dm+d

39138711000001105

New Medicines

ZeposiaRelapsing-remitting multiple sclerosis (MS)

Information

Zeposia
New molecular entity
Bristol-Myers Squibb
Celgene

Development and Regulatory status

Launched
Launched
Launched
November 2020
Nov 20Available in the UK. Cost is: Initiation pack=£343.25 (4 x 230 microgram grey cap, 3 x 460 microgram grey/orange cap) and 28 x 920 microgram capsule pack=£1373.00 [29].
Jun 20Zeposia launched in US after the pandemic caused a delay in March.[27]
May 20Licensed for RRMS in EU [28].
Mar 20FDA approved ozanimod for the treatment of adults with relapsing forms of multiple sclerosis (RMS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.[24]
Mar 20Recommended for EU approval by CHMP - the full indication is "The treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease as defined by clinical or imaging features." It should be prescribed by physicians experienced in the treatment of multiple sclerosis [25].
Feb 20Analysts predict this will be one of the top 10 most-anticipated new US drug launches of 2020 based on estimated global sales in 2024 [23].
Nov 19Celegene Corporation aquired by Bristol Myers Squibb
Jun 19MA application accepted by EMA. The Submission was based on pivotal efficacy and safety data from the SUNBEAM and RADIANCE past B trials [22].
Jun 19The FDA accepted the NDA that Celgene had submitted in March 19 [22].
Mar 19Filed in EU [19].
Mar 19Celgene refiles for FDA approval of ozanimod in MS after looking to ongoing clinical pharmacology programs for data to address the FDA’s demands to address shortcomings in the preclinical and clinical pharmacology parts of its original data package.[18]
Mar 19Celgene announced plans to file for regulatory approval in the EU, with plans to refile in the US this month.[17]
May 18Celgene also intends to file in the EU Q1 2019 [16].
May 18Celgene plans to file 2nd NDA for Ozanimod in 2019. They confirmed that the FDA will not require any additional human studies although there will be some necessary non-clinical bridging studies.[16]
Feb 18Filing in the US refused due to incomplete nonclinical and clinical pharmacology information [15].
May 17Celgene plans to file an NDA with the FDA by end of 2017 in relapsing forms of MS [13].
Apr 17Celgene expects to file a US New Drug Application (NDA) soon; based on clinical trial data, the company expects to highlight an improved safety profile, particularly cardiac, as differentiation from fingolimod (Gilyena) [12].
Apr 15Receptos continues to be on track to complete this Phase 3 clinical development program in the first half of 2017 [7].
Dec 14Receptos is on track to complete the PIII clinical development program in 2017 [6].

Category

Selective sphingosine 1-phosphate 1 receptor (S1P1R) modulator
In a population of 100,000, 110 people will have MS and 39 will have RRMS. 31% of these are on, or will have received, disease modifying agents. In 2011-12, there were 33,566 hospital admissions due to MS in England.
Relapsing-remitting multiple sclerosis (MS)
Oral

