GlaxoSmithKline and Adolor Present Positive Results From a Clinical Study of alvimopan (Entereg®)
Statistically Significant Improvement in Opioid-Induced Gastrointestinal Side Effects and Health-Related Quality of Life in Phase 2b Entereg Trial
LONDON and EXTON, Pennsylvania, May 4, 2006 GlaxoSmithKline (LSE: GSK ; NYSE:GSK) and Adolor Corporation (NASDAQ: ADLR) today presented at the American Pain Society Meeting in San Antonio, Texas, positive results from a Phase 2b clinical study of alvimopan (Entereg), an orally administered investigational drug that blocks peripheral mu-opioid receptors(1). In this large study, evaluating alvimopan for the treatment of opioid-induced gastrointestinal side effects, patients reported a significant improvement in common and bothersome gastrointestinal (GI) symptoms associated with opioid use, including constipation, abdominal pain and bloating.
"Millions of people worldwide take opioids chronically to treat moderate to severe pain and about half of them will suffer from associated constipation, abdominal pain, discomfort and bloating(2). Constipation can lead to serious complications and in some cases can be life threatening. Often patients cannot receive enough opioid to manage their pain due to constipation. The findings from this study suggest that alvimopan may play an important role in treating these GI side effects in patients by blocking the effects opioids have on the gut without adversely impacting the effect on pain control," said Dr. Lynn Webster, Lifetree Clinical Research and Pain Clinic, Salt Lake City, Utah, USA.
This large double-blind study (SB-767905/011) randomized 522 patients taking opioids for persistent non-cancer pain to:
- alvimopan 0.5mg twice a day (BID) (group 1) or
- alvimopan 1mg once a day (QD) (group 2) or
- alvimopan 1mg twice a day (BID) (group 3) or
- placebo
for 6 weeks. The average increase in spontaneous bowel movements (defined as a bowel movement in the absence of laxatives within the previous 24 hours) per week was approximately:
- 3.5 in groups 1 and 2 (p<0.001) and
- 4.3 in group 3 (p<0.001) compared with
- 1.7 in placebo group
The increase in spontaneous bowel movements for each alvimopan dose group was double that of placebo, became apparent within 1 week and was sustained throughout the 6-week treatment period, returning towards baseline promptly after discontinuation of study therapy.
All groups reported an average frequency of 1 spontaneous bowel movement a week at baseline. During treatment, 63-68% of alvimopan-treated patients reported 3 or more spontaneous bowel movements a week, compared with 39% receiving placebo. In addition to seeing improvements in typical measures of constipation (reduction in straining, improved stool consistency, and greater frequency of complete evacuation), patients taking alvimopan also showed improvements in other measures of GI function such as abdominal pain and bloating.
The most common adverse events reported in the trial were abdominal pain, nausea and diarrhea. The frequency of these adverse events was similar between placebo and alvimopan treated patients at the 0.5mg BID dose. There was an increase in frequency at the 1mg dose of alvimopan for the three most common adverse events.
The baseline characteristics and opioid induced GI symptoms of the 522 patients who were enrolled into the study were also reported at the meeting. The patients, on average, were approximately 50 years old, and had taken opioids for more than 6 years for various conditions, including back pain (58%), neuralgia (42%), fibromyalgia (8%) and arthritis (7%). Despite 80% of patients reporting use of laxatives and/or stool softeners, those entering the study reported typical constipation symptoms including, straining (83%), hard stools (87%) and incomplete evacuation (87%). Other GI symptoms reported consistently were bloating (79%), discomfort (80%) and abdominal pain (65%)(3).
