Voyager Therapeutics Inc. struck another big pharma partnership for its gene therapy platform, attracting Abbvie Inc. to a strategic collaboration and option agreement to develop and commercialize vectorized antibodies against tau in Alzheimer's disease (AD) and other neurodegenerative diseases. Abbvie, of North Chicago, committed $69 million up front and $155 million in preclinical and phase I option payments. Voyager, of Cambridge, Mass., is eligible to receive $895 million in development and regulatory milestones if three vectorized tau antibodies emerge from the alliance, along with tiered royalties on global net sales of commercial products.

During the initial stage of the partnership, each company will identify up to five antibodies to include in the collaboration. The partners then will select up to three antibody candidates to advance to research compounds, with Abbvie having the right to name two of the three. Voyager will assume responsibility for advancing the compounds through investigational new drug application-enabling and phase I trial activities. Through phase I, Abbvie may exercise exclusive options to advance any or all of the candidates into phase II development and beyond, at which point the pharma also will assume R&D costs in return for an exclusive global license to the assets.

In addition to the up-front, Abbvie's payments to Voyager would come in the form of an $80 million development option for the first compound and product candidate, $30 million each for the two additional candidates and a one-time payment of $75 million upon exercise of the license option. Milestone payments for the AD indication total $550 million, followed by $230 million for the first indication beyond AD and $115 million for a subsequent non-AD indication. Voyager also is set to receive tiered royalties that escalate from a high-single digit to the mid-to-high teens on net sales. Should Voyager exercise a separate cost-sharing option, royalties could increase to the low-twenties.

Investors liked the deal, lifting Voyager's shares (NASDAQ:VYGR) $4.30, or 22.2 percent, to close at $23.66.

Steven Paul, Voyager's president and CEO, said the companies had been talking for "six to 12 months" before the deal was struck.

"We know that Abbvie has had a strong interest in Alzheimer's disease – particularly in pursuing tau-related types of disease modifying therapies," Paul said. Last year, for example, the pharma inked a neuro-immunology pact with Alector LLC, of South San Francisco, for $205 million up front, and it's a long-time participant in a tau research program with AD researchers at Washington University School of Medicine in St. Louis (WashU). (See BioWorld Today, Sept. 12, 2016, and Oct. 25, 2017.)

Paul, a venture partner at Third Rock Ventures and former Eli Lilly and Co. executive who served as vice president of discovery research and neuroscience research and president of Lilly Research Laboratories, shared a personal interest in advancing therapies to prevent or treat AD.

"I've become quite interested in the possibility of delivering monoclonal antibodies to the brain, the muscles, etc., using AAV vectors," he told BioWorld.

The company's gene therapy platform is built on adeno-associated virus (AAV) technology. In January 2017, scientists from Voyager and Weill Cornell Medical College published a paper in the Journal of Neuroscience describing reduced tau pathology, including neurofibrillary tangles and neurodegeneration, following treatment with a single dose of an AAV vector designed to administer the tau monoclonal antibody (MAb), PHF1, to the hippocampus of mutant tau transgenic mice. The findings showed that, by placing a MAb directed against tau into an AAV vector, "we can achieve higher brain levels of the antibody, which has been one of the rate-limiting aspects of immunotherapy for Alzheimer's," Paul said.

The experiment worked, he conceded, "at least in an animal model." Given Abbvie's pioneering work in MAb development, Voyager's expertise in AAV technology and a mutual interest in AD, "it seemed like a nice partnership," Paul added.

The partners are fully cognizant of the AD landscape, which is littered with failures, but they also see merit to their approach in pursuing the tau pathology.

"Pursuing clinical trials in Alzheimer's disease is not for the faint of heart," Paul acknowledged. "It's a tough area, but arguably one of the great unmet medical challenges of our time.

"We feel pretty good about the biology we're pursuing," he added. "Having worked on amyloid for so many years, I'm convinced tau is the more relevant biology to go after in Alzheimer's disease – one that tracks much more closely with the progression of the disease and the neurodegeneration that characterizes the disease."

Voyager has the tau protein inhibitor, VY-TAU-01, in discovery, targeting AD, frontotemporal dementia and progressive supranuclear palsy, according to Cortellis Competitive Intelligence. Abbvie, meanwhile, has moved a tau protein inhibitor, ABBV-8E12, that emerged from the WashU program into phase II.

Both the structure and economics of the deal bore similarities to a pact that Voyager struck in 2015 with Sanofi SA unit Genzyme, which continues but without the lead VY-AADC gene therapy program in advanced Parkinson's disease (PD), after Genzyme passed on that development and commercialization option in November. (See BioWorld Today, Feb. 12, 2015, and Nov. 1, 2017.)

Both are option arrangements, but the Sanofi deal is focused on specific programs. The Abbvie alliance will, instead, start with AD and allow that work to inform additional potential targets.

"Tau is but one of a whole number of misfolded proteins that aggregates both inside and outside of cells," Paul explained. "It's very clear that, in a number of neurodegenerative disorders, facilitating clearance of these misfolded proteins with antibodies, for example, or preventing their spread in the brain with antibodies appears – at least in animal models – to be therapeutically quite relevant. We think this whole area of vectored immunotherapy could have applications outside of Alzheimer's disease."

He cited PD, amyotrophic lateral sclerosis and Huntington's disease (HD) as additional potential targets.

"Obviously, if we came up with a treatment for Alzheimer's, that would be a pretty big deal, medically and commercially, and the deal structure reflects that potential," Paul pointed out.

The companies must do considerable work before advancing an AD asset to the clinic, he said, declining to estimate a timetable.

The Abbvie deal "is the right move" for Voyager's ambitions in AD, BTIG analyst Dane Leone wrote in company note. "We think the move is highly strategic, as it reaffirms investor confidence in the platform and provides a cash source of funding following the cancellation of the prior agreement with Sanofi."

Abbvie is ahead of competitors with its lead tau antibody, Leone pointed out.

With "bio-bucks galore," AAV vectors and CNS targets will likely remain in focus, added H.C. Wainwright's Debjit Chattopadhyay in an update on gene therapy company Uniqure NV, citing the collaboration disclosed the same day between Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, and Wave Life Sciences Ltd., of Cambridge, Mass. In that deal, focused on central nervous system (CNS) disorders, Wave is set to receive $110 million up front, $60 million in equity investment and at least $60 million in research funding, with the potential to reach $2 billion in potential milestones, along with tiered royalties.

The two transactions highlight the growing acceptance of AAV-based delivery of proteins into the CNS, emerging focus on the treatment of HD and other CNS indications with no disease-modifying options and "pharma's willingness to engage CNS targets through once-and-done, gene therapy-based solutions as opposed to chronic therapy," Chattopadhyay wrote. "Importantly, this gradual embrace of gene therapy is also a nod for value-based pricing models that is likely to dominate pricing discussions for years to come."

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