Voyager Therapeutics, a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases have announced positive interim results from their Phase I posterior trajectory trial of VY-AADC, concluding that the posterior approach will continue to serve as the preferred surgical route of administration.
The characteristic motor degeneration in Parkinson’s disease is largely due to the death of dopamine neurons in the substantia nigra, a part of the brain which converts levodopa to dopamine, in a reaction catalyzed by the enzyme AADC. Neurons in the substantia nigra release dopamine into the putamen where the receptors for dopamine reside, and in Parkinson’s, neurons in the substantia nigra degenerate and the enzyme AADC is markedly reduced limiting the brain’s ability to convert oral levodopa to dopamine. However, the intrinsic neurons in the putamen do not degenerate. VY-AADC, which has been granted Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA, is comprised of the adeno-associated virus-2 capsid and a cytomegalovirus promoter to drive AADC transgene expression, and has been designed to deliver the AADC gene directly into neurons of the putamen where dopamine receptors are located, bypassing the substantia nigra neurons, allowing the neurons of the putamen to express the AADC enzyme to convert levodopa into dopamine. This could potentially enhance the conversion of levodopa to dopamine and provide clinically meaningful improvements by restoring motor function in patients and improving symptoms following a single administration.
In the Phase I trial of VY-AADC, eight patients with Parkinson’s were successfully dosed with the therapy, administered through the posterior trajectory and using the same dose as given to patients in the third cohort of the previous Phase 1b trial. This trajectory resulted in a greater average coverage of the putamen (50%) and saw a reduction of 2-3 hours in total procedure time in comparison to cohorts 1, 2 and 3 from the Phase 1b trial that employed a transfrontal, or top of the head, delivery approach into the putamen. Treatment with VY-AADC has been well tolerated in all eight patients, with no serious adverse events reported so far. Following six months from administration, there has been increased AADC enzyme activity in the patients, as well as improved motor function in the four of the eight patients who have been assessed (assessed in a clinically-meaningful manner and consistent with results from Cohorts 2 and 3 from the Phase 1b trial during the same period of time).
Voyager have also announced feedback from the FDA regarding a Type C meeting which saw the discussion of the regulatory pathway for VY-AADC for the treatment of Parkinson’s disease in patients with motor fluctuations that are refractory to medical management. Based on this feedback, voyager plans to to submit for review a biologics license application (BLA) for VY-AADC based on the non-clinical and clinical safety and efficacy data gathered so far, including the potential to file a BLA based on safety and efficacy results from the Phase 2 trial, or from the Phase 3 trial if needed.
Source: Voyager Therapeutics Receives FDA Guidance on Development Path for VY-AADC for Parkinson’s Disease and Provides Clinical Update Press Release