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Voyager’s Gene Therapy for Parkinson’s Shows Promise in Small Study

Xconomy Boston — 

Voyager Therapeutics this afternoon is providing very early evidence that an experimental gene therapy it’s been developing might have a chance to help patients with Parkinson’s disease for whom standard treatment is no longer working well.

Cambridge, MA-based Voyager (NASDAQ: VYGR) is disclosing interim data from a small, open-label, Phase 1 trial among volunteers with a waning response to levodopa, a decades-old drug that most Parkinson’s patients take to deal with their symptoms. Voyager has treated 10 patients so far: five apiece on a low or high dose of its gene therapy, VY-AADC01. Today’s data includes results from all 10 patients after six months of follow-up, and eight patients (five on a low dose and three on a high dose) after a year of follow-up.

These are very small numbers in a trial that doesn’t include a placebo arm. Voyager needs to treat many more patients, over a longer period of time, to really prove the worth of VY-AADC01. Voyager’s biggest test—a placebo-controlled study that should begin by the end of 2017—will be much more telling than the results of this trial.

But Voyager officials say the data so far show that the gene therapy appears to be helping this small group of patients respond better to levodopa than they were before treatment, and that that benefit is translating to improvements in motor function. These patients have also been able to cut down the amount of levodopa they’re taking since undergoing treatment with VY-AADC01.

The high dose appears to work better than the low dose, and the benefits have come without any significant side effects from the gene therapy agent. (Earlier this year, Voyager reported one significant health problem in the study, a blood clot in the lungs, that resulted from the brain surgery required to administer VY-AADC01; VP of clinical development Bernard Ravina says the company has since tweaked the procedure and hasn’t seen any further problems arise.)

“We’re seeing all the clinical stuff stack up in the right direction,” Ravina says.

According to the National Parkinson Foundation, about 1 million Americans and 4 to 6 million people worldwide suffer from the disease, which causes motor symptoms like tremors, loss of movement, and stiff limbs, and cognitive problems like confusion and memory loss. Those numbers are expected to increase substantially in the next few decades as the population ages. As the disease progresses, patients can have trouble walking, speaking, or functioning without the help of a caregiver.

Voyager estimates that about 10 percent of Parkinson’s patients, some 100,000 in the U.S., are “refractory” to treatment with levodopa—the standard of care for Parkinson’s since the 1960s—or other drugs. Those are the folks who would be eligible for a treatment like VY-AADC01, according to Ravina.

Much remains unknown about the disease’s underlying biology, but one thing that’s clear is that its hallmark motor symptoms arise from the death of neurons in the brain that produce the neurotransmitter dopamine. There are no drugs that actually slow or reverse the course of the disease, but levodopa has made a monumental difference in the treatment of the disorder since its discovery (which earned a Nobel prize for Swedish scientist Arvid Carlsson in 2000). It helps nerve cells make dopamine, which in turn helps patients manage symptoms and function normally for a longer period of time.

Patients who start taking levodopa go through a “honeymoon” phase where the treatment is so effective they don’t have any symptoms. But over time patients’ responses start to levodopa start fluctuating. There are fewer hours per day of “on” time, when the drug is working, and more “off” time. To compensate, patients increase their levodopa doses, but that can cause dyskinesia, or uncontrollable, spastic movements.

There are a few drugs in development meant to combat the fluctuating response problem—inhalable forms of levodopa being advanced by Acorda Therapeutics (NASDAQ: ACOR) and Sunovion Pharmaceuticals are supposed to be rescue therapies for “off” episodes. Other experimental drugs in development aim to slow or reverse the course of the disease. Voyager has taken a different approach. It’s using gene therapy—a method of shuttling genetic instructions into the body to fix a disease-related malfunction—to, Ravina says, “turn back the clock” and enable patients to respond to levodopa the way they may have earlier in their disease.

As Parkinson’s progresses, patients have lower levels of the enzyme—aromatic L-amino acid decarboxylase (AADC)—that converts levodopa to dopamine, which is why they stop responding to the drug. Voyager puts a gene that produces AADC into an engineered virus and injects it directly into the putamen, a part of the brain associated with motor function. The surgery takes about 8 to 10 hours, Ravina says. Patients leave the hospital a day or two later.

