Grace Sciences' GS-100 AAV9 Therapy Selects Pivotal Dose After Immune-Mediated Events Halt Highest Cohort

Dose-dependent immunogenicity in Grace Sciences' GS-100 program has forced a pivotal dose selection at 1e15 vector genomes and triggered a substantive revision to prophylactic immunosuppression protocols, developments with direct implications for CMC strategy, batch release criteria, and ATMP regulatory submissions. Interim data from the ongoing phase 1/2/3 trial (NCT06199531), presented at the 2026 ASGCT Annual Meeting, confirm that the highest tested dose of 3e15 vg was discontinued following immune-mediated adverse events including two cases of thrombotic microangiopathy.

Seven patients were treated across four dose cohorts, accumulating 309 weeks of cumulative exposure as of the September 30, 2025 data cutoff, with a median follow-up of 45 weeks. Adverse event frequency tracked sharply with dose: 56% of all events occurred in the 3e15 vg cohort versus 18% in the lowest-dose group. Serious adverse events were confined to the two higher cohorts, with three recorded at the highest dose and none at the lowest.

The immunosuppression regimen evolved materially over the course of the study. Investigators moved from corticosteroids alone to a combination of corticosteroids, rituximab, and sirolimus following the TMA cases, a protocol shift that QA and regulatory teams will need to reflect in investigational medicinal product dossiers and informed consent documentation. For manufacturing operations, the shift underscores the sensitivity of AAV9 vector genome titration precision at ICV-administered doses; small deviations at the upper end of the dose range carry disproportionate immunogenic risk in this pediatric population.

Efficacy signals at the two lower dose levels were encouraging among patients with at least 52 weeks of follow-up. Some of the most severely affected children demonstrated gains in motor milestones, including sitting, standing, and walking with assistance, alongside improvements in attention and caregiver interaction. NGLY1 Deficiency, caused by mutations impairing deglycosylation pathways, currently has no approved therapy, placing GS-100 in a field with no established comparator for benefit-risk assessment.

GS-100 holds orphan drug, rare pediatric disease, fast track, and Regenerative Medicine Advanced Therapy (RMAT) designations from FDA, the last granted earlier in 2026. RMAT designation enables more frequent FDA interaction and rolling review, which will bear directly on how Grace Sciences structures its CMC data packages as the pivotal cohort, targeting 10 total enrolled patients, generates additional follow-up. The selected 1e15 vg dose now anchors the pivotal phase, and the adequacy of vector genome titration controls at that specification will be a central question for any pre-BLA manufacturing assessment.

With the pivotal cohort now enrolling at the confirmed dose, the sufficiency of the revised immunosuppression protocol and the reproducibility of vector genome titration at 1e15 vg across commercial-scale batches will define the next critical checkpoint for the program.

Source: CGTLive via cgtlive.com, 14 May 2026.