MK-7622

The cleanest test the field has run of the idea that M1 selectivity buys tolerability, and it failed on both counts; no cognitive benefit at all, and more cholinergic side effects than placebo. Worth knowing as the cautionary case rather than as something to look for.

In the phase 2 trial, 21% of participants on MK-7622 reported cholinergically related adverse events against 8% on placebo, and 16% stopped study drug for an adverse event against 6%; diarrhea was the single commonest event at 15.1% versus 5.8% ^[2]. The investigators concluded that activating M1 alone is sufficient to produce unwanted cholinergic effects, which removes the main tolerability argument for M1-selective drugs ^[2].

The mechanism behind that is intrinsic agonist activity; MK-7622 switches M1 on without acetylcholine present, and in mice it induces severe behavioral convulsions, the same seizure liability seen with other M1 ago-PAMs ^[4]. Later comparative pharmacology places MK-7622 among the M1 PAMs with high allosteric agonism, strong cooperativity and preferential enhancement of beta-arrestin signalling, the profile that tracks with cholinergic adverse effects ^[6]. What longer exposure or a higher dose would do in people is not known, because the adverse event profile at 45 mg was judged to rule out testing higher doses ^[2].

MK-7622 was declared a first-in-class M1 positive allosteric modulator development candidate by Beshore and colleagues at Merck, the endpoint of a medicinal chemistry effort aimed at the physicochemical and safety properties earlier compounds in the series lacked ^[1]. Merck ran a randomized, double-blind, placebo-controlled phase 2 proof-of-concept trial (NCT01852110) at 59 sites in the United States and Canada from October 2013 to April 2016, randomizing 240 people with mild to moderate Alzheimer's disease 1:1 to 45 mg once daily or placebo on top of their existing acetylcholinesterase inhibitor.

A prespecified futility analysis, run once 188 participants had reached 12 weeks and set to stop the trial if the conditional power of a significant 12-week ADAS-Cog result fell below 20%, triggered, and the trial was terminated ^[2]. The final read showed a 0.18 point difference on ADAS-Cog at 12 weeks (p = 0.762) and no functional effect at 24 weeks.

Among muscarinic pharmacologists MK-7622 is the reference failure of the class, cited as evidence that an M1 PAM carrying intrinsic agonist activity delivers neither the cognitive benefit nor the clean tolerability the approach was sold on ^[7]. Reviews list it as the most advanced M1 PAM from Merck and record the phase 2 program as discontinued ^[8]. Outside that literature it has no standing; it was never approved, never marketed, and belongs in no consumer product.