The experimental class of compounds — called Rycal drugs by ARMGO — is designed to normalize the way skeletal muscle fibers and heart muscle cells handle calcium.
The lead compound, named ARM210, is aimed at treating DMD or BMD, which are caused by mutations in the dystrophin gene, but the strategy is not dependent on the specific disease-causing genetic mutation and could potentially have application to other muscle disorders (myopathies).
"This is a very interesting potential therapeutic," said Jane Larkindale, MDA’s vice president for research. "It works in a different way from the other potential therapeutics in development, which suggests that in addition to being effective on its own, it also might be able to be added on to other treatments, when other treatments become available."
In DMD and BMD, calcium is handled abnormally as a downstream effect of the primary problem. (Dietary calcium intake does not influence this process.)
In DMD, the primary problem is a complete lack of the muscle protein dystrophin, which is associated with the muscle cell membrane; in BMD, the primary problem is a partial lack of dystrophin.
Rycals are compounds developed by ARMGO for treating DMD and BMD by stabilizing a structure called the ryanodine receptor, a "doorway" that, when open, allows calcium to leave a storage area inside the cell, and when closed, prevents calcium from leaving.
The ryanodine receptor has to provide an open door for calcium to leave the storage area during each skeletal muscle contraction and for each heart muscle cell contraction (heartbeat). After opening, the doorway has to close completely so the cell can relax and replenish the calcium in the reservoir, in preparation for the next signal to contract.
In DMD and BMD, the ryanodine receptor is not normal and often stays partly open, permitting a constant leak of calcium from the muscle cell’s calcium storage reservoir. In this situation, the muscle cell is never completely contracted or completely relaxed — adding to the weakness associated with these disorders.
Rycal compounds have been shown in animal models of muscle disease to “fix” the calcium leak by restoring the ryanodine receptor’s normal function, and to improve both muscle force and exercise capacity.
ARM210 is a small molecule that can be given by mouth and, via circulating blood, is able to reach skeletal muscles, including the diaphragm and the heart. It can be given either by itself or in conjunction with other approved treatments.
The MDA award to ARMGO Pharma of Tarrytown, N.Y., was made through MDA Venture Philanthropy, the drug development arm of the Association's translational research program. The award will support laboratory work which will enable the company to submit an investigational new drug(IND) application to the U.S. Food and Drug Administration. An IND application is a step a company must take before it can test a new drug in humans. Receiving an IND approval will allow ARMGO Pharma to prepare for clinical trials with ARM210 in healthy volunteers and for subsequent clinical studies in people with DMD.
Rycal Stabilizing Video, an animation of the action of the ryanodine receptor and calcium release, is available on the ARMGO website.