Further information

Yes

Trial or other data

Oct 21Celgene announce data from DAYBREAK extension study (n=2494); treatment with ozanimod demonstrated a low annualised relapse rate of 0.103 and ≥70% of patients were relapse-free at four years. Safety was consistent with prior findings and established safety profile in up to 5 years of follow-up [30].
Sep 19PIII RADIANCE RCT (n=1,695) is published; it found a lower annualised relapse rate for ozanimod 1mg and 0.5 mg vs interferon beta-1a (0.17, 0.22 and 0.28 respectively; RR for 1mg vs interferon = 0.62, 95% CI 0.51-0.77, RR for 0.5 mg vs interferon = 0.79, 0.65-0.96 [21].
Sep 19PIII SUNBEAM RCT (n=1,346) is published; it found a lower annualised relapse rate for ozanimod 1mg and 0.5 mg vs interferon beta-1a (0.18, 0.24 and 0.35 respectively; RR for 1mg vs interferon = 0.52, 95% CI 0.55-0.86, RR for 0.5 mg vs interferon 0.69, 0.55-0.86) [20].
Mar 19Potential next-to-market oral agent for the treatment of relapsing multiple sclerosis
May 18Since the initial Refusal to File letter issued by the FDA, Celgene released additional ozanimod data from new analyses of the SUNBEAM and RADIANCE Part B trials. The new analyses show dose-dependent effects of ozanimod on annualized relapse rate (ARR) vs. Avonex that were consistent with the overall ARR primary endpoint. Celgene said exploratory endpoints showed reductions in cortical grey matter and thalamic volume loss consistent with the reductions in whole brain volume loss in previous reports and noted that the clinical efficacy and safety data from these trials should support its efforts in gaining approval.[16]
Oct 17Celgene announce efficacy and safety data from SUNBEAM trial. Study (n=1346) reported a reduction in annualised relapse rate (ARR) for oral ozanimod 1 mg (ARR=0.18, p<0.0001) and ozanimod 0.5 mg (ARR=0.24, p=0.0013) compared with weekly intramuscular interferon beta-1a (ARR=0.35) over an average of 13.6 months of treatment [14].
May 17Celgene announces late-stage data from a second pivotal RADIANCE trial showing ozanimod was better than Avonex in reducing annualized relapse rates, hitting its primary endpoint. Unfortunately, when data from this study was pooled with data from the PIII SUNBEAM trial, there was a very low rate of disability progression across the three treatment groups, and ozanimod did not reach statistical significance compared to Avonex when it came to meeting its disability endpoint. Both doses of ozanimod (0.5mg and 1mg) did show statistically significant reductions in brain atrophy compared to Avonex in each phase 3 trial [13].
Feb 17Celgene reports that ozanimod hit its targets in a phase 3 trial, beating out Avonex, at annualized relapse rates among patients with relapsing forms of the disease [11].
Sep 16Celgene announce extension data following the RADIANCE study (n=258). The unadjusted annualized relapse rate (ARR) was 0.3 for ozanimod 0.5mg and 0.19 for ozanimod 1mg at weeks 96. ARR was 0.26 and 0.15 at week 48 for the respective doses [10].
