Making good on a promise detailed during its earnings call with investors last month, Voyager Therapeutics Inc. kicked off Restore-1, a phase II, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of gene therapy VY-AADC for Parkinson's disease (PD) in patients with motor fluctuations refractory to medical management.

But Wall Street still "seeks clarity on the potential regulatory holdup" that the company described in October, said H.C. Wainwright analyst Debjit Chattopadhyay in a report. That's when investors learned that the FDA had sent the Cambridge, Mass.-based company an addendum to the agency's earlier stance regarding whether positive results from the phase II could be enough to file for approval.

Over the summer, Voyager said it received from the FDA written type C meeting feedback assuring officials that the phase II data, if positive, "likely may be considered sufficient" for the BLA filing. Several months later, though, the company said U.S. gatekeepers conveyed their opinion that the trial is "an early-phase exploratory" effort. CEO Andre Turenne said during a conference call on earnings last month that a type B meeting would be held with the agency before the end of the year and Voyager will provide an update when possible. The company could not be reached.

Voyager's phase II study will enroll patients with PD for at least four years, who are not responding adequately to oral medications and have at least three hours of "off" time during the day as measured by a validated self-reported patient diary. Patients who meet the eligibility criteria will be randomized 1-to-1 to a single treatment with VY-AADC (for a total dose of up to 2.5×10^12 vector genomes) or placebo surgery. The primary endpoint is "on" time without troublesome dyskinesia, or good "on" time, as measured by the diary at 12 months.

Secondary endpoints include diary "off" time, other motor function and quality of life measures from the United PD Rating Scales, the PD Questionnaire and the patient's global function as measured by the proportion of those to show improvement on the Clinical Global Impression score. The trial will also measure non-motor symptoms from the Non-Motor Symptom Scale, as well as safety.

Biomarker data will be gathered, too, including measurements of the coverage of the specific region of the brain (putamen) targeted with VY-AADC and measurements of AADC enzyme expression and activity in the putamen measured by positron emission tomography using fluorodopa F-18. Changes in patients' daily doses of oral levodopa and related medications will be recorded as well.

Less concerned about the would-be regulatory hitch cited by Chattopadhyay is Raymond James' Dane Leone, whose firm in mid-November raised its Voyager rating from "outperform" to "strong buy," and set a price target of $28. Shares (NASDAQ:VYGR) closed Monday at $11.04, up 31 cents. "Our investment thesis is based upon three key points," Leone wrote in a report. "VY-AADC efficacy data has demonstrated a clear equivalence to alternative PD treatments that have been approved across the same primary endpoints, supporting our expectation of FDA approval during 2022; clinical data suggest VY-AADC has the potential to become the first-in-line therapy for advanced PD patients and could expand to the moderate PD patient population; and Voyager has a solid pipeline of central nervous system [CNS] therapeutic candidates that could move into clinical testing during the next several years."

Leone said his more sanguine view "factor[s] in potential outcomes from a FDA type B meeting later this year, if a phase II clinical trial alone doesn't support a BLA filing and a phase III clinical trial is needed to meet FDA requirements for approval. We currently model VY-AADC reaching about $203 million in revenues during about 2023, based upon utilization within the advanced PD patient population." Bottom line: "concerns discounted, 2019 de-risking," by Leone's reckoning.

About a week and a half ago, Voyager signed collaborations with Brammer Bio Inc., of Alachua, Fla., and with Morrisville, N.C.-based Fujifilm Diosynth Biotechnologies to further expand manufacturing capabilities, especially as they relate to the baculovirus/Sf9 system for turning out adeno-associated virus (AAV) gene therapies. "Of note, Brammer's cGMP facility in Florida has been supporting gene therapy clinical development for roughly 12 years now," said Wainwright's Chattopadhyay. It would be interesting to follow the processes being developed by Brammer and Voyager for the Sf9-based manufacturing to circumvent Uniqure's [Wim] Hermens' patent family, with claims covering the expression of both Rep78 and Rep52 proteins from a Rep78 nucleic acid sequence in insect cells."

Uniqure NV, of Amsterdam, made headlines last month with its hemophilia B gene therapy, AMT-061. Top-line data on the three patients enrolled in the phase IIb study showed that therapeutic levels of factor IX (FIX) activity were achieved and sustained at 31 percent of normal six weeks following a single administration, exceeding threshold FIX levels generally considered sufficient to reduce the risk of bleeding events. (See BioWorld, Nov. 16, 2018.)

"Voyager transitioned from a mammalian cell line-based production to the baculovirus/Sf9 production system for recombinant AAV [rAAV], which is potentially more compatible with 2,000L stir tank reactor systems, currently being deployed by Uniqure's scalable system that can produce large quantities of high-quality rAAV product," Chattopadhyay noted. Meanwhile, Brammer also is collaborating with Cambridge, Mass.-based Sarepta Therapeutics Inc. to scale up its mammalian cell line-based production for Sarepta's lead Duchenne muscular dystrophy therapy as well as limb girdle muscular dystrophy programs, with the former expected to begin patient enrollment in the planned pivotal program before the end of this year.

Research grinding away

Gene therapy in PD and other CNS disorders gained airtime last month at the Neurosciences 2018 conference in San Diego, where findings at the FIMA-University of Navarra, Spain, were detailed. PD results from a mutation that reduces the function of glucocerebrosidase (GBA1) gene in up to 10 percent of patients; the rest tend to have glucocerebrosidase activity that is below normal levels. Glucocerebrosidase breaks down alpha-synuclein, which aggregates in Lewy bodies, resulting in death of neurons. To test the idea that more glucocerebrosidase could fix the alpha-synuclein-induced neurodegeneration, Jose Lanciego's lab at FIMA developed a glucocerebrosidase gene therapy using an AAV9 vector. It worked in mice. (See BioWorld, Nov. 6, 2018.)

Making news in the space recently was London-headquartered Meiragtx Holdings plc, which acquired through an all-stock deal Vector Neurosciences Inc., bringing aboard an AAV-encoding glutamic acid decarboxylase gene therapy candidate poised for continued phase II development in PD. (See BioWorld, Dec. 10, 2018.)

PD researchers continue to roll out intriguing discoveries. Work at Penn State College of Medicine, published in NPJ Parkinson's Disease, found that exposure to even "subthreshold" amounts of the once-common (but now outlawed) herbicide paraquat can lead to PD-like symptoms in rats. The connection was known before but in earlier experiments, very high levels of the chemical was given to rats. Penn State's research is important because it shows the way paraquat journeys from the gut to the brain. In 2016, a paper in Parkinson's Disease described how digestive problems often precede the better-known motor symptoms of PD.

Scientists at Rutgers University published in the Proceedings of the National Academy of Sciences work that suggests a fatty acid derivative of the neurotransmitter serotonin, called EHT (eicosanoyl-5-hydroxytryptamide), found in the coating of coffee beans, protected the brains mice against PD's abnormal protein accumulation. The paper, titled "Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and Dementia with Lewy Bodies," pointed out that coffee "is not the only botanical extract that contains agents that act to inhibit PME-1-mediated PP2A methylation. As we begin to unravel the polypharmacology of the micronutrients in commonly consumed botanical extracts such as coffee, it seems likely that it will be possible to optimize their composition to enhance efficacy so as to provide widely available, inexpensive, and effective therapeutics for the prevention and treatment of neurodegenerative diseases," including PD and others.