This article was sourced from Endpoints.
Since heading up GlaxoSmithKline’s protein degradation unit in 2012, Ian Churcher has witnessed a rapid explosion of interest in the idea of leveraging the body’s garbage disposal system to eliminate problematic proteins. Huge amounts of money are flowing in from biotech VCs and Big Pharma players, bankrolling a huge volume of projects — some of which have now made it to the clinic.
“What I would say hasn’t changed is the focus is still very much on a small number of mechanisms, around say VHL and cereblon, and we knew about these mechanisms very early,” he told Endpoints News. “So I think what that suggests is it’s really quite difficult to identify novel mechanisms.”
He has since moved on to other discovery fields, but that feeling was what got him excited about focusing on targeted protein degradation again and taking up the CSO post at Amphista last May, just after the UK-based biotech debuted with a $7.5 million Series A.
The hypothesis at Amphista, incubated at academic founder Alessio Ciulli’s lab in Scotland, has been that you can target proteins for degradation by engaging other parts of the ubiquitin-proteasome system, said CEO Nicki Thompson.
Less than a year later, they’ve scored $53 million in fresh financing to prove it further.
Novartis and Eli Lilly hopped onto the syndicate alongside Gilde Healthcare and Forbion, co-leaders of the round, and Amphista’s existing backers at BioMotiv and Advent Life Sciences.
Amphista, Churcher noted, isn’t the only company realizing the limitations of PROTACs as pioneered by Craig Crews (with whom Ciulli had worked as a fellow) and others like Jay Bradner before he became the chief of Novartis Institutes for BioMedical Research. Their respective spinouts, Arvinas and C4 Therapeutics, are some of the first to start Phase I studies — in prostate cancer and hematologic malignancies, respectively.
There’s Lycia, the startup pursuing Carolyn Bertozzi’s ideas for targeting extracellular proteins; a string of others, like Monte Rosa, are moving into “molecular glues” — smaller compounds that they hope would have better drug-like properties.
But glues would ultimately only work for a small number of targets, he added. So they chose to keep the traditional two-part construct of bifunctional degraders, with one half binding to the drug target and the other half being a “warhead” that would recruit a protein to initiate the degradation. By engineering the warheads to enlist things other than those E3 ligases — they still can’t reveal what exactly makes it “genuinely different” — they believe they will open up whole new areas for exploration.
“We think we’ve overcome a lot of those problems,” Churcher said. “So our bifunctional approach gives us the best of both worlds — great drug-like properties and a broad target scope.”
With a goal to bring the lead program into the clinic in 2023, Thompson noted the Series B will drill down on those initial oncology indications and potentially expand to others that are currently out of bounds for protein degradation.
Despite the number of companies in the space, after all, Kymera is pretty much the only one that’s publicly gone after something outside of cancer by exploring inflammation with Sanofi.
Thompson and Churcher envision going even further, producing next-gen molecules that might even address diseases of the central nervous system.
With 15 full-time employees at the moment, they expect to at least double over the coming 12 to 18 months while pursuing a “limited number of” strategic partnerships.
“The field will continue to grow — there’s a huge amount of effort, very smart minds going into the area,” Churcher said. “But we really do need to break out of the limitations that the current mechanisms do bring upon the field. I think they will be successful, but I think there’s so much more scope to be even more successful.”