Eli Lilly, Novartis back a biotech startup boasting ‘best of both worlds’ protein degraders

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.”

Amphista Therapeutics Is Silencing Disease Proteins to Treat Cancer

This article was sourced from La Biotech.

Amphista Therapeutics, based in Glasgow, Scotland, is the latest company to develop drugs called PROTACs, which are designed to make the cell degrade harmful proteins to treat cancer.

Small molecule drugs have shown incredible potential for the treatment of cancer by blocking harmful proteins in the cell. However, many promising protein targets for cancer treatments are considered ‘undruggable’, often because they have no obvious location where a small molecule drug can bind.

To take on this challenge, Amphista was founded in 2017. Spun out of the labs of protein degradation researcher Alessio Ciulli at the University of Dundee, it is based at the BioCity incubator in Glasgow.

The startup is one of many companies that have taken on the challenge of targeting so-called undruggable proteins. It designs drugs called proteolysis targeting chimeras, or PROTACs.

Broadly speaking, PROTACs are fusions of two molecules — one that binds to the target protein, and another that recruits an ‘executioner’ protein, called a ligase, to degrade the target. They have several advantages over traditional small molecule drugs, such as being able to degrade many undruggable proteins and being harder for tumors to resist via mutations to the target protein.

Examples of PROTACs in development include drug programs by the US biotech Arvinas, the Polish company Captor Therapeutics, and the UK startup Polyprox.

However, according to Nicola Thompson, CEO of Amphista, current PROTACs tend to activate ligases called E3 ligases, which can be altered by tumors to become resistant to PROTACs.

The field has quickly realized that relying on the current ligase and associated chemistry toolbox constitutes a limitation in terms of scope of degradable targets, resistance profile, and the ability to address cell type-specific toxicity,” Thompson told me.

Amphista aims to make PROTACs that activate a different type of executioner protein machinery called the ubiquitin-proteasome system. This would give a lot more chemical tools for making PROTACs, and could help to overcome tumor resistance to E3 ligase-based PROTACs.

To fund the preclinical development of its first-in-class cancer treatments, the company raised a Series A round of €7M earlier this month and is also on the lookout for potential partnering deals. Thompson also said that Amphista aims to raise a Series B round later this year.

The field of PROTACs is a very young field, with its most advanced player, Arvinas, at phase I. This makes it a daunting task to develop a drug in this class. However, Thompson told me that it is also an opportunity to hit previously unreachable targets, and could prove cheaper to manufacture than RNAi, another type of therapy that aims to degrade disease targets.

Targeted protein degradation will open up the druggable target space and deliver much-needed medicines, not only to treat cancer but many other diseases,” confirmed Thompson.

According to Maria Sagan, Knowledge Manager at Captor Therapeutics, the research of Ciulli’s group has contributed a lot to the field of PROTACs, and Amphista has a lot of expertise backing it.

The interest in targeted protein degradation both from pharma and from investors is substantial, so we can expect more and more biotechs joining in the upcoming years,” she told me. “With a number of targets that remain to be drugged, there’s enough work for everyone.