Gastrointestinal Diseases and Disorders

March 26, 2018

Antibe Therapeutics announced that its lead drug, ATB-346, met its primary endpoint in the Phase IIB gastrointestinal (“GI”) safety study. The double-blind study was conducted in 244 healthy volunteers and was designed to demonstrate the superiority of ATB-346 in GI safety compared to naproxen, the most prescribed nonsteroidal anti-inflammatory drug (“NSAID”) in the USA. Subjects on ATB-346 exhibited an ulceration rate of 2.5 percent versus an ulceration rate of 42.1 percent for subjects on naproxen at the end of the 2-week treatment period, with a very high degree of statistical significance (p<0.001). Subjects received either 250 mg of ATB-346 once-daily, a dose previously shown to be very effective in reducing osteoarthritis-associated pain, or 500 mg of naproxen twice-daily. The primary endpoint for the study was the incidence of gastric or duodenal ulcers of at least 3 mm diameter with unequivocal depth, considered the gold standard in assessing the GI safety of NSAIDs.

November 24, 2014

Boehringer Ingelheim Pharmaceuticals reported results of a retrospective analysis of Pradaxa (dabigatran etexilate mesylate) showing reduced rates of stroke, major bleeding, death and other types of bleeding, along with increased lower gastrointestinal bleeding, compared to patients treated with warfarin. In this retrospective analysis, which evaluated the safety and effectiveness of Pradaxa v. warfarin in 25,586 non-valvular atrial fibrillation patients, Pradaxa was associated with a 27% reduced risk of stroke, a primary outcome (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.55-0.97, event rate per 100 patient-years [ER] 0.92 v. 1.32, respectively). The risk of major bleeding, the second primary outcome, was 13% less with Pradaxa (HR 0.87, CI 0.74-1.02, ER 3.08 v. 3.70, respectively).

May 27, 2013

Intercept Pharmaceuticals released preliminary results from a phase IIa trial of obeticholic acid for primary bile acid diarrhea (PBAD). This open-label study, OBADIAH, enrolled 10 patients with PBAD, IBS-D or secondary bile acid diarrhea due to Crohn’s disease. Subjects received OCA 25mg daily for two weeks. Data demonstrated OCA 25mg resulted in a statistically significant increase in median fasting fibroblast growth factor 19 (FGF19) from 133pg/mL to 237pg/mL, with most patients achieving a >60% increase (p=0.007). In addition, clinical improvements were seen in all patients with reductions in median stool frequency from 23 to 14 per week (p=0.03) and an improvement in the median Bristol Stool Form Scale assessing stool type from 5.15 to 4.34 (p=0.05). Notably, during the two-week follow-up period after stopping OCA therapy, stool frequency returned to pre-treatment baseline values. OCA was well tolerated. Intercept Pharmaceuticals anticipates final results for all three patient groups to be available in the second half of 2013.

February 11, 2013

Synageva BioPharma reported results from a phase I/II extension study of sebelipase alfa for the treatment of lysosomal acid lipase (LAL) deficiency. This long-term, open-label extension study enrolled seven patients with LAL deficiency. Subjects received four once-weekly infusions of sebelipase alfa 0.35mg/kg, 1.0mg/kg or 3.0mg/kg, and then transitioned to every other week infusions of sebelipase alfa 1.0mg/kg or 3.0mg/kg. Data demonstrated sebelipase alfa produced mean percent decreases for ALT and AST from the initial baseline to week 12 of the extension study of 52% and 36%, respectively (p<0.05 for both). In addition, sebelipase alfa resulted in mean percent decreases from the initial baseline to week 12 of the extension study for LDL-C of 27% (p=0.078), total cholesterol of 22% (p=0.047), triglycerides of 28% (p=0.016), as well as mean increases in HDL of 15% (p=0.016). Sebelipase alfa was well tolerated. The most frequent adverse events were diarrhea and abdominal cramping. Synagenva Biopharm did not note its plans for sebelipase alfa.

