Yumanity Therapeutics Inc. said that Merck & Co. Inc. is making a big bet on its nascent neurodegenerative disease pipeline, licensing exclusive rights to programs addressing amyotrophic lateral sclerosis (ALS) and a rare type of dementia in a deal with up to $500 million in potential milestone payments. The collaboration also includes an up-front payment, money toward a series C financing and potential royalties on net sales of the licensed programs, though the value of those elements wasn't disclosed.

Yumanity will carry the Merck-licensed programs, each targeting protein misfolding, through preclinical research. Merck will then move them into the clinic and on to commercialization, if warranted.

The Cambridge, Mass.-based company "has an incredibly prolific discovery platform in neurology and we just can't develop everything on our own," said Yumanity CEO Richard Peters. The deal fulfills a goal he's held since the get-go of his 11-months tenure at the company, providing "an incredible validation” of its scientific platform and underlining the importance of developing drugs for neurodegenerative diseases, he said.

In addition to Merck, Fidelity Management & Research Company, Redmile Group, Pfizer Ventures, Alexandria Venture Investments, Dolby Family Ventures and Yumanity co-founder Tony Coles backed the financing. The company previously raised $47 million in a 2016 series A financing led by Fidelity – slightly more than initially announced – and raised an additional $36 million in equity and $10 million in venture debt in 2018. The new series C financing will take it "well past next critical value inflection point for the company," a readout of its phase I trial in Parkinson's disease (PD) in 2021, Peters said.

A growing need

Both ALS and frontotemporal lobar dementia (FTLD), the other indication in the deal, present significant unmet medical needs. ALS, the larger of the two indications, is expected to grow in prevalence across the world's seven most mature pharmaceutical markets by 21% over the next 20 years, due to demographic trends, according to DRG, a unit of Clarivate. It's divided into two major types. Sporadic ALS is the most common form of the disease in the U.S., accounting for as much as 95% of all cases, while familial or inherited cases make up the remainder.

Though some newer therapies, such as Mitsubishi Tanabe Pharma Corp.'s Radicava (edaravone), have offered ALS patients functional benefits and/or slowed the progression of the disease, "we don't think it's enough," said Peters. "You need to have transformative treatment to really alter the course of the disease. And the programs that we've partnered with Merck, if they work, could really change the natural history," he said. To do that, Yumanity researchers have identified genes in familial ALS that, when mutated, lead to misfolded proteins that cause neuronal degeneration.

It could take a similar approach in FTLD, the most common type of which is frontotemporal dementia, which the NIH’s National Library of Medicine describes as a behavioral variant of FTLD characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. Scientists think that FTLD is the most common cause of dementia in people younger than age 60, according to the NIH.

A multitude of misfolding plays

Yumanity's foundational science comes from the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology, where it was developed in the lab of late company co-founder Susan Lindquist. It identifies compounds using phenotypic screens to identify compounds that would help overcome the toxicity of those misfolded proteins in brain cells. Each is immediately tested, using neurons evolved from stem cells created from skin biopsies of donors with a disease of interest.

The company's focus on the cellular toxicity caused by misfolded proteins appears to be opening the door to a multitude of neurodegenerative indications, such as PD – the focus of its lead internal candidate, YTX-7739 – and Alzheimer's disease (AD). Another program for Lewy Body dementia is poised to enter the clinic next, Peters said.

Despite the potential, neurological indications have also offered no shortage of challenges, including to companies that have sought to address them by dealing with protein misfolding. Prothena Corp. plc, another company in the space, has several partnered programs, including prasinezumab (PRX-002/RG-7935), which it's pursuing with Roche Holding AG for the potential treatment of PD and other related synucleinopathies. Prothena has also pursued programs that target tau and an undisclosed target in collaboration with Bristol-Myers Squibb Co. for the potential treatment of Alzheimer’s disease, ALS, frontotemporal dementia or other neurodegenerative diseases. Year-to-date, Prothena’s share value (NASDAQ:PRTA) has dipped about 34%.

A clinical trial disappointment for prasinezumab was one of the contributing factors, with Roche reporting in its Q1 earnings that the phase II Pasadena study of the compound in patients with early PD did not meet the primary objective, though it showed signals of efficacy. Biogen Inc., Takeda Pharmaceutical Co. Ltd., and Abbvie Inc. have also advanced programs that target misfolding of alpha-synuclein in PD.

Yumanity’s Peters, who worked closely with Tony Coles during their days at Onyx Pharmaceuticals Inc., sounded ready to weather any challenges the company could face in its work. "What this field needs, in neurodegeneration, is new ways of attacking these diseases,” he said. “Yumanity was founded to do just that.”

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