Abdominal Surgery

July 6, 2009

AcelRx released positive results from a phase II trial of ARX-01 Sufentanil NanoTabs for the treatment of post-operative pain following major abdominal surgery. This randomized, double blind, placebo controlled study enrolled 88 subjects undergoing major abdominal surgery. The subjects were randomized to receive either 10 mcg or 15 mcg doses of ARX-01, or placebo for post-operative pain. ARX-01 was administered sublingually, as needed to treat pain with a minimum re-dosing interval of 20 minutes. The primary outcome was analgesic effect, as measured by pain intensity scores over the 12 hour study period based on SPID-12. Both doses of ARX-01 showed statistically significant reductions in pain intensity over the study period (p<0.001 for each). The proportion of subjects who dropped out due to inadequate analgesia, a clinically meaningful secondary endpoint, was also significantly different from placebo for both treatment groups (p<0.001). ARX-01 was well tolerated.

October 6, 2008

Tranzyme issued positive results from a phase IIb trial of TZP-101 for the treatment of post-operative ileus. This multinational, double-blind, placebo-controlled study enrolled 200 subjects undergoing open bowel resection surgery. The subjects received either TZP-101 or placebo administered intravenously within the first hour after surgery, followed by once-daily dosing for up to seven days. The primary endpoint was time to first bowel movement. TZP-101 was superior to placebo at all doses tested. For the two most effective doses, 80g/kg and 480g/kg , the median times to first bowel movement were 70.5 and 68.0 hours, respectively, versus 89.6 hours for placebo (p=0.056 and p=0.029, respectively). In addition, 64% of subjects in both the 80g/kg and 480g/kg dose groups had a bowel movement within 72 hours, versus only 25% in placebo; (p=0.001 for both dose groups). The secondary endpoint, the percentage of subjects achieving gastrointestinal recovery within 72 hours of surgery, also reached statistical significance. The median times for this endpoint were 70.5 and 68.0 hours for the 80g/kg and 480g/kg groups, respectively, versus 91.3 hours for placebo (p=0.034 and p=0.044, respectively). TZP-101 was well tolerated. Based on the results Tranzyme plans to commence phase III trials early in 2009.

June 11, 2007

Roxro announced positive results from a phase III trial of ROX-888 for the treatment of acute pain following major abdominal surgery. This multi-center, double-blind, placebo-controlled trial enrolled 321 subjects who were randomized to receive either intranasal ROX-888 (30 mg) or placebo when their pain reached a moderate level following surgery. All subjects had access to patient-controlled morphine. Results demonstrated that the subjects who received ROX-888 reported greater improvement in pain relief and required 22% less morphine in the first 24 hours following surgery compared to subjects who had access to morphine alone. Based on the results, Roxro plans to file a NDA with the FDA in the first half of 2008.

February 26, 2007

CeNeS announced positive preliminary results from a phase III trial of M6G for the treatment of post-operative pain. This randomized, double-blind trial enrolled 517 subjects in Europe undergoing abdominal surgery. Subjects received an initial loading dose of intravenous M6G or morphine prior to administration on the ward. Once on the ward, subjects self-administered treatment as required to control their pain. The primary endpoint was for non-inferiority in pain level management with M6G when compared to morphine and that treatment with M6G would result in lower levels of nausea and vomiting when compared to morphine. Preliminary results revealed that M6G was as good as morphine in terms of analgesia up to 48 hours post-operatively. In addition, treatment with M6G led to a 28% reduction post-operative nausea and vomiting 6 to 24 hours after treatment when compared to morphine (p=0.018). Dry retching/vomiting was reduced by 32% in the M6G arm when compared to placebo 24 hours post treatment (p= 0.044) and post-operative nausea was reduced by 26% when compared to placebo 6-24 hours after treatment (p=0.052). Based on the results, CeNeS plans to file an IND with the FDA in Q1 of 2007.

