Trevi Therapeutics (TRVI) Study Update summary

Study background and rationale

• Nalbuphine is a mixed agonist-antagonist opioid with a 40-year history of being unscheduled and low abuse in real-world use.

• The FDA required a Human Abuse Potential (HAP) study to meet current regulatory standards, despite nalbuphine's established safety profile.

• The HAP study compared oral nalbuphine to IV butorphanol (Schedule IV) and placebo, with FDA input on study design, route, and doses.

• The study included therapeutic and supratherapeutic doses of nalbuphine, exceeding those used in clinical programs.

Study design and methodology

• Randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover in recreational opioid users.

• Subjects were recreational opioid users who passed qualification tests for opioid tolerance and drug-liking discrimination.

• Primary endpoint: peak drug-liking visual analog scale (VAS Emax) comparing nalbuphine, butorphanol, and placebo.

• Study included three oral nalbuphine doses (81mg, 162mg, 486mg), 6mg IV butorphanol, and placebo.

• Safety, pharmacodynamic markers, and patient-reported outcomes were also evaluated.

Key results and interpretation

• Statistically significant lower drug-liking for 81mg and 162mg oral nalbuphine compared to 6mg IV butorphanol (p<0.0001 and p=0.0008, respectively).

• Supratherapeutic 486mg dose of oral nalbuphine showed numerically lower drug-liking than butorphanol, but not statistically significant.

• No clear dose-response relationship was observed; higher doses did not consistently increase drug-liking or willingness to take again.

• Secondary endpoints, including "Take Drug Again" and "I Feel High," were generally consistent with primary endpoint results and showed lower scores for nalbuphine versus butorphanol.

• No serious adverse events were reported in the study.