Results of a phase 1, open-label, dose-escalation study of gene therapy with AAV2-hAQP1 as treatment for grade 2 and 3 radiation-induced late xerostomia and parotid gland hypofunction

Objective

Grade 2/3 late xerostomia is a chronic, debilitating complication of radiotherapy for head and neck cancers. We assessed the safety and efficacy of AAV2-hAQP1 gene therapy as a treatment for this condition.

Methods

Twenty-four participants with grade 2/3 xerostomia at least 5 years after completing radiotherapy (2 years if HPV+) were enrolled in this multicenter, open-label, dose-escalation study. AAV2‑hAQP1 was delivered to the parotid gland(s) via cannulation of the Stensen duct. Twelve participants received AAV2-hAQP1 in 1 gland and 12 in both glands. Participants were followed for 12 months posttreatment. 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 and stimulated whole saliva flow rates (UWSFR, SWSFR).

Results

No treatment-related serious adverse events or dose-limiting toxicities were reported, and all participants completed the study. Statistically significant improvements were seen in the patient-reported outcome instruments by day 30 and were maintained through month 12, with greater improvement in the bilateral versus unilateral cohorts. At month 12, the mean percent change from baseline (%CFB) was −39.5% and −42.2% for the XQ Total Score and the Dry Mouth question of the MDASI-HN, respectively, and the mean GRCQ symptom score was 3.8. Overall, 16 of 24 participants reported an improvement of ≥8 points in the XQ Total Score, and 19 of 24 participants reported important improvements in xerostomia symptoms based on the GRCQ. The improvement reported across patient-reported outcome instruments, measuring different aspects of xerostomia symptoms, provides compelling evidence of treatment effectiveness. The mean %CFB in UWSFR at month 12 was 112.5%, and a trend toward improved SWSFR was observed.

Conclusion

Treatment with AAV2-hAQP1 was safe and well-tolerated at all doses and resulted in meaningful improvements in xerostomia symptoms and unstimulated whole saliva flow rate.