MapLight Therapeutics (MPLT) Study result summary

Study design and objectives

• The IRIS Phase 2 trial was a multicenter, randomized, double-blind, placebo-controlled study evaluating ML-004 in 161 participants (102 adolescents, 59 adults) with ASD, focusing on social communication as the primary endpoint and irritability as a key secondary outcome.

• Participants were randomized 1:1 to ML-004 or placebo, with flexible dosing and a 12-week maintenance period; multiple caregiver- and clinician-rated scales were used.

• ML-004 is a reformulation of zolmitriptan, a 5-HT1B/1D agonist, hypothesized to reduce aggression via suppression of striatal D1 medium spiny neurons.

• The study included prespecified analyses by age group and baseline irritability severity.

• The trial was designed as an exploratory signal-finding study to generate clinically coherent, biologically plausible signals for future development.

Efficacy results

• ML-004 did not meet the primary endpoint of improving social communication deficits in ASD.

• Adolescents with moderate to severe baseline irritability (ABC-I ≥16) showed significant improvement in irritability over placebo, with effect sizes of 1.33 (ABC-I, p=0.013) and 1.08 (CGI-I, p=0.036).

• Treatment effects were greater among adolescents with higher baseline irritability, with effect sizes increasing as baseline severity increased.

• In the total population with high irritability (ABC-I ≥16), effect sizes were 0.64 (ABC-I, p=0.13) and 0.61 (CGI-I), though not statistically significant.

• Numerical improvement over placebo emerged early and increased over the 12-week maintenance period.

Safety and tolerability

• ML-004 was generally well-tolerated, with no severe or serious adverse events in the active arm; all such events occurred in the placebo arm.

• Most treatment-emergent adverse events were mild or moderate, transient, and resolved without dose reduction; two adolescents discontinued due to headache and somnolence.

• No extrapyramidal events were observed, and mean weight gain was lower with ML-004 (1.1 kg) than placebo (1.9 kg) in adolescents; no adverse events related to weight gain were observed.

• Adolescents experienced fewer adverse events than adults.

• Events commonly associated with zolmitriptan, such as jaw/chest tightening and paresthesias, were rare, and no cardiovascular or vasoactive safety signals were detected.