September 11, 2006

Adolor reported positive and negative results from two identical phase III trials of Entereg for the treatment of opioid-induced bowel dysfunction (OBD). The primary endpoint was statistical significance in the proportion of subjects who had a weekly average of three or more spontaneous bowel movements (SBM), defined as bowel movements with no laxative in the previous 24 hours and an increase from baseline of one or more SBMs a week, over a 12-week treatment period. The first trial, 012, enrolled 518 patients with chronic non-cancer pain who had experienced symptoms of OBD. Subjects received 0.5 mg of Entereg, or placebo, once or twice daily for 12 weeks. This trial met the primary endpoint with 61% of the subjects treated with Entereg once daily and 72% of those treated with Entereg twice daily achieving SBM compared with 48% of those receiving placebo (p=0.065 and p less than 0.001, respectively). The second trial, 013, enrolled 485 patients with chronic non-cancer pain. Treatment schedule and administration, as well as the primary endpoint, were identical to trial 012. This trial did not achieve statistical significance, with 56% of the subjects treated once-daily, meeting the primary endpoint compared to placebo (p=0.259) and 63% of those treated twice daily meeting the primary endpoint compared to placebo ((p=0.214). Adolor plans to continue future advancement of Entereg.

Epicept reported negative results from a phase III trial of LidoPain for the treatment of post-surgical pain. This randomized, double-blind, placebo-controlled trial enrolled 400 subjects who underwent hernia repair surgery. Subjects received a LidoPAIN or placebo patch for 48 hours following surgery. The trial failed to meet the primary endpoint of self-assessed pain intensity at 4 and 24 hours, measured by the area under the curve (p= 0.4). In addition the secondary endpoint, patient use of "rescue" medications 4 to 24 hours post-surgery, was not met (p= 0.09). EpiCept plans to further analyze data to determine a future course of action for LidoPAIN.

April 3, 2006

Corgentech announced negative results of a phase II trial of ALGRX 4975 for the treatment of hernia repair pain. This randomized, double-blind, placebo-controlled parallel-group pilot study enrolled 41 patients in Denmark, who received single doses of the drug or placebo into the surgical wound site 1 minute prior to closure; following surgery, all subjects received palliative therapy with acetaminophen and ibuprofen for 1 week. Efficacy follow-up occurred one and four weeks after surgery. Trial data yielded no significant differences in pain scores on the visual analog scale for surgical wounds treated with ALGRX 4975 (VAS score = 14.4), compared to placebo (VAS score = 17.5; p>0.05). The drug was well tolerated at all time points. Additional phase II trials of the drug, for the treatment of tendonitis of the elbow, post- bunionectomy pain, Morton's neuroma, total knee replacement and cholecystectomy, were ongoing.

February 28, 2005

InKine issued positive results of a phase III study of INKP-102, their investigational purgative drug for gastrointestinal clearing prior to colonoscopy. Trial data indicated that the drug met its primary endpoint of non-inferiority to approved therapy with Visicol, with 94% of patients receiving INKP-102 achieving an overall colon cleansing rating of "excellent" or "good" (p<0.0001). With respect to secondary endpoints, the drug demonstrated statistical superiority in ascending colon clearing, total irrigation fluid required, and patient acceptance of treatment (p<0.05). Safety data indicated that the drug was well tolerated, and adverse events generally occurred less frequently with INKP-102 than Visicol. No difference in efficacy was noted between the low and high dose regimens of INKP-102. This investigator-blinded, approved-therapy-controlled study enrolled 706 adults scheduled to undergo colonoscopy, who received one of two doses of !NKP-102 (32 mg or 40 mg), or an approved dose of Visicol (40 mg). The company announced that they believed the data from this trial satisfied the terms of their SPA, and announced plans to submit an NDA for the drug in Q2 2005.

January 24, 2005

Progenics Pharmaceuticals has reported top-line results of their phase II trial of MTNX (methylnaltrexone), a peripheral opioid-receptor antagonist, for the treatment of post-operative bowel dysfunction. Preliminary data yielded significant improvements in a number of statistical measures of efficacy, relative to placebo. Specifically, significant improvements were noted in time to first bowel movement (23 hours faster; p=0.01) and time to discharge eligibility (30 hours faster; p=0.03); non-significant but positive-trending improvements were noted in time to tolerance of first full-liquid meal (30 hours faster; p=0.05), time to tolerance of first solid meal (25 hours faster; p=0.12), time to tolerance of first solid meal and first bowel movement (27 hours faster; p=0.06), and time to actual discharge (25 hours faster; p=0.09). The drug was safe and well tolerated, with no serious drug-related adverse events, no drug-related trial withdrawals, and an incidence of the most common adverse events (fever and nausea) similar to placebo. This double-blind, placebo-controlled proof of concept study enrolled a total of 65 patients across 8 sites undergoing segmental colectomies (primarily due to cancer or diverticular disease), who were randomized to receive either 0.3mg/kg MNTX or placebo 4 times daily for up to 7 days. Based on these results, the company announced plans to meet with the FDA to discuss the design of a phase III trial of the drug in post-operative bowel dysfunction.