Gene therapy has been tried for this purpose in Parkinson’s before—initial research by UCSF scientist Krystof Bankiewicz, now a co-founder of Voyager, was done in the 1980s. But so far, those efforts haven’t led to an approved product. Voyager believes a big reason it can succeed where others have failed is the availability of tools and imaging techniques that can help neurosurgeons deliver the therapy to the right spot, and track the levels of the AADC enzyme. Whether that will truly make a difference for patients remains to be seen, but Voyager’s VY-AADC01 program is the first major test of the theory.

In the Phase 1 data released today, five patients on a high dose who completed six months of follow-up saw their “on” time increase by an average of 2.2 hours/day compared to before they received gene therapy and “off” time decrease by an average of 1.1 hours/day. For the three patients that are out a year, their “on” hours jumped by 4.1 per day from the start of the study, and their “off” hours declined by 2.2 hours. (The five patients given a high dose of VY-AADC01 had an average of 4.2 total “off” hours/day before treatment with the gene therapy.)

Voyager also measured the gene therapy’s effects via changes in scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), a well-established measure of patients’ motor symptoms. (Ravina says a roughly 7 to 8 point drop on UPDRS is seen as a moderate, clinically meaningful effect.)  These measures were taken when patients were on levodopa, and off of it. The levodopa doesn’t fully “wash out” between doses, so there’s still some around when patients are off their medication that gets converted to dopamine, Ravina says.

On levodopa, patients who had received the high dose of VY-AADC01 saw a 9.6 point average drop in UPDRS scores after six months compared to their point totals before the study, and that improvement held up for the three patients out a year. Off levodopa, patients had a 17.8 point drop in UPDRS scores after six months, and 14.4 points after a year.

Patients in the study were also able to reduce their levodopa intake by 34 percent, for those who received high-dose gene therapy and 14 percent, for those who got the low dose. That could be important for patients with advanced Parkinson’s disease who have to take pills every few hours. These folks take their last pill before bed but then can have trouble sleeping, and as a result constantly deal with fatigue, according to Peter Schmidt, the senior vice president of the non-profit National Parkinson Foundation. (The NPF isn’t involved with Voyager or the development of VY-AADC01.)

“People with advancing Parkinson’s need innovation,” Schmidt says. “If [VY-AADC01 could help patients] feel like they’re well medicated during sleep, or reduce the burden of pill taking across the day, many people would find that valuable.”

Schmidt cautions, however, that more patients would have to be followed for much longer—at least a year or year and a half—to determine whether the benefits Voyager is seeing aren’t just a mirage. One potential complication: When patients experience a placebo effect their dopamine levels rise which is, of course, the ultimate goal of the gene therapy itself. “We need to be very careful that we ensure that the placebo response is not the cause of a benefit,” Schmidt says.

Ravina acknowledges that this concern won’t be definitively addressed until Voyager runs a trial with a placebo control. But he says the magnitude of the effects Voyager is seeing —combined with the increases in AADC enzyme levels the company can see through MRI imaging tools—suggest that they are real. “Those are not things that have happened as part of placebo effects to our knowledge in any previous trial,” he says.

And it’s possible those effects could be more substantial when Voyager reports data next year from a group of patients taking an even higher dose of VY-AADC01. Voyager will also run a separate trial using a different, perhaps shorter and more efficient, surgical technique, in early 2017.

Will bumping up the dose lead to problems? Schmidt is concerned the gene therapy might work too well, create too much dopamine, and lead to “runaway dyskinesia.” Ravina says, however, that since the goal of the gene therapy is to get greater impact from less levodopa, patients can cut down their meds and reduce any possible dyskinesia effects. Voyager hasn’t seen such effects so far, though it’s worth watching going forward.

Check out this story for more on Voyager, which developing gene therapies for other neurological disorders such as Friedreich’s ataxia and amyotrophic lateral sclerosis. Voyager shares rights to the VY-AADC01 program with Genzyme as part of an alliance the two struck in 2015.

Shares of Voyager climbed over 33 percent, to $18.35 apiece, in post-market trading Wednesday.