In the more than two years since Casma Therapeutics Inc. raised its series A and completed its new $50 million series B, the company has advanced its agonist program for treating muscular dystrophy and identified new targets.

But in that time it also lost a co-founder to cancer. Beth Levine died in June, leaving behind not only a promising company but also her work as professor of internal medicine and microbiology and autophagy at the University of Texas Southwestern Medical Center.

Keith Dionne, CEO, Casma

“She was a forerunner and pioneer in autophagy research,” Keith Dionne, Casma’s CEO, told Bioworld. “I think she could have been in the running for a Nobel.”

Levine discovered the mammalian autophagy gene, BECN1, and other components of the autophagy pathway, work similar to the discovery of key mechanisms of autophagy that earned Yoshinori Ohsumi the 2016 Nobel Prize for Physiology or Medicine.

Her work continues at the Cambridge, Mass.-based company, spurred on by the new series B financing designed to develop its TRPML1 agonist program for treating muscular dystrophy and to help refine its autophagy degrader platform.

“When we began the company, this was uncharted space with a lot of potential. And now it’s turning into reality,” Dionne said.

The initial research conducted by Casma's scientific co-founders provided foundational evidence about autophagy initiation, the formation of autophagosomes that encapsulate material slated for degradation and the process of capturing that cargo, then fusing with lysosomes where the materials are degraded and released.

Autophagy is the natural process by which cells break down surplus or dysfunctional protein, organelles such as mitochondria, and viruses and other pathogens. The company said it wants to arrest or reverse the progression of lysosomal storage disorders, muscular disorder, cancer, inflammatory disorders and neurodegeneration by boosting autophagy.

That’s a tall order of indications to handle and Dionne said the company definitely needs partners to move the program along. It would make no sense to choose just one or two of the indications and leave the others untouched, he added.

“As a small company, we can’t handle those,” he said. “We are in discussions with large pharmas and other potential partners.”

TRPML1 is foremost in the mammalian mucolipin TRP channel subfamily. The cation-permeable channel is mostly localized on membranes of late endosomes and lysosomes in all mammalian cell types. It regulates repair of the plasma membrane of muscle cells if they are damaged. It is thought to play a role in lysosomal function by promoting autophagy and lysosomal exocytosis to help deal with the toxic accumulation of proteins, fats or other cellular macromolecules. Casma’s program is designed to degrade larger, diverse disease targets than those relying on E3 ligase-based or proteasomal degradation approaches, Dionne said, by preventing muscle cells from becoming necrotic.

While the company is doing in vivo studies at the moment, Dionne said he sees Casma’s TRPML1 program starting a clinical trial in early 2022.

The series B funding will also help the company enable preclinical proof of concept for its autophagy degrader program for identifying and drugging specific autophagy drivers. The product engine is designed to span all facets of the autophagy system from its initiation to autophagosome formation, onto fusion with lysosomes and then to lysosomal biogenesis and function.

Dionne said the company’s scientists keep driving their work forward despite the COVID-19 pandemic. Casma, like many companies, had many employees working from homes but also had scientists in the lab.

“We’re back up right now to over 80% of our employees who come into the office or the lab at least for some time during the week,” he said.

Casma does COVID-19 testing for employees but none have tested positive, he said.

The industry is changing during the pandemic, he said, and some but not all of the changes will be permanent. Working from home or in isolation has been productive, he continued, but it’s the hallway conversations in which unexpected connections are made in a casual setting that is “the hardest part to recreate.”

Third Rock Ventures launched Casma in 2018 and also participated in the series B, which was led by The Column Group. New investors include Eventide Asset Management LLC and Schroder Adveq.

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