Adolor Corporation provided the updates related to its research and development programmes of Opioid Bowel Dysfunction (OBD), delta agonists, ADL5859 in DPN, ADL5859 in RA and Entereg (alvimopan) in Postoperative Ileus (POI).
Following an internal and external evaluation, the company has determined that it will not pursue further development of alvimopan to treat chronic OBD. The company based this determination principally on its assessment of the cost and timeline for an additional phase-3 study relative to the remaining commercial life of alvimopan in OBD.
"Over the past few months, we have conducted an extensive analysis of our OBD programme," said Michael R Dougherty, president and chief executive officer. "While we have made the difficult decision to discontinue development of alvimopan in OBD, we remain committed to finding treatments for the millions of patients suffering from this debilitating condition. We are excited by the potential opportunity that ADL7445 represents for patients and Adolor."
The company is collaborating with Pfizer Inc for the development and commercialization of two delta opioid receptor agonist compounds, ADL5859 and ADL5747, for the treatment of pain. The two compounds also have been assigned Pfizer compound designations PF-04856880 and PF-04856881, respectively. Delta opioid receptor agonists represent a new class of compounds to address moderate-to-severe pain that are intended to provide pain relief without the deleterious side effects of traditional mu opioid receptor agonists. Phase-2(a) trials of ADL 5859 were recently completed in patients with pain associated with diabetic peripheral neuropathy (DPN) (Study 231) and pain associated with rheumatoid arthritis (RA) (Study 232).
The DPN trial enrolled 226 patients in a phase-2(a), randomized, double-blind, placebo and active-controlled parallel group study to assess the safety and efficacy of ADL5859 in patients with neuropathic pain associated with diabetic peripheral neuropathy. Subjects were randomized to placebo, 60 milligrams of duloxetine (once daily) and 100 milligrams of ADL5859 (twice daily). The primary outcome measure was change from baseline to week four in the pain intensity score via the Numeric Pain Rating Scale assessment measured three times daily.
Top-line results of the study showed no statistically significant difference between ADL5859 and placebo. In addition, there was no statistically significant difference between patients treated with duloxetine and placebo. There was a large variability in response seen in all three arms of this trial, which may have contributed to the inconclusive results. In addition, a high degree of variability was observed in plasma levels of ADL5859 at the same doses. ADL5859 was well-tolerated, with no significant adverse events reported.
The RA trial enrolled 46 patients in a two-part study designed to assess the safety and efficacy of ADL5859 in patients with inflammatory pain associated with rheumatoid arthritis.
Part A was a single dose, randomized, double-blind, placebo- and active-controlled, 3-period crossover phase using a model of evoked pain produced by physical activity. Each subject received 200 milligrams of ADL5859, 500 milligrams of naproxen and placebo. The primary outcome measure of efficacy in Part A was the average difference between baseline and post-dose Evoked Lower Extremity Pain Intensity, or ELEPI, after a treadmill walk over the six hours after dosing.
Part B was a multiple-dose, randomized, double-blind, placebo-controlled, parallel group phase. Patients were re-randomized to receive either 100 milligrams of ADL5859 or matching placebo twice daily for 14 consecutive days. The primary measure of efficacy was the mean daily Lower Extremity Pain Intensity score measured three times daily over the two-week period.
There were no statistically significant differences between ADL5859 200 mg and placebo in Part A of the study or between ADL5859 100 mg and placebo in Part B of the study. In Part A, there was a statistically significant decrease in ELEPI over six hours for patients receiving 500 mg of naproxen versus placebo. As in the DPN study, ADL5859 was well-tolerated, with no significant adverse events reported.
"Pfizer and we believe that delta agonists represent an exciting new class of drugs to treat pain, warranting further clinical development," said Eliseo O Salinas, senior vice president, Research and Development and chief medical officer. "We will be working with Pfizer to address the pharmacokinetic variability observed with ADL5859, before we will commence additional trials. At the same time, will be continuing further clinical work with ADL5747, our other delta agonist compound, which is progressing well through its phase-1 clinical programme."
Adolor's first commercial product, Entereg, was approved by the FDA earlier this year for the management of POI following bowel resection surgery. Entereg is specifically indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.
In January, the company will begin recruitment of patients in a phase-4 clinical trial intended to evaluate the safety and efficacy of Entereg for POI in patients undergoing radical cystectomy for bladder cancer. Radical cystectomy is an extensive abdominal and pelvic surgical procedure often associated with a significant POI burden. The company also is undertaking other near-term initiatives, including studies intending to address pharma co-economic and health outcomes associated with accelerated GI recovery.
Adolor Corporation is a biopharmaceutical company specializing in the discovery, development and commercialization of novel prescription pain management products.