January 14, 2013

Synergy Pharmaceuticals issued results from a phase IIb/III trial of plecanatide for the treatment of chronic idiopathic constipation (CIC). This randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study enrolled 951 patients with CIC. Subjects received 0.3mg, 1mg or 3mg of plecanatide, or placebo, for 12 weeks. Results showed evidence of increasing efficacy at increasing dose levels. Notably, the 3mg dose demonstrated a 19% (p=0.009) overall responder rate (versus placebo of 10.7%), as well as demonstrating a mean increase in complete spontaneous bowel movements (CSBMs) over the 12-week treatment period of 2.13 (p<0.001). In addition, statistically significant improvements (9.7%) in the incidence of diarrhea were observed in the 3mg arm (versus placebo incidence of 1.3%). Plecanatide was well tolerated. Synergy also is conducting a phase IIb study in IBS with constipation (IBS-C).

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,

June 11, 2012

Bayer Healthcare and Onyx Pharmaceuticals released results from a phase III trial of regorafenib for the treatment of metastatic and/or unresectable gastrointestinal stromal tumors (GIST). This randomized, double-blind, placebo-controlled, multi-center, cross-over study, GRID, enrolled 199 patients who had been treated unsuccessfully with imatinib and sunitinib. Subjects received either 160mg regorafenib daily for three weeks followed by a week off plus best supportive care or placebo plus best supportive care. The GRID study met its primary endpoint of improvement in progression-free survival (PFS) (HR≡0.27, p<0.0001). The median PFS was 4.8 months in the regorafenib arm versus 0.9 months in the placebo arm. The most common adverse events included hand-foot skin reaction, hypertension, diarrhea, fatigue, oral mucositis, alopecia, hoarsness and anorexia, among others. Based on these data, Bayer plans to submit an NDA in the second half of 2012.

August 15, 2011

Genentech issued results from a phase II trial of telotristat etiprate for the treatment of carcinoid syndrome. The U.S-based, randomized, double-blind, placebo-controlled study enrolled 23 subjects with carcinoid syndrome who were refractory to currently available therapy. The subjects received either placebo or one of four doses of telotristat etiprate daily for 28 days. Five subjects in the telotristat etiprate arm achieved clinical responses characterized by reductions of at least 30% in the number of bowel movements per day for two weeks or more during the study. The difference between telotristat etiprate and placebo in bowel movement frequency ranged between 1.6 and 2.9 bowel movements per day across telotristat etiprate doses. In addition, six subjects receiving telotristat etiprate reported adequate relief of carcinoid symptoms at the end of the study and nine subjects showed a complete biochemical response, defined as a reduction of at least 50% in urinary 5-HIAA. Telotristat etiprate was well tolerated and adverse events were mild to moderate.

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.

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

Ocera released positive preliminary results from an ongoing phase II trial of AST-120 for the treatment of pouchitis. This open-label trial enrolled 20 subjects with active pouchitis in the US. The subjects were treated with AST-120, 2 grams three times a day. The primary endpoint was remission as defined by a Pouchitis Disease Activity Index (PDAI) of less than 7 points. Results showed a significant decrease in symptoms of pouchitis and endoscopy scores in the first ten subjects enrolled in the study. Clinical remission was achieved in 44.4% and 55.6% achieved a clinical response. Pending positive top-line results, Ocera plans to pursue the development of AST-120 for this population.

August 13, 2007

Iomai released positive results from a phase I trial of their TIM ETEC patch-based vaccine for the treatment of travelers' diarrhea caused by enterotoxigenic Escherichia coli. This safety and immunogenicity trial enrolled 19 elderly subjects and 17 young adult subjects, in Ireland. The subjects received two patches, 21 days apart, containing "heat labile" toxin, or LT, and were followed for 42 days. The trial was designed to compare the number of elderly subjects who seroconverted to the number of young adult subjects who seroconverted. Results showed that all subjects who received the Iomai patch, regardless of age, seroconverted with IgG antibodies. In addition, 18 of 19 elderly subjects and 15 of 17 adult subjects also seroconverted with IgA antibodies. The patch was well tolerated, with no treatment related adverse effects reported. Based on the results, Iomai plans to initiate phase III trials in 2008.

