Date: 2016-05-05
Type of information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in The New English Journal of Medicine
Company: Celgene (USA - NJ)
Product: ozanimod (RPC1063)
Action
mechanism: sphingosine 1-phosphate receptor (S1PR) modulator. Ozanimod is a small molecule sphingosine 1-phosphate 1 and 5 receptor modulator in development for immune-inflammatory indications including relapsing multiple sclerosis and inflammatory bowel disease. Treatment with S1P receptor modulators is believed to work by interfering with S1P signaling and blocks the response of lymphocytes to exit signals from the lymph nodes, sequestering them within the nodes. The result is thought to be a downward modulation of circulating lymphocytes and anti-inflammatory activity by inhibiting cell migration to sites of inflammation.
Disease: moderate to severe ulcerative colitis
Therapeutic area: Autoimmune diseases - Inflammatory diseases - Digestive diseases
Country:
Trial
details: TOUCHSTONE is a phase 2, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of Ozanimod (also known as RPC1063) with placebo in patients with moderate to severe active ulcerative colitis. A total of 197 patients were randomized and treated once daily with 1 mg ozanimod (n=67), 0.5 mg Ozanimod (n=65) or placebo (n=65) for 8 weeks (the induction phase). The primary endpoint was the proportion of patients in remission (Mayo score ? 2, no subscore > 1) at week 8. 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, Holter monitoring, pulmonary function testing, optical coherence tomography and AEs.
For the maintenance phase, patients who achieved a clinical response at week 8 continued with their original treatment through week 32.
Latest
news: * On May 5, 2016, the phase II TOUCHSTONE trial evaluating ozanimod induction and maintenance in patients with moderate-to-severe ulcerative colitis was published in The New England Journal of Medicine . Histologic data from the phase II TOUCHSTONE trial were presented at the Digestive Disease Week meeting in May. The phase III TRUE NORTH trial evaluating ozanimod in patients with moderate-to-severe ulcerative colitis continues to enroll with data expected in 2018. * On October 26, 2015, Celgene presented results from the maintenance phase of the TOUCHSTONE phase 2 clinical trial of Ozanimod, an investigational compound, in patients with moderate to severe ulcerative colitis at the United European Gastroenterology (UEG) Week in Barcelona, Spain . This abstract was awarded a UEG Week Top Abstract Prize, which is given to the top five abstracts submitted to UEG Week. * On October 19, 2015, Celgene announced detailed results from the maintenance phase of the TOUCHSTONE phase 2 clinical trial of ozanimod, in patients with moderate to severe ulcerative colitis at the American College of Gastroenterology (ACG) Annual Scientific Meeting in Honolulu . In the trial, a significantly greater proportion of patients on ozanimod achieved or maintained clinical remission at 32 weeks compared with those on placebo.
* On March 18, 2016, Celgene announced that additional data of exploratory endpoints from the TOUCHSTONE phase 2 clinical trial of ozanimod in patients with moderate to severe ulcerative colitis were presented at the 11th Congress of the European Crohn's and Colitis Organisation (ECCO) in Amsterdam . Ozanimod is an investigational selective S1P 1 and 5 receptor modulator. These results, included in a digital oral presentation, showed that ozanimod 1 mg resulted in improvements in histologic features and remission in patients treated over 32 weeks. The trial evaluated the efficacy and safety of 0.5 mg and 1 mg doses of ozanimod compared with placebo after eight weeks of treatment (induction phase) in 197 patients with moderate to severe active ulcerative colitis. Patients who achieved a clinical response at week 8 continued with their original treatment through week 32 in a maintenance phase. The primary endpoint was the proportion of patients in remission at week 8. Secondary endpoints were: the proportion of patients achieving a clinical response, the proportion of patients with mucosal improvement and the change from baseline in Mayo score. Histologic improvement and remission with ozanimod at the same time points was assessed as an exploratory endpoint. Biopsies were scored by a central pathologist blinded to treatment and sequence. Previously reported results showed TOUCHSTONE met its primary endpoint and secondary endpoints with statistical significance for patients on the 1 mg dose of ozanimod versus placebo.
