Our Parkinson's Place: A Wormhole View Of Voyager's Parkinson's Gene Therapy

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Tuesday, July 10, 2018

A Wormhole View Of Voyager's Parkinson's Gene Therapy

John Kastanes Jul. 10, 2018

The initial phase 1 trial results were comparable to several prior Parkinson's therapies that weren't approved.

A large percentage of patients opted to undergo deep brain stimulation surgery relatively shortly after the gene therapy.

Sanofi funded both studies yet decided to walk away.

The FDA grants Voyager's Parkinson's gene therapy special designation allowing an accelerated review process.

With less than $7 cash per share, an equity offering is likely before phase 1b and posterior trajectory data is released.

In my previous Voyager Therapeutics (VYGR) article I gave a bird’s eye view of its Parkinson’s gene therapy, or VY-AADC, originally AAV-hAADC. In this article I swoop down and take a closer look at the initial phase 1 trial conducted by the University of California San Francisco, or UCSF, prior to Voyager taking ownership.

I will breakdown this article by examining two studies conducted by UCSF: the initial short-term study, and the initial long-term follow-up study.

The initial phase 1 trial was conducted on 10 moderately advanced Parkinson’s patients with safety and tolerability primary endpoints. The 10 patients were divided into two cohorts, five in a low-dose, and five in a high-dose.

These patients were prescribed dopaminergic medication on average 8.4 years because of relentless motor fluctuations that didn’t respond to optimal pharmaceutical therapy.

AAV-hAADC infusion

Of the 10 patients undergoing the gene therapy, asymptomatic hemorrhage occurred in two patients and symptomatic hemorrhage occurred in another patient. The hemorrhages occurred along the injection route, not near the infusion area. No significant SAEs were related to AAV-hAADC.

UPDRS and motor diaries

Patients were evaluated using standardized Unified Parkinson’s Disease Rating Scale, or UPDRS, at baseline then monthly for six months, and the stand-walk-sit test at baseline and at six months. The UPDRS is a standard that evaluates cognitive, functional, motor deficits and medication-related complications. The off-state is measured 12 hours after the last dose of dopaminergic medication, and the on-state is approximately one hour after taking the usual morning medication. UPDRS decreasing scores indicates improvement.

Motor state diaries entries were recorded at baseline, at three months, and at six months after surgery. Patients were trained to record in diaries motor conditions at baseline, and three and six months after surgery. Possible motor choices were: ‘asleep,’ ‘off,’ ‘on without dyskinesia,’ ‘on with nontroublesome dyskinesia,’ and ‘on with troublesome dyskinesia.’ Total on-time was calculated by adding ‘on without dyskinesia,’ plus ‘on with nontroublesome dyskinesia,’ plus ‘on with troublesome dyskinesia.’ Patients completed motor diaries on three days: before baseline, at three months, and at six months.

At six months, all patients measured improvements. Total UPDRS decreased by 31% for off-state, and 32% for on-state. UPDRS motor scores, improved by 36% for the off-state and 28% for the on-state.

Improvements were also observed for motor state diaries as measured by a decrease in off-time and increase in on-time. The average off-time was reduced by 3.1 hours and average on-time increased by 3.3 hours. Patients recorded in their diaries gradual improvement in on-time and in mobility for six months following surgery.

Cognitive and behavioral evaluations were stable during the six months post-surgery.

Positron emission tomography, or PET

PET scans using an AADC tracer were conducted at baseline and six months to measure gene expression. PET scans did demonstrate increased enzymatic activity at one and six month post-surgery.

Medications

Parkinson’s medications were decrease by 8 of the 10 patients, three low-dose cohorts and all five high-dose cohorts. The decrease wasn’t statistically significant.

Short-term analysis

The AAV-hAADC procedure was well tolerated in both dose cohorts, however, SAEs did occur during the procedure. While asymptomatic and symptomatic hemorrhages do occur during deep brain stimulation, hemorrhages did occur with greater frequency during this study. The independent safety monitoring board didn’t specify any particular surgical factors for the increased frequency of hemorrhaging.

Two additional phase 1 Parkinson’s gene therapy trials were conducted with 12 patients each. In a glutamic acid decarboxylase gene therapy study, sponsored by Neurologix Inc (OTC:NRGXQ), UPDRS scores decrease by 28% for off-state and 26% for on-state at six months. In a neurturin gene therapy study, sponsored by Sangamo Therapeutics (SGMO), the off-state decreased by 31% at six months.

Unlike the above mentioned gene therapies, AAV-hAADC trial used PET scans to verify AADC gene expression that was dose-dependent. While dose-dependent PET scans activity make placebo effects less likely, it cannot be ruled out.

Long-term follow-up study

UCSF conducted a long-term follow-up study of the 10 patients in the initial phase 1 AAV-hAACD trial by performing an annual PET scan and conducting a clinical examination using UPDRS.

PET scans

Patients underwent PET scans to measure AADC enzymatic activity at baseline, one month, and six months. In the follow-up study, PET scans were done annually for up to five years.

UPDRS evaluations

Patients were initially evaluated clinically at baseline, and then monthly for six months. Evaluation with UPDRS and the stand-walk-sit test were done at baseline, six months, then annually in the off- and on-medication states.

Long-term follow-up results

PET scans demonstrated a significant increase in AADC enzyme activity during the first six months and persisted during the four-year follow-up study. The initial activity increases in both low-dose and high-dose didn’t significantly change in either group.

One patient didn’t return after the first year follow-up. Four patients decided to undergo deep brain stimulation, or DBS, at 10, 18, 30, and 50 months post-surgery. Data from these patients were not included after DBS.

Mild worsening of dyskinesia occurred in four patients, which was alleviated by medication adjustments.

While UPDRS scores were significantly improved for both on- and off-states during the first 12 months in all patients, deterioration during the following years did occur. There were no significant differences between the low-dose and high-dose ‘on’ and ‘off’ scores.

Long-term analysis

The follow-up study demonstrated AADC gene expression was maintained for years in comparison to other studies that have shown decreases in AADC enzyme expression over time.

Adverse events, not including the initial three intracranial hemorrhages, were not greater than expected for a long-term Parkinson’s disease study.

While UPDRS did improve during the first 12 months, placebo effects cannot be ruled out. In two comparable controlled studies with placebo, UPDRS scores improved for both placebo and the active arm.

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.

With 32 million shares outstanding that equates to less than $7 cash per share.

What investors need to know

While the gene therapy did show improvement UPDRS scores, and PET scans demonstrated dose-dependent enzyme activity, placebo effects cannot be ruled out. Also disturbing, 4 out of 10 patients opted to undergo deep brain stimulating not long after the gene therapy.

Funding for both studies were provided by Genzyme, now part of Sanofi (SNY). If results were as good as Voyager is claiming them to be, why would Sanofi walk away? The only explanation is Sanofi doesn't consider the potential reward worth the risk.

With less than $7 cash per share and no near-term drug approval, Voyager will raise cash, most likely through an equity offering. It would be wise to wait until data from the phase 1b and posterior trajectory are released, and additional cash is raised.

Recently, the FDA granted Voyager the special designation Regenerative Medicine Advanced Therapy, or RMAT. This designation provides for an accelerated review of the application and guidance on development. Special designation or not, Voyager will have to generate robust data during the phase 2 or else it is game over for this therapy.

If you are itching to place money on this high risk high reward venture, invest only an amount that will not cause you to lose sleep if things go awry. However, I would wait until trial data is released and cash is raised.

Good fortune to all.

Disclosure:

I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure:

I am neither a medical doctor nor do i have a life science degree.

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