May 15, 2017
Synergy Pharmaceuticals issued results of phase III studies of Trulance (plecanatide) for the treatment of adults with irritable bowel syndrome with constipation (IBS-C). In two large phase III studies of more than 2,100 total patients with IBS-C, Trulance 3mg and 6mg doses met the primary endpoint showing statistical significance in the percentage of patients who were Overall Responders compared to placebo during the 12-week treatment period (Study 1: 30.2% in 3mg and 29.5% in 6mg dose groups compared to 17.8% in placebo; p<0.001 for 3mg and p<0.001 for 6mg; Study 2: 21.5% in 3mg and 24.0% in 6mg dose groups compared to 14.2% in placebo; p=0.009 for 3mg and p<0.001 for 6mg). In a pooled analysis of both studies, a statistically significant percentage of patients treated with Trulance achieved at least a 30% reduction in abdominal intensity pain compared to placebo for at least six weeks of the 12-week treatment period (36.8% in 3mg and 39.1% in 6mg dose groups compared to 27.3% in placebo; p<0.001). A statistically significant percentage of patients treated with Trulance also saw improvement in stool frequency compared to placebo for at least six weeks of the 12-week treatment period, as measured by an increase in at least one CSBM per week from baseline (40.9% in 3mg and 41.9% in 6mg dose groups compared to 31.4% in placebo; p<0.001). In both studies, treatment with Trulance also resulted in a significantly greater percentage of sustained efficacy responders, as measured by patients who were Overall Responders in the last two of four weeks of treatment (24.3% in 3mg and 25.5% in 6mg dose groups compared to 15.6% in placebo; p<0.001). Synergy has submitted a supplemental New Drug Application (sNDA) to the FDA for Trulance for the treatment of adults with IBS-C. Trulance is approved by the FDA for the treatment of adults with chronic idiopathic constipation (CIC).
February 8, 2016
Synthetic Biologics reported results of a phase II trial of SYN-010 for the treatment of irritable bowel syndrome with constipation (IBS-C). Topline data from all patients who completed the second phase II clinical trial of SYN-010 showed a statistically significant decrease in methane production (p=0.002) from the beginning of the first phase II study (Study 1 baseline—day 1) to the end of the second phase II study (12 weeks of treatment—day 84), thus meeting the study’s primary endpoint. There were no serious adverse events observed. Topline data also showed a statistically significant reduction in the mean IBS Symptom Severity Score (IBS-SSS; p<0.0001), which includes abdominal pain, bloating, stool frequency and quality of life scores, for all patients from study 1 baseline to the end of the second phase II study. The second phase II, open-label SYN-010 clinical trial was conducted for eight weeks at multiple centers in the U.S. The primary endpoint of this extension study was to evaluate the sustainability of the effect of one daily dose strength (42mg) of SYN-010 on breath methane production in breath methane-positive patients with IBS-C. Secondary endpoints included evaluation of the reduction in abdominal pain and bloating, the improvement in stool frequency and overall quality of life. Fifty-four patients, who completed the first phase II clinical trial of SYN-010 (a four-week study of patients randomly assigned to receive placebo, a 21mg SYN-010 dose or a 42mg SYN-010 dose once daily), rolled over into the second phase II clinical trial of SYN-010. Synthetic Biologics is actively planning a phase III program for SYN-010.
