Serologic Response and Clinical Outcomes of SARSCoV-2 Infection and Vaccination in Ozanimod-Treated Participants With Relapsing Multiple Sclerosis

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.

Safety patterns with ozanimod during phase 3 and openlabel extension trials in patients with relapsing multiple sclerosis

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.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: interim analysis of the DAYBREAK open-label extension study

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.

Treatment-naive patients with early-stage relapsingremitting multiple sclerosis showed low disease activity after 2-year ocrelizumab therapy, with no new safety signals' the Phase IIIb ENSEMBLE study

Background: Early high-efficacy treatment of multiple sclerosis (MS) may provide long-term clinical benefits, improving disease outcomes and patient quality of life. ENSEMBLE is a multicentre, open-label, single-arm Phase IIIb study, evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Aim(s): To report 2-year interim efficacy and safety data of the full cohort of patients with early-stage RRMS from the ENSEMBLE trial (NCT03085810), using no evidence of disease activity (NEDA)-3 as the primary endpoint. Method(s): Treatment-naive patients with early-stage RRMS (age 18-55 years;disease duration <=3 years;Expanded Disability Status Scale [EDSS] <=3.5;with one or more clinically reported relapse(s) or one or more signs of MRI activity in the prior 12 months) received OCR 600 mg every 24 weeks for 192 weeks (planned study duration). Key endpoints were NEDA-3 (defined as no relapses, 24-week [W] confirmed disability progression [CDP] and MRI activity [T1-weighted contract enhanced images or new/enlarging T2-weighted lesions, with MRI measurements rebaselined at W8]), annualised relapse rate (ARR), mean change in EDSS score from baseline (BL) and a safety overview. Result(s): BL demographics and disease characteristics of the ENSEMBLE population (N=1,225) were consistent with earlystage RRMS disease (patients <=40 years, 78.9%;female, 64.0%;median: Age, 32.0 years;duration since MS symptom onset, 0.74 years;duration since RRMS diagnosis, 0.22 years;BL EDSS score, 1.75;mean BL EDSS score [SD], 1.80 [0.93]). At W96, the majority of patients (n=857, 77.3%) had NEDA, 88.9% had no MRI activity, 93.4% had no relapses and 90.7% had no 24W-CDP. The adjusted ARR at W96 was low, 0.033 (95% CI, 0.026-0.042), and the mean (SD) EDSS score showed a statistically significant improvement between BL and W96, decreasing by 0.13 (0.89;p<0.0001), from 1.80 (0.93) to 1.67 (1.12). Safety results were consistent with prior OCR studies. Infections were reported by 760 (62.0%) patients;rates of serious infections were low (n=33 [2.7%] patients);32 (2.6%) of patients contracted a COVID-19 infection. Conclusion(s): In the ENSEMBLE study of treatment-naive patients with early-stage RRMS, disease activity based on clinical and MRI measures was minimal in most patients treated with ocrelizumab over 2 years;safety was consistent with prior ocrelizumab experience, with no new safety signals.

COVID-19 infections and vaccinations among patients receiving ozanimod in the daybreak open-label extension trial

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.

Effects of the COVID-19 Pandemic on Caregivers of Young Children with Sickle Cell Disease Enrolled in the Engage-HU Trial

