin A, a scaffolding protein that interacts with µ receptors (PLoS One 2008; 3(2): e1554, here; PLoS One 2009; 4(1): e4282, here).
Da Capo for Thalidomide – Alzheimer’s and IPF
Thalidomide‘s revival for multiple myeloma is a classical example of repurposing, second in citations only to the unavoidable sildenafil for erectile dysfunction. WO/2014/122638(Individual [IE/AU]; Aug. 14, 2014) claims yet another use for this decades-old drug: thalidomide maintains and increases stem cell factor levels, which are decreased in Alzheimer’s disease patients with fast cognitive decline (J Alzheimers Dis. 2011; 26(1): 39-45; here) and probably also in idiopathic pulmonary fibrosis where involvement of bone marrow mesenchymal stem cells has been shown (Respir Med.2010; 104(10): 1535-42; here). A study carried out to perform a comparison study to determine if thalidomide is equally effective as matrix metalloprotease-9 gene deletion in delaying cardiac sarcopenia in a mouse model. Echocardiography showed improvements in stroke volume, cardiac output and fractional shortening with thalidomide, indicating a direct effect on cardiac myocyte contractility. Survival rates were not significantly improved.