December 14, 2015
Astellas Pharma and Ironwood Pharmaceuticals released results of a phase III trial of linaclotide conducted in Japan in adults with irritable bowel syndrome with constipation (IBS-C). The double-blind, placebo-controlled trial randomized 500 adults with IBS-C in Japan. Patients were randomized 1:1 to receive either 500mcg of linaclotide or placebo for 12 weeks. The co-primary endpoints of the trial were (i) Global Assessment of Relief of IBS Symptoms Responder Rate, in which patients rated their improvement in IBS symptoms over each week compared to the baseline period and achieved significant or moderate relief for at least six out of 12 weeks, and (ii) Complete Spontaneous Bowel Movement (CSBM) Overall Responder Rate, in which patients reported experiencing at least three CSBMs per week and an increase of at least one CSBM from baseline in the same week, and achieved both of these measures for at least six out of 12 weeks. The trial also includes an additional 40-week, open-label follow-on study period, which is ongoing. Top-line data indicate linaclotide-treated patients showed statistically significant improvement compared to placebo-treated patients for both of the two co-primary endpoints. Regarding the first primary endpoint, 34% of linaclotide-treated patients were Global Assessment of Relief of IBS Symptoms Responders, compared to 18% of placebo-treated patients (p<0.001). Regarding the second primary endpoint, 35% of linaclotide-treated patients were CSBM Overall Responders, compared to 19% of placebo-treated patients (p<0.001). Additionally, improvements were achieved in pre-specified secondary endpoints in this trial covering abdominal and constipation symptoms, including bloating and abdominal pain/discomfort. Diarrhea rates in this trial were 9.6% for linaclotide v. 0.4% for placebo; all cases were characterized as mild or moderate in severity. Linaclotide is a guanylate cyclase-C (GC-C) agonist currently approved in the U.S. for the treatment of adults with IBS-C and chronic idiopathic constipation (CIC). It is also approved for adults with IBS-C or CIC in more than 30 other countries. Astellas expects to submit a new drug application to the Ministry of Health, Labor and Welfare in Japan in 2016.
October 29, 2012
Teva Pharmaceutical released results from a phase IIa trial of laquinimod for Crohn’s disease (CD). This multi-center, randomized, double-blind, placebo-controlled study enrolled 180 patients with moderate to severe CD, based on a CD Activity Index (CDAI) of 220-450 and serum C-reactive protein (CRP) levels of >5mg/L or mucosal ulcerations evident on a recent endoscopy. Subjects received daily doses of laquinimod 0.5mg, 1mg, 1.5mg, 2mg, or placebo for eight weeks, with four weeks follow-up. Data demonstrated that laquinimod 0.5mg/day resulted in a robust, early and consistent effect on remission (48.3% versus 15.9% of patients, respectively) and response rates (62.1% versus 34.9% of patients, respectively) versus placebo. No effect was noted on remission/response at higher doses. The drug was well tolerated.
September 17, 2012
Santarus reported results from a phase II trial of rifamycin SV MMX for the treatment of travelers’ diarrhea. This multinational, multi-center, randomized, double-blind, placebo-controlled study enrolled 264 patients. Subjects received rifamycin SV MMX 400mg twice daily or placebo for three days. Results showed that the trial met its primary endpoint of reducing time to last unformed stool (TLUS) in patients with travelers’ diarrhea. The primary endpoint was defined as the time (hours) between the administration of the first dose of study drug and the time that the last unformed stool was passed before the start of clinical cure. In the intent-to-treat population (n=264), the median TLUS was 46.0 hours for rifamycin SV MMX (n=199) compared with 68.0 hours for placebo (n=65), p=0.0008. The drug was well tolerated. The most frequent adverse events were headache, diarrhea, infectious diarrhea, constipation, amoebic dysentery and gastrointestinal infection. A second phase III trial of rifamycin SV MMX, compared to ciprofloxacin,
July 16, 2012
Theravance released results from a phase IIb trial of TD-1211 for the treatment of opioid-induced constipation (OIC) in chronic, non-cancer pain. This randomized, double blind, placebo-controlled, parallel-group, dose-ranging study, 0084, enrolled 217 patients with five or fewer spontaneous bowel movements (SBMs) and at least one additional symptom of constipation during the two-week baseline period. Subjects received TD 1211 5mg for the first four days and then TD 1211 5mg, 10mg or 15mg for the remainder of the treatment period, or placebo for all five weeks. The study met its primary efficacy endpoint: the change from baseline in average SBMs per week over the last four weeks of treatment for the three doses of TD 1211. An increase in SMBs was seen in subjects treated with TD-1211 5mg from 0.1 to 1.6 (0.97; p=0.0413); 10mg from 0.3 to 3.0 (1.61; p=0.0010); and 15mg from 0.2 to 2.7 (1.79; p=0.0003). TD 1211 was generally well tolerated. The most frequent adverse events were abdominal pain, nausea, diarrhea and headache. Theravance noted that the results support progression into phase III development.
