Voyager's Parkinson's Gene Therapy Is Likely To Fail

July 1, 2018    About: Voyager Therapeutics (VYGR)   By John Kastanes

Summary

Initial phase 1 Parkinson's gene therapy results were similar to placebo in other Parkinson's surgeries.

Sanofi reviewed the Parkinson's gene therapy clinical data and walked away.

Voyager needs to raises money; it will most likely be an equity offering before phase 1b and phase 1 posterior trajectory data is released.

Voyager Therapeutics (VYGR) is a clinical-stage gene therapy company focused on developing treatments for patients suffering from severe neurological diseases using an adeno-associated virus, or AAV, gene therapy approach, that either increases or decreases the production of a specific protein.

(source: 2017 annual report)

Voyager's pipeline consists of six programs for severe neurological indications, including advanced Parkinson’s disease; a monogenic form of amyotrophic lateral sclerosis, or ALS; Huntington’s disease; Friedreich’s ataxia; tau-related diseases including Alzheimer’s disease, frontotemporal dementia, and progressive supranuclear palsy; and severe, chronic pain.

Given VY-AADC in the only gene therapy in clinical trials, this article will focus on the consequences of success or failure of VY-AADC.

Financials

From Voyager's Q1 2018 earning report

As of March 31, 2018 cash, cash equivalents, and marketable debt securities were $218.2 million. Based on the current operating plan, Voyager continues to expect to end 2018 with total cash, cash equivalents and marketable debt securities of approximately $125 million to $135 million and projects that its existing cash, cash equivalents and marketable debt securities will be sufficient to fund operating expenses and capital expenditure requirements through 2019.

VY-AADC clinical trials and results

Initial phase 1A phase 1 clinical trial conducted at University of California San Francisco, or UCSF, in a total of 10 patients with advanced Parkinson's. Two does of VY-AADC were tested. The primary endpoints of this trial were safety and tolerability. These endpoints were met with no treatment related severe adverse events, or SAEs.

The 10 patients were assessed clinically for up to four years after treatment and a durable, dose-dependent expression of AADC was observed. Patients treated with the low dose gene therapy were observed to have an increased PET signal indicative of AADC expression and activity that persisted for up to four years. Patients treated with the high dose gene therapy were observed to have an increased PET signal that was greater on average when compared to the low dose cohort, which also persisted for up to four years.

A similar phase 1 clinical trial was conducted at Jichi Medical University, or JMU, in Japan using the same vector that was used in the UCSF trial. Six patients were treated in this trial and an enhanced PET signal was observed in a subset of patients monitored 96 weeks following treatment. Patients remain in follow up in an open-label Phase 1/2 trial currently being conducted at JMU.

Phase 1b

In 2014, UCSF initiated an open-label phase 1b clinical trial to optimize the development of VY-AADC. The primary endpoints of this trial were safety and tolerability. Secondary endpoints of this trial, which are being used to assess the potential pharmacologic activity of VY-AADC, include Unified Parkinson's Disease Rating Scale, or UPDRS, AADC PET imaging and a behavioral test using intravenous levodopa treatment to measure changes in a patients’ sensitivity to levodopa as well as endpoints to measure motor functions.

Phase 1 posterior trajectory

During 2017, Voyager dosed seven patients in a phase 1 trial designed to optimize the intracranial delivery of VY-AADC. This phase 1 trial was designed to explore using a posterior delivery approach of drug into the putamen, compared to a transfrontal delivery approach used in Cohorts 1 through 3 of the ongoing phase 1b study. A posterior approach better aligns the infusion of VY-AADC with the anatomical structure of the putamen to potentially reduce the total procedure time and increase the total coverage of the putamen.

Posterior trajectory (source: 2017 annual report)

 

Voyager expects to provide longer-term safety data from the phase 1b and phase 1 posterior trajectory trials during the second half of 2018.

Planned pivotal phases 2 and 3

Voyager plans to dose the first patient in the global pivotal phase 2 in mid-2018. Based on estimates of patient enrollment and a 12-month blinded treatment period, Voyager expects top-line data from the phase 2 study in the second half of 2020. Voyager anticipates enrollment in the phase 3 trial will begin during the first half of 2019. Based on estimates of patient enrollment and a 12-month blinded treatment period, Voyager anticipate top-line data from the phase 3 trial during the first half of 2022.

What investors need to know

Voyager's 2017 annual report mentioned the following in regards to the initial phase 1 conducted by UCSF and phase 1b

The magnitude of the clinical responses seen in the phase 1 clinical trial of AAV2-AADC conducted by UCSF were similar to placebo effects observed in previous surgical therapies for Parkinson’s disease.

In February 2015, Voyager entered into a strategic collaboration with Sanofi (SNY) to develop AAV gene therapies for certain severe neurological diseases including ex-U.S. rights to VY-AADC. Under the agreement, Voyager received $65.0 million in upfront cash, a $30.0 million upfront equity investment, and an in-kind commitment of $5.0 million, totaling $100.0 million. At the inception of the agreement, Voyager was eligible to receive up to $745.0 million in option and milestone payments.

In October 2017, Sanofi notified Voyager that it had decided not to exercise its option for the ex-U.S. rights to VY-AADC.

On June 28th, Voyager appointed G. Andre Turenne as its new President and CEO, as well as a director. Previous CEO Dr. Steven Paul will continue to serve on Voyager’s Board of Directors and as a member of Voyager’s Science & Technology Committee.

Oxford BioMedica (OTCPK:OXBDF) developed a similar gene therapy for Parkinson's OXB-101, or ProSavin, that delivers three genes encoding a set of enzymes required for dopamine synthesis in the brain. 

Oxford completed a Phase 1/2 study for OXB-101, which met its primary end-point, according to the company. The results, published in The Lancet stated:

ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients.

However, according to Raymond Bartus, PhD chief science officer at Ceregene, Inc. (a non-public company) who led an experimental gene therapy for Parkinson's stated:

the modest efficacy improvements reported in The Lancet paper also are comparable to those reported in many, prior gene therapy Parkinson's studies; importantly, studies of those treatments could not adequately differentiate between treatment and placebo.

Oxford designed a second-generation Parkinson's gene therapy, OXB-102, and licensed it and OXB-101 to Axovant Sciences (AXON).

Conclusion 

Patients in the initial phase 1 trial were observed to have an increased PET signal indicative of AADC expression and the activity persisted for up to four years, yet results were similar to placebo effects observed in other Parkinson's surgeries.

Sanofi reviewed VY-AADC clinical data and walked away.

Voyager has enough money to operate through 2019. With top-line phase 2 data not anticipated until late 2020, Voyager has to raise money. I expect Voyager to announce an equity offering before phase 1b and phase 1 posterior trajectory data is released later this year, further diluting shareholders.

If you are contemplating investing in Voyager, I recommend waiting for phase 1b and phase 1 posterior trajectory data. If data is less than compelling, shares could see a significant price drop. If you are a shareholder, I recommend exiting your position.

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