Infection by the Schistosoma worm, called 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). Standard PZQ is highly metabolized, so very high doses are required to treat each patient. 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.
Schistosomiasis, or bilharzia, is caused by parasitic Schistosoma worms and is a neglected tropical disease 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, and washing. The parasites mature over several weeks and reside largely in the blood vessels, releasing eggs that can travel to the intestine, liver or bladder and cause inflammation and scarring.
The current standard of care for schistosomiasis is treatment with oral 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, 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. 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. 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. Based on its experience with numerous deuterium-modified drugs, CoNCERT Pharmaceuticals expects these compounds to retain the positive pharmacologic effects of PZQ while potentially enabling lower or less frequent doses. Additionally, the company has prepared R enantiomers of its analogs, which may further facilitate smaller pill sizes, fewer pills per dose and 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, the company 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.
CoNCERT Pharmaceuticals, Inc., Lexington, Massachusetts
Julie Liu, Ph.D.
Public Health Impact
More than 200 million people worldwide are infected with schistosomiasis. The current standard of care involves multiple large doses of oral PZQ, which is highly metabolized, resulting in low effective bio-availability. PZQ also has an extreme bitter taste that can cause vomiting and negatively affects patient compliance with dosing.
TRND researchers optimized the synthesis of a deuterated R-PZQ analog and evaluated R-PZQ and deuterated analogs in in vitro and in vivo studies. These studies included metabolite identification and quantification, confirmation of relative metabolic stability in vitro, and demonstration of stabilization to metabolism in vivo. TRND researchers completed in vitro efficacy studies comparing R-PZQ and its major metabolites as well as a pilot PZQ efficacy study in vivo. During the conduct of this research, Merck KGaA, as part of the Pediatric Praziquantel Consortium, announced a commitment to develop pediatric formulations of PZQ and R-PZQ. In light of this announcement, TRND staff concluded that the medical need for developing deuterated R-PZQ to treat schistosomiasis in pediatric patients has been met. Consequently, this TRND project has been discontinued.