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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.