Omigapil

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Omigapil (also known as TCH346 or CGP3466) is a drug that was developed by Novartis. It was tested in people for Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), but these programs ended because the drug didn’t show a clear benefit. Santhera Pharmaceuticals later bought the compound to pursue treatment for congenital muscular dystrophy (CMD).

History and development
- Omigapil was first made at Ciba-Geigy in Basel, Switzerland.
- Santhera took over its development for CMD and started preclinical work.
- In May 2008, it received orphan designation to begin clinical trials.
- Planned pharmacokinetic studies in 2012 aimed to determine safe and appropriate dosing for children with laminin-α2–deficient CMD (MDC1A) and related muscle disorders, comparing pediatric results with adults. Trials were planned in the United States (NINDS/NIH) and the United Kingdom (Great Ormond Street).

How it works
- Omigapil helps prevent programmed cell death (apoptosis) by interfering with a pathway that involves the enzymes GAPDH and SIAH1.
- When stimulated by nitric oxide, GAPDH moves to the cell nucleus and helps turn on genes that promote cell death. Omigapil blocks this cascade by preventing GAPDH activation and stopping its interaction with SIAH1, protecting both nerve and muscle cells.
- The drug is not an MAO inhibitor, unlike the similar-looking drug selegiline.

Pharmacology and trials
- Omigapil can cross the blood-brain barrier and is orally available as a salt.
- In animal and cell studies, it showed neuroprotective effects in models of PD and other neurodegenerative injuries. It has a bell-shaped dose-response curve, with an optimal range explored in studies.
- Dosing used in early human PD trials included 0.5, 2.5, and 10 mg daily, with a goal range around 0.3 to 3 mg daily for a 70 kg person. A reliable biomarker to measure brain exposure was not established, so researchers used blood levels to gauge distribution.
- In some models, omigapil protected neurons from various toxins and helped preserve dopaminergic neurons in MPTP-treated monkeys, but it could not reverse established PD symptoms in these animals. This contributed to stopping PD and ALS studies, though the drug appeared safe in humans.

CMD and potential benefits
- For CMD, especially MDC1A caused by laminin-α2 deficiency, omigapil showed promise in mouse studies. It reduced muscle cell death, lessened weight loss and skeletal problems, improved movement, and lowered early mortality.
- When combined with overexpression of mini-agrin (an extracellular matrix protein), results were even better in mice. Since delivering mini-agrin to humans isn’t yet available, omigapil alone is considered ready for human CMD trials.
- The safety profile looked favorable in early studies, supporting further exploration in CMD. There has also been some in vitro research into potential rapid-acting antidepressant–like effects, but this is exploratory.