In recent years, the AAV gene therapy field has received significant attention based on clinical breakthroughs in the treatment of Hemophilia B, and a genetic form of blindness called Leber's Congenital Amaurosis. However, these successes have not translated over to diseases of the Central Nervous System (CNS), where AAV treatments have been met with repeated failures despite multiple clinical trials. A particular area of focus has been Parkinson disease, a neurodegenerative disorder characterized by progressively worsening motor symptoms that result from the death of dopamine producing neurons that connect to the putamen, an area of the brain responsible for coordinating movement. Despite encouraging results in preclinical animal models, human trials with AAV have failed to meaningfully impact disease progression. The investment in Voyager Therapeutics is based on belief that the company will break from this trend and produce the first clear demonstration of clinical benefit in Parkinson patients.
Unlike other players in the AAV space, Voyager Therapeutics is composed of experienced leaders in drug development for neurological diseases, and is the only AAV company that is exclusively focussed on CNS indications. Its strategy is based on key lessons learned from over 10 years of challenges that have stymied prior AAV clinical trials for Parkinson. Some of these challenges stem from the complexity of intra-cerebral interventions, and include the lack of an ability to monitor AAV dosing, coverage, and transgene expression. Other challenges have resulted from the limited understanding of Parkinson etiology, and the reliance on potentially misleading preclinical data from animal models that may have failed to adequately replicate the mechanisms and complexities of the disease in humans.
Voyagers’s Parkinson AAV program, VY-AADC01, is based on pioneering work carried out by Krystof Bankiewicz at UCSF, and is designed to help restore levels of dopamine in the brain that are depleted over the course of the disease. The current treatment of Parkinson consists in oral dosing of L-Dopa, which is able to cross the blood brain barrier and is readily converted to dopamine by the AADC enzyme. Unfortunately, as Parkinson progresses, AADC expression decreases and increasingly higher doses of L-Dopa are needed to maintain function. With elevated dosing pharmacological control becomes problematic, and it becomes exceedingly difficult to sustain dopamine at efficacious exposures without causing the adverse event dyskinesia (uncontrolled movements).
VY-AADC01 consists of an AAV vector designed to express the AADC enzyme in the putamen. Although a Phase I trial showed only limited benefit in Parkinson patients, it became clear that only a small percentage of putamen neurons had been targeted by the vector, and that higher doses would be needed. Going forward, pharmacological optimization via fine tuning of dose concentration and volume is enabled by an MRI guided delivery procedure to ensure accurate targeting of the putamen, and PET scans to quantify the percent of putamen neurons modified. Dose escalation is in progress, and initial results have shown significantly improved levels of expression in the putamen. Thus far, one patient from dose cohort 2 (out of 4 cohorts) has been evaluable for efficacy (reduction in “off time” when L-Dopa is not effective, and improvement in motor performance) has been evaluated. A promising response has been observed, but many more patients will need to be treated to properly evaluate the therapy. Proof of concept data are expected in the second half of 2016.
In addition to Parkinson disease, Voyager is also pursuing research stage programs in Amyotrophic Lateral Sclerosis, Friedreich’s Ataxia, Huntington Disease, and Spinal Muscular Atrophy. Genzyme has entered into an option agreement for co-commercialization of all the of Voyager’s programs, with the exception of Spinal Muscular Atrophy.
