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In a Phase 2 trial (NCT04879628), frexalimab demonstrated effi cacy and safety with high-dosetreatment showing 89% reducti on (versus placebo) in new gadolