Alvimopan [ADL 82698, LY 246736, Entereg™] is an oral, peripherally selective μ-opioid receptor antagonist. It was originally developed by Eli Lilly in the US for the treatment of gastrointestinal (GI) dysfunction, such as irritable bowel syndrome, idiopathic constipation and GI adverse effects caused by opiate analgesics. Alvimopan was licensed to Roberts Pharmaceutical from Eli Lilly for further development and marketing.
Adolor Corporation acquired an exclusive worldwide license from Roberts Pharmaceutical (now Shire Pharmaceuticals Group) for alvimopan for the treatment of acute and chronic opiate-induced constipation in June 1998. Under the August 2002 Adolor-Lilly licensing agreement, Adolor paid Roberts an up-front fee of $US300 000, thereby expanding their intellectual property rights related to alvimopan. Both Eli Lilly and Roberts will receive royalties based on product sales.
In April 2002, Adolor Corporation and GlaxoSmithKline entered into a collaborative agreement for the exclusive worldwide development and commercialisation of alvimopan. Both companies agreed to co-develop alvimopan for a number of other indications, including both acute-care and chronic-care indications. Under the terms of the agreement, GlaxoSmithKline payed Adolor a signing fee of $US50 million, followed by clinical and regulatory milestone payments of up to $US220 million over the term of the agreement, depending on the progress of the various indications. In the US, Adolor and GlaxoSmithKline will co-develop and co-promote alvimopan, sharing both development expenses and commercial returns. Adolor will lead the development, marketing and co-promotion strategy for acute-care indications, which will be targeted to hospitals and surgeons. GlaxoSmithKline will lead the development, marketing and co-promotion for chronic-care indications targeted to community-based physicians. Outside the US, GlaxoSmithKline will be responsible for the development and commercialisation of alvimopan, with Adolor receiving royalties on any sales revenues.[1]
Adolor submitted an NDA for alvimopan in the US in 2004. The tradename for alvimopan is Entereg™.
Adolor has successfully completed its phase II clinical programme for alvimopan for the management of opioid-induced bowel dysfunction. Phase II trials in patients undergoing chronic opioid therapy have shown that alvimopan relieves or prevents opioid effects on the GI tract (constipation) without antagonising narcotic analgesia or withdrawal. In November 2002, Adolor announced preliminary results in a phase III clinical trial of alvimopan for relief of opioid-induced bowel dysfunction, enrolling 168 patients from 15 to 22 centres in the US. Additional clinical trials will be required before filing any regulatory approval applications.
According to information presented at the JP Morgan H&Q 23rd Healthcare Conference (JP Morgan - 2005), GlaxoSmithKline is conducting two phase IIb clinical trials with alvimopan. These double-blind trials are of longer duration and involve patients with cancer pain and non-malignant pain who are receiving chronic opioid therapy. The studies are being carried out at centres in North America, Europe and Asia-Pacific. NDA/MAA submissions for this indication in the US and Europe are being targeted for 2007.
GlaxoSmithKline is also evaluating alvimopan in an early stage phase II study involving patients with chronic constipation. Alvimopan 3mg twice daily will be compared with placebo in 22 patients with chronic constipation. Results from this trial are expected in the second quarter of 2005. Preliminary data have shown alvimopan to have a 32% faster GI transit rate compared with placebo.
Adolor plans to submit an MAA application in Europe for alvimopan for the treatment of postoperative ileus in the first half of 2005.