February 21, 2011
Alkermes reported preliminary results from a phase II trial of ALKS-37 for the treatment of opioid-induced bowel dysfunction (OBD). This randomized, double-blind, placebo-controlled, multi-dose study enrolled 87 subjects experiencing OBD during treatment with opioids for chronic, non-cancer pain. The subjects received placebo or escalating doses of oral ALKS 37 once daily (1-100 mg) for two weeks. The primary efficacy endpoints were the change in average number of spontaneous bowel movements (SBMs) per week from baseline and the change in average number of complete SBMs per week from baseline. The two highest doses tested (30 mg and 100 mg once daily) demonstrated a statistically significant increase in the number of SBMs compared to placebo. Subjects in the 100 mg arm the mean change from baseline in the average number of SBMs per week of 4.6 versus 0.7 in the placebo group (p≡0.003), or a net increase of 3.9 SBMs over placebo. The 100 mg dose also showed a statistically significant increase in the average number of CSBMs per week from compared to placebo. The mean change from baseline in the average number of CSBMs per week was 3.6 versus 0.8 in the placebo group (p≡0.006), or a net increase of 2.8 CSBMs over placebo. There was no reversal of analgesia.
February 7, 2011
NPS Pharmaceuticals issued results from a phase III trial of Gattex for the treatment of short bowel syndrome (SBS). This international, double-blind, placebo-controlled study, dubbed STEPS (Study of TEduglutide in PN-dependent Short-bowel syndrome), enrolled 86 adults with SBS and dependent on parenteral nutrition (PN). The subjects received once daily subcutaneous dosing of 0.05 mg/kg of Gattex or placebo over a 24-week treatment period. The primary efficacy endpoint was the percentage of subjects who achieved a 20 percent or greater reduction in weekly PN volume at week 20 and maintained that response at week 24, when compared to baseline. In an intent-to-treat analysis, 63% of the Gattex arm responded versus 30% of the placebo arm (p≡0.002). The subjects treated with Gattex also achieved significantly greater reductions in weekly PN volume versus placebo. On average, the subjects in the Gattex arm experienced a 4.4 liter reduction in weekly PN volume from a pre-treatment baseline of 12.9 liters; those in the placebo arm experienced a 2.3 liter reduction from a pre-treatment baseline of 13.2 liters (p less than or equal to 0.001). Gattex was well tolerated.
July 27, 2009
Sucampo and Takeda reported positive results from two phase III trials of lubiprostone for the management of opioid-induced bowel dysfunction (OBD) in subjects with chronic, non-cancer pain. These identical 12-week, double-blind, placebo-controlled studies, OBD0631 and OBD0632, enrolled 875 subjects in the US and Canada. The subjects received placebo or one 24-mcg gel capsule of lubiprostone twice a day for 12 weeks, along with different opioid pain medications. All subjects had fewer than three spontaneous bowel movements (SBMs) per week at baseline. In study OBD0631, the primary endpoint of a statistically significant change from baseline in the frequency of SBMs at Week 8 of treatment was met when lubiprostone was compared to placebo. The increase in the frequency of SBMs in the lubiprostone arm went from a baseline of 1.42 to 4.54 SBMs at Week 8. Statistical significance was also achieved for eight of the twelve secondary endpoints, including key symptoms associated with OBD. Study OBD0632 did not achieve statistical significance for the same primary endpoint. Statistically significant improvements with lubiprostone were achieved for two of the secondary endpoints and positive trends were observed in four of the other secondary endpoints. There was a high rate of response in the placebo arm of the 632 trial. Approximately 58% of subjects treated with placebo experienced more than three SBMs per week during each week of the trial. Treatment was well tolerated and the adverse event profile was similar between the active and placebo arms.
