Ulcerative Colitis

March 26, 2018

Arena Pharmaceuticals announced positive topline Phase II results from the OASIS trial for etrasimod, an investigational, once-daily, orally administered, selective sphingosine 1-phosphate (S1P) receptor modulator in development for the treatment of ulcerative colitis (UC). Patients receiving the 2 mg dose of etrasimod achieved statistically significant improvements versus placebo in the primary, all secondary, and clinical remission endpoints. OASIS was a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to assess safety and efficacy of two orally administered doses (1 mg and 2 mg) of etrasimod in patients with ulcerative colitis (UC) across 71 sites in 16 countries. Relative to placebo, there was a statistically significant (p = 0.009) 0.99 point improvement in a 3-component (stool frequency, rectal bleeding and findings on endoscopy) Mayo Clinic Score (ranging from 0 to 9) with etrasimod 2 mg at week 12. In the 1 mg group, there was a 0.43 point improvement in 3-component Mayo Clinic Score at week 12 relative to placebo, which was not statistically significant (p = 0.146). Significantly more patients in the etrasimod 2 mg group achieved endoscopic improvement compared with placebo (41.8 percent vs. 17.8 percent, p = 0.003).

October 30, 2017

Celgene released positive phase II data of ozanimod for ulcerative colitis. TOUCHSTONE was a phase II, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of ozanimod (RPC1063) with placebo in patients with moderately to severely active ulcerative colitis. A total of 197 patients were randomized and treated once daily with 1mg ozanimod (n=67), 0.5mg ozanimod (n=65) or placebo (n=65) for eight weeks (the induction phase). The primary endpoint was the proportion of patients in remission (Mayo score ≤2, no subscore >1) at week eight. Secondary endpoints were the proportion of patients achieving clinical response (reduction in Mayo score of ≥3 and ≥30% with a decrease in the rectal bleeding score of ≥1 or a rectal bleeding score ≤1), proportion of patients with mucosal improvement (endoscopy score ≤1) and the change in Mayo score. Safety assessments included ECG testing, pulmonary function testing, optical coherence tomography and adverse events. At week 92, of the 100 patients who underwent efficacy evaluations, 91% had little or no active disease based on the physician global assessment (PGA 0 or 1), 97% had little or no blood in their stools (rectal bleeding subscore [RBS] 0 or 1) and 86% had no blood in the stools (RBS 0). The safety profile at week 92 was similar to that reported in the placebo-controlled portion of the study. The most common AEs were UC flare, anemia, upper respiratory tract infection and back pain. The only SAEs in two or more patients were anemia and UC flare.

October 3, 2016

Takeda Pharmaceutical reported results of a multicenter, phase III, randomized, placebo-controlled trial of Entyvio (vedolizumab) therapy in patients with ulcerative colitis (UC). As part of the eligibility criteria for GEMINI 1, patients had demonstrated, within the previous five-year period, an inadequate response to, loss of response to or intolerance of one of the following therapies: corticosteroids (outside the U.S. only), immunosuppressives (azathioprine or mercaptopurine) and/or infliximab, as this was the only TNF antagonist approved for the treatment of UC at the time of enrollment. GEMINI 1 enrolled 464 patients without prior TNF antagonist therapy (TNF-naïve) and 367 who had failed therapy because of inadequate response, loss of response or intolerance (TNF-failure). Investigators found greater absolute differences between vedolizumab and placebo for TNF-naïve patients than for TNF-failure patients at week six and the risk ratios (RRs) were similar. Week six response rates with vedolizumab and placebo were 53.1% and 26.3%, respectively, in TNF-naïve patients (AD: 26.4%; 95% confidence interval [CI]: 12.4, 40.4; RR: 2.0; 95% CI: 1.3, 3.0) and 39.0% and 20.6%, respectively, in TNF-failure patients (AD: 18.1%; 95% CI: 2.8, 33.5; RR: 1.9; 95% CI: 1.1, 3.2). During maintenance, the absolute differences were similar and the RRs were higher for TNF-failure patients for most outcomes. Week 52 remission rates with vedolizumab and placebo were 46.9% and 19.0%, respectively, in TNF-naïve patients (AD: 28.0%; 95% CI: 14.9, 41.1; RR: 2.5; 95% CI: 1.5, 4.0) and 36.1% and 5.3%, respectively, in TNF-failure patients (AD: 29.5%; 95% CI: 12.8, 46.1; RR: 6.6; 95% CI: 1.7, 26.5). Vedolizumab was approved as a gut-selective humanized monoclonal antibody in the European Union. Entyvio was also approved in the U.S. in 2014.

