The company’s work has disproved old wisdom on how cells rid themselves waste.
CEO: Keith Dionne, Ph.D.
Based: Cambridge, Massachusetts
Clinical focus: Using the cell’s garbage disposal to clear out accumulated cell substrates and restore cells to health and homeostasis
The scoop: After a couple of years’ incubation at Third Rock, Casma Therapeutics launched in May 2018 with $58.5 million to create treatments aimed at autophagy, or the cell’s garbage disposal. The company hasn’t disclosed specific programs, but its work could yield disease-modifying treatments for neurodegenerative and inflammatory diseases.
What makes Casma fierce: Casma went after autophagy because it saw a promising angle that was underdeveloped.
“The Nobel Prize was granted in 2016 for autophagy, but as of yet, no drugs have launched in the space,” Casma CEO Keith Dionne told FierceBiotech. “It is a major pathway, perhaps the major pathway, by which cells clear out all the byproducts of their function, whether they are proteins, aggregated proteins, dysfunctional mitochondria or invading pathogens like bacteria.”
The buildup of these unwanted materials leads to various ailments, including rare genetic diseases such as lysosomal storage disorders and liver and muscle diseases, as well as inflammatory and neurodegenerative conditions.
Blocking autophagy and overloading the cell with waste is one way to cause cell death, which can be useful in cancer treatment. But under certain conditions, boosting autophagy can promote cell death too. Casma believes that dialing up autophagy will be more broadly useful than inhibiting it.
“But the challenge has always been, no one really knows how to induce autophagy,” Dionne said.
This is where Casma comes in.
“We found a number of targets we believe can do this and we are advancing these now into cellular in vitro studies, in vivo studies and hopefully soon, going into people,” Dionne said.
Casma has figured out how to reconstruct the protein complexes that drive the autophagy pathway.
“This creates targets that are very specific to autophagy. Each core complex has four to five proteins and we have recreated these with full-length human proteins,” Dionne said.
The company’s work has disproved old wisdom around how cells get rid of waste: “People thought the way that autophagy worked was sort of like fishing with a net—the cell encloses a part of the cytoplasm inside the autophagosome [the structure that carries out autophagy] and whatever is inside that structure is then degraded,” he said. “In fact, autophagy is a very directed process, and a very selective process, by which very specific molecules attach to the autophagosome through a variety of linkers. In some cases, these linkers begin the formation of an autophagosome around a dysfunctional structure, such as dysfunctional mitochondria.”
Because Casma has been able to link the forming autophagosome to the specific structure it’s trying to get rid of, the company can work on drugs that zero in on specific molecules or substrates for cells to clear out.
“We have shown the ability to selectively degrade dysfunctional mitochondria by encapsulating them inside an autophagosome, leading to digestion with a lysosome, which opens us up to a number of diseases in which mitochondria are dysfunctional, such as Parkinson’s,” Dionne said.
As one can imagine, the potential applications of this approach are vast.
“The list continues to expand. What we are seeing, both in our labs and in discussions with potential partners, is a very strong interest in three areas that are coming to the forefront,” he said.
The first is rare genetic diseases, including lysosomal storage disorders, in which problems in the lysosomes—which contain enzymes to break down large molecules—lead to the aggregation of substances in the cell.
“The second area where we see strong interest, both internally and externally, is neurodegenerative disease,” Dionne said. Casma received a grant from the Michael J. Fox Foundation in May to work on drugs that promote autophagy to clear a toxic protein from the brain.
"And the third area is inflammation, both metabolic-induced inflammation, such as that seen in NASH, as well as more of an inflammatory disease, such as Crohn’s disease,” he said.
Casma aims to have its first clinical candidate in the first half of next year.
“We’re talking to major biotech and pharma companies that have programs that can span fairly large therapeutic areas. The interest is potentially applying autophagy to a number of different applications,” he said.
Since launch, the company has swelled from 10 staffers to more than 40. It’s also got about 40 people outside of Casma, through its collaborations and CROs. It has struck up several partnerships with academic centers, including the University of California, Berkeley, Washington University and the University of Texas Southwestern Medical Center—the birthplace of Casma’s technology.
“The goal is to continue hiring primarily on the science and disease biology side to support programs that we have moving forward right now. And to expand those programs—we want to expand the number of programs as well as the programs themselves,” Dionne said.
Investor: Third Rock Ventures