ABSTRACT
Background: Ozanimod, an oral sphingosine 1-phosphate receptor modulator, is approved in the European Union and United States for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS). A previous analysis of data from UC and multiple sclerosis (MS) open-label extension (OLE) studies showed that most patients with confirmed coronavirus infection (COVID-19) had nonserious infections, recovered, and did not require ozanimod discontinuation. Some immunomodulators and biologics may attenuate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response;therefore, this analysis evaluated humoral immune responses and predictors of response to SARS-CoV-2 vaccination in patients with RMS treated with ozanimod. Method(s): RMS participants who completed a phase 1-3 ozanimod trial could enter an OLE trial (DAYBREAK;NCT02576717) of ozanimod 0.92 mg/d. This analysis (January 2020-October 2021) included DAYBREAK participants receiving mRNA or non-mRNA SARS-CoV-2 vaccines (1-2 doses, vaccine-dependent) with no evidence of recent infection (ie, nucleocapsid antibody negative). Receptor binding domain (RBD) antibody titers were analysed (Elecsys Anti-SARS-CoV-2 assay;Roche Diagnostics, Basel, Switzerland) prevaccination, after 1 dose, and <4, 4-8, 8-12, and >12 weeks after full vaccination. Fisher's exact tests and regression models determined association with seroconversion and log2 antibody levels. Result(s): Demographics were similar between the mRNA and nonmRNA vaccine recipients (Table). Seroconversion (>=0.8 U/mL spike RBD antibody) occurred in 100% (80/80) of fully vaccinated mRNA recipients and 62% (18/29) of fully vaccinated non-mRNA vaccine recipients. Higher spike RBD antibody levels were seen with mRNA (grand mean: 512.6 U/mL, range: 1.3-4572.0) vs non-mRNA (grand mean: 39.3 U/mL, range: 0.4-368.5) vaccines at all time points studied. Vaccination with a non-mRNA vaccine predicted lower antibody levels (beta: -5.90 [95% CI: -6.99 to -4.82];P<0.0001) and less seroconversion (Fisher's exact: P<0.0001), whereas age, sex, body mass index, and absolute lymphocyte count (ALC) did not. Conclusion(s): Participants receiving ozanimod developed humoral immune response to SARS-CoV-2 vaccines, with 100% seroconversion after mRNA vaccination;this was independent of demographic characteristics and ALC levels at time of vaccination. However, some participants developed lower antibody concentrations and may benefit from booster doses. These findings provide important information for physicians managing ozanimod-treated patients with UC or MS.
ABSTRACT
Introduction: Multiple sclerosis disease-modifying therapies, including sphingosine 1-phosphate receptor modulators, may attenuate the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. Objective(s): To describe the serological response and clinical outcomes of SARS-CoV-2 infection and vaccination in ozanimodtreated participants with relapsing multiple sclerosis (RMS) in an open-label extension (OLE) trial. Method(s): Participants with RMS who completed a phase 1-3 ozanimod trial could enter an OLE trial (DAYBREAK-NCT02576717) of ozanimod 0.92 mg/d. This analysis (January 2020-October 2021 [serology] and January 2022 [clinical outcomes]) included DAYBREAK participants who received SARSCoV-2 vaccines (fully vaccinated) and/or had COVID-19 adverse events. Receptor binding domain (RBD) antibody levels and nucleocapsid antibody positivity were analysed using Roche Elecsys assays. Log2 RBD antibody levels were compared between groups using t-tests. Result(s): Among the 148 vaccinated participants with serological data, 39 participants had serologically confirmed SARS-CoV-2 exposure. After full vaccination, RBD seroconversion occurred in 100% (n=39/39) of nucleocapsid antibody positive and most (n=98/109) nucleocapsid antibody negative participants (with 100% seroconversion in nucleocapsid antibody negative participants receiving mRNA vaccines [n=80/80]). Significantly higher RBD antibody levels were observed in the vaccinated nucleocapsid antibody positive vs negative vaccinated participants (median [range], U/mL: 2259 [12.4-44260.0] vs 138 [0.4-4572.0], respectively, P<0.0001). COVID-19 adverse events were reported in 15/148 participants, all nonserious events (confirmed=12, suspected= 3). Ozanimod treatment was continued in 9 participants and interrupted in 5 (1 unknown). Eleven participants recovered by the time of data cut off, and one recovered with sequelae (cough and loss of sense of smell). Conclusion(s): Participants with RMS receiving ozanimod mount a serologic response to SARS-CoV-2 infection and vaccination. COVID-19 events in these fully vaccinated participants were nonserious. A limitation of this research is its retrospective nature and the potential for selection bias towards higher-risk individuals.