April 1, 2013

Santarus published results from a phase III trial of Uceris (budesonide) for the treatment of ulcerative colitis in Gut. This randomized, placebo-controlled, active-controlled study, CORE II, enrolled 410 patients with active, mild to moderate ulcerative colitis. Subjects received 9mg or 6mg Uceris once daily, or 9mg Entocort EC, or placebo. Data demonstrated Uceris 9mg had a statistically significant benefit over placebo in the primary endpoint of inducing combined clinical and endoscopic remission at week eight. The percentage of patients achieving the primary endpoint of combined clinical and endoscopic remission at week eight in the Uceris 9mg group was significantly greater than that seen in the placebo group (17.4% versus 4.5%, p=0.0047; odds ratio (OR): 4.49). Uceris was well tolerated. The most frequent adverse events were ulcerative colitis relapse, headache, abdominal pain, flatulence, nausea, nasopharyngitis and blood cortisol decrease. Based on these data, the FDA approved Uceris for the indication of remission in patients with active, mild to moderate ulcerative colitis.

February 27, 2012

Takeda issued preliminary results from a phase III trial of vedolizumab for the treatment of ulcerative colitis. This randomized, placebo-controlled, blinded, multicenter trial, GEMINI I, enrolled 895 subjects with moderate-to-severe UC. The subjects received vedolizumab at weeks 0, 2, 6 and then at 4- or 8-week intervals for up to 1 year. The trial met the primary endpoints, providing statistically significant improvements in clinical response in the induction phase and clinical remission in the maintenance phase.

June 27, 2011

Lipid Therapeutics issued results from a phase IIb trial of LT-02 for ulcerative colitis. This randomized, double-blind, placebo-controlled, dose ranging study enrolled 156 subjects with mesalazine-refractory ulcerative colitis who received one of three doses of LT-02 or placebo for a period of 12 weeks. The primary endpoint was the change in SCCAI (Simple Clinical Colitis Activity Index). The subjects who were treated with the highest dose of LT-02 (0.8g four times a day) had a 51% reduction versus a 33% reduction with placebo (p<0.05). The subjects who received one of two lower doses of LT-02 also showed a positive benefit. The safety profile of LT-02 treatment was comparable to placebo at all three doses.

May 16, 2011

Abbott issued results from a phase III trial of Humira for the treatment of ulcerative colitis (UC). This trial enrolled 494 adults with UC who did not respond well to conventional therapy. The subjects were randomized to placebo or Humira (160 mg, week zero; 80 mg, week two; 40 mg every other week starting at week four). Co-primary endpoints were the proportion of subjects with clinical remission at week eight and at week 52. Clinical remission was defined as a Mayo Score of two or less with no individual subscore greater than one. At week eight, 16.5% of subjects treated with Humira achieved clinical remission compared to 9.3% on placebo (p≡0.019). At week 52, 17.3% achieved clinical remission compared to 8.5% on placebo (p≡0.004). The incidence of injection site reaction-related adverse events and hematologic adverse events were greater the Humira arm compared to placebo.

October 4, 2010

Santarus and Cosmo Pharmaceuticals released positive results from a phase III trial of budesonide MMX for the treatment of ulcerative colitis. This U.S and India-based, randomized, double-blind, double-dummy, placebo-controlled four-arm study, CB-01-02/01, enrolled 500 subjects with mild or moderate active ulcerative colitis. The subjects received budesonide MMX 6 mg or 9 mg dosed once daily or placebo. The study also included a reference arm using standard of care: two Asacol 400 mg delayed-release tablets dosed three times a day for a total of 2400 mg daily. The study results show that budesonide MMX 9 mg taken once daily met the primary endpoint of superiority to placebo (p≡0.0143) in achieving clinical remission as measured by the ulcerative colitis disease activity index score after eight weeks of treatment. Both doses were generally well tolerated and the frequency of treatment emergent adverse events was similar to placebo.

