Rycarma Therapeutics, Inc.

A new discovery may explain why so many people abandon cholesterol-lowering statins because of muscle pain and weakness. Researchers found that certain statins can latch onto a key muscle protein and trigger a tiny but harmful calcium leak inside muscle cells. That leak may weaken muscles directly or activate processes that slowly break them down, offering a long-sought explanation for statin-related aches.Many people who are prescribed statins to lower cholesterol end up stopping the medication because of muscle pain, weakness, or ongoing fatigue. These symptoms are among the most common reasons patients abandon the drugs. New research from Columbia University suggests a possible explanation for why this happens in some individuals. The study indicates that certain statins can attach to a protein inside muscle cells, triggering a leak of calcium ions that disrupts normal muscle function. "It is unlikely that this explanation applies to everyone who experiences muscular side effects with statins, but even if it explains a small subset, that's a lot of people we could help if we can resolve the issue," says Andrew Marks, chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons. Statins are widely used in the United States. Roughly 40 million adults take them to control cholesterol levels, and about 10 percent develop muscle related side effects. "I've had patients who've been prescribed statins, and they refused to take them because of the side effects. It's the most common reason patients quit statins, and it's a very real problem that needs a solution," Marks says. A Longstanding Puzzle Around Statin Muscle Pain Scientists have been trying to understand statin related muscle problems since the drugs first became available in the late 1980s. Statins work by binding to an enzyme involved in cholesterol production, but they can also attach to other unintended targets in the body. Earlier research hinted that muscle side effects might occur when statins interact with a specific protein in muscle tissue. Until now, the details of that interaction were unclear. Using cryo-electron microscopy, a powerful imaging method that allows researchers to see structures down to individual atoms, the Columbia team was able to directly observe how a statin interacts with muscle cells. Calcium Leaks Inside Muscle Cells The images showed that a commonly prescribed statin, simvastatin, binds to two specific sites on a muscle protein known as the ryanodine receptor. This binding opens a channel in the protein, allowing calcium to leak into areas of the cell where it does not normally flow. According to Marks, this calcium leak may explain muscle pain and weakness linked to statins. The excess calcium can weaken muscle fibers directly or activate enzymes that gradually break down muscle tissue. Toward Safer Cholesterol Drugs The findings point to new possibilities for reducing statin side effects. One approach would be to redesign statins so they continue to lower cholesterol but no longer bind to the ryanodine receptor in muscle cells. Marks is currently working with chemists to develop statins that avoid this unwanted interaction. Another potential strategy focuses on stopping the calcium leak itself. The researchers showed that in mice, statin related calcium leaks can be closed using an experimental drug created in the Marks laboratory for other disorders involving abnormal calcium flow. "These drugs are currently being tested in people with rare muscle diseases. If it shows efficacy in those patients, we can test it in statin-induced myopathies," Marks says Study Details and Disclosures Andrew Marks is also the Clyde and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons, a professor of biomedical engineering, and director of the Wu Center for Molecular Cardiology. The study was published Dec. 15 in "Structural basis for simvastatin-induced skeletal muscle weakness associated with RyR1 T4709M mutation," in the Journal of Clinical Investigation. The full author list includes Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao (University of Rochester), Linda Groom (University of Rochester), Jennifer Leigh (University of Rochester), Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen (University of Rochester), and Andrew R. Marks. Funding for the research came from the NIH (R01HL145473, R01DK118240, R01HL142903, R01HL140934, R01NS114570, R01AR070194, R01AR078000 , R25HL156002, R25NS076445, P01HL164319, and T32HL120826. Marks owns stock in RyCarma Therapeutics Inc., which is developing compounds that target the ryanodine receptor, and is a coinventor on U.S. patent nos. US8022058 and US8710045. Gunnar Weninger, Haikel Dridi, Marco Miotto, and Marks are also inventors on the patent application titled "STATIN INNOVATION FOR MUSCLE-FRIENDLY CHOLESTEROL MANAGEMENT" [Invention Report (IR) #CU24350], which will be filed by Columbia University.