January 3, 2005

Adolor Corporation reported initial results from a phase III trial investigating alvimopan (Entereg), a peripherally-restricted mu opioid receptor antagonist for the treatment of postoperative ileus. The multi-center, randomized, double-blind, placebo controlled parallel group study, designated SB-767905/001, enrolled 911 subjects who had undergone bowel resection or radical hysterectomies. The primary endpoint of the study is the time to recovery of GI function, as defined by the later of the following two events: time from surgery until the patient first tolerates solid foods and time from surgery until the patient first passes flatus or has a bowel movement. Results showed a hazard ratio of 1.22 and 1.13 for the 6mg and 12mg respectively, each as compared to the placebo group, a non-statistically significant result. Secondary endpoints included an additional measure of time to recovery of gastrointestinal function (GI2), which measures GI recovery based on tolerating solid food and bowel movement. These results were statistically significant as compared to the placebo group. Alvimopan was generally well tolerated in this study. The study was conducted in Europe, Australia and New Zealand and was performed to support a Marketing Authorization Application (MAA) in the European Union. GSK and Adolor are collaborating on the worldwide development and commercialization of alvimopan.

September 27, 2004

Adolor and GlaxoSmithKline reported positive results of their phase III trial of Entereg, their peripheral mu-opioid-receptor antagonist, for the treatment of post-operative ileus (POI) and gastrointestinal recovery in subjects undergoing bowel resection or radical hysterectomy. Trial data met their primary endpoints, significantly reducing time to GI function rebound and hospital discharge at the higher dosing regimen. Furthermore, the drug did not interfere with opioid analgesia. The double-blind, placebo-controlled multi-center study randomized 510 subjects scheduled for bowel resection or complete radical hysterectomy to receive one of two doses of Entereg (6 mg or 12 mg) or placebo prior to surgery, then twice daily until hospital discharge (up to 7 days). The drug was found to be safe and well tolerated at both treatment doses. These data are part of Entereg’s NDA, currently under review by the FDA. If approved, the drug would become the only marketed therapy for post-operative ileus.

January 19, 2004

Adolor reported positive results from a phase III trial investigating Entereg (alvimopan), an opioid narcotic antagonist for the treatment of postoperative ileus (POI). Results showed a positive trend with regards to the time to recovery of gastrointestinal function, when Entereg (6 mg and 12 mg groups) was compared to placebo. Data demonstrated a statistically significant differences in time to hospital discharge order written in each of the 6 mg and 12 mg treatment groups (14 and 15 hours sooner) as compared to placebo group. The study (called 14CL308) enrolled 666 subjects who were scheduled to undergo large or small bowel resections, or simple or radical hysterectomy. The treatments were generally well tolerated with the most frequently adverse events being nausea, vomiting, and pruritus.

October 27, 2003

Adolor reported positive results from a phase III trial investigating Entereg (alvimopan), an opioid narcotic antagonist for the treatment of postoperative ileus. Entereg was generally well tolerated with over 90% of subjects completing treatment in both groups. The most frequently observed adverse events in both groups were nausea, vomiting and constipation. Discontinuations due to adverse events were 4% in the treatment group and 5% in the placebo group. The double-blind, randomized, placebo-controlled, multi-center study enrolled 519 subjects who received either Entereg (12 mg) or placebo, at least two hours prior to surgeries, and then twice a day on the first postoperative day. The study was designed to evaluate the safety of Entereg in subjects undergoing total abdominal simple hysterectomies. The company plans to report additional results at a later date.

October 6, 2003

Adolor reported positive results from a phase III trial investigating Entereg (alvimopan), an opioid narcotic antagonist for the treatment of postoperative ileus. Results showed a statistically significant difference in the primary endpoint, time to recovery of gastrointestinal function, with Entereg (6 mg - 12 mg) compared with placebo. The mean times of recovery were 120 hours, 105 hours, and 98 hours for the placebo, 6 mg, and 12 mg groups, respectively. Data showed a statistically significant difference in the 12 mg treatment group, in time to hospital discharge order written, compared with placebo. The multi-center, double-blind, placebo controlled study enrolled 510 subjects and was designed to for patients set to undergo major abdominal surgery and who were taking opioids for pain relief. Subjects were scheduled to undergo small bowel resections, large bowel resections or radical hysterectomies.

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