The effect of alvimopan on the health-related quality of life (HRQOL) of patients in the study was also reported at the meeting. HRQOL was assessed using the Patient Assessment of Constipation Quality of Life (PAC-QOL) instrument, which consists of 28 questions on physical discomfort (4 questions), psychosocial discomfort (8 questions), worries/concerns (11 questions) and satisfaction (5 questions). At baseline the patients' scores, ranging from 1.87 to 2.1, indicated that their HRQOL was moderately impaired. Alvimopan significantly improved PAC-QOL total scores after 6 weeks in all treatment groups compared with placebo (p<0.02). Changes in overall scores from baseline to week 6 were 2 to 1.61 for placebo, 1.9 to 1.27 for alvimopan 0.5mg twice a day, 1.87 to 1.26 for alvimopan 1mg once a day, and 2.1 to 1.33 for alvimopan 1mg twice a day. Statistically significant improvements were observed on the satisfaction subscale (p<0.05), physical discomfort and psychosocial discomfort subscales (p<0.05, alvimopan twice daily only) and the worries and concerns subscale (p<0.05)(4).
About Opioid Gastrointestinal Side Effects
Opioids, such as morphine, are highly effective in the treatment of pain and are widely used to treat moderate to severe pain such as pain associated with or as a result of back pain, arthritis and other pain conditions. However, the use of opioids is associated with persistent GI side effects such as constipation, characterised by infrequent, difficult or incomplete bowel movements, abdominal pain and discomfort, and bloating(5). Other GI side effects related to opioids include acid reflux and loss of appetite.
Opioids reduce pain by binding to opioid receptors in the brain. However, there are also opioid receptors in the GI tract. GI side effects occur because opioids also bind to mu-opioid receptors in the gut, reducing GI motility and secretions.
Constipation is the most common, persistent and debilitating of the GI side effects(6) although its prevalence and impact are seriously under-recognised by healthcare professionals(7). It is ranked by most cancer patients as an even more common source of distress than pain, impacting quality of life(8). Studies have shown that constipation is experienced by between 50-90% of patients who take opioids(2, 9, 10, 11).
GI side effects can be distressing for patients causing a significant burden of illness and reduced quality of life. Some patients receiving long-term opioid treatment for pain would rather endure their pain than the severe, incapacitating constipation that opioids may cause(10).
There is currently no approved drug specifically for the treatment of gastrointestinal side effects associated with opioid use for persistent pain. Taking stool softeners, bowel stimulants, increasing daily fluid and fiber intake and increasing exercise are methods often used to manage this condition. Laxatives may provide limited relief for some patients, but can also be associated with side effects such as abdominal cramping, bloating and unpredictability of effect, and are not recommended for long-term use.
References
1. Webster L et al. A randomized, double-blind, placebo controlled, multicenter phase IIb study to evaluate the efficacy and safety of multiple alvimopan dosage regimens for the treatment of gastrointestinal adverse events (GIAEs) associated with opioid use in subjects with persistent non-cancer pain (SB-767905/011). Poster presented at the American Pain Society meeting, May 2006.
2. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112:372-380.
3. Irving G et al. Gastrointestinal adverse events (GIAEs) associated with long-term opioid analgesic therapy in large, persistent non-cancer pain population. Poster presented at the American Pain Society meeting, May 2006.
4. Tark M et al. Effect of alvimopan, a peripheral opioid receptor antagonist, on health related quality of life (HRQOL) in patients who develop gastrointestinal adverse events (GIAEs) while taking opioids for persistent non-cancer pain: an assessment using the PAC-QOL instrument. Poster presented at the American Pain Society meeting, May 2006.
5. Joint Formulary Committee. British National Formulary. 50 ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2005.
6. Pappagallo P. Incidence, prevalence, and mangement of opioid bowel dysfunction. Am J Surg 2001; 182 (5A Suppl): 11S-18S.
7. McMillan SC. Assessing and managing opiate-induced constipation in adults with cancer. Cancer Control 2004; 11 (3), Suppl 1, 3-9.
8. Fallon MT. Constipation in cancer patients: prevalence, pathogenesis and cost-related issues. Eur J Pain 1999; 3(suppl 1): 3-7.
9. Allan L, Hays H, Jensen NH, Le Polain de Waroux B, Bolt M, Donald R, Kalso E. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. British Medical Journal 2001; 322: 1-7.
10. Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage 2002; 24: 71-90.
11. Quigley C. The role of opiods in cancer pain. British Medical Journal 2005; 331: 825-828.
About Alvimopan (Entereg®)
Alvimopan is an investigational peripherally acting mu-opioid receptor (PAM-OR) antagonist designed to inhibit the negative effects of opioids, like morphine or codeine, on the gastrointestinal system without interfering with the analgesic effects on the central nervous system. Alvimopan is the first of this new class of compounds with a New Drug Application (NDA) that has been accepted for review by the U.S. Food and Drug Administration (FDA) for postoperative ileus (POI).
Adolor Corporation and GlaxoSmithKline are collaborating on the worldwide development and commercialization of alvimopan for POI and gastrointestinal side effects associated with the use of opioids to treat persistent pain. As previously announced, GSK is conducting studies investigating efficacy and safety in non-cancer and cancer patients taking opioids for treatment of persistent pain.
About GlaxoSmithKline
GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies and is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For more information, visit GlaxoSmithKline on the World Wide Web at www.gsk.com.
About Adolor Corporation
Adolor Corporation (Nasdaq: ADLR) is a biopharmaceutical company specializing in the discovery, development and commercialization of novel prescription pain management products. Entereg(R) (alvimopan) is Adolor's lead product candidate under development for the management of the gastrointestinal side effects associated with opioid use. Adolor is developing a sterile lidocaine patch which is in Phase 2 clinical development for post-surgical incisional pain. Adolor also has a number of discovery research programs focused on the identification of novel compounds for the treatment of pain. By applying its knowledge and expertise in pain management, along with ingenuity, Adolor is seeking to make a positive difference for patients, caregivers and the medical community. For more information, visit www.adolor.com.
GlaxoSmithKline Forward-Looking Statements
Under the safe harbor provisions of the US Private Securities Litigation Reform Act of 1995, the company cautions investors that any forward-looking statements or projections made by the company, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect the Group's operations are described under 'Risk Factors' in the Operating and Financial Review and Prospects in the company's Annual Report on Form 20-F for 2005.
Adolor Corporation Forward-Looking Statements
This release, and oral statements made with respect to information contained in this release, constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those which express plan, anticipation, intent, contingency, goals, targets or future development and/or otherwise are not statements of historical fact. These statements are based upon management's current expectations and are subject to risks and uncertainties, known and unknown, which could cause actual results and developments to differ materially from those expressed or implied in such statements. Such known risks and uncertainties relate to, among other factors: the risk that the results of the alvimopan (Entereg(R)) Phase 3 Studies in opioid induced gastrointestinal side effects are not positive; the risk that regulatory approvals for use of alvimopan in patients taking opioids for persistent pain are not achieved; the risk that Adolor may not obtain FDA approval for the new drug application for Entereg(R) in postoperative ileus (POI); the risk that further studies of Entereg(R) are not positive or have adverse safety findings; the costs, delays and uncertainties inherent in scientific research, drug development, clinical trials and the regulatory approval process; Adolor's history of operating losses since inception and its need for additional funds to operate its business; Adolor's reliance on its collaborators, including GlaxoSmithKline in connection with the development and commercialization of Entereg(R); market acceptance of Adolor's products, if regulatory approval is achieved; competition; and securities litigation.
Further information about these and other relevant risks and uncertainties may be found in Adolor's Reports on Form 8-K, 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Adolor urges you to carefully review and consider the disclosures found in its filings, which are available in the SEC EDGAR database at http://www.sec.gov and from Adolor at http://www.adolor.com. Given the uncertainties affecting pharmaceutical companies in the development stage, you are cautioned not to place undue reliance on any such forward-looking statements, any of which may turn out to be wrong due to inaccurate assumptions, unknown risks, uncertainties or other factors. Adolor undertakes no obligation to (and expressly disclaims any such obligation to) publicly update or revise the statements made herein or the risk factors that may relate thereto whether as a result of new information, future events, or otherwise.
