Results of a Phase 1 Open-Label, Dose-Escalation Study of Gene Therapy With AAV2-hAQP1 for Grade 2 and 3 Radiation-Induced Late Xerostomia and Parotid Gland Hypofunction

PURPOSE: Grade 2 and 3 late xerostomia is a chronic, debilitating complication of radiation therapy for head and neck cancers. We assessed the safety and efficacy of AAV2-hAQP1 gene therapy as a treatment for this condition. METHODS AND MATERIALS: Twenty-four participants who reported grade 2 and 3 late xerostomia at screening, ≥5 years after completing their final radiation therapy treatment (≥2 years if human papillomavirus-positive), were enrolled in this open-label, multicenter, dose-escalation study. AAV2-hAQP1 was delivered to the parotid gland(s) via cannulation of Stensen's duct. Twelve participants received AAV2-hAQP1 in 1 gland and 12 in both glands. Participants were followed for 12 months. Safety parameters included adverse events, physical examinations, laboratory tests, and electrocardiograms. Efficacy assessments included the Xerostomia-specific Questionnaire (XQ), MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN), Global Rate of Change Questionnaire (GRCQ), and measurement of unstimulated whole saliva flow rates (UWSFR). RESULTS: No treatment-related serious adverse events or dose-limiting toxicities were reported, and all participants completed the study. When the data from all cohorts were pooled, statistically significant improvements were seen on all patient-reported outcomes by day 30. These were maintained through month 12 with greater improvement in the bilateral cohort. At month 12, the mean percent change from baseline (%CFB) was -39.5% and -42.2% for the XQ Total Score and the MD Anderson Symptom Inventory-Head and Neck Module dry mouth question, respectively, and the mean GRCQ-Symptom Change Score was 3.8. Overall, 16 of 24 (67%) participants reported an improvement of ≥8 points in XQ Total Score, and 19 of 24 (79%) participants reported important improvements in xerostomia symptoms based on the GRCQ. The mean %CFB in UWSFR at month 12 was 112.5%. CONCLUSIONS: Treatment with AAV2-hAQP1 was safe and well-tolerated at all doses and resulted in meaningful improvements in xerostomia symptoms and UWSFR.