Merck acquires Calporta Therapeutics for its autophagy-boosting molecules

Merck & Co. will spend up to $576 million to acquire Calporta Therapeutics, a San Diego–based start-up that is developing small molecules to boost autophagy, the process of cellular self-renewal.

Calporta was founded in 2015 at COI Pharmaceuticals, a start-up incubator funded by GlaxoSmithKline and the venture capital firm Avalon Ventures. Today, Calporta is one of more than a dozen start-ups developing drugs that alter autophagy.

Studies in cells and animals show that boosting autophagy helps brain cells clean up cellular debris, including the toxic proteins that accumulate in neurodegenerative conditions such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. Calporta says its drug candidates could help these diseases, but its initial focus will be on Niemann-Pick disease type C, a lysosomal storage disease.

Its candidates are small-molecule agonists of TRPML1, a calcium channel found in lysosomes, the enzyme-filled sacs that break down cellular debris. TRPML1 is important for lysosomal health, and mutations in the TRPML1 gene cause a severe childhood neurodegenerative disease.

When TRPML1 is activated, it releases calcium from the lysosome and triggers a chain reaction that ultimately boosts autophagy. The calcium first binds a protein called calcineurin, which then binds to and dephosphorylates a nearby transcription factor called TFEB. Next, TFEB moves from the cell’s cytosol to its nucleus, where is acts as a master key for turning on autophagy and lysosomal genes.

Various academic groups and companies are interested in tapping into different parts of this process—all with the goal of activating TFEB. Casma Therapeutics and Rheostat Therapeutics are also developing TRPML1 agonists.