Roche released positive interim results from a phase IIIb trial of Invirase for the treatment of HIV. This randomized, open-label trial, dubbed GEMINI, enrolled 337 subjects internationally. Subjects received Invirase plus ritonavir or lopinavir plus ritonavir given at their approved twice-daily dosages in combination with two nucleoside reverse transcriptase inhibitors (NRTIs; emtricitabine/tenofovir), once daily. The primary endpoint was the number of subjects with an HIV-1 RNA viral load of less than 50 copies per mL of blood at week 48. Secondary endpoints included measurement of lipid safety parameters. Efficacy results at 24 weeks showed that 69.9% and 69% of subjects treated with Invirase/ritonavir and lopinavir/ritonavir, respectively, achieved undetectable HIV levels (less than 50 copies per mL of blood). The same proportion of subjects in both groups achieved undetectable of less 400 copies per mL of blood. The increases in CD4 counts were comparable in both groups, with a median increase from baseline of 127 cells per cubic mL of blood for those in the Invirase/r group, and 134 cells for subjects in the lopinavir/r group. In addition, at 24 weeks, subjects treated with Invirase/r showed a lower median increase in their total cholesterol (TC) and total triglycerides (TG) than subjects treated with lopinavir/r (increase of 17 versus 26 mg/dL for TC, and an increase of 14 versus 43 mg/dL for TG). Based on the results, Roche planned to continue with the study.

October 2, 2006

Axcan released negative results from a phase III trial of Itopride for the treatment of functional dyspepsia. The trial failed to meet the co-primary endpoints of change in upper abdominal pain from baseline on the Leeds Dyspepsia Questionnaire (LDQ), and change in Patient's Global Assessment (PGA) of Efficacy score. Based on these results Axcan has decided to suspend further development of Itopride.

March 13, 2006

Novogen has issued positive results of a phase I trial of their investigational synthetic isoflavone analogue NV-52, for the treatment of inflammatory bowel disease. Pharmacokinetic results indicated a rapid absorption profile and fairly consistent bioavailability, with peak plasma concentration achieved approximately 4 hours after administration, and a plasma elimination half-life of 8 hours. In addition, safety data yielded no reported adverse events. This open-label study enrolled 6 healthy male volunteers at the Gold Coast Hospital in Australia, under the direction of Professor Laurie Howes. Subjects received single oral administrations of the drug.

January 9, 2006

GlaxoSmithKline has reported positive results of a clinical trial of their investigational rotavirus vaccine, in the New England Journal of Medicine. The vaccine was shown to provide 85% protection against severe rotavirus disease, and 100% against more severe disease. This protection covered the 4 most common strains of the virus (G1P[8], G3P[8], G4P[8], and G9P[8]). Safety data revealed a lover incidence of serious adverse events among subjects receiving the vaccine, vs. placebo. No increase in rates of intussusception was noted among subjects receiving the vaccine (a serious complication associated with previous rotavirus vaccines). This double-blind, placebo-controlled study enrolled 63,225 infants from 12 countries, who received two doses of the drug or placebo two months apart.

Salix has issued positive results of a phase III trial of Xifaxan (rifaximin) for the prevention of traveler's diarrhea (TD). The drug demonstrated efficacy in the trial's primary endpoint, with 84% of subjects remaining free of primary TD symptoms over the treatment period, compared to 50% of subjects receiving placebo (p < 0.0001). This placebo-controlled study enrolled 210 US subjects planning travel to Mexico, who received 200 mg Xifaxan tablets (n=106) or placebo (n=104) thrice daily for the first 14 days of travel. Based on these results, the company planned to initiate a second phase III trial of the drug in the first half of 2006.

