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At MDA, we take a big picture perspective across the full spectrum of neuromuscular diseases to uncover scientific and medical breakthroughs that accelerate treatments and cures. The power in our research approach is that we can often apply learnings from one disease to progress in others to bring urgently-needed answers to our families.

Toxicology: What Are the Side Effects?

This is perhaps the most obvious stage of preclinical development — determining if the drug has unwanted side effects that will preclude development. Typically, a developer will do some toxicology studies early on during the optimization stage to see if the drug has a reasonable safety profile — there’s no point in bringing forward an unsafe candidate.

More formal toxicology is done later on with the final drug substance that will be used in clinical trials, in case there are toxic effects of the drug when combined with other ingredients in the formulation.

During toxicology studies, developers look at many different doses. Typically, they will attempt to find an upper dose which is toxic, to know how far they can push the dose in people (which will be to a level significantly less than the level where they first saw adverse events in animals).

Early versions of these studies inform the company as to what types of delivery are feasible while later studies support the probability that the trial will be safe.

There are standard tests mandated by the FDA that are required for all drugs, as well as more generalized animal studies to look for unexpected signs of toxicity. Developers pay careful attention to any toxicity that might be caused by the drug’s action (e.g., if working with a growth factor that increases the growth of blood vessels, you would be looking for any signs of bleeding).

Toxicology studies that are required before a short phase 1 safety study may be relatively short (e.g., 12-week studies in mice), but the FDA requires longer studies prior to initiation of longer studies, in case toxic effects take a while to become obvious.

Obviously, not all safety issues will show up in animal studies. Sometimes, as was the case for ACE-031, Acceleron’s drug for DMD, signs of a side effect were not recognized until the drug was already administered to patients. When minor bleeding was observed in some trial participants, the company stopped the trial, tried to resolve the problem, and eventually had to cease development as more serious issues were likely to occur on longer dosing. Toxicology studies are designed to reduce the chances of this happening.

Next: Manufacturing

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