Nalbuphine ER, experimental drug for moderate chronic pain developed by Penwest Pharmaceuticals Co. did not meet the main goal of a mid-stage trial, but achieved a number of secondary goals deflowered by patient dropouts in the first week of the study, according to the company.
This was Penwest's first clinical trial of nalbuphine hydrochloride extended release tablets (nalbuphine ER) in a chronic pain population. The company designed the trial with multiple endpoints related to clinical pain relief in an effort to understand the activity of the drug and provide the basis for designing the phase IIb study.
The primary endpoint of the study was the Sum of Pain Intensity Differences between baseline and day 21. Nalbuphine ER did not meet this endpoint, which the company believes was primarily due to patient dropouts in the first week of dosing. The drug did, however, achieve a number of the secondary endpoints in the trial leading the company to conclude that proof of concept had been established for the drug. For instance, nalbuphine ER demonstrated statistical significance in the intent-to-treat population when compared to placebo, as measured by the Global Assessment of Pain Control (p=0.006) and by the Integrated Assessment of Pain Intensity and Rescue Medication Use (p=0.009).
Penwest said the results of this study showed efficacy sufficient to support its continued development of the drug, and it plans to conduct a phase IIb trial commencing in the second half of this year.
No drug related serious adverse events were reported during the trial. Twenty four percent of the nalbuphine ER patients reported no side effects, 66 per cent reported side effects that were characterized as mild or moderate in severity, and 10 per cent reported severe side effects.
Jennifer L. Good, president and CEO, Penwest, said, "Nalbuphine ER is our lead product candidate, and in establishing the proof of concept in chronic pain, we have reached an important milestone for this program. Our development team will continue to evaluate the data generated from this trial and use it in designing our planned phase IIb study. We are also initiating partnering discussions for nalbuphine ER in Europe, and at this point in time plan to retain the US rights for Penwest."
The goal of the phase IIb trial will be to demonstrate statistically significant analgesic efficacy of the drug versus placebo using an accepted clinical endpoint, characterize a clinically meaningful titration regimen, and demonstrate that the analgesic efficacy is sustained over the twelve hour dosing interval. The company believes this trial will take approximately one year to complete.
The phase IIa trial was a randomised, double-blind, placebo controlled design, with a forced weekly dose escalation. The main objective of this trial was to evaluate the analgesic efficacy of nalbuphine ER in a patient population experiencing chronic pain. There were 138 patients with chronic pain secondary to osteoarthritis of the knee or hip in the intent-to-treat population of this trial. Patients enrolled in the trial were given the lowest dose of the drug for week one, increased to a mid-dose level for week two, and increased to the highest dose studied for week three. The study group included a 2-to-1 randomisation of patients on drug versus placebo.
Nalbuphine ER, designed to be taken as a twice-daily tablet, is formulated using Penwest's TIMERx drug delivery technology. Penwest previously conducted multiple phase I studies on nalbuphine ER to establish the pharmacokinetic profile and generate safety data. The company has also conducted a phase IIa study of nalbuphine ER for an acute pain model in which a single dose of nalbuphine ER reduced mean pain intensity in a dose-dependent manner over a 12-hour study period when compared to placebo. Nalbuphine is currently available only as an injection medication.