August 22, 2005

NPS Pharmaceuticals issued positive results of a phase II study of teduglutide, for the treatment of short bowel syndrome (SBS), in the journal Gut. Trial data produced significant increases in absolute and relative wet weight absorption, urine weight and urine sodium excretion, all of which are indications of reduced intravenous fluid requirements in SBS patients. Further, decreases were noted in fecal weight and energy excretion, and tissue biopsies showed a positive effect of teduglutide on villus height and crypt cell depth. This open-label study enrolled 16 SBS patients, who received one of 3 daily doses of the drug (0.03 mg/kg, n=3; 0.10 mg/kg, n=10; 0.15 mg/kg, n=3). Based on these results, the company initiated a phase III trial of the drug in SBS in April 2004; to date, roughly 50% of patients had been enrolled.

March 14, 2005

BioMarin has announced positive results from a phase III extension study of Aryplase (galsulfase, rhASB), their investigational enzyme replacement therapy for the treatment of mucopolysaccharidosis VI (MPS VI), also called Maroteaux-Lamy Syndrome. Results from the 6-month extension indicated that the drug improved muscular endurance over the already-significant improvements seen at the end of the initial trial, during extension period (weeks 24-48). This included an improvement of 36 meters in distance walked in 12 minutes, an improvement in 2.9 stairs in total stairs climbed in 3 minutes, and maintained initial reduction in urinary glycosaminoglycan levels, at 48 weeks, versus the baseline levels obtained at the end of the initial study (24 weeks). This open-label extension study enrolled all 38 patients who had completed the initial 24 week trial; all patients received 1.0 mg/kg Aryplase via weekly infusion.

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.

August 11, 2003

Santarus reported positive results from a phase III trial investigating SAN-05, an immediate-release omeprazole suspension for the treatment of ventilated patients at risk for upper GI bleeding. Results showed that the primary endpoint of the study, the occurrence of clinically significant bleeding, was statistically significant for both the per protocol and intent-to-treat populations. The blinded study enrolled 359 critically ill subjects at more than 50 sites and was designed to compare SAN-05 with intravenous cimetidine, an approved histamine-2 receptor antagonist. After an initial loading dose, cimetidine was delivered by continuous intravenous infusion and SAN-05 was administered once daily through a nasogastric tube.

April 7, 2003

BioMarin reported positive results from a phase II trial investigating Aryplase (recombinant human arylsufatase B), an enzyme replacement therapy for the treatment of mucopolysaccharidosis VI (MPS VI). Results showed the drug was well tolerated and that subjects experienced improvement in endurance. Subjects achieved an average improvement of 64 meters (62%) in the 6-minute walk test and an average improvement of 155 meters (98%) in the 12-minute walk test. Subjects also exhibited functional improvements in joint pain and stiffness scores, which were reduced on average by 57% and 54% respectively. The open-label study enrolled 10 subjects with MPS VI and was conducted at two sites in the U.S. and one in Australia. The study evaluated clinical and biochemical measures of saftey and efficacy of Aryplase in subjects aged 6 to 22 for 22 weeks.

April 1, 2002

Results of a pilot phase II trial of ALX-0600 showed statistically significant improvement in intestinal function of 11 subjects with short bowel syndrome. Subjects received one of three doses of ALX-0600 by daily subcutaneous injections during a treatment period of 21 days. Results of three 72 hour balance studies measuring improvement in intestinal function showed significant improvements in the absorption of wet-weight from all dietary sources, decreases in fecal volume, increases in urine volume and decreases in fecal energy excretion. A result of this improved intestinal function was a statistically significant increase in body mass. NPS Pharmaceuticals also reported that histological examination of tissue from patient biopsies showed a significant increase in the number and size of epithelial cells that line the small bowel.

February 11, 2002

Phase IV trial results suggest that a Visicol regimen with fewer tablets and a reduced volume of clear liquid is as effective for bowel cleansing as the currently recommended regimen. The multicenter, investigator-blinded trial included 98 subjects scheduled for a colonoscopy. Subjects were randomized to receive 28 or 32 tablets of Visicol, with 20 tablets taken the evening before the procedure and either eight or 12 tablets taken the morning of the procedure. For both regimens, significant reductions were observed in time to dose completion and the volume of ingested liquid compared to the currently recommended 40-tablet dosing regimen. Additionally, cleansing with both dosing regimens was comparable to the 40-tablet regimen. Visicol is a product of InKine Pharmaceutical.