Adolor reported initial top-line results from the completed phase III study (SB-767905/001), Study 001, of alvimopan capsules for the management of postoperative ileus in December 2004. GlaxoSmithKline conducted this study in Europe, Australia and New Zealand, and results from this study will support the MAA in the EU.[2]
In May 2004, Adolor submitted the first portion of its NDA for alvimopan capsules in the management of postoperative ileus in the US. The submission was made under the US FDA's Continuous Marketing Application (CMA) Pilot 1 Program. Adolor submitted NDA Item 5, which is nonclinical pharmacology and toxicology data.[3] Adolor submitted the second reviewable unit of its NDA in June 2004, Item 4: Chemistry, Manufacturing and Controls (CMC), for alvimopan in the management of postoperative ileus and completed the entire NDA submission at the end of June 2004.[4] The FDA accepted this NDA submission for review in September 2004 and subsequently extended the Prescription Drug User Fee Act (PDUFA) action date from 25 April 2005 to 25 July 2005 for completion of its NDA review of alvimopan capsules for the management of postoperative ileus. The final component of the requested information, the clinical study report from GlaxoSmithKline Study 001, was submitted to the FDA in April 2005.[5] Adolor received an approvable letter from the FDA in July 2005. Prior to approval, the company has to provide additional proof of efficacy to the FDA to support the use of alvimopan following bowel resection surgery. This could be addressed with positive results from Adolor's ongoing Study 14CL314 or from an additional study.[6]
Under the CMA Pilot 1 Program, Adolor can submit a limited number of predefined portions of the NDA, known as reviewable units, for FDA review before submitting the complete NDA for alvimopan. The FDA requested information from the GlaxoSmithKline European phase III clinical study (SB-767905/001) of alvimopan in postoperative ileus in January 2005, as part of its review of Adolor's NDA for alvimopan. Study 001 was conducted by GlaxoSmithKline in order to support a MAA in the EU.[7]
Preliminary results from the phase III study 14CL314 have been reported. The study enrolled 654 bowel resection patients who received alvimopan 12mg or placebo, twice daily; the primary study endpoint was time to recovery of GI function. The initial dose of alvimopan was administered 30-90 minutes prior to surgery. In previous phase III studies, the first dose of alvimopan was administered 120 minutes prior to surgery. Alodor expects to submit final results from the study to the FDA by June 2006.[8]
Adolor announced results from its first phase III trial, 14CL302, of alvimopan for the treatment of postoperative ileus in April 2003. This double-blind, placebo-controlled, postoperative ileus phase III trial enrolled 451 patients who were undergoing partial colectomies, simple or radical hysterectomies, using both a 6mg and a 12mg twice-daily dose of alvimopan.
Adolor completed two more pivotal phase III trials of alvimopan for the treatment of postoperative ileus, known as study 14CL313 and study 14CL308. These two double-blind, placebo-controlled, phase III trials enrolled patients from approximately 30 centres in the US or Canada. The primary endpoint in the above three studies is a composite measure of the time to recovery of both the upper and lower GI function, as defined by time to tolerability of solid foods and time to first flatus or first bowel movement. Adolor announced results from its second phase III trial, 14CL313, in September 2003 and announced results from its third phase III trial, 14CL308, in January 2004.[9]
In October 2003, top-line results from a fourth phase III clinical trial, known as 14CL306, which was designed to assess the safety of alvimopan, was announced. This double-blind, placebo-controlled, multicentre study enrolled 519 patients scheduled to undergo total abdominal simple hysterectomy while receiving opioids for pain relief. Patients were randomised to receive either alvimopan 12mg or placebo, with patients receiving initial doses of alvimopan in the hospital and continuing to take alvimopan twice daily at home for a maximum of 7 days of continuous treatment. This study assessed the safety and efficacy of alvimopan in this postoperative ileus patient population.[10]
This study will also allow Adolor to assess the potential for conducting additional clinical trials in acute opioid bowel dysfunction. If successful, Adolor intends to develop alvimopan for this indication by submitting a supplemental NDA to the FDA, following approval of Adolor's NDA for the management of postoperative ileus.
In August 2002, Adolor expanded their intellectual property rights related to alvimopan by entering into an exclusive licensing agreement with Eli Lilly, under which Adolor obtained an exclusive license to six issued US patents and related foreign equivalents and know-how relating to peripherally selective opioid antagonists.
Adolor have rights to patents related to alvimopan, which expire between 2011 and 2019, and include a US patent claiming composition of matter, which expires in 2011 and may be eligible for a patent term extension.
Adolor was granted two additional patents related to alvimopan from the US Patent and Trademark Office. The US Patent 6,469,030 (issued on 22 October 2002) covers novel methods for use of alvimopan in the treatment or prevention of ileus, including postoperative ileus, postpartum ileus, and other forms of postsurgical ileus. The second patent, Patent 6,451,806 (issued on 17 September 2002), covers methods of use and fixed-dose combinations of alvimopan, methylnaltrexone and other peripheral µ-opioid antagonists in combination with a variety of opioid analgesics for the treatment of pain. Both these patents expire in 2019.[11]