ABSTRACT
Introduction: Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator approved in multiple countries for treatment of adults with relapsing forms of MS (RMS) or moderately to severely active ulcerative colitis. Objective(s): To describe incidence rates (IRs) of treatmentemergent adverse events (TEAEs) in patients with RMS treated with ozanimod 0.92 mg in phase 3 and open-label extension (OLE) trials. Method(s): In phase 3 trials, adults with RMS were randomised to oral ozanimod 0.46 or 0.92 mg/d or intramuscular interferon beta-1a 30 mug/wk for >=12 months (SUNBEAM-NCT02294058) or 24 months (RADIANCE-NCT02047734). Completers were eligible to enrol in the ongoing OLE trial (DAYBREAK-NCT02576717) of ozanimod 0.92 mg/d. IRs and 95% confidence intervals (CI)/1000 person years (PY;100,000 PY for malignancies) were calculated for TEAEs during the pooled phase 3 trials and at yearly intervals during the OLE (2 Feb 2021 cutoff). Result(s): In patients treated with continuous ozanimod 0.92 mg (n=882), the IR [95%CI]/1000 PY decreased over time (from phase 3 to OLE >36 months) for overall TEAEs (896.1 [826.8-971.3] vs 259.1 [180.0-372.8]);infections (300.5 [268.9-335.9] vs 144.9 [109.2-192.3]);opportunistic infections (12.0 [7.4-19.6] vs 4.3 [1.4-13.3]);cardiac disorder TEAEs (22.8 [16.0-32.7] vs 4.2 [1.4-13.0]);and hepatic disorder TEAEs (77.0 [63.1-94.0] vs 15.1 [8.1-28.1]). The most common opportunistic infections in phase 3 trials and the OLE were oral herpes and herpes zoster (including varicella zoster virus). IRs remained relatively stable for serious TEAEs (31.2 [23.0-42.4] vs 30.5 [19.7-47.3]), malignancies (372.2 [120.8-868.5] vs 276.7 [33.5-999.6]/100,000 PY), confirmed macular edema (n/N, 1/882;0.7 [0.1-5.3] vs n/N, 1/687;1.4 [0.2-9.8]), and pulmonary TEAEs (11.3 [6.8-18.7] vs 0.0 [0.0-9.9]). The IR for serious infections remained relatively stable until OLE >36 months, at which time the IR increased (6.7 [3.5-12. 9] vs 9.8 [4.7-20.6]), which may be partially due to the COVID-19 pandemic. The most common serious infections were appendicitis (n/N, 3/882) and pyelonephritis acute (n/N, 1/882) (phase 3), and pneumonia (n/N, 4/762) and coronavirus infection (n/N, 3/762) (OLE). Most coronavirus infections were nonserious (31/34 [91.2%]). Conclusion(s): In this post hoc analysis, IRs of TEAEs in patients with RMS treated with continuous ozanimod 0.92 mg in phase 3 and OLE trials generally declined or remained stable over up to 5 years of observation time.
ABSTRACT
Introduction: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of adults with either relapsing forms of multiple sclerosis (RMS) or moderately to severely active ulcerative colitis. Objective(s): To report the safety and efficacy of extended exposure to ozanimod from an ongoing open-label extension (OLE) trial. Method(s): Patients with RMS who completed a phase 1, 2, or 3 ozanimod trial were eligible to enrol in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d. The primary objective was to evaluate safety in the overall population;treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualised relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/ enlarging T2 and gadolinium-enhancing (GdE) magnetic resonance imaging (MRI) brain lesions were reported for patients who entered the OLE from an active-controlled phase 3 trial. Result(s): In total, 2639 patients completed the parent trials;this interim analysis (datacut 1 February 2022) included 2494 patients with mean (range) ozanimod exposure of 56.4 (0.03- 74.7) months (11732.2 patient-years) in the OLE. In the OLE, 2199 patients (88.2%) had any TEAE, 352 (14.1%) had a serious TEAE (SAE), and 89 (3.6%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent trial treatment group. The most common TEAEs (based on preferred terms) were nasopharyngitis (20.6%), headache (16.9%), upper respiratory tract infection (11.9%), COVID- 19 infection (11.5%), and lymphopenia (10.5%), which were generally similar to parent trial observations (excluding COVID-19 infection). Adjusted ARR in the OLE was 0.099 (95% CI, 0.083-0.119). After 60 months of treatment, 68% of patients were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 15.9% and 14.0% of patients in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 60 months was similar, regardless of parent trial treatment group (range, 0.77-0.98), as was mean number of GdE lesions at month 60 (range, 0.057-0.065). Conclusion(s): The safety and tolerability profile of ozanimod in DAYBREAK was consistent with prior reports. Ozanimod treatment demonstrated sustained efficacy on clinical and MRI measures of disease activity and on disability progression.