November 16, 2009

Hutchison Medipharma reported positive results from a phase IIb trial of HMPL-004 for the treatment of ulcerative colitis. This multi-center, randomized, double-blind, and placebo-controlled study enrolled 223 subjects with active mild-to-moderate UC. The subjects received either 1,200mg or 1,800mg of HMPL-004 per day or placebo for eight weeks. The primary efficacy endpoint was clinical response, defined as the percentage of subjects with a decrease in Mayo score from baseline ≥ 3 and ≥ 30% decrease in the Mayo score, along with either a decrease in rectal bleeding score 1 or absolute rectal bleeding score ≥ 1 at Week 8. For the Intent-To-Treat population, the total clinical response of the two treatment arms at Week 8 was 64% for HMPL-004 vs. 44% for placebo (p ≡ 0.006). For the higher dose 1800 mg/day arm, the clinical response at Week 8 was 73% for HMPL-004 vs. 44% for placebo (p < 0.001). Secondary endpoints included clinical remission, defined as the percentage of patients with a Mayo score ≤ 2 with no individual score > 1 at Week 8; and the mucosal healing rate. The clinical remission at Week 8 was 43% vs. 28% for HMPL-004 vs. placebo (p ≡ 0.03). The mucosal healing rate at Week 8 was 53% vs. 36% for HMPL-004 vs. placebo (p≡0.02). For the higher dose 1800 mg/day arm, the clinical remission at Week 8 was 45% for HMPL-004 vs. 28% for placebo (p ≡ 0.04); and the mucosal healing rate at Week 8 was 60% for HMPL-004 vs. 36% for placebo (p≡0.007). HMPL-004 demonstrated a good safety profile at both dose levels and there were no treatment-related serious adverse events in either of the HMPL-004 arms.

July 9, 2007

Hutchison MediPharma issued positive results from a phase II trial of HMPL-004 for the treatment of ulcerative colitis (UC). This randomized, double-blind, comparator study enrolled 120 subjects with mild to moderate UC in China. Subjects received HMPL-004 at 400 mg doses taken three times a day, orally, or Mesalazine, the current first-line standard of care for eight weeks. The four trial endpoints were clinical symptom score; overall clinical evaluation; colonoscopic score; and safety. In the Intent to Treat population, the clinical symptom score reduction for HMPL-004 was 56% versus 59% for Mesalazine. The overall remission rate (complete and partial remissions) for HMPL-004 was 57% compared to 53% for Mesalazine and 47% for HMPL-004 versus 42% for Mesalazine by colonoscopy. Treatment with HMPL-004 was well tolerated; with the adverse events rate half of that for the Mesalazine group. Hutchison is currently conducting additional phase II trials of HMPL-004 in the United States.

September 19, 2005

Shire announced positive results of a phase II trial of their high-potency formulation of the approved drug mesalamine, SPD476, for the treatment of ulcerative colitis (UC), at the World Congress of Gastroenterology in Montreal. Trial data yielded evidence of efficacy, with subjects in middle and high-dose groups experiencing improvements in symptom severity. There were no withdrawals due to adverse events. This randomized, multi-center, double blind parallel group dose ranging study enrolled patients with mildly-to-moderately active UC, who received one of 3 doses of SPD476 (1.2 g, 2.4 g or 4.8 g) once daily.

May 23, 2005

Centocor announced positive results of a pair of phase III trials of their approved anti-inflammatory Remicade, for the treatment of ulcerative colitis (UC). The drug was seen to produce significantly higher clinical response rates at 8 weeks in both the first (5 mg/kg Remicade: 69%; 10 mg/kg: 62%; placebo: 37%; p<0.001) and second studies (5 mg/kg: 65%; 10 mg/kg: 69%; placebo: 29%; p<0.001). The drug also produced significant efficacy in maintaining response through week 30, achieving clinical remission, promoting mucosal healing, and allowing patients to discontinue corticosteroid therapy. Each trial was a randomized, placebo-controlled study which enrolled 364 UC patients, who received one of two doses of Remicade (5 mg/kg or 10 mg/kg) or placebo on weeks 0, 2, and 6, followed by maintenance doses every 8 weeks. The first trial treated patients through week 22, with final observation at week 30, while the second ran through week 46, with final observation at week 52. These trials served to support the sNDA filing for Remicade in UC, submitted in March 2005.

Enzo Biochem announced positive results from a phase IIb trial of Alequel, for the treatment of Crohn's Disease. Trial data indicated that the drug produced significant efficacy, with 58% of subjects achieving remission, vs. 29% for placebo. Furthermore, clinical response was seen in 67% of subjects receiving Alequel (vs. 29%), and 43% of patients noted improvements in quality of life (vs. 12%). This randomized, placebo-controlled, double blind study enrolled 31 patients with moderate to severe disease, who received oral doses of Alequel or placebo for 27 weeks. Based on these results the company announced that they were planning larger, confirmatory trials.