Feb 16Results of RADIANCE study (NCT01628393) published in the Lancet Neurology. In this RCT (n=258) ozanimod 0.5mg and 1mg reduced the mean cumulative number of gadolinium-enhancing lesions at week 24 (OR 0.16 [95%CI 0.08-0.30] and OR 0.11 [0.06-0.21] respectively). No serious infectious or cardiac adverse events were reported [9].
Oct 15Receptos completes enrolment in a PIII trial in USA, Belarus, Bosnia and Herzegovina, Bulgaria, Canada, Croatia, Estonia, Georgia, Germany, Hungary, Latvia, Lithuania, Moldova, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, Serbia, Spain, Sweden, Ukraine and United Kingdom (NCT02294058) [8].
Jun 15The RADIANCE trial met the primary endpoint, reduction in the cumulative number of total gadolinium-enhancing (GdE) lesions determined by MRI from wk 12 to wk 24 of study treatment. Pts on RPC1063 experienced a statistically significant reduction in GdE lesions of 86% at both 0.5 mg and 1.0 mg compared to pts on placebo. [5]
Apr 15Enrolment into the RADIANCE PIII study complete [7].
Dec 14PIII SUNBEAM trial Of RPC1063 In relapsing Multiple Sclerosis (MS) initiated. SUNBEAM trial is a randomised, double-blind study designed to compare 0.5 mg and 1.0 mg of RPC1063 against interferon beta-1a (Avonex®) in 1,200 patients with RMS. The primary objective for the RADIANCE and SUNBEAM trials is to assess whether RPC1063 is superior to Avonex® in reducing the annualized relapse rate in patients after two years of therapy and one year of therapy, respectively. Both Phase 3 trials are being conducted under Special Protocol Assessment (SPA) agreement with the FDA [6].
Feb 14NCT02047734 (RADIANCE study) is a PII/III, multi-centre, randomized, double-blind, placebo-controlled (part a) and double-blind, double-dummy, active-controlled ( vs IFN β-1a, part b), parallel group study to evaluate the efficacy and safety of RPC1063 in 1200 patients with relapsing multiple sclerosis. The primary outcome is annualized relapse rate (ARR) at the end of Month 24. The study starts Nov 13 and is due to complete Nov 17 [4].
Jan 14First patients in the PIII portion of RADIANCE enrolled [3]
Dec 13Receptos has completed a pre-planned interim analysis of the PII portion of the PII/III RADIANCE study (NCT01628393). The PII portion is a randomized, double-blind study comparing 0.5mg and 1mg of RPC1063 vs placebo in 210 patients with RMS. The Data Monitoring Committee has approved continuation of the PII portion and initiation of the PIII portion of the study. Interim data suggest that the overall adverse event profile appears relatively balanced between RPC1063 and placebo groups, with no serious adverse events; modest impact on heart rate for RPC1063-treated patients with no cardiac adverse events observed to date; low rates of liver enzyme elevations appear supportive of a favourable hepatotoxicity profile [1]
Jan 13Receptos has obtained Special Protocol Assessment (SPA) agreement from the FDA on the clinical trial design for both the PIII portion of RADIANCE as well as a second planned RMS PIII study. The second PIII study is planned to begin after the top-line results of the PII portion of RADIANCE are reported, expected in mid-2014 [2]

