Voyager still has a long way to go with Parkinson’s gene therapy

Voyager Therapeutics believes that it has found the best dose for a pivotal trial of its Parkinson’s disease gene therapy, VY-AADC01, but there are reasons to be cautious about the early data reported from its phase Ib trial today.

A major one is that only one cohort of three – the medium dose studied – showed a clinically meaningful improvement in Parkinson’s symptoms. The investment case now rests on the validity of Voyager’s explanation for the lack of a dose response.

The company blamed the poor performance in the highest-dose cohort on a high rate of dyskinesia at baseline in this group. As these jerky movements are thought to be caused by levodopa therapy patients in this arm dropped their levodopa doses to a greater extent than the other cohorts, which might also have led to a reduced treatment effect, Voyager said.

This could have been compounded by overactivity of the highest dose of the gene therapy, which is designed to enhance the conversion of levodopa to dopamine, the company added. Investors initially seemed convinced, with the group trading up as much as 8% early this morning before falling 5% later.


Voyager’s project is designed to be given alongside levodopa. VY-AADC01 contains the gene for the enzyme AADC, which converts levodopa to dopamine, and as AADC is reduced in the brains of patients with Parkinson’s this could bolster efficacy versus levodopa alone.

Levodopa has been used in Parkinson’s for years but is an imperfect therapy. It does not address the underlying causes of disease and, as affected cells continue to die, the brain’s ability to convert levodopa into dopamine wanes, and treatment becomes less effective.

Voyager still has a long way to go to prove itself. True, the phase Ib trial found an apparently impressive response in the mid-dose second cohort, with a clinically meaningful increase in patient-reported diary “on” time without troublesome dyskinesia, which will be the primary endpoint of the pivotal programme. However, this was not seen in the high-dose third cohort.

Source: company presentation.

Interestingly, Voyager’s chief medical officer, Bernard Ravina, claimed on a conference call today that this might also have been a function of very strong activity of VY-AADC01 at the highest dose – which led to overproduction of dopamine that further contributed to a decrease in levodopa doses to avoid dyskinesia.

Phase Ib trial doses
Cohort Vector genomes
1 7.5 x 1011
2 1.5 x 1012
3 4.5 x 1012

The mixed results could raise general doubts about the phase II/III trial set to begin mid-year. Voyager will likely study the dose used in cohort 2, and could also opt to use posterior delivery of the gene therapy into the brain, instead of the transfrontal method employed in the most recent study.

Transfrontal delivery can take 8-10 hours; this could be reduced by two to three hours with the posterior method, which could also lead to better coverage of the target brain area, the putamen, Voyager believes. An ongoing trial of the posterior method is set to report this year.

Company executives were adamant today that the latest data did not indicate a placebo effect. While investors appear to have taken their explanations at face value, it will be a while until it becomes apparent whether this is really the case.

Study Trial ID Details Data
Phase Ib NCT01973543 Transfrontal delivery Reported
Phase Ib NCT03065192 Testing posterior delivery in 16 pts; route shown to reduce admin time by 2-3 hrs H2
Phase II/III TBC 30 pts in ph II, 100 in ph III Dosing to start Q2  

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter

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