In the histology results from the TOUCHSTONE study presented at ECCO, histologic improvement, which was determined by assessing the change from baseline in Geboes score (12.92 in ozanimod 1 mg, 14.36 in ozanimod 0.5 mg and 13.94 placebo; a decrease in absolute score indicates an improvement), was significantly greater for the 1 mg dose than for placebo at both week 8 [Geboes (-4.37 vs. -2.20, p=0.0345)] and week 32 [Geboes (-5.50 vs. -2.24, p=0.0033)]. The 0.5 mg dose resulted in greater improvement than placebo but the difference did not reach statistical significance at either time point.
At week 8, although there was an apparent numerical dose response in the proportion of patients reaching histologic remission, defined as a Geboes score less than 2, there were no significant differences. However at week 32, 31 percent (21/67) of patients on ozanimod 1 mg achieved histologic remission compared with 8 percent (5/65) on placebo (p=0.0006), and 23 percent (15/65) of patients on ozanimod 0.5 mg achieved histologic remission (p=0.0164 vs. placebo).
Adverse events (AEs) from the phase 2 study occurred in 26/67 (38.8 percent) patients in the ozanimod 1 mg arm, 26/65 (40.0 percent) in the ozanimod 0.5 mg arm and 26/65 (40.0 percent) in the placebo arm. The most common AEs were worsening of ulcerative colitis (3, 2 and 5 patients in the arms outlined above, respectively) and anemia (0, 3 and 4 patients in the arms outlined above, respectively). No AEs of special interest (cardiac, pulmonary, ophthalmologic, hepatic or serious infection) were reported during the induction or maintenance phase.
Previously reported results showed TOUCHSTONE met its primary endpoint and secondary endpoints with statistical significance for patients on the 1 mg dose of Ozanimod versus placebo in the 8-week induction phase.
The abstract is titled "A randomized, double-blind, placebo-controlled trial of ozanimod, an oral s1p receptor modulator, in moderate to severe ulcerative colitis: results of the maintenance period of the touchstone study. The week 32 results from Touchstone" Based on this trial results, Celgene looks forward to continued study in phase 3 trials.
The TOUCHSTONE trial evaluated the efficacy and safety of 0.5 mg and 1 mg doses of ozanimod compared with placebo after eight weeks of treatment (induction phase) in 197 patients with moderate to severe ulcerative colitis. The primary endpoint was the proportion of patients in remission at week 8. Secondary endpoints were: the proportion of patients achieving a clinical response, the proportion of patients with mucosal improvement and the change from baseline in Mayo score. Previously reported results showed TOUCHSTONE met its primary endpoint and secondary endpoints with statistical significance for patients on the 1 mg dose of Ozanimod versus placebo in the 8-week induction phase.
For the maintenance phase, 103 patients who achieved a clinical response at week 8 continued with their original treatment for an additional 24 weeks; of these, 91 patients completed 32 weeks of treatment.
Twenty one percent (14/67) of patients on Ozanimod 1 mg achieved or maintained clinical remission at week 32 [compared with 6 percent (4/65) on placebo (p=0.0108) and clinical response at week 32 was achieved or maintained by 51 percent (34/67) and 20 percent (13/65) of patients, respectively (p=0.0002)].
Mucosal improvement was also significantly more likely with Ozanimod 1 mg than with placebo at week 32 [22/67 (32.8 percent) vs. 8/65 (12.3 percent); p=0.0046)].
Adverse events (AEs) occurred in 11/42 (26.2 percent) patients in the Ozanimod 1 mg arm, 4/36 (11.1 percent) in the Ozanimod 0.5 mg arm and 8/25 (32.0 percent) in the placebo arm. The most common AEs were worsening of ulcerative colitis (1, 0 and 2 patients, respectively) and urinary tract infection (0, 1 and 1). No AEs of special interest (cardiac, pulmonary, ophthalmologic, hepatic, malignancy or serious infection) were reported during the maintenance phase.
