Shares of Voyager Therapeutics Inc. and its partner, Neurocrine Biosciences Inc., fell in early trading Dec. 23 after Voyager announced an FDA clinical hold on the phase II Restore-1 trial of VY-AADC, an adeno-associated virus-based gene therapy Neurocrine is developing as NBIb-1817 for the treatment of Parkinson's disease (PD). The trial had been paused since at least November as its data safety monitoring board (DSMB) reviewed MRI abnormalities in some study participants.

By Wednesday’s close, Voyager shares (NASDAQ:VYGR) dropped 6.5% to $8.44, while Neurocrine shares (NASDAQ:NBIX) recovered ground lost earlier in the day, falling just 0.8% to $97.93.

Speaking to the Restore-1 trial's status one month ago, during a pre-recorded interview that was part of the Piper Sandler Healthcare Conference, Neurocrine Chief Medical Officer Eiry Roberts said that the DSMB had met to review data from treated participants in the study. They "identified an observation in the one-year scan of a couple of patients and requested more information as a result of that," she said.

Neurocrine, she said then, would file a safety report to the FDA. After that, the DSMB was expected to meet by year-end to give the company "more guidance, in terms of if there are any particular changes that need to be made to the trial moving forward," Roberts said. That meeting is now scheduled for the first week of January, at which point Neurocrine’s team will determine next steps as well as plans for further interaction with the FDA, a company representative told BioWorld.

Neurocrine secured rights to VY-AADC as part of a four-asset deal announced in January 2019 in which it paid Voyager $165 million up front and pledged to pay up to $1.7 billion in potential milestone payments.

Brain surgery

The Restore-1 trial DSMB did not advise Neurocrine's team to pause or halt the trial back in November, Roberts said. However, it did recommend that the company discontinue its use of the neurosurgical procedure used in the trial at the time, she said. That was presumably a reference to the brain surgery procedure by which NBIb-1817 and another Voyager asset, VY-HTT-01, are designed to be delivered to targeted areas and cells in the brain.

In a previous phase I trial, conducted by the University of California, San Francisco, three patients experienced hemorrhages caused by the surgical procedure for administering VY-AADC, Voyager reported in its most recent quarterly report, on Nov. 9.

In response, in Restore-1, investigators began using Clearpoint Neuro Inc.'s Clearpoint System "to provide accurate placement of the cannula in the putamen and allow for real-time, intra-operative MRI to assist the physician in visualizing the delivery of VY-AADC (NBIb-1817) to the putamen and to avoid specific blood vessels during the duration of the surgical procedure, with the goal of reducing the risk of hemorrhages," Voyager said.

In the same quarterly filing, Voyager said that it might begin using V-TAG, a real-time, intra-operative, MRI-compatible device that it developed with Clearpoint for the procedures.

Even with those changes, the Restore-1 study had been on pause since earlier in the year due to what Roberts called a "major amendment to the study over the course of the summer," one that appears to have included a major streamlining of the trial's primary and secondary outcome measures. Furthermore, screening for the study had been paused as well, particularly in light of the need for trial participants to travel, sometimes across state lines for study-relating brain scans.

Neurocrine's efforts to resolve those issues weren't clear on Wednesday. But Cowen analyst Phil Nadeau remained cautiously optimistic. "The risk to NBIb-1817's further development, as well as the duration of the delay, can't be estimated without understanding the specific issues that the DSMB has identified," he said.

Voyager and Neurocrine "may be able to resolve the issue by revising the Restore-1 protocol from posterior to transfrontal delivery. Thus, we are hopeful that the MRI findings can be expeditiously resolved, permitting a resumption of dosing in 2021," he said.

Relatively undisturbed

Minimal share movement for San Diego-based Neurocrine following the trial news may be indicative of how much the company had already communicated about challenges to the PD-focused gene therapy program. It may also be reflective of stability created by the company’s commercial portfolio, led by the vesicular monoamine transporter (VMAT) 2 Ingrezza (valbenazine) that, in April 2017, became the first FDA-approved therapy for the movement disorder tardive dyskinesia. Though sales of the drug fell slightly in the third quarter vs. the second quarter, Piper Sandler analyst David Amsellem said in November that “we believe that the product is well positioned for sustainable double-digit annual sales growth over the long term owing in no small part to growing rates of diagnosis of tardive dyskinesia.”

Furthermore, in April, Neurocrine added FDA approval of Ongentys (opicapone), a once-daily add-on therapy for PD patients that extends the half-life of levodopa, increasing doses of which are required to achieve motor control as PD progresses.

A second hold?

Even as Voyager and Neurocrine worked to resolve the FDA's clinical hold on Restore-1, it wasn't immediately clear whether a second hold on Voyager's plate had been resolved.

In October, the FDA notified Voyager that the IND application for its planned phase Ib trial for VY-HTT-01 in patients with Huntington’s disease was on a clinical hold pending the resolution of certain chemistry, manufacturing and controls (CMC) matters. VY-HTT-01 is composed of an AAV capsid and a transgene that harnesses the RNA interference pathway to selectively knock down, or reduce, levels of huntingtin mRNA.

In November, Voyager said that with specific written feedback from the FDA regarding the cause of the clinical hold in hand, its team might seek a type A meeting with the agency to discuss steps to resolve the underlying CMC information requests and, if possible, advance its development of VY-HTT01.