Evidence based evaluations

Moderate-to-severe active ulcerative colitis

Information

Licence extension / variation
Bristol-Myers Squibb
Celgene

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Launched
Oct 21Recommended for EU approval by CHMP – the additional indication is “for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent” [15].
May 21U.S. FDA has approved ozanimod 0.92 mg for the treatment of adults with moderately to severely active ulcerative colitis [13].
Feb 21US FDA accepts sNDA with priority review [12].
Dec 20EMA has validated its Marketing Authorization Application for ozanimod for the treatment of adults with moderately to severely active ulcerative colitis (UC) [11].
Jun 20Trade name is Zeposia [10]
Dec 18Still in PIII trials in the UK, EU and US [8]

Category

Selective sphingosine 1-phosphate 1 receptor (S1P1R) modulator
About two in 1,000 people in the UK develop UC; prevalence is about 120,000 to 150,000 people. 50% will experience a relapse in any year
Moderate-to-severe active ulcerative colitis
Oral

Further information

Yes

Trial or other data

Oct 21PIII RCT (NCT02435992; n=1012) reports higher rate of clinical remission in patients who received ozanimod vs placebo during both induction (18.4 vs. 6.0%, p<0.001) and maintenance (37 vs. 18.5% [among patients with response at week 10], p<0.001) [14].
Jun 20PIII results from True North trial found both primary endpoints were highly statistically significant (p-value < 0.0001) for induction of clinical remission at Week 10 and maintenance at Week 52. The study also met key secondary endpoints of clinical response and endoscopic improvement [10].
Dec 19A PIII induction and maintenance trial (NCT02435992), and its open-label extension (NCT02531126) are still recruiting subjects, with estimated primary completion dates of Jun 2020 and Feb 2022, respectively [9].
Dec 18Recruitment in the PIII TRUE NORTH registration trial (NCT02435992) is still ongoing, with an estimated primary completion date of July 2020. The open-label extension trial (NCT02531126) is ongoing, with an estimated primary completion date of March 2022 [8].
Dec 17PIII study ongoing, with an estimated primary completion date of Sept 2018 [7]
Oct 16Celgene announces positive midstage data from its PII Touchstone study. These data came from across three treatment arms in those that entered the open-label extension of the trial if they did not respond to treatment after the induction phase, relapsed during the maintenance phase, or completed the maintenance phase (170 of the 197 patients). The point of this open-label extension phase was to look at how well the higher dose 1-mg form of the med might work long-term, and its safety profile. During the extension period, Celgene said ozanimod resulted in a decrease in mean partial Mayo Score (pMS) in all treatment arms. For patients who had been treated with the lower dose ozanimod 0.5-mg during the double-blind portion of the study--and were then switched to the higher 1-mg dose--mean pMS score decreased from 4.5 at entry into the extension period, to 1.7 after 44 weeks. And for patients who had been treated with ozanimod 1-mg initially, and then stayed on it for the extension phase of the study, mean pMS score decreased from 3.3 at entry into the extension period to 1.9, again after 44 weeks. Lastly, for those on placebo who were switched to ozanimod 1-mg for the extension phase of the study, mean pMS score decreased from 4.6 to 1.7 at week 44. Celgene also said its data from the extension phase showed a decrease in the proportion of patients with rectal bleeding and moderate or severe diarrhoea [6].
May 16Results of PII (NCT01647516) study, published in the New England Journal of Medicine, found ozanimod, an oral agonist of sphingosine-1-phosphate receptor subtypes 1 and 5 at daily dose of 1mg resulted in slightly higher rate of clinical remission vs. placebo (16 vs. 6%; p=0.048). Trial was not large/long enough to establish clinical efficacy/safety [5].
Oct 15Celgene announces results from the maintenance phase of the TOUCHSTONE trial. 103 patients who achieved a clinical response at week 8 (reduction in Mayo score of ≥3 and ≥30 percent with a decrease in rectal bleeding score of ≥1 or a rectal bleeding score ≤1) 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 [4].
Jul 15A Phase III trial of ozanimod in UC is currently underway with data expected in 2018 [3]
Mar 15The maintenance period of the TOUCHSTONE trial is ongoing. If results are favourable, Receptos plans to initiate a PIII program in 2015 to compare the safety and efficacy of 1mg RPC1063 to placebo in patients with UC [2].
Oct 14Positive early results for the PII TOUCHSTONE trial of RPC1063 (n=199) in Ulcerative Colitis (UC) reported. This randomised, double-blind, placebo-controlled trial assessed efficacy, safety and tolerability of two orally administered doses (0.5 mg and 1 mg) of RPC1063 vs. placebo in pts with UC across 57 sites in 13 countries. The primary endpoint (proportion of pts in clinical remission at week 8 as defined by the Mayo scoring criteria), was achieved by 16.4% and 13.8% of pts on RPC1063 1mg and 0.5mg respectively, vs. 6.2% on placebo, p < 0.05 for 1mg dose vs. placebo and not significant for the 0.5mg dose. Clinical response was achieved by 58.2% of pts on the 1 mg dose of RPC1063 and 36.9% of pts on placebo (p < 0.05). RPC1063 was generally well tolerated with similar incidence of adverse events across the active and placebo groups and no concerning safety signals. The maintenance period of the trial is ongoing and plans to initiate a PIII study programme of RPC1063 in UC in 2015 are underway. [1]

Moderate-to-severe active Crohn's disease in adults

Information

Licence extension / variation
Bristol-Myers Squibb
Celgene

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Selective sphingosine 1-phosphate 1 receptor (S1P1R) modulator
The incidence and prevalence of Crohns disease is increasing worldwide, with a systematic review reporting the highest incidence in Australia (29.3 per 100,000 population), Canada (20.2 per 100,000 population) and northern Europe (10.6 per 100,000). Prevalence in the UK is about 145 per 100.000 population [1].
Moderate-to-severe active Crohn's disease in adults
Oral

Trial or other data

Jan 21Four PIII trials are ongoing: Induction trials 1 and 2, and an open-label extension are still recruiting subjects with estimated primary completion dates of Jun 23, Apr 23, and Jun 26, respectively. A maintenance trial is also recruiting subjects, with an estimated primary completion date of Jun 24 [6]