Sucampo Pharmaceuticals, Inc. (SPI), an international biopharmaceutical company focused on the discovery, development and commercialization of medicines based on prostones, and Takeda Pharmaceuticals USA, Inc. announced that lubiprostone met the primary endpoint in a phase 3 clinical trial for the treatment of opioid-induced bowel dysfunction (OBD) in patients with chronic, non-cancer pain, excluding those taking methadone.

Patients received lubiprostone 24-mcg capsule or placebo capsule twice daily for 12 weeks. The primary endpoint was the overall spontaneous bowel movement (SBM) response rate. The response rate for lubiprostone-treated patients was 26.9% (n=219) versus 18.6% (n=220) for placebo-treated patients (p=0.035).

M Mazen Jamal, chief of endoscopy, Long Beach Veterans Affairs’ Medical Center, Long Beach, California, Professor, Department of Medicine, University of California College of Medicine at Irvine, an investigator in the trial, said, “The results from this phase 3 trial demonstrate that lubiprostone has the potential to be the first FDA-approved orally administered medicine with the indication to treat OBD in non-cancer, non-methadone patients. OBD can be a painful and debilitating side effect affecting many non-cancer pain patients taking opioids chronically. There are more than 200 million prescriptions for opioid use in the US annually and a substantial portion of these prescriptions are for non-cancer chronic pain. Many patients are not getting the desired relief and there is a significant need for a new medicine to treat this condition.”

Ryuji Ueno, chairman and CEO of SPI, commented, "These data confirm the results from a previous phase 3 trial of lubiprostone in OBD patients and together with data from the associated long-term safety trial, complete what we believe are the data requirements to support the submission of a supplemental New Drug Application (sNDA). We expect to submit the sNDA to the US Food and Drug Administration (FDA) in the first half of 2012. In addition, we will discuss the potential for priority review, as we believe that physicians and their patients are actively seeking new therapies to address this condition. If approved, lubiprostone could be the first orally-administered medicine with the indication for OBD, providing another option for patients who need it and further differentiating lubiprostone from the competition.”

This phase 3 trial was a randomized, placebo-controlled double-blinded trial of the efficacy and safety of lubiprostone in patients with opioid-induced bowel dysfunction. The trial enrolled and treated a total of 439 patients in the US and Europe. Patients were evenly randomized to receive either placebo or lubiprostone 24-mcg gel capsule twice daily throughout the 12-week treatment period. Eligible patients must have been treated for chronic, non-cancer related pain with any opioid other than methadone for at least 30 days prior to screening, and continued opioid therapy throughout the study. Patients were confirmed to have OBD, which is defined as having an average of fewer than three SBMs per week during the three-week screening period and at least one of the following for at least 25 per cent of SBMs during each week of the screening period: hard or very hard stools; sensation of incomplete evacuation; moderate to very severe straining associated with SBMs.

Responders were determined based on patients’ daily record of bowel movements. In order to be defined as a treatment responder, patients were required to demonstrate at least =1 SBM improvement over baseline SBM frequency for all treatment weeks for which observed data were available, and must additionally have demonstrated a full response (= 3 SBMs per week) for at least 9 of the 12 treatment weeks. An SBM was defined as any BM that does not occur within 24 hours after rescue medication use.

There were no drug-related serious adverse events reported for patients taking lubiprostone. Overall, the percentage of patients discontinuing treatment due to adverse events was 5.9% for the lubiprostone group compared with 2.3% in the placebo group. The most common treatment-related adverse events (experienced by >5 percent of patients) were diarrhoea (9.6% vs. 1.4%), nausea (8.2% vs. 2.7%), and abdominal pain (5.5% vs. 0.0%) for lubiprostone vs. placebo, respectively. A majority (91.7%) of lubiprostone patients who reported diarrhoea described the events as mild to moderate in severity. The incidence rates of severe nausea were 1.4% for placebo-treated patients and 0.9% for lubiprostone treated patients.

“We at Takeda are pleased that this study met its primary endpoint and will continue to work closely with our partner, Sucampo, in preparing for the anticipated sNDA filing this year,” said Gilles Delecoeuillerie, executive medical director for gastroenterology at Takeda.

Results of this phase 3 trial will be submitted for presentation at an appropriate medical meeting and for publication in an appropriate peer-reviewed journal.

OBD comprises a variety of gastrointestinal conditions brought on by the use of opioid-based medications such as morphine and codeine. OBD encompasses a range of adverse gastrointestinal effects which includes severe constipation, infrequent and incomplete bowel movements, hard stool consistency, straining associated with bowel movements and abdominal discomfort/pain and bloating. Opioid drugs are used to treat moderate to severe pain. Constipation is one of the most common side effects of opioids, affecting up to 81% of patients, and rarely spontaneously resolves without treatment. Despite their pain-relieving efficacy, opioids are known to produce gastrointestinal effects that lead to OBD, including inhibition of large intestine motility, decreased gastric emptying and hard stools. In addition to a delay in intestinal transit, the reduction in secretion, upregulation of water and absorption of electrolytes in the gut may contribute to the constipating effects of opioids. In a 2011 Cochrane Collaboration Review on the use of laxatives in opioid pain patients (palliative care) they reported there have been no randomized clinical trials on any laxative that evaluated laxation response rates, patient tolerability and acceptability. Some patients discontinue opioid therapy and thereby endure pain rather than suffer from the constipation the opioids cause.