Background

Developed by Suven Inc., the Delaware-based subsidiary of Indian company Suven Life Sciences, SUVN-502 is an orally available, brain-penetrant, selective antagonist of the 5-HT6 serotonin receptor (Nirogi et al., 2017). This G protein-coupled receptor is expressed mostly in the brain, where it mediates neurotransmission for functions including cognition and memory. Blocking this receptor increases cholinergic and glutamatergic signaling, and other 5-HT6 receptor antagonists have been reported to improve cognition. Several were being developed as treatments for Alzheimer's, and all were discontinued due to lack of efficacy (Upton et al., 2008; Intepirdine; Idalopirdine; Dimebon; PF-05212377).

In preclinical work, one rat study reported that masupirdine had procognitive effects, reversed age-related memory decline, increased brain acetylcholine and glutamate levels, and potentiated the effects of memantine and donepezil on brain neurotransmitters and electrical activity (Nirogi et al., 2018).

Findings

According to the company's website, Phase 1 studies were conducted in Switzerland in 2008. Suven scientists reported positive safety and pharmacokinetic data from single and multiple doses in healthy young adults and elderly volunteers (Nirogi et al., 2018).

In September 2015, a Phase 2a proof-of-concept trial began enrolling what would be 564 patients with probable Alzheimer's disease as diagnosed by the 1984 NINCDS-ADRDA criteria and an MMSE of between 12 and 20. The trial compared 26 weeks of treatment with 50 or 100 mg of SUVN-502 daily to placebo, all given in addition to donepezil and memantine. Conducted at 57 sites in the United States, this trial measured change on the ADAS-Cog11 as primary, and change on the CDR and various clinical and functional scales as secondary outcomes. The trial missed its primary outcome, according to data presented at the 2019 CTAD (Dec 2019 conference news, slide presentation, Nirogi et al., 2022). After 26 weeks, there was no difference between groups on the ADAS-cog, nor were there changes in any secondary measures.

The company stated in a Nov 2019 press release that it would continue developing masupirdine based on subgroup analyses indicating potential benefit in some patients. Suven provided masupirdine to eligible trial participants under an expanded access protocol, without evaluation for efficacy or safety, but had ended this program by September 2020.

In June 2022, Suven began a Phase 3 trial for the treatment of agitation in people with Alzheimer’s dementia. This was based on a subgroup analysis that claimed improvement in the agitation/aggression domain of the Neuropsychiatric Inventory scores in the Phase 2 study presented at CTAD 2021. The new trial is enrolling 375 Alzheimer’s patients with agitation for 12 weeks of 50 or 100 mg daily masupirdine or placebo, against a primary outcome of the Cohen-Mansfield Agitation Inventory. The secondary outcome will be a modified ADCS-CGIC focusing on agitation. Running at 18 sites in the U.S. and Poland, the trial is set to run until January 2025.

For trials of this compound, see clinicaltrials.gov.

Clinical Trial Timeline