Phase 2 Analysis of ML-004 for Autism Spectrum Disorder Fails to Meet Endpoint

Prespecified analysis of a phase 2 trial for ML-004 in autism spectrum disorder showed no significant change in social communication deficits, but a meaningful improvement in irritability.¹ The phase 2 IRIS trial did not meet its primary endpoint for change in social communication scores, but the drug was generally well-tolerated.

The phase 2 double-blind, placebo-controlled study was designed for exploratory signal finding, testing multiple clinical endpoints including social communication and irritability.² A primary endpoint for social communication was measured from baseline to week 12 by the caregiver-reported Autism Behavioral Inventory (ABI) Social Communication Domain score. Both adolescent and adult participants (aged 12 to 45) were included, with 161 total participants and 26 in the specified analysis. Participants received either placebo or 12, 24, 48, or 72 mg doses of ML-004 once daily.

“We are very encouraged by the robust improvements observed in adolescents with clinically significant irritability,” said Erin Pennock Foff, chief medical officer of MapLight.¹ “These results are consistent with our compelling pre-clinical evidence for reduction in aggression/irritability in animal models. Given that there is an established regulatory path in this indication using the ABC-I, and given the magnitude of the effect on this measure observed in this study, we look forward to engaging with the FDA to discuss a possible path forward,” she added.

Analysis of adolescents (age 12 to 17) with moderate or higher baseline irritability who received ML-004 showed meaningful improvement in irritability compared with placebo. Improvement in irritability was significant on both the ABI Social Communication Domain and the Clinical Global Impression-Improvement domain. Lessened irritability was more pronounced in adolescents with greater baseline irritability. ML-004 was generally well-tolerated, with only mild to moderate treatment-emergent adverse events. Overall, adolescents experienced fewer adverse events than adults (62.7% vs 86.7% for treatment groups, respectively). The most common adverse events were headache, nausea, somnolence, vomiting, fatigue, and dizziness. No extrapyramidal adverse events were observed with active treatment and there was no notable weight gain in the treatment group.

ML-004 is a bilayer immediate-release and extended-release formulation of zolmitriptan, a 5HT1B/1D agonist; the drug is taken once daily by mouth in tablet form. The compound is also currently approved for acute treatment of migraine.

Developers of the drug noted plans to discuss with the FDA for an end-of-phase 2 meeting to determine the future clinical path of the medication.

References

1. MapLight announces topline results from phase 2 IRIS study for ML-004 in autism spectrum disorder. Press release. June 22, 2026. Accessed June 23, 2026. https://www.globenewswire.com/news-release/2026/06/22/3315170/0/en/maplight-announces-topline-results-from-phase-2-iris-study-for-ml-004-in-autism-spectrum-disorder.html

2. ML-004 in adolescents and adults with autism spectrum disorders (ASD). ClinicalTrials.gov. May 19, 2026. Accessed June 23, 2026. https://clinicaltrials.gov/study/NCT05081245