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Voyager Therapeutics (VYGR): Gene Therapy for Severe Neurological Diseases

Voyager Therapeutics is developing targeted gene therapies for severe neurological diseases.

An estimated 10 million people worldwide live with Parkinson’s disease, according to the Parkinson’s Disease Foundation. In the US alone, as many as 1 million people live with Parkinson’s, with 60,000 new diagnoses each year. Parkinson’s is a chronic and progressive movement disorder that involves the
malfunction and death of neurons. As Parkinson’s progresses, the amount of dopamine
produced in the brain decreases, leaving a person unable to control movement and coordination normally.

We’ve been following a company called Voyager Therapeutics (Nasdaq: VYGR) that is developing targeted gene therapies for Parkinson’s and other severe neurological diseases. The company has been focusing on those diseases for which it believes an adeno-associated virus (AAV) gene therapy approach that either increases or decreases the production of a specific protein can slow or reduce the symptoms experienced by patients, and therefore have a clinically meaningful impact.

AAV Gene Therapy Delivery

AAV is a common, naturally occurring virus that has been shown to be a well-tolerated and effective gene therapy delivery vehicle in clinical trials. Advances in AAV vector design and related dosing techniques that enable widespread gene delivery in the brain and spinal cord have made AAV particularly well-suited for the treatment of neurological diseases. Improvements in related technology and approaches have made AAV production more easily scalable and efficient to meet clinical and commercial requirements, and members of Voyager’s team team have co-discovered many of the known naturally occurring AAV capsids, which are the outer viral protein shells that enclose the target gene, and have also created promising genetically engineered AAV capsids.

Parkinson’s Disease

The company’s lead program is for advanced Parkinson’s disease, which affects up to 150,000 patients in the US. There are currently no therapies that effectively slow or reverse the progression of Parkinson’s. Levodopa, which was discovered more than 40 years ago, remains the standard of care treatment, and while patients are generally well-controlled with oral levodopa in the early stages of the disease, they become less responsive to treatment as the disease progresses. Patients experience longer periods of reduced mobility and stiffness (“off-time”) and shorter periods of “on-time” when their medication is effective. Other drawbacks of

  • Significant fluctuating on-off time (oral levodopa)
  • Cognitive side effects (oral levodopa)
  • Invasive continual delivery required (continuous levodopa)
  • Infusion site infections (continuous levodopa)
  • In-dwelling hardware requiring revisions, replacements and adjustments (deep brain stimulation)
  • Awake during surgery (deep brain stimulation)

AADC Enzyme

The progressive motor symptoms of Parkinson’s disease are largely due to the death of dopamine neurons in the substantia nigra, a part of the brain that converts levodopa to dopamine, in a single step catalyzed by the aromatic L-amino acid decarboxylase (AADC) enzyme. Neurons in the substantia nigra release dopamine into the putamen, where the receptors for dopamine reside.

In advanced Parkinson’s disease, neurons in the substantia nigra degenerate and AADC is markedly reduced in the putamen, which limits the brain’s ability to convert oral levodopa to dopamine. Voyager’s lead candidate, VY-AADC, comprised of an AAV capsid and a viral promoter to drive AADC expression, is designed to deliver the AADC gene directly into the putamen where the dopamine receptors are located, bypassing the substantia nigra neurons and enabling the neurons of the putamen to express the AADC enzyme to convert levodopa into dopamine. VY-AADC therefore has the potential to durably enhance the conversion of levodopa to dopamine and provide clinically meaningful improvements in motor symptoms following a single administration.

Voyager’s VY-AADC is designed for:

  • A one-time treatment
  • Durable (>6 month)
    improvement in motor symptoms, function and
    quality of life measures
  • Reductions in daily oral
    levodopa and associated side-effects
  • No in-dwelling
    hardware, no persistent injection-site reactions

Clinical Pipeline

Source: Voyager Therapeutics Corporate Presentation, July 2017

Sanofi Genzyme agreement

Voyager has broad strategic collaboration agreements with Sanofi Genzyme (NYSE: SNY) and the University of Massachusetts Medical School (UMMS). The company also has license and other agreements with UMMS, the University of California San Francisco and Stanford University to access relevant technology and data. The Sanofi Genzyme agreement was initiated in 2015 and resulted in an upfront payment of $65 million to Voyager plus an additional $30 million in consideration for 10 million shares of Series B preferred. Sanofi Genzyme has an option to license, develop and commercialize several of Voyager’s programs, mostly outside the US, and there are potential payments of up to $645 million to Voyager if specified regulatory and commercial milestones are achieved.

The company has numerous near term milestones that it expects to achieve during the balance of this year into 2018. While the stock will have to navigate through significant event risk as the company sails through this development gauntlet, Voyager’s successful achievement of these milestones and continued clinical progress would bear significant fruit for investors and Sanofi Genzyme, making the current valuation of $275 million seem like a potential bargain.

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