Synta Pharmaceuticals issued result of a phase IIa trial of STA-5326, for the treatment of Crohn's disease. Trial data yielded significant evidence of efficacy, with 82% of patients in the optimal dosing group (35 mg. once daily) yielding a 70 point or greater reduction in symptom severity score on the Crohn's Disease Activity Index (CDAI). Furthermore, 64% of subjects achieved a 100 point reduction or greater, and 36% achieved a 150 point reduction. No serious adverse events were associated with treatment. This multi-center, open-label study enrolled 73 subjects into one of 5 dosing regimens (ranging from 14 mg-70 mg total daily dose) for 4 weeks. Based on these results, the company announced plans to initiate a large, randomized, double-blind, placebo-controlled Phase 2b trial by the end of 2005.

December 6, 2004

Isis Pharmaceuticals also issued negative results of a pair of identical phase III trials of alicaforsen, for the treatment of Crohn’s disease. Combined results from the two trials indicated that the drug did not meet its primary endpoint, with no significant increase in the incidence of remission at 12 weeks (as defined by a Crohn’s Disease Activity Index (CDAI) score of 150 or less), compared with placebo. Trial data did meet secondary safety endpoints, with a well tolerated intravenous treatment experience and no serious adverse events reported. Both trials were double-blind, placebo-controlled studies, enrolling a total of 331 subjects (151 in the US, 180 in Europe and Israel), who were randomized to receive daily intravenous doses of either 300 mg alicaforsen or placebo thrice weekly for 4 weeks. Based upon these results, Isis announced that they were discontinuing investigation of the drug for the treatment of Crohn’s disease, but still planned to move forward with development for ulcerative colitis.

Isis Pharmaceuticals issued positive results of three phase II trials of alicaforsen for the treatment of ulcerative colitis (UC). The first study compared the drug with placebo, and the results demonstrated that the drug produced significant improvements in disease activity index (DAI), a standardized measure of symptom severity, with a mean 51% reduction at week 18 and 50% reduction at week 30, compared with 18% and 11% for placebo (P=0.04, p=0.03 respectively). Furthermore, mean response duration was more than 6 months for subjects receiving alicaforsen, vs. less than 3 for placebo, and subjects experienced significant improvements in secondary endpoints, including incidence of rectal bleeding, stool frequency, and mucosal healing. The second trial compared the drug with mesalamine (standard therapy), and found that alicaforsen produced non-inferior efficacy and significantly more durable responses than the approved treatment, with average response time greater than 6 months (p<0.05). Finally the third pharmacokinetic study found that patients experienced minimal systemic absorption (<1% of dose), and 75% of subjects experienced improvements in DAI after only 6 weeks of treatment. All three trials demonstrated an excellent tolerability profile, with no discontinuations due to lack of efficacy. Both the placebo-controlled and mesalamine studies were conducted in a randomized, double-blind fashion for 6 weeks. The placebo-controlled study randomized 112 subjects in the US and Europe to receive one of four regimens of the drug via enema (nightly, 10 nightly doses then every other night, every other night, or a half dose nightly for 10 days then every other night) or placebo for 6 weeks. The mesalamine study randomized 159 US subjects to receive nightly doses of either half or full dose alicaforsen (120 mg or 240 mg) or standard therapy nightly for 6 weeks. The pharmacokinetic study was an open-label investigation, enrolling 12 subjects at one US site, all of whom received the drug once nightly for 6 weeks. The company announced plans to begin designing phase III trials for alicaforsen in UC, based on these results.

June 7, 2004

Otsuka America Pharmaceutical and Otsuka Maryland Research Institute reported results from a phase III trial investigating OPC-6535, an oral investigational compound for the treatment of ulcerative colitis (UC). Results showed that both the 25mg and 50mg groups did not reach statistical significance compared with placebo, but did demonstrate superior clinical improvement. The randomized, double-blind, placebo-controlled enrolled 186 subjects with UC who received a once daily dose of OPC-6535 (25 or 50 mg) or placebo for eight weeks. Subjects were also permitted the use of 5-ASA products or sulfasalazine. The primary efficacy endpoint was the proportion of subjects showing a three-point reduction in Disease Activity Index (DAI) from the Baseline score to week eight. The average use of 5-ASA was 2.20 g/day. Results were reported at the 2004 Digestive Disease Week in New Orleans.