Background: Hydroxyurea (HU) is the primary medication used to prevent the significant medical and neurologic morbidities of pediatric sickle cell disease (SCD;HbSS or HbSB0 thalassemia). Despite the benefits of HU, it remains under-utilized likely due to lack of clinician knowledge/training and negative caregiver perceptions. Thus, we developed the Engage-HU randomized controlled trial (NCT03442114) as a novel approach to address HU utilization barriers. Engage-HU is designed to assess how clinicians can engage caregivers in a shared discussion that considers their values, preferences, and scientific evidence about HU. The COVID-19 pandemic has resulted in significant changes to healthcare delivery for children with SCD, as they are at increased risk of severe illness from COVID-19 infection. Given their risk status, it was recommended that patients with SCD complete telehealth visits when possible. Some families also chose to delay care because they feared their child would get infected at hospitals/healthcare clinics that care for COVID-19 positive patients. Since the lives of all families enrolled in the Engage-HU trial have been affected to some extent, we incorporated measures to capture the impact of the COVID-19 pandemic and the usability of telemedicine implementation and services. Methods: Engage-HU is a randomized control trial comparing two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD. Study outcomes include caregiver confidence in decision-making and perceptions of experiencing shared decision-making as well as HU uptake and child health outcomes. Eligible children are 0 to 5 years, candidates for HU, and their caregiver has not decided about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a unidirectional crossover design. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using the intent-to-treat principle, and all participants will remain in the arm to which they were randomized. A multiple group comparison analysis will be performed to assess significant response variable differences by group randomization. The Engage-HU study aims to recruit 174 caregivers who are considering initiating HU. The trial is being conducted at 9 sites in the United States. Data collection is ongoing, and 160 caregiver-participants have been enrolled to date. Since May 2020, caregiver-participants have completed the COVID-19 Exposure and Family Impact Scales (CEFIS), which contain 2 subscales (exposure to potentially traumatic aspects of the pandemic, impact on families), and the COVID-19 telemedicine use survey during a study visit. Results: Currently, 8 of the 9 sites have collected data from 48 caregivers (93.8% mothers), most of whom (93.8%) identify as African American/Black (see Figure 1). Correlations indicated that older caregivers experienced greater exposure (Mean = 7.0, SD = 4.1, range = 1-19) to potentially traumatic aspects of the pandemic (r =.31, p =.04). Distress related to COVID-19 varied widely across the sample, for both caregivers (Mean = 5.9, SD = 2.9, range = 1-10) and children (Mean = 4.1, SD = 3.4, range = 1-10). Scores on the telemedicine usability survey were generally high, indicating that caregivers are happy with the quality of care delivered via telehealth. However, caregivers (r =.30, p =.09) and children (r =.32, p =.07) experiencing more pandemic-related distress reported less satisfaction with telehealth. Conclusion: Although Engage-HU has resumed research operations, recruitment has not reached pre-pandemic targets, as fewer eligible patients are scheduled for routine care visits at SCD clinics. Our preliminary analyses suggest a significant continued impact of the pandemic on families and general satisfaction with the quality of healthcare delivered via telemedicine. These findings indicate that targeted screenings to identify and intervene for those who emonstrate more COVID-19 pandemic-related distress are needed. [Formula presented] Disclosures: Quinn: Forma Therapeutics: Consultancy;Aruvant: Research Funding;Novo Nordisk: Consultancy;Emmaus Medical: Research Funding. Yates: Agios Pharmaceuticals: Current Employment. Badawy: Sanofi Genzyme: Consultancy;Vertex Pharmaceuticals Inc: Consultancy;Bluebird Bio Inc: Consultancy. Thompson: bluebird bio, Inc.: Consultancy, Research Funding;Baxalta: Research Funding;Biomarin: Research Funding;Celgene/BMS: Consultancy, Research Funding;CRISPR Therapeutics: Research Funding;Vertex: Research Funding;Editas: Research Funding;Graphite Bio: Research Funding;Novartis: Research Funding;Agios: Consultancy;Beam: Consultancy;Global Blood Therapeutics: Current equity holder in publicly-traded company. Smith-Whitley: Global Blood Therapeutics: Current Employment. King: National Cancer Institute: Research Funding;National Heart, Lung, and Blood Institute: Research Funding;Health Resources and Services Administration: Research Funding;Global Blood Therapeutics: Research Funding. Meier: CVS Caremark: Consultancy;Forma Therapeutic: Membership on an entity's Board of Directors or advisory committees;NovoNordisk: Membership on an entity's Board of Directors or advisory committees;Novartis,: Other: Data Safety Monitoring Board membership;NHLBI: Other: Data Safety Monitoring Board membership;Global Blood Therapeutics: Other: Steering Committee membership, grant funding;CDC,: Other: grant funding;Indiana Department of Health: Other: grant funding. Tubman: Global Blood Therapeutics: Consultancy, Research Funding;Novartis Pharmaceuticals: Honoraria, Research Funding;Forma Pharmaceuticals: Consultancy;Perkin Elmer: Honoraria. Crosby: Forma Therapeutics: Honoraria;PCORI: Research Funding;HRSA: Research Funding;Global Blood Therapeutics Panel: Honoraria;Children's Hospital of Philadelphia: Honoraria;Professional Resource Exchange: Patents & Royalties: $30-$60 every other year;SCDAA: Honoraria;NHLBI: Other: Payment for review of LRP Proposals, Research Funding. OffLabel Disclosure: Hydroxyurea has been FDA approved for the treatment of sickle cell disease for patients ages 2 years and above but NHLBI and ASH Guidelines recommend it be offered to children as young as age 9 months.

Safety and efficacy of inebilizumab in NMOSD over a mean treatment duration of 3.2 years: End of study data from the N-M. Omentum trial

Introduction: Inebilizumab is approved in the USA and Japan for aquaporin 4 immunoglobulin (Ig)G seropositive neuromyelitis optica spectrum disorder (NMOSD). Objective: Report final safety and efficacy data from the N-MOmentum trial of inebilizumab in NMOSD. Methods: Participants with NMOSD (aged 18+, EDSS score of ≤8, recent history of attacks) were randomized 3:1 to inebilizumab or placebo monotherapy for 28 weeks or up to attack occurrence;the randomized controlled period (RCP). Primary outcome was time to adjudicated attack. Participants could then enter the inebilizumab open label period (OLP). Final study data are presented, including attack risk and safety outcomes. Results: Of the 230 participants randomized and dosed, 216 (93.9%) entered and 174 (80.6%) completed the OLP. In the RCP, 87.0% were attack free with inebilizumab and 59.9% with placebo (72.8% risk reduction, p<0.001). In the OLP, 87.7% were attackfree in those continuing inebilizumab and 83.4% in those switched from placebo. Regardless of randomization, 225 participants received inebilizumab. Mean (SD) treatment duration was 3.2 (1.4) years;36.8% were treated for >4 years (maximum of 5.5 years). Total exposure was 730.36 person-years (py) with an annualized attack rate of 0.092;40/63 (63.5%) attacks occurred in the first year. Treatment-emergent adverse events (AE) were reported by 89 (39.6%) participants, most frequently urinary tract infection (26.2%), nasopharyngitis (20.9%) and arthralgia (17.3%). Infusion-related reactions with inebilizumab occurred in 28 (12.9%) participants (rate per 100-py: whole study, 11.1;RCP, 37.6). The rate (95% confidence interval) of infections per 100-py did not increase with continued treatment: year 1, 116.3 (102.4-131.6);year 2, 68.1 (57.2-80.6);year 3, 61.9 (50.3-75.5);year 4, 55.1 (41.7-71.4). 105 participants had transient low IgG (<700 mg/dL) during treatment, but no correlations were found between the worst IgG, IgM or IgA levels recorded and the occurrence of any infection or an infection ≥ grade 3 (Fisher exact test, all p>0.05). Three trial participants died: one from complications of NMOSD attack, one from a CNS event of unclear etiology and one due to COVID-19, after 9, 224 and 1225 days of inebilizmab treatment, respectively. Conclusions. During the 5.5 years of N-MOmentum, the risk of attack in participants receiving inebilizumab remained low with no evidence of unexpected serious adverse events, including serious infection.