Negative Readouts: Updates on an NMDAR PAM, an MK2 inhibitor, and a Porcupine inhibitor

This article discusses scientifically interesting molecules that have unfortunately had negative recent readouts. Aptinyx’s therapeutic approach of targeting positive allosteric modulators (PAMs) of NMDA receptors has hit another setback in Ph. II for NYX-458. The oral, twice-daily MK2 inhibitor from Aclaris Therapeutics has results from its Ph. IIa for the treatment of moderate-to-severe hidradenitis suppurativa (HS). Redx Pharma has released initial results for their oral porcupine inhibitor in Ph. II for the treatment of advanced biliary tract cancer (BTC). 

Read more about the molecules from halted, discontinued or altered clinical trials from March 2023 below! 

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[structure(s) not disclosed]

NYX-2925, example NMDAR PAM from Aptinyx
oral, once-daily NMDA receptor PAM
failed Ph. II for improved cognitive impairment

Aptinyx’s therapeutic approach of targeting positive allosteric modulators (PAMs) of NMDA receptors has hit another setback. A Ph. II trial of NYX-458 failed to show clinically meaningful improvements in the cognitive impairment associated with patients with Parkinson’s disease or dementia with Lewy bodies (30 mg QD, n = 99, NCT04148391). These endpoints evaluated everyday function (PDAQ-15) and cognition (ECog-12), plus cognitive performance of patients over 12 weeks. The compound was well-tolerated, but Apinyx is halting NYX-458 development based on these results, as well as that of its only other Ph. II/III clinical candidate for the treatment of PTSD, NYX-783 (50 mg QD, n = 121, NCT05181995).  Previous trials of a third compound, NYX-2925, for the treatment of DPN-associated neuropathic pain and fibromyalgia also failed Ph. II studies (four studies).

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