Schering AG reported positive follow up results from a phase II trial investigating Leukine (sargramostim/GM-CSF) for the treatment of Crohn's disease. Results showed that clinical response, remission, and improved quality-of-life, were maintained after drug therapy was discontinued. Data showed that 15% of subjects had a response to therapy maintained for at least six months. Leukine was generally well-tolerated and not associated with serious adverse events. The multi-center, randomized, double-blind, placebo-controlled study enrolled 124 patients Subjects were administered Leukine or placebo daily for eight weeks.<

June 1, 2004

Protein Design Labs reported negative results from a phase II trial investigating daclizumab, a humanized antibody being developed for the treatment of ulcerative colitis. Results showed the study did not reach its primary endpoint, the proportion of patients who achieved remission at week eight, at either of the dose levels tested. Data showed that treatment with daclizumab was well tolerated. The randomized, double-blind, placebo-controlled study enrolled 159 subjects at 40 sites in North America and Europe. Subjects received daclizumab 1 mg/kg at a four-week interval, or 2 mg/kg every two weeks, or placebo. The primary study objectives were safety and achievement of remission, defined by the Mayo score. Due to these results the company will stop development of daclizumab as a treatment for ulcerative colitis.

January 12, 2004

VSL Pharmaceuticals reported positive results from a clinical trial investigating VSL#3, a probiotic therapy for the treatment of ulcerative colitis. Results showed that the once daily treatment of VSL#3 was shown to be highly effective in maintaining antibiotic induced remission of post-surgical pouchitis in subjects with ulcerative colitis (UC). Data showed that remission was maintained at one year in 17 subjects (85%) with VSL#3 and one subject (6%) with placebo. The placebo-controlled, double-blind study enrolled 36 subjects with recurrent or refractory pouchitis as defined by a Pouchitis Disease Activity Index (PDAI) score of greater than or equal to 7. It was conducted at St. Mark's Hospital in the UK and in Bologna, Italy. Results were reported in the December issue of the journal Gut.

June 2, 2003

Axcan Pharma reported positive results from a pilot study investigating mesalamine rectal gel, an anti-inflammatory agent for the treatment of ulcerative colitis. Results showed a statistically significant difference between baseline and end-of- treatment Disease Activity Index, a measure of disease severity based on symptom scores. The pilot study was designed to test the efficacy and safety of mesalamine gel in subjects with mild to moderate distal ulcerative colitis. Subjects were included in this study based on a disease activity index greater than three. All received a single rectal dose of 4 g of mesalamine in 60-mL gel and received a similar dose for four consecutive days 48 hours.

May 26, 2003

Millennium Pharmaceuticals reported positive results from a phase II trial investigating MLN02, a monoclonal antibody for the treatment of ulcerative colitis. Results showed statistically significant improvements in the clinical remission rates in subjects treated with MLN02 compared with placebo. On day 43, remission rates for the two MLN02 dose groups (0.5 mg/kg and 2.0 mg/kg) were 33% and 34%, compared to 15% for subjects in the placebo group. Data also showed that 29% of subjects in the 0.5 mg/kg group and 14% of subjects in the 2.0 mg/kg group had an Modified Baron Score of zero, compared with 8% of those who received placebo A modified Baron score of zero implies the presence of normal epithelium when observed during an endoscopy. The double blind, multi-center study enrolled 181 subjects with mild to moderately active ulcerative colitis. The results were presented at Digestive Disease Week.

April 14, 2003

SangStat reported mixed preliminary results from two-phase II trials investigating RDP58, an anti-inflammatory for the treatment of ulcerative colitis and Crohn’s disease. In the ulcerative colitis study, results showed a peak response rate of 77% and a 71% remission rate among subjects taking RDP58 (200mg/day). Subjects taking RDP58 (300mg/day) achieved similar statistically significant response and remission rates. In the Crohn's disease study, although 66% of subjects treated with RDP58 (200mg/day) achieved a response, it was not a statistically significant difference from placebo. The randomized, blinded, placebo-controlled, multi-center studies enrolled a total of 231 subjects. Subjects received placebo, 100mg/day, 200mg/day, or 300mg/day of RDP58 for 28 days.

September 3, 2002

In a phase IIa study of P54 involving 27 subjects with steroid-dependent ulcerative colitis or Crohn's disease, the primary endpoint was not achieved. The main objective of the study was to determine whether or not treatment with P54 could reduce the dose of steroid required to maintain disease remission. There was a 45% reduction in steroid use for study subjects treated with P54. The same measure for the placebo group was not significantly different. However, in a sub-group of subjects whose baseline calprotectin level was below 450 mg I-1, all P54-treated subjects were able to withdraw from steroid therapy, while in the placebo group, only 44% of subjects were able to discontinue steroid use. P54 is being developed by Phytopharm.