ABSTRACT
Introduction: COVID-19 emerged in late 2019. It is unclear whether selective sphingosine 1-phosphate (S1P) receptor modulators affect clinical outcomes of COVID-19 in patients with relapsing multiple sclerosis (RMS), including those who received SARS-CoV-2 vaccination. Objective(s): To characterise COVID-19 outcomes and vaccine breakthrough infections during ozanimod use, an S1P1 and S1P5 modulator, for treatment of RMS in an ongoing open-label extension (OLE) study. Method(s): DAYBREAK (NCT02576717), an OLE study of ozanimod 0.92 mg/d, began 16Oct2015. Patients who completed a phase 1-3 ozanimod RMS trial were eligible;>90% are from Eastern Europe. In this post hoc analysis, COVID-19 events from 1Nov2019 to 28Jan2022 in DAYBREAK were identified by MedDRA 24.1 COVID-19 SMQ (narrow scope). Each patient's most recent infection and all postvaccination infections were characterised. Result(s): Of 2181 patients in DAYBREAK during the analysis period, 319 (14.6%) developed COVID-19 (274 confirmed, 45 suspected). COVID-19 was nonserious in 291 (91.2%). During COVID-19, ozanimod was continued in 220 (69.0%) patients, interrupted in 94 (29.5%), and permanently discontinued in 3 (0.9%);action was unknown in 2 (0.6%) patients. At data cutoff, 285 (89.3%) had recovered (including 195 who had continued ozanimod), 6 (1.9%) recovered with sequelae, 5 (1.6%) were recovering, 16 (5.0%) had not recovered, and 5 (1.6%) died;a sixth COVID-19-related death due to lung abscess occurred after recovery with sequelae from COVID-19 infection. Of 1984 patients in DAYBREAK on 11Dec2020, when COVID-19 vaccines emerged, 596 (30.0%) received >=1 vaccine dose (415 [69.6%] mRNA;99 [16.6%] replication-defective viral vector;65 [10.9%] inactivated SARS-CoV-2;26 [4.4%] other);504 (25.4%) were fully vaccinated. COVID-19 occurred in 39/596 (6.5%) vaccinated patients and 213/1388 (15.3%) unvaccinated patients;3 postvaccination cases (including 1 case after 2 mRNA doses) were serious. Of 39 patients with postvaccination infections, 28 (71.8%) recovered (including 2/3 serious cases), 1 (2.6%) recovered with sequelae, 3 (7.7%) were recovering, and 7 (17.9%, including the third serious case) had not recovered at data cutoff. There were no COVID-19-related deaths among vaccinated patients. Conclusion(s): COVID-19 cases were largely nonserious, and the majority of infected patients recovered while continuing ozanimod. Few vaccinated patients developed COVID-19;most who did recovered without sequelae.
ABSTRACT
Introduction: Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients in active phase 3 open-label extension studies. Methods: A database search identified COVID-19 infection reports in ozanimodtreated patients with UC in the True North open-label extension and MS in the DAYBREAK open-label extension. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all patients with ³1 event was analyzed. Results: Among 2792 ozanimod-treated patients with UC or MS, 258 developed COVID-19 (confirmed: 215);thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most patients with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated patients with UC, 68 (11.1%) developed COVID-19 (confirmed: 55;Figure 1). A majority of UC patients with confirmed cases (45/55 [81.8%]) had nonserious COVID-19;most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC patient with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19-related deaths were reported in UC patients. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160;Figure 2). Most MS patients with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases;most (158/160 [98.8%]) recovered (5 with sequelae) (Figure 1). No MS patients with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC patients (Figure 1) and 30 additional MS patients (Figure 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19-related deaths in the MS program. Conclusion: In the UC and MS open-label extension studies, most patients with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (case-fatality rate 1.6% in MS, 1.2% overall). (Figure Presented)(Figure Presented)