Forvisirvat

metpharmacodynamicQuantitative EEG / Brain Network Analytics profile after 1 day and 15 days of dosing (Cohort 1, healthy adults, n=12)

EXPLORATORY, no pre-specified success criterion and no p-values disclosed. In Cohort 1 (12 healthy subjects, 8 active / 4 placebo, 20 mg once daily over 15 days) forvisirvat was centrally active: frontal-central beta power increased versus placebo, interpreted by the sponsor as stronger synaptic connectivity, and delta power decreased, a change associated with reduced cortical arousal and with depressive states. Evoked-response measures suggested improved early perceptual efficiency and decision-making speed. Assessed with Firefly Neuroscience's BNA platform. The outcome is recorded as met on the sponsor's characterisation of the results as positive; these are pharmacodynamic signals in healthy volunteers, not evidence of antidepressant efficacy.

metefficacy_subgroupMADRS total score, change from baseline to Week 4 in female participants (post-hoc subgroup, n=205) — 3.9-point greater reduction vs placebo at Week 4 (0.008)

POST-HOC, not pre-specified. In the 205 female participants (about two-thirds of the study), forvisirvat 20 mg produced a 3.9-point greater MADRS reduction than placebo at Week 4 (p=0.008), with statistically significant separation as early as Week 3 (p=0.011) and continued separation on MADRS and CGI-S at Week 5, one week after treatment stopped (p<0.01). Among females on forvisirvat, 25% met remission (MADRS <=10) and 38% met response (>=50% reduction from baseline) at Week 4; the release does not give the corresponding placebo rates. Male participants showed no effect on any scale. This subgroup finding, not the failed primary, is what the confirmatory Phase 2b/3 study was built to test.

missedsecondaryQIDS-SR total score, change from baseline to Week 4 (all participants) — LS mean difference -0.9 (95% CI -2.0 to 0.2); SP-624 -5.0 vs placebo -4.1 (0.091)

Not significant in the overall population.

missedsecondarySheehan Disability Scale, change from baseline to Week 4 (all participants) — LS mean difference -1.0 (95% CI -2.5 to 0.5); SP-624 -5.6 vs placebo -4.6 (0.188)

Not significant in the overall population.

metsafetySafety and tolerability over 4 weeks

Forvisirvat 20 mg once daily was well tolerated. The most common adverse events were headache and nausea, both of which occurred more frequently in the placebo group, and no dose reductions were required.

missedsecondaryQ-LES-Q-SF, change from baseline to Week 4 (all participants) — LS mean difference 1.7 (95% CI -1.2 to 4.6); SP-624 9.5 vs placebo 7.8 (0.243)

Not significant in the overall population.

missedprimaryMADRS total score, change from baseline to Week 4 (all participants) — LS mean difference -1.8 (95% CI -4.1 to 0.5); SP-624 -12.6 (SE 0.83) vs placebo -10.8 (SE 0.84) (0.133)

The primary endpoint was not met in the overall population of 319 randomised adults with MDD treated for 4 weeks with forvisirvat 20 mg once daily or placebo.

missedsecondaryCGI-S total score, change from baseline to Week 4 (all participants) — LS mean difference -0.3 (95% CI -0.5 to 0.0); SP-624 -1.2 vs placebo -0.9 (0.059)

Numerically favoured forvisirvat but did not reach significance in the overall population.

missedsecondaryHAM-D-17 total score, change from baseline to Week 4 (all participants) — LS mean difference -1.1 (95% CI -2.7 to 0.4); SP-624 -8.3 vs placebo -7.1 (0.159)

Not significant in the overall population.

metefficacy_subgroupCGI-S, HAM-D-17, SDS and QIDS in female participants (post-hoc subgroup)

POST-HOC. The sponsor reported statistically significant improvement versus placebo on CGI-S, HAM-D-17, SDS and QIDS in female participants. No point estimates or p-values for these female-only secondary analyses were disclosed in the release, so effect_size and p_value are null rather than guessed.