Subgroup analyses boost masupirdine potential for AD

Post hoc data from a phase II study presented at AAIC 2022 continue to demonstrate the potential of masupirdine (SUVN-502), a selective 5-HT₆ receptor antagonist, as a treatment alternative for the management of neuropsychiatric and cognitive symptoms of Alzheimer’s disease (AD).

Agents that could improve these symptoms are warranted to improve the quality of life of AD patients, as well as the caregiver and socioeconomic burden that comes with the condition. In the primary analysis (n=543 [mITT* cohort]; mean age 74 years, 55 percent female) wherein participants were randomized 1:1:1 to receive masupirdine 50 or 100 mg or placebo, masupirdine has shown promise in improving behavioural symptoms in AD patients. [Alzheimer’s Dement 2022;8:e12307]

Agitation/aggression, psychosis

On subgroup analysis, symptoms of agitation/aggression (A/A) were reduced significantly in participants on masupirdine 50 mg by week 26, be it among those with a baseline NPI-12** A/A score of ≥1 (n=53; p<0.001) or ≥3 (n=30; p=0.031). Steep declines were observed as early as week 4 for both scores, which continued to drop by week 13 (p<0.001 and p=0.012 for scores ≥1 and ≥3, respectively) and through week 26. [AAIC 2022, abstract 62695]

Among masupirdine recipients who had psychosis or symptom emergence at baseline (n=98), the symptom improvements were remarkable at weeks 4 and 13 (p=0.03 and p=0.016, respectively).

Regarding ADAS-Cog*** 11 scores in patients with psychosis, the effect with masupirdine 50 mg was prominent by week 26 (p=0.067). “[This was] consistent with the evaluable population,” said Ramakrishna Nirogi from Suven Life Sciences Ltd, Hyderabad, India, during the poster presentation.

“[Taken together,] masupirdine significantly reduced A/A and psychosis in AD patients and the effects were clinically meaningful [and] independent of the severity of baseline symptoms,” he continued. “Masupirdine also showed beneficial effects on cognition in patients with psychotic symptoms.”

Given the sustained and durable efficacy of masupirdine in the evaluated parameters across the 26-week period, the findings suggest that masupirdine may be a novel therapeutic alternative for the management of A/A and psychosis in AD patients, said Nirogi.

The potential of masupirdine for the treatment of agitation in this patient subgroup is being investigated in a phase III study.

As add-on therapy

Another exploratory analysis looked into the effects of masupirdine as add-on therapy to patients concurrently receiving donepezil and memantine (n=243). Patients were stratified according to memantine dose (10 mg BID [IR^#] or 28 mg QD [XR^#]) and week-26 trough memantine concentrations (≤25, ≤50, ≤100, or >100 ng/mL). [AAIC 2022, abstract 62688]

At week 26, lesser cognitive decline was seen among participants on masupirdine 50 mg and memantine IR vs XR, noted Vinod Kumar Goyal, also from Suven Life Sciences Ltd.

In participants whose memantine plasma concentrations were ≤100 ng/mL, there was less decline in ADAS-Cog 11 scores in masupirdine recipients vs those on placebo (p=0.0008 [50 mg] and p=0.04 [100 mg]).

Of note as well were the observed improvements in ADAS-Cog 11 scores with masupirdine 50 mg as opposed to placebo among those with memantine plasma concentrations of ≤50 ng/mL, both at week 13 (p=0.012) and week 26 (p=0.005). This effect was similarly seen in patients with memantine plasma concentrations of ≤25 ng/mL (p=0.0013 [week 13] and p=0.0023 [week 26]).

Additionally, either dose of masupirdine seemed better than placebo in terms of MMSE^## improvements in patients with memantine plasma concentrations of ≤100 ng/mL (p=0.058 and p=0.045 for the 50- and 100-mg doses, respectively).

“Overall, masupirdine may show potential therapeutic benefits in combination with donepezil, with donepezil and [low-dose] memantine, or with no background therapy,” said Goyal. The effect of masupirdine without background therapy or in combination with either donepezil or low-dose memantine should therefore be further ascertained, he added.

The findings also underscore drug interactions in AD treatment, which may have important implications.