GTP-004 is an investigational medicine being developed by GT Biopharma to treat muscle weakness associated with the autoimmune disease myasthenia gravis.

It consists of a combination therapy of Mestinon (pyridostigmine) with Zofran (ondansetron).

How GTP-004 works

In autoimmune diseases, immune system antibodies that normally help fight off infections, mistakenly attack healthy cells and tissues in the body.

In the case of myasthenia gravis, these antibodies are directed against the acetylcholine receptors found on muscle cells. A signaling molecule called acetylcholine that is released from nerve cell endings normally binds to these receptors, transmitting the nerve signal to the muscle and ensuring it contracts.

When the acetylcholine receptors are damaged by the immune system, acetylcholine cannot bind to the receptors and is destroyed by an enzyme called acetylcholinesterase. This results in lack of communication between nerve and muscle cells, leading to muscle weakness and fatigue.

Mestinon is an acetylcholinesterase inhibitor, meaning that it works by blocking the enzyme that degrades acetylcholine. The medicine ensures there is more acetylcholine available in the space between nerve and muscle cells that can bind to any remaining acetylcholine receptor on the muscle cells. This way, Mestinon improves muscle strength and reduces the weakness and fatigue seen in people with myasthenia gravis.

However, Mestinon can also cause severe gastrointestinal side effects, such as diarrhea, nausea, and vomiting. To overcome this issue, GTP-004 combines Mestinon with Zofran, which blocks the action of chemicals in the body that can trigger nausea and vomiting.

By blocking the adverse effects of Mestinon, while maintaining its effectiveness, it is hoped that GTP-004 will improve patients’ comfort and enhance their compliance with treatment.

GTP-004 in clinical trials

The efficacy of GTP-004 has been evaluated in a Phase 1 proof-of-concept clinical trial in five healthy volunteers. The primary objective of the trial was to test whether GTP-004 can lead to a reduction in gastrointestinal side effects.

During the trial, participants received single doses of Mestinon (ranging from 30 to 120 mg) until they reached the first intolerable dose (FID). They then stopped taking Mestinon for two to seven days. The same procedure was then repeated, but this time, participants received Mestinon in combination with Zofran (GTP-004).

According to the results of the trial that were announced in March 2018, three people reached FID, which occurred at 60 mg for two people and 90 mg for the third person. When patients received GTP-004, the gastrointestinal side effects were substantially reduced or completely eliminated and all participants tolerated doses as high as 120 mg —  the maximum allowed by the protocol.

Researchers also measured the blood concentrations of GTP-004 and Mestinon and saw nearly identical levels of Mestinon in the blood of the participants. This led them to conclude that the reduced side effects were due to a benefit of GTP-004, rather than a decreased absorption of Mestinon when given in combination with Zofran.

GT Biopharma plans to start a Phase 2 clinical trial testing the efficacy of GTP-004 in myasthenia gravis patients in the third quarter of 2018.


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