Gary Grosser

Schistosomiasis, a neglected tropical disease caused by infection with parasitic blood flukes of the genus Schistosoma , affects more than 250 million people worldwide. Currently, patients rely on a single medicine, praziquantel (PZQ), discovered half a century ago. To combat drug resistance and reach elimination of the schistosome parasite, alternative drugs to PZQ are required that treat and prevent disease. Here, we describe a drug candidate, M5493, with potent activity against multiple parasite life cycle stages. The target is a parasite transient receptor potential ion channel, distinct from the target of PZQ. To circumvent its limited bioavailability, the active agent was converted to prodrug M5493, which displayed robust activity against the schistosome parasite at doses as low as 5 milligrams per kilogram in mice infected with Schistosoma mansoni . Unlike the benzodiazepine meclonazepam, which displays clinical antihelminthic activity through the same target, M5493 showed no sedating side effects given that it did not engage GABA _A receptors. Overall, this compound has the potential to provide single-dose treatment, broad-spectrum efficacy against schistosome parasites at different life cycle stages, and transmission blocking activity.

Tuvusertib is an investigational, orally administered inhibitor of ATR protein kinase, currently in Phase II clinical development. Here, we present an integrated nonclinical and clinical assessment of the effect of tuvusertib on QTc interval. In vitro inhibition by tuvusertib of the hERG potassium channel was evaluated, and in vivo ECG assessments evaluated the effect on QTc in dogs. PK‐matched triplicate ECGs in patients receiving tuvusertib in Part A1 of the Phase I DDRiver Solid Tumors 301 study ( N = 55; dosing regimens: 5–270 mg QD, 180–220 mg QD 2 weeks on/1 week off, or 150 mg BID 4 days on/3 days off) contributed to concentration‐QTc analyses via linear mixed‐effects modeling. In vitro, tuvusertib inhibited hERG with an IC ₅₀ of 2.83 μM, which is ~2.5 times its steady‐state unbound C _max at the clinical RDE (180 mg QD 2 weeks on/1 week off). In vivo, tuvusertib did not affect QTc up to 5 mg/kg/day in dogs (unbound C _max comparable to that at clinical RDE). In patients with advanced solid tumors receiving tuvusertib at up to threefold higher plasma concentrations than at the RDE, the risk for clinically relevant QTc prolongation was assessed to be low (upper limit of 90% CI of model‐predicted ΔQTcF < 20 ms). There was no relationship between tuvusertib plasma concentration and RR interval, suggesting no effect on HR. Early integrated concentration‐QTc assessments of tuvusertib monotherapy in Phase I were crucial in informing the low risk for clinically relevant QTc prolongation, thereby facilitating efficient evaluation of investigational tuvusertib combination strategies in ongoing clinical development.