March 31, 2008
NPS issued positive results from a phase III extension study of Gattex for the treatment of short bowel syndrome in subjects who are dependent upon parenteral nutrition (PN). This extension study enrolled sixty five of the seventy one subjects who had completed a twenty-four week randomized phase III study that evaluated low-dose Gattex (0.05 mg/kg/day) and high-dose Gattex (0.10 mg/kg/day) versus placebo. The primary objective of the study was to assess the long-term safety and tolerability of daily Gattex dosing for up to fifty two weeks. Sixty-eight percent of the subjects who had received low-dose Gattex therapy and continued on low-dose Gattex, and 52% of the subjects who had received high-dose Gattex therapy and continued on high-dose Gattex achieved a 20% or greater reduction in PN after a total of fifty two weeks of therapy. Subjects treated with low-dose Gattex showed a mean 51% reduction in PN volume from pretreatment baseline to the end of fifty two weeks (p< 0.001) and those treated with high-dose Gattex experienced a mean 24% reduction (p< 0.001). All of the subjects (100%) who had previously received placebo in the phase III study and were randomized to low-dose Gattex therapy, and two out of seven subjects who had previously received placebo in the phase III study and were randomized to high-dose Gattex therapy, achieved a 20% or greater reduction in PN after a total of twenty eight weeks of therapy in the extension study. Two low-dose subjects and one high-dose subject who were able to discontinue PN in the phase III study remained off PN after fifty two weeks of Gattex therapy. Treatment was well tolerated in both dose groups, with no statistical differences in the rate of adverse events compared to the placebo group, with the exception of injection site reactions. Based on positive phase III results, NPS is meeting with the FDA to discuss the path towards regulatory approval.
October 22, 2007
NPS Pharmaceuticals reported positive results from a phase III trial of Gattex for the treatment of short bowel syndrome. This randomized, double blind trial enrolled 83 subjects, 71 of whom completed the study. Following an evaluation period and a period of stabilization, the subjects received daily subcutaneous injections of Gattex (0.05 mg or 0.10 mg/kg of body weight) or a placebo for six months. The primary endpoint was a reduction in parenteral nutrition of at least 20% from baseline to weeks 16 and 24. This endpoint was reached with statistical significance in the low dose Gattex arm, with 45.7% of the subjects achieving this goal (p-value 0.007). In the high dose Gattex arm 25% of the subjects attained this endpoint (p-value 0.161) versus 6% in the placebo arm. Treatment was well tolerated, with no statistically significant differences in adverse events between the two Gattex arms and placebo. Based on the results, NPS plans to meet with the FDA to discuss the next steps towards US regulatory approval.
April 16, 2007
Adolor and GlaxoSmithKline reported negative preliminary results from a phase III trial of Entereg for the treatment of opioid-induced bowel dysfunction (OBD). This double blind, placebo-controlled trial enrolled 805 subjects taking opioids for chronic non-cancer pain and experiencing opioid-induced bowel dysfunction (OBD). Subjects were randomized to receive alvimopan (0.5 mg twice daily) or placebo for 12 months. The proportion of subjects reporting most serious adverse events was similar between the Entereg and placebo groups. However, the number of subjects reporting serious adverse events involving cardiovascular or neoplasm actions increased in the Entereg treated group. In addition, an increase in the incidence of fractures was observed in those subjects iterated with Entereg. Adolor and GlaxoSmithKline plan to further evaluate the data. However, based on these results a previously submitted phase III protocol has been withdrawn and enrollment has been suspended in all Entereg extension studies.