Ozempic for Sleep

Concept

A cutting edge drug discovery startup focused exclusively on sleep indications, ideally expanding from narrower ones to AD/PD or even to the relatively healthy population

Longer Description

Sleep has received shockingly little pharma attention despite the following:

• Everyone spending 1/3 of their life doing it
• 35% of adults report not getting the sleep they desire
• There’s existence proof of highly efficient sleep, with a small proportion of the population needing <7hr to function normally (or even better) and no apparent adverse effects.
• Deep sleep shows high variance within and amongst individuals. In population samples, conventionally scored SWS can vary from ~2% to ~30% of the night within age-matched older adults. Sleep deprivation yields deeper sleep both in terms of SWS and SWA. And, deep sleep wains with age.
• A handful of sleep-related disease indications with unmet needs that have previously produced four blockbuster drugs plus several more doing $300M+ a year in sales. These include obstructive sleep apnea, insomnia, REM sleep behavior disorder, type 1 narcolepsy, restless leg syndrome
• A clear path (that has been attempted before) to expand from initial sleep indication to very broad neurological diseases like Alzheimer’s, Parkinson’s, and Dementia given sleep’s core role in brain health, memory, etc. Those populations also have systematically worse sleep. It also plays a role in other large-scale diseases including obesity, diabetes, cardiometabolic risk, and psychiatric conditions from depression to schizophrenia.
• A longer-term theoretical path to one of the only population-scale indications, including one that could in theory be taken by effectively every person every day for the rest of their lives

The major clinical trials to date are detailed below.

Pharmacological Approaches

Results have largely been mixed with only a few demonstrably successes including Ambien, Jazz’s sodium oxybate, and Takeda’s recent OX2R-selective agonist. The latter improved T1 narcolepsy patients to normal functioning at 12 weeks in PIII. Other than that, most core sleep-related diseases remain unsolved.

Moreover, almost all clinical attempts have clustered around the same select few targets of GABA, orexin, serotonin, and calcium-channels.

A cutting edge startup focused exclusively on the biology of sleep could develop new therapeutic approaches to these known targets and discover novel sleep-related targets.

The dream target would a readily druggable master regulator like GLP-1s.

Unfortunately for those of us looking for an instant gold rush, it appears that the gene variants linked to claimed “natural short sleepers” are candidate genes invalidated by modern population-scale GWAS studies that find no reason to believe they replicate or are meaningfully related to sleep. Moreover, studies of 400K+ adults found that of the few dozen loci associated with short sleep, the one with the largest single effect contributed just 2.4 minutes.

However, just because sleep is a polygenic, complex phenomena likely regulated by many circuits doesn’t mean there aren’t fulcrums with disproportionate leverage like GLPs.

There’s a handful of other known targets and therapeutic approaches we’ve come across that could make for appealing starting grounds:

• NPSR1 and SIK3 may be the only short sleep pathways possibly worth pursuing, as no carriers of its variants were found in that 127K-person study and thus weren’t actively discredited.
• If NPSR1 proves to be a hit, it could the world’s first anti-anxiety stimulant but would go against orexin antagonists which are already quite good drugs.
• SIK3’s role as a regulator of sleep need has been replicated by multiple labs in different animal models, though it hasn’t been identified in human GWAS studies