UCB SA, a Belgian company developing an antibody targeting a toxic protein tied to Alzheimer’s disease (AD), said Roche Holding AG has negotiated an exclusive global license to the potential therapy for $120 million up front, plus almost $2 billion in milestone payments following positive proof of concept for the anti-tau candidate, UCB-0107, in AD. UCB will continue the drug’s development for progressive supranuclear palsy (PSP), with a confirmatory phase III trial due to start in the second quarter of 2021.
The deal gives Roche, which is already well underway with efforts to explore tau aggregation inhibition in AD through its partnership with AC Immune SA, the opportunity to deepen its understanding of the approach while diversifying its portfolio in a high-risk, high-reward indication.
"We're well into the world of an anti-tau aggregation approach," Roche's global head of neurodegeneration, Rachelle Doody, told BioWorld. But just as clinical research has played an important role in illuminating the many differences between anti-amyloid monoclonal antibodies (MAbs), she said, there's call to look at the differences between anti-tau Mabs, too.
With 13 tau aggregation inhibitors under clinical evaluation as potential treatments for AD, there's still much to learn, and new advantages to be delineated.
"There are fundamental key differences between the different molecules, including the way in which they bind to toxic tau in the brain and/or how they remove the toxic tau," UCB's head of neurology, Charl van Zyl, told BioWorld. “We believe that based on the specific design of our molecule, we have the potential to deliver differentiated efficacy and outcomes.
"By partnering with Genentech, we combine UCB’s science-driven, patient-centric development approach with Genentech’s deep and wide-ranging expertise, capacity and know-how in Alzheimer’s disease, optimizing our chances for success, and maximizing the potential to make a new treatment available to people living with Alzheimer’s disease," he said.
A toxic tangle
Tau, a microtubule-associated protein expressed in the CNS, supports the assembly and stabilization of neuronal microtubules. In tauopathies, such as AD, progressive supranuclear palsy (PSP) and frontotemporal dementia, it becomes pathogenic, forming tangles, which cause cell damage and ultimately neuronal death.
"Changes in brain proteins amyloid and tau, and their formation into clumps known as plaques and tangles, respectively, are defining physical features of Alzheimer’s disease in the brain," the Alzheimer's Association noted recently. New research on showcasing the value of blood-based biomarker testing for phosphorylated tau-217 was showcased at the association’s annual conference, now underway. "Buildup of tau tangles is thought to correlate closely with cognitive decline," it said.
UCB's UCB-0107 is a recombinant, humanized, full-length IgG4 MAb that targets a central tau epitope to block and/or reduce the spread of tau pathology. In May 2019, data published in Brain demonstrated the potential for the antibody in mice. In September of that year, the company followed with phase I data finding the candidate both well-tolerated and acceptably safe in 52 healthy men.
That research helped lay the groundwork for UCB's ongoing effort in PSP, but given scale and complexity of clinical development in AD, the company didn't consider itself to have the full capabilities to fully maximize value for patients in the Alzheimer’s disease space, van Zyl said. "Additionally, our R&D capacity is currently fully focused on our exciting late-stage clinical pipeline," he added.
Still, the company will move the ball down the field a bit further in AD before potentially handing it off. In working with Roche and its subsidiary, Genentech Inc., UCB will fund and perform a proof-of-concept study in the condition. Then, once the results of that study are available, Genentech has the right to either move ahead with the development on Roche's behalf or return full rights back to UCB. Should it move ahead, UCB will be eligible to receive potential cost reimbursement, development and sales milestone payments as well as royalties with a total approaching $2 billion upon receipt of certain regulatory approvals and satisfying certain clinical and sales milestones.
A busy field
So far, just one anti-tau program – Taurx Pharmaceuticals Ltd.'s oral tau and synuclein aggregation inhibitor, LMTX – has made it to phase III. Four phase II candidates, including medicines partnered with CNS heavyweights Biogen Inc. and Eli Lilly and Co., are also in the mix, followed by two phase I programs. AD vaccine programs, such as AC Immune's phase I ACI-35.030, are also underway.
Meanwhile, on the treatment front, Genentech remains deeply engaged with AD. It remains in the midst of running the global phase III Graduate program, which includes two multinational, double-blind placebo-controlled trials testing high doses of the anti-amyloid human MAb gantenerumab. An active exploration of the AC Immune-originated anti-tau IgG4 antibody semorinemab also remains underway. A phase II trial of semorinemab in patients with moderate AD is expected to be completed in late 2021.
Shares of UCB, which trades under the symbol UCB on the Brussels Euronext exchange, fell 1.7% to €110.10 on Wednesday. The company's transaction remains subject to obtaining antitrust clearance.