Groundbreaking pharmaceuticals for treating
Based on the expertise and commitment of our R&D and management teams, Neurim’s in-depth understanding of the Central Nervous System enables us to realize the clinical potential of pharmaceutical formulations that address crucial unmet patient needs in significant markets. Our efforts are reinforced by fruitful collaborations with academic and independent research institutes and contract research organizations.
Piromelatine in Alzheimer Disease
Alzheimer’s disease, the leading cause of dementia in the elderly population, currently affects more than 5 million Americans and more than 40 million people worldwide, and these numbers are growing rapidly. In addition to cognitive impairment, patients suffering from Alzheimer’s disease often suffer from poor sleep and circadian rhythms control.
Piromelatine’s novel, multi-targeted mechanism of action represents new thinking on Alzheimer’s Disease pathogenesis and holds potential breakthrough benefits in sleep disorders and Alzheimer’s Disease. Due to its multimodal mechanism, it is expected to improve memory and mood, and increase cognition and neurogenesis in addition to its proven effect of improving sleep, circadian rhythms control, enhance slow-wave sleep and reduce wakefulness during the night.
Mode of Action:
Melatonin MT1, 2, and 3 and serotonin 5-HT-1A and -1D receptors agonist. Simultaneous activation of melatonergic and 5HT 1a receptors may synergistically promote neurogenesis. Melatonin receptor agonism, which maintains the NREM SWS, appears beneficial for cognition and functioning in mild to moderate AD patients.
In preclinical studies in cell and animal models of Alzheimer’s Disease, Piromelatine was found to protect from neural damage, facilitate memory performance and improve cognitive impairment and attenuate Alzheimer’s disease risk factors such as insulin resistance, hypertension and sleep disorders.
Neurim has already completed a Phase II study with Piromelatine for insomnia, in which the drug has demonstrated dose-dependent efficacy in improving sleep maintenance, and a good safety profile.
References: 1. Fava, M., et al., An exploratory study of combination buspirone and melatonin SR in Major Depressive Disorder (MDD): A possible role for neurogenesis in drug discovery. Journal of psychiatric research, 2012. 46(12): p. 1553-63. 2. Arbon, Emma L et al. Randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people. J Psychopharmacol. 2015;29(7):764-776. 3. Wade, A.G., et al., Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clinical interventions in aging, 2014. 9: p. 947-61. 4. He, Pingping et al. A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer’ disease. Horm Behav. 2013 Jun;64(1):1-7. 5. She, M., et al., NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats. Pharmacol Res, 2009. 59(4): p. 248-53. 6. She, Meihua et al. Piromelatine, a novel melatonin receptor agonist, stabilizes metabolic profiles and ameliorates insulin resistance in chronic sleep restricted rats. Eur J Pharmacol. 2014;727:60-65. 7. Wang, Ping-Ping et al. Piromelatine decreases triglyceride accumulation in insulin resistant 3T3-L1 adipocytes: role of ATGL and HSL. Biochimie. 2013;95(8):1650-1654. 8. Liu, Yuan-Yuan et al. Piromelatine exerts antinociceptive effect via melatonin, opioid, and 5HT1A receptors and hypnotic effect via melatonin receptors in a mouse model of neuropathic pain. Psychopharmacology (Berl). 2014;231(20):3973-3985.
Gal-475 in Sleep Apnea
Between 3 – 7% of the population suffer from obstructive sleep apnea (OSA), and between 1.1% – 7.5% of males aged 65 years and older suffer from central sleep apnea (CSA). First-line OSA therapy includes continuous positive airway pressure (CPAP), upper airway surgery and oral appliances, while CSA treatments include addressing associated medical conditions and CPAP. Because these approaches suffer from low compliance rates as well as unpredictable efficacy and safety, there is a need for new pharmacological approaches.
GAL-475 is a novel therapeutic agent for the treatment of sleep apnea syndromes. In a series of in vitro and in vivo studies in various animal models it demonstrated improvements in sleep apnea indices with reductions in both the frequency and severity of events, without stimulating minute ventilation or disturbing sleep. Preclinical pharmacology studies with GAL-475 suggest that the compound acts predominantly as a peripheral chemoreception modulator, and indicate that the compound is effective in increasing respiratory drive to the upper airways and ameliorating obstructive apneas and their attendant sequelae in rodent models of obstructive apnea at relatively low plasma levels.
Mode of Action:
The primary site of action for GAL-475 appears to be at the level of the carotid body, a peripheral polymodal chemosensory organ, located at the carotid bifurcation, responsible for sensing changes in partial pressures of O2, CO2 or pH, and activating the brainstem respiratory center to produce hyperventilation.
GAL-475 was evaluated for toxicological effects via several in vitro and in vivo studies of daily oral treatment in rats and dogs. GAL-475 has an acceptable pharmacokinetic, ADME and tolerability profile in preclinical species that render it suitable to enter clinical phases.
Currently underway is a Phase 1, randomized, placebo-controlled, double-blind, first-in-man, single escalating dose study, meant to evaluate the safety, tolerability, pharmacokinetics and pharmadynamics of GAL 475 in healthy male volunteers and male subject with sleep apnea.
References: 1.Libman, E et al. CPAP Treatment Adherence in Women with Obstructive Sleep Apnea. Sleep Disord. 2017;2017:2760650. 2.Caples, Sean M et al. Surgical modifications of the upper airway for obstructive sleep apnea in adults: a systematic review and meta-analysis. Sleep. 2010;33(10):1396-1407. 3. López-Barneo, J et al. Carotid body oxygen sensing. Eur Respir J. 2008;32(5):1386-1398. 4. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008;5(2):136-143. doi:10.1513/pats.200709-155MG. 5.Donovan LM, Kapur VK. Prevalence and Characteristics of Central Compared to Obstructive Sleep Apnea: Analyses from the Sleep Heart Health Study Cohort. Sleep. 2016;39(7):1353-1359.