Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Neurim Pharmaceuticals Ltd.
Piromelatine is a multimodal sleep drug. It acts primarily as an agonist of MT1/MT2/MT3 melatonin receptors and serotonin 5-HT1A and 5-HT1D receptors, but reportedly also is a low-affinity antagonist of 5-HT2B, P2X3, and TRPV1 receptors.
Neurim Pharmaceuticals claims that this compound may benefit control of circadian rhythm, metabolism, cognition and mood. Preclinical studies have reported cognitive improvement in rats that received hippocampal Aβ42 injections to simulate Alzheimer’s disease (He et al. 2013). There are also reports on painkilling and hypnotic effects in a mouse model of neuropathic pain (Liu et al., 2014), as well as blood pressure lowering in rats (Huang et al., 2013).
Disrupted sleep is common in Alzheimer's disease. A prior clinical trial of melatonin itself was negative (see Dec 2003 news), but since then, numerous human and animal studies have implicated poor sleep quality in Alzheimer's pathogenesis. Proposed mechanisms relate to theta wave memory consolidation, protein translation, as well as nocturnal clearance of Aβ and other waste proteins (e.g. Sep 2009 news; Aug 2012 news; Aug 2012 news; Jun 2014 news; May 2016 news, Varga et al., 2016).
Between 2010 and 2013, Neurim Pharmaceuticals ran Phase 1 and 2 trials of piromelatine in primary insomnia. Results are not reported in the peer-reviewed literature, but the company announced that various sleep parameters improved in a Phase 2 trial in 120 participants who took a four-week course of piromelatine (see 2013 company release).
In September 2016, the company started enrolling for ReCOGNITION, a Phase 2 study of neuromelatine in Alzheimer's disease (see 2016 company release). This study will compare a six-month course of 5, 20, or 50 mg once daily to placebo in 500 people with a clinical diagnosis of mild Alzheimer's disease as per NIA-AA criteria. The primary outcome is a computerized version of the neuropsychological test battery (cNTB); secondary outcomes include functional, clinical, global and neuropsychiatric AD scales, as well as safety and a sleep quality index. In other words, this trial evaluates neuromelatine on its ability to affect AD itself, not merely sleep in AD patients. The trial is being conducted at 72 centers across the United States.
In addition, piromelatine was evaluated for irritable bowel syndrome, and is being evaluated for glaucoma, in Spain.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|Neurim Pharmaceuticals Ltd.||NCT02615002||
Last Updated: 09 Dec 2016
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- He P, Ouyang X, Zhou S, Yin W, Tang C, Laudon M, Tian S. 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. PubMed.
- Liu YY, Yin D, Chen L, Qu WM, Chen CR, Laudon M, Cheng NN, Urade Y, Huang ZL. 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 Oct;231(20):3973-85. Epub 2014 Apr 4 PubMed.
- Huang L, Zhang C, Hou Y, Laudon M, She M, Yang S, Ding L, Wang H, Wang Z, He P, Yin W. Blood pressure reducing effects of piromelatine and melatonin in spontaneously hypertensive rats. Eur Rev Med Pharmacol Sci. 2013 Sep;17(18):2449-56. PubMed.
- Varga AW, Wohlleber ME, Giménez S, Romero S, Alonso JF, Ducca EL, Kam K, Lewis C, Tanzi EB, Tweardy S, Kishi A, Parekh A, Fischer E, Gumb T, Alcolea D, Fortea J, Lleó A, Blennow K, Zetterberg H, Mosconi L, Glodzik L, Pirraglia E, Burschtin OE, de Leon MJ, Rapoport DM, Lu SE, Ayappa I, Osorio RS. Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly. Sleep. 2016 Nov 1;39(11):2041-2048. PubMed.
No Available Further Reading