Background

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 had received hippocampal Aβ42 injections to simulate Alzheimer’s disease (He et al., 2013). There are also reports on analgesic and hypnotic effects in a mouse model of neuropathic pain (Liu et al., 2014), as well as blood pressure lowering and metabolic benefits in rats (Huang et al., 2013; Zhou et al., 2017).

Disrupted sleep is common in Alzheimer's disease. A prior clinical trial of melatonin itself was negative (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 conference news; Jun 2014 news; May 2016 conference news; Varga et al., 2016).

Findings

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 at the time that various sleep parameters improved in a Phase 2 trial in 120 participants who took a four-week course of piromelatine.

In September 2016, the company started enrolling for ReCOGNITION, a Phase 2 study of piromelatine in Alzheimer's disease. This study compared a six-month course of 5, 20, or 50 mg once daily to placebo in 371 people with a clinical diagnosis of mild Alzheimer's disease as per NIA-AA criteria. The primary outcome was a computerized version of the neuropsychological test battery (cNTB); secondary outcomes included functional, clinical, global, and neuropsychiatric AD scales, as well as safety and a sleep-quality index. In other words, this trial evaluated piromelatine on its ability to affect AD itself, not merely sleep in AD patients. The trial was conducted at 56 centers across the United States, and finished in November 2019. According to results presented at the 2021 CTAD conference, piromelatine did not significantly change the cNTB, or secondary outcomes of the ADAS-Cog14, and Pittsburg Sleep Quality Index (PSQI). The drug was safe. A subsequent GWAS for drug responsiveness in 107 participants identified a cluster of six polymorphisms in chromosome 2q12, present in one-quarter of participants, that was associated with improvement on the cNTB, but significant deterioration on the ADAS-Cog14 and PSQI. Participants without the polymorphisms significantly improved on the ADAS-Cog14 and PSQI with piromelatine. The work was published after peer review (Schneider et al., 2022).

In March 2022, the company registered a new prospective trial in AD that will exclude carriers of this polymorphism. The study will enroll 225 participants for six months of 20 mg piromelatine daily, or placebo, followed by a one-year, open-label extension. The primary outcome is ADAS-Cog14, with secondaries of ADCS-Instrumental Activities of Daily Living, ADCS-Clinical Global Impression of Change, MMSE, and safety. The study is planned to run from May 2022 to June 2025.

In addition, piromelatine has been evaluated in Spain for insomnia, irritable bowel syndrome, and  glaucoma.

For all trials of piromelatine, see clinicaltrials.gov and WHO ICTRP registries.

Clinical Trial Timeline