Trevi Therapeutics, a New Haven, Conn.-based late-stage clinical development company developing oral Nalbuphine ER for chronic pruritus conditions, has announced statistically significant results from its phase II/III trial for the treatment of moderate to severe uremic pruritus. Uremic pruritus is a persistent and debilitating itch in patients on dialysis that has been associated with increased mortality, and currently has no approved therapies in the U.S. or Europe. Nalbuphine ER has a dual mechanism of action, as it is a mu receptor antagonist and kappa receptor agonist, and both mechanisms have been separately shown to be effective in abolishing itch.
The multicenter, randomized, double-blind, placebo-controlled, parallel, three-arm study evaluated the safety and anti-pruritic efficacy of Nalbuphine ER tablets dosed twice-daily at 60mg and 120mg in approximately 370 patients on hemodialysis in the U.S. and Europe. Patients with a wide range of mean moderate-to-severe itch intensity, ranging from 4.5 to 10 on the 10-point Numerical Rating Score (NRS) scale, were enrolled to evaluate efficacy across a representative patient population for this chronic indication.
The study consisted of a titration period of two weeks, followed by a six-week blinded period on a fixed dose of drug or placebo and a wash-out period. At the end of the wash-out period, patients were eligible to roll over into a six-month open label extension study. The company expects the open label extension study to be completed by year-end.
Patients receiving 120mg of Nalbuphine ER (n=120) experienced a 3.5 point reduction in itch intensity from baseline, resulting in a highly statistically significant mean reduction in itch intensity as compared to placebo (p=0.017). A statistically significant mean reduction for Nalbuphine ER compared to placebo was observed as early as one week following titration to the Nalbuphine ER fixed dose, and there was a statistically significant separation from placebo throughout the remaining blinded period.
Sustained duration of drug effect continued to trend away from placebo through the eighth week of the study. On average, patients entered the study with a baseline mean NRS itch score of 6.9 (just under severe NRS score of 7), and at the end of the eight-week dosing period, average itch scores had been reduced to an NRS score of 3.4, which is considered mild on the NRS scale. Severe itch patients (those with NRS scores greater than or equal to 7) experienced on average an NRS score reduction of 4.5 points from baseline, (p=0.007). The 60mg dose showed a numerically favorable reduction over placebo, but did not achieve statistical significance.
The secondary endpoints, the Skindex-10 Disease Domain and the Itch MOS Sleep index, provided confirmatory evidence of a favorable Nalbuphine ER effect on itching compared to placebo.
Only one serious adverse event was attributed to the drug in the study, with the most common adverse events being nausea, vomiting, dizziness and somnolence. The rates of those events, however, quickly resolved and were approaching placebo rates after the first week of titration. Because of the challenging nature of the patient population, the company elected to put in place a Data Safety Monitoring Board (DSMB) to oversee the safety of the study. The DSMB raised no issues that affected the continuation of the study.
Thomas R. Sciascia, M.D., Trevi’s chief medical officer, said, “This is a difficult patient population to study over an extended period of time because of multiple co-morbidities. There was strong patient and physician interest in both the blinded portion of the study as well as the ongoing six-month open label extension trial. We look forward to a discussion with both the FDA and the EMA about next steps in our program.”