Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis

Infection by the schistosoma worm (schistosomiasis) is second only to malaria as the most devastating parasitic disease, affecting more than 200 million people worldwide. Standard therapy requires high doses of praziquantel (PZQ), but owing to the high doses required and poor metabolism of standard PZQ, it is currently impossible to treat more than 10 percent of affected patients. The purpose of this project is to develop modified forms of PZQ that will improve potency and drug metabolism, thereby lowering the dose needed to clear infection and allowing much more widespread patient treatment, with a goal of global eradication. CoNCERT Pharmaceuticals' platform technology to increase exposure of currently approved therapeutics could be applied to other therapeutics in the rare and neglected tropical disease areas.

Scientific Synopsis

Schistosomiasis (bilharzia) is caused by parasitic Schistosoma worms and is one of the neglected tropical diseases in need of further research and treatment efforts. Schistosomiasis is second only to malaria as the most devastating parasitic disease, and more than 200 million people are infected worldwide in Africa, South America, the Caribbean, the Middle East, Southern China and parts of Southeast Asia, Laos and the Philippines. Humans contract the parasites following exposure to contaminated fresh water through bathing, wading, swimming, washing, etc. The parasites mature over several weeks and reside largely in the blood vessels, releasing eggs which can travel to the intestine, liver or bladder and cause inflammation and scarring. 

Current standard of care for schistosomiasis is treatment with oral praziquantel (PZQ). It is well absorbed (80 percent) but is highly metabolized via a pronounced first-pass effect, resulting in low effective bio-availability. Over 99 percent of the dose is converted to oxidative metabolites via liver enzymes. As a result, in order to achieve therapeutic blood levels, patients must be dosed repeatedly with multiple 600-mg tablets of PZQ at a level of 40-60 mg/kg over one to two days. According to the World Health Organization, there are insufficient quantities of PZQ and less than 10 percent of the appropriate population receives treatment. PZQ is dosed as a racemate (50:50 mixture of R and S enantiomers), but only the R enantiomer contributes to the anti-parasitic efficacy. The extreme bitter taste of the drug can lead to vomiting, and attempts to mask the taste in a cost-effective manner have been unsuccessful. Interestingly, the bitter taste is more associated with the unneeded S enantiomer than with the active R enantiomer. 

CoNCERT Pharmaceuticals has synthesized deuterated analogs of PZQ and has demonstrated that selective deuterium incorporation imparts significant metabolic stabilization in vitro. These compounds are expected, based on CoNCERT's experience with numerous deuterium-modified drugs, to retain the positive pharmacologic effects of PZQ while potentially enabling lower doses and/or less frequent doses compared with the PZQ treatment regimen. Additionally, the company has prepared R enantiomers of its analogs, which may further facilitate smaller pill sizes, fewer pills per dose, and potentially a more palatable taste profile through the elimination of the unneeded S enantiomer. By metabolically stabilizing PZQ through deuterium substitution and selectively producing the R enantiomer, CoNCERT anticipates producing a significant improvement over the current standard of care. The first proof-of-concept milestone for the Deuterated Praziquantel project was achieved via the demonstration of metabolic stabilization in vitro for deuterated analogs versus PZQ.

Key Investigator

CoNCERT Pharmaceuticals, Inc., Lexington, Mass.
Julie Liu, Ph.D.

Public Health Impact

More than 200 million people are infected worldwide. Current standard of care for schistosomiasis involves multiple large doses of oral PZQ, which is highly metabolized resulting in low effective bio-availability. PZQ also has an extreme bitter taste which can cause vomiting and negatively impacts patient compliance with dosing. Insufficient quantities of PZQ are available and less than 10 percent of the appropriate population receives treatment.

Outcomes

TRND is currently performing pharmacokinetic studies in animals, confirmation of antischistosomal activity, manufacturing sufficient quantities of drug to support initial toxicology studies, completion of toxicology studies in animals, and high-stringency drug product manufacturing of sufficient quantities of drug to support the human clinical trials.