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BackgroundSjögren's syndrome (SS) is a chronic, systemic autoimmune disease affecting exocrine glands, primarily the salivary and tear glands, with potentially severe manifestations in multiple organs. No approved disease-modifying therapies exist. Dazodalibep (DAZ) is a biologic antagonist of CD40L.ObjectivesThe objective of this study was to evaluate the efficacy and safety of DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity (NCT04129164).MethodsWe conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity, as defined by a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ≥ 5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses. Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks. The primary endpoint was the change from Baseline in ESSDAI at Day 169. Safety assessments included the incidence of adverse (AEs), serious AEs (SAEs), and AEs of special interest (AESIs).ResultsThe 74 randomized subjects all received ≥1 dose of study medication (DAZ, N=36;PBO, N=38). The baseline demographics and disease characteristics were balanced between the two groups. The change from Baseline to Day 169 in ESSDAI score (LS mean ± SE), was -6.3 ± 0.6 in DAZ-treated subjects compared to -4.1 ± 0.6 in the PBO group, a difference of -2.2 (p = 0.0167). Compared to the PBO group, the DAZ group showed positive trends in the EULAR Sjögren's Syndrome Patient Reported Index score, and Functional Assessment of Chronic Illness Therapy-Fatigue score at Day 169. A post-hoc responder analysis of subjects achieving high levels (5 and 6 points) of improvement on ESSDAI favored DAZ (61.1% and 60.0%) over PBO (35.1% and 34.3%).The reported AEs were generally mild through Day 169 and similar in frequency between treatment groups. The most frequently reported AEs occurring in ≥5% of DAZ-treated subjects and >PBO were COVID-19, diarrhea, dizziness, ligament sprain, upper respiratory tract infection, contusion, device allergy, fatigue, hypertension, and oropharyngeal pain. Two SAEs were reported in a single DAZ-treated subject: this subject was a 59-year-old female who experienced a grade 3 SAE of COVID-19 infection and later died of unknown cause 46 days after last administration of DAZ (12 days after COVID-19 diagnosis). There was a single AESI of herpes zoster in a DAZ-treated subject.ConclusionDAZ is a potential new therapy for the treatment of systemic disease activity in patients with SS. SS subjects with moderate-to-high systemic disease receiving DAZ experienced a statistically significant reduction in disease activity relative to PBO as measured by the improvement in ESSDAI score. Except for a case of severe COVID-19 infection, DAZ therapy in SS subjects appeared to be well tolerated. Larger controlled trials of DAZ therapy for SS are warranted to further explore its safety profile and confirm its clinical efficacy.Table 1.Efficacy and Safety DataPBO N=38DAZ 1500 mg N=36EfficacyΔESSDAI, LS mean (SE) †-4.1 (0.6)-6.3 (0.6)*ΔESSPRI, LS mean (SE) †-1.12 (0.29)-1.80 (0.31)ΔFACIT-Fatigue, LS mean (SE) †5.8 (1.6)8.1 (1.6)AE Summary, n (%)≥1 AE23 (60.5)28 (77.8)≥1 related AE8 (21)10 (27.8)≥1 SAE01 (2.8)≥1 related SAE00≥1 AE leading to discontinuation00≥1 AESI01 (2.8)≥1 Death01 (2.8)Efficacy endpoints as of Day 169;† Analyzed using MMRM;Comparisons vs PBO;*p<0.05;AE summaries based on AEs that occurred through Day 169;AE, adverse event;AESI, adverse event of special interest;ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index;ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index;FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue;PBO, placebo;SAE, serious adverse eventFigure 1.AcknowledgementsFunded by Horizon herapeutics. Medical writing support provided by B Lujan, PhD, an employee of Horizon Therapeutics.Disclosure of InterestsE. William St. Clair Consultant of: Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics. Royalties: UpToDate, Liangwei Wang Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Ilias Alevizos Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, William Rees Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Alan Baer Consultant of: Bristol Myers Squibb, Wan Fai Ng Consultant of: Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen and UCB, Ghaith Noaiseh Consultant of: Novartis, Chiara Baldini Consultant of: GSK, and Sanofi.
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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.