Alongside its rebrand, RyCarma Therapeutics unveiled a new pipeline program to develop its lead candidate, ARM210, in heart failure with reduced ejection fraction. Armgo Pharma is making a fresh start this new year, as the Boston-based biotech announced Tuesday that it will henceforth be known as RyCarma Therapeutics.The new name draws from the company’s nearly two decades of work in ryanodine receptor (RyR) biology, which it has used to develop a new class of small-molecule drugs dubbed Rycals, with the help of RyR technology licensed exclusively from Columbia University and stemming from the research of RyCarma founder Andrew Marks, M.D.Alongside the rebrand, RyCarma also unveiled a new pipeline program to develop its lead candidate, ARM210, in heart failure with reduced ejection fraction. If ultimately approved, per the company, it stands to become the first heart failure therapy that not only improves heart function but also addresses the common symptom of skeletal muscle weakness. ARM210 is also being tested in the much rarer setting of ryanodine receptor 1-related myopathies (RYR1-RM), which comprise neuromuscular diseases caused by mutations in the RYR1 gene.In another set of changes for the biotech, RyCarma also named a handful of new executives, including the appointments of CEO Adam Rosenberg and of Jonathan Alspaugh and Sanjay Jalota to serve as chief strategy officer and senior vice president of regulatory, respectively.Marks said in a statement that he was “thrilled” with the new direction of the company he founded in 2004.“The past decade has seen an incredible convergence of structural, genetic and physiological data on RyR biology," he added. "RyCarma is at the forefront of advancing therapeutics that target RyR to treat serious and devastating diseases like RYR1-RM and heart failure." RyCarma has previously dabbled in applying its Rycals to cardiac conditions: In its early days, one candidate reached phase 2 trials in heart failure and arrhythmias before being scrapped in favor of a focus on neuromuscular disorders.In 2021, the company then known as Armgo brought in $35 million from Forbion and other VC backers that it said would be used to test ARM210 in a phase 2 trial of catecholaminergic polymorphic ventricular tachycardia, a rare inherited cardiovascular disease that’s characterized by abnormal heart rhythm. At the time, the biotech pitched ARM210 as a potential “pipeline-in-a-product.”As of this week, however, only the heart failure and RYR1-RM programs are listed as ARM210’s ongoing projects on RyCarma’s site.Editor's note: This story was updated to correct a mention of Armgo's founding year. It was founded in 2004, not 2006.

BOSTON--( BUSINESS WIRE )-- RyCarma Therapeutics, Inc. , formerly known as ARMGO Pharma (the “Company” or “RyCarma”), a clinical-stage biotech company developing first-in-class small molecule therapeutics for cardiovascular and skeletal muscle diseases, today unveiled its new leadership and company name change from “ARMGO Pharma, Inc.” to “RyCarma Therapeutics, Inc.” and introduced a new program in heart failure. The name RyCarma references the Company’s foundational work and leadership in ryanodine receptor (RyR) biology and in establishing the therapeutic potential of Rycals ® , a novel class of small molecule drugs. RyCarma’s new program focuses on developing its lead candidate ARM210 in heart failure with reduced ejection fraction, which affects millions of people worldwide. ARM210 is also currently being investigated in ryanodine receptor 1-related myopathies (RYR1-RM), a group of rare neuromuscular diseases caused by mutations in the RYR1 gene. The Company also introduced several new members of its leadership team, who bring a track record of success in leading biotech companies and guiding novel biological discoveries through drug development. Adam Rosenberg, Chief Executive Officer, most recently served as the chief executive officer of Aliada Therapeutics and Sionna Therapeutics and brings decades of experience leading innovative biotechnology companies. Also joining the leadership team are Jonathan Alspaugh, President & Chief Strategy Officer, who brings 15 years guiding biotech and biopharma companies on financial and strategic matters and Sanjay Jalota, Senior Vice President of Regulatory, an experienced regulatory strategist steering both early- and late-stage compounds through development. “RyCarma will expand on our long-term focus on the central role of RyRs in human biology, building on the pioneering work of our founder Dr. Andrew Marks, a globally recognized leader in RyR science, who cloned the receptor and described its structure at atomic resolution,” said Adam Rosenberg, Chief Executive Officer of RyCarma. “Despite other therapeutic advancements in heart failure, there continues to be serious unmet need with high levels of mortality and hospitalizations. Our experienced team is committed to translating our expertise with the Rycal mechanism into innovative treatments for patients.” RyCarma’s lead candidate ARM210 is designed to repair leaky ryanodine receptors, ion channels that regulate the intracellular flow of calcium that is essential for muscle contraction. In a Phase 1b trial in patients with RYR1-RM, ARM210 showed improvement of fatigue and proximal muscle strength, and was well-tolerated with no dose-dependent safety signals or serious adverse events. For patients with heart failure, ARM210 has the potential to be the first therapy that directly repairs leaky RyRs in both cardiac and skeletal muscle, potentially improving heart function as well as skeletal muscle weakness, a common symptom that is not addressed by existing treatment options. “I am thrilled with the new strategic direction of RyCarma, the additions to the leadership team and the potential for Rycals first-in-kind mechanism,” said Dr. Andrew Marks. “The past decade has seen an incredible convergence of structural, genetic and physiological data on RyR biology. RyCarma is at the forefront of advancing therapeutics that target RyR to treat serious and devastating diseases like RYR1-RM and heart failure.” About RyCarma Therapeutics RyCarma (formerly ARMGO Pharma) is a clinical-stage biotech company developing first-in-class small molecule therapeutics for cardiovascular and skeletal muscle diseases. RyCarma’s drug discovery platform is built from deep expertise on ryanodine receptors (RyRs), channels that regulate the intracellular flow of calcium ions in nearly all cell types. RyCarma holds an exclusive license from Columbia University for its RyR technology based on the research of the Company’s founder, Dr. Andrew Marks. RyCarma’s lead program, ARM210, is in development for the treatment of heart failure and ryanodine receptor 1-related myopathies (RYR1-RM). For more information, visit www.rycarma.com .