One of our biggest news stories happened as 2020 wound to a close when Roivant Pharma acquired University of Michigan (U-M) startup Oncopia Therapeutics, a targeted protein degradation company co-founded by prolific inventor and U-M Professor Shaomeng Wang.
Under the deal, announced December 7, 2020, Roivant Sciences will add to its new targeted degradation pipeline several preclinical small molecule degraders that were initially developed in Wang’s lab against four cancer targets. As part of the new alliance, Roivant will also begin sponsoring research in Professor Wang’s U-M lab, and Wang said he aims to produce another suite of degraders with the additional funding.
Small molecule degraders work by bringing together a target protein with an E3 ligase, another protein that flags the target for degradation. Historically, small molecule medicines work by inhibiting or activating the activity of a target, but degraders eliminate the target from the cell altogether rather than turning its activity on or off.
“Degradation is one of the most transformative technology platforms that has been developed in small molecule therapeutics in the last 30-40 years,” said Wang.
It all comes down to the fact that more proteins in more diseases can be targeted with degraders than small molecule inhibitors or activators. This means that degraders present opportunities to treat diseases where there are currently no approved therapies and improve therapeutics where marketed therapies aren’t very effective or cause unwanted side effects.
Wang lists three reasons why: the first is that small molecule inhibitors and activators can only bind to one part of a protein – the active site. However, some proteins don’t have active sites that can bind small molecules and others might have active sites that are highly similar to those of other proteins, so the small molecule binds to both proteins, resulting in unwanted side effects. Small molecule degraders don’t need to bind the active site, and thereby bypass these requirements.
Additionally, inhibitors and activators work at a 1:1 ratio with their target. One inhibitor needs to stay bound to the active site to keep a protein turned off. With small molecule degraders, however, that ratio is one to many because once one molecule has caused the protein to be degraded, that molecule can move on to the next protein and cause its degradation, and the process can continue.
The patented portfolio of targeted degraders Roivant acquired from Oncopia include those that target the oncoprotein STAT3 and the androgen receptor. The former is a novel target for which no drugs are approved, whereas the latter is one where a drug has been approved but patients often don’t respond to it or become resistant.
Because small molecule degraders have such transformative potential, it has become a highly competitive field in the last few years.
A handful of startups have been built around small molecule degrader platforms and have raised significant capital from venture capitalists and public markets, formed partnerships with big pharma, and/or been acquired outright. The company with the most clinically advanced degrader, Arvinas Therapeutics, is valued at $2.8 billion after raising over $100 million in a 2018 IPO.
Professor Wang is no stranger to creating competitive, protectable intellectual property in his U-M lab. Since 2002, he has submitted 111 inventions to U-M’s Office of Technology Transfer, executed 63 commercialization agreements, and founded five startups. His largest U-M startup is Ascentage Pharma, which houses seven preclinical and clinical U-M-discovered compounds. In 2019, Ascentage raised $53 million in an IPO on the Hong Kong exchange and as of December 2020, the company was valued at $870 million.
Wang pointed to two factors supporting his ability to create impactful medicines at U-M: the university’s research infrastructure and U-M Tech Transfer
For the former, he highlighted the support available for researchers and U-M’s core facilities, which provide a range of drug discovery capabilities to the campus.
Wang said that Tech Transfer “has been there every step of the way to help us make sure that we have the IP protected, and to make sure that we negotiate the right research or licensing agreement. Not just to protect the interests of the university, but also allow us to be able to move things forward in development and ultimately to patients.”
“The very progressive tech transfer policy at University of Michigan has been critically important for the formation and success of the companies that I’ve been involved in,” he added.