Targeted degradation: putting autophagy to work

Casma Therapeutics has built an autophagy-inducing platform for targeted degradation across a host of age-related diseases.

Late last year, biotech Casma Therapeutics closed a $46 million funding round for its approach to harnessing the potential of autophagy to develop innovative new treatments for cancer, inflammation, neurodegeneration, and metabolic disorders. The company, which recently appointed Dr Frank Gentile its new CEO, will use the funding to drive its programs in lymphoma and solid tumors through to IND-enabling studies.

Longevity.Technology: Autophagy is the main method by which a cell’s damaged components are recycled to maintain cellular health. As with many of our biological processes, autophagy becomes impaired with age and is implicated in many age-related diseases. While Casma’s lead programs are focused on cancer, the company is also working on age-related inflammatory and neurodegenerative diseases. To learn more, we caught up with Dr Keith Dionne, Casma board member and its former CEO.

Casma has validated definitive autophagy targets that can be drugged to enable a targeted form of degradation. Through selective degradation of specific disease targets, the company expects to halt or reverse the progression of disease, a process it calls Degradation 2.0.

Targeted degradation: putting autophagy to work

“We didn’t start the company based on Degradation 2.0 – we started with Degradation 1.0, which is really a nonspecific general induction of autophagy, such as the effect you get from fasting or exercise,” says Dionne. “Along the way, we realized that potentially we could use autophagy to degrade specific disease targets that are undegradable by the proteasome system. No one has ever been able to do that before.”

Degradation on-demand

This shift, adds Dionne, was driven by research which showed that autophagy was an “on-demand degradation system.”

“In other words, it’s the presence of the disease target itself when it comes in contact with one of the key molecular drivers of autophagy that drives the formation of an autophagosome around that specific disease target,” he says. “This led us to pursue the goal of driving the formation of an autophagosome around specific disease targets that we want to degrade, as opposed to simply inducing more autophagosomes and hoping they’ll also degrade some of the things we want to get rid of.”

This brought about the concept of Degradation 2.0 and Casma’s subsequent development of its technology platform, called PHLYT.

“PHLYT is a bifunctional molecule, one side of which binds to one of a couple of key molecular proteins involved in autophagosome formation,” says Dionne. “On the other side, is any kind of a binder, a small molecule for example, to whatever disease target of interest we want to degrade.”

Targeted degradation: putting autophagy to work

When these two sides are brought together, Casma observed that things happen that otherwise wouldn’t happen if they’re kept apart.

“Bringing the appropriate autophagy protein in proximity with the disease target initiates the formation of an autophagosome around that disease target,” he says. “Which means it holds potential well beyond general autophagy induction. In fact, we believe we can take off-the-shelf molecules that have already been optimized to a particular disease target of interest and use them on the binder side. Once you combine our proprietary side of the molecule with one of these disease targeting molecules, they become a novel bifunctional PHLYT molecule that gives us a very strong starting point from which to optimize its properties.”

Autophagy and neurodegeneration

While Casma’s most advanced programs are in oncology, Dionne tells us that the company’s approach has potential in many other disease indications, and uses neurodegeneration as an example.

“The only system in the body that can degrade many molecular plaques, like Alzheimer’s plaques, is the autophagy system,” he says. “It’s much larger than the proteasome and can degrade larger, more complex disease targets such as organelles, protein aggregates, and large signaling complexes that the proteasome simply cannot. Most, if not all, of the disease targets that drive neurodegeneration are large multiprotein complexes that are just way too large to be able to be degraded by the proteasome.”

Targeted degradation: putting autophagy to work

Dionne says that Casma has talked to several potential pharma partners, and almost all have expressed interest in partnering with the company in the neurodegeneration space. So why did the company choose to go down the oncology route first?

“Neurodegenerative diseases are challenging and expensive – it’s several hundred million dollars to run a Phase 3 Alzheimer’s trial, so that’s a difficult area to start for a small biotech company,” says Dionne. “Also, getting bifunctional molecules across the blood brain barrier is not the easiest thing to do, and can require significant optimization. So, we decided to start with peripheral disease targets that don’t take as much optimization, don’t take as much time and are in a cost basis where we can not only develop the platform, but we can also advance the molecules to the clinic and even launch them in the marketplace. That was why our decision was to start with oncology.”’

Cancer progress drives other programs

The new funding is expected to take Casma through all its preclinical work in lymphoma and solid tumors, including demonstrating in vivo efficacy, to show that the platform is indeed capable of degrading complex disease targets of interest. The bifunctional nature of Casma’s platform means that the company is also working on neurodegeneration and other conditions, albeit indirectly.

Targeted degradation: putting autophagy to work

“We’re simultaneously working on multiple indications, because the key breakthrough is on the autophagy machinery side of the molecule,” says Dionne. “We believe the target autophagy inducing proteins we have identified can be universal degraders that can drive degradation in an oncology context or a neurodegenerative context. So, by developing degraders for oncology, we are also doing the bulk of the work to develop degraders for other indications like neurodegeneration.” 

“For example, it’s not that hard to then switch the target binder side of the bifunctional molecule to target tangles of mutated huntingtin protein as found in Huntington’s disease. So indirectly, we’re working on multiple therapeutic areas, it’s just right now our immediate focus is oncology.”

Photograph: Casma Therapeutics