TRPML1

Merck is shoring up its neuroscience pipeline with the acquisition of Caraway Therapeutics, a preclinical startup with programs in Parkinson’s disease and amyotrophic lateral sclerosis. Specific financial terms were not disclosed, but Merck said Tuesday that the acquisition agreement could pay out up to $610 million, which includes upfront and milestone payments. Cambridge, Massachusetts-based Caraway develops drugs addressing genetically defined neurodegenerative and rare diseases. The company aims to treat them with small molecules that leverage processes in a cell for clearing away toxic cellular components. Mutations can impair the function of lysosomes, cellular components for breaking down and eliminating toxic substances. Caraway’s small molecules modulate lysosomal function. Caraway has two compounds in its program addressing TRPML1, an ion channel located on lysosomes. One of the molecules is in development for Parkinson’s disease stemming from mutations to the GBA gene, which codes for glucocerebrosidase (GCase), an enzyme key to maintaining lipid metabolism. Deficiency of that enzyme leads to lysosomal dysfunction. By activating TRPML1, Caraway aims to address the pathway that is impaired in GBA-Parkinson’s patients. There’s potential competition in treating genetically driven Parkinson’s. Chicago startup Vanqua Bio is developing small molecules that cross the blood-brain barrier to activate GCase and restore lysosomal function. Gene therapies in development by Neurocrine Biosciences and Eli Lilly offer the potential for a one-time fix of Parkinson’s driven by GBA1 mutations. Another TRPML1-targeting small molecule from Caraway is in development for an undisclosed rare disease that is a non-central nervous system disorder. The company is also researching loss-of-function genetic variants of TMEM175, a potassium channel key to lysosomal function. Caraway is developing small molecules that increase TMEM175’s activity to enhance the activity of the lysosome as a potential treatment for Parkinson’s and ALS. “Caraway’s multidisciplinary approach has yielded important progress in evaluating novel mechanisms of modulation of lysosomal function with potential for the treatment of progressive neurodegenerative diseases,” George Addona, senior vice president, discovery, preclinical development and translational medicine, Merck Research Laboratories, said in a prepared statement. “We look forward to applying our expertise to build upon this work with the goal of developing much needed disease-modifying therapies for these conditions.” Caraway was initially called Rheostat Therapeutics. The startup was incubated by SBV Ventures and the Dementia Discovery Fund, which provided seed financing. In 2018, the startup announced a $23 million Series A round co-led by MRLV, the venture investment group of Merck, and AbbVie Ventures. In 2019, Rheostat changed its name to Caraway Therapeutics. Neuroscience is a tiny portion of Merck’s drug portfolio and pipeline, which is dominated by oncology, mainly the cancer immunotherapy Keytruda. But the company has previously looked at TRPML1 as a way to treat neurodegeneration. In 2019, the pharma giant committed up to $576 million to acquire Calporta Therapeutics, a startup that was developing small molecule agonists of TRPLM1. It’s not clear what became of those programs, which are not listed in the company’s pipeline or financial reports. Merck has also turned to partnerships to bolster its neuroscience prospects. Last year, it paid Cerevance $25 million up front to begin a collaboration discovering new targets for potential Alzheimer’s disease drugs. Image: Dr_Microbe, Getty Images

Two of Caraway Therapeutics' preclinical candidates are compounds designed to modulate TRPML1, an ion channel that is shown to be dysregulated in neurodegenerative diseases. Merck & Co. has made no secret of its ongoing hunt for acquisitions, and, now, the Big Pharma is rounding off the year by swelling its preclinical pipeline with a selection of programs aimed at Parkinson’s disease and beyond. The New Jersey company has signed off on up to $610 million in combined upfront payment and potential milestones to buy Caraway Therapeutics—although no breakdown of the exact costs was given in the relatively sparse Nov. 21 release. Originally named Rheostat Therapeutics, the company was incubated at SV Health Investors and the Dementia Discovery Fund before arriving on the scene in 2018 with $23 million in series A funding. Merck has been a backer from the start, having co-led that funding round along with AbbVie. Rebranding to Caraway the following year, the Cambridge, Massachusetts-based company billed itself as a “leader in the cutting-edge science of activating autophagy, the cellular recycling processes to clear toxic materials and defective cellular components.” Since the rebrand, the biotech hasn’t made much noise, but the company’s website currently lists four programs in the works, none of which have entered the clinic. They include two different compounds designed to modulate TRPML1, a transient receptor potential ion channel that is shown to be dysregulated in neurodegenerative diseases. One of the compounds is being developed for Parkinson’s associated with a mutated GBA gene, while the other is focused on non-central nervous system rare diseases. Also in the pipeline is a TMEM175 modulator designed to increase activity of this lysosomal potassium channel in patients with Parkinson’s or amyotrophic lateral sclerosis. There is also another potential Parkinson’s drug that remains in the discovery stage. Merck already made an M&A splash this year with the almost $11 billion acquisition of Prometheus Biosciences and its late-phase bowel disease drug, followed by a $4 billion payment last month to secure three antibody-drug conjugates from Daiichi Sankyo. As the Big Pharma continues to plot out its post-Keytruda future, executives have been open about the ongoing need to refill the pipeline this year. “Caraway’s multidisciplinary approach has yielded important progress in evaluating novel mechanisms of modulation of lysosomal function with potential for the treatment of progressive neurodegenerative diseases,” George Addona, Ph.D., senior vice president of discovery, preclinical development and translational medicine at Merck Research Laboratories, said in this morning’s release. “We look forward to applying our expertise to build upon this work with the goal of developing much needed disease-modifying therapies for these conditions,” Addona added.

Merck & Co. agreed to acquire Caraway Therapeutics for up to $610 million, bolstering its pipeline with a number of preclinical small-molecule compounds mainly focused on Parkinson’s disease. The deal announced Tuesday includes an undisclosed upfront payment as well as milestones linked to certain experimental drugs.“Caraway’s multidisciplinary approach has yielded important progress in evaluating novel mechanisms of modulation of lysosomal function with potential for the treatment of progressive neurodegenerative diseases,” remarked George Addona, senior vice president for discovery, preclinical development and translational medicine at Merck Research Laboratories.Caraway’s pipeline includes two compounds targeting the TRPML1 ion channel, with one focused on GBA-Parkinson’s disease and the other on an undisclosed non-CNS rare disease. The other two preclinical assets targeting TMEM175 and ATP13A2 are under development for Parkinson’s disease, with the former also being investigated for amyotrophic lateral sclerosis.In 2021, AbbVie paid $17 million upfront for an option on Caraway’s programme targeting the lysosomal potassium ion channel TMEM175. Meanwhile, Merck has been a shareholder of Caraway since 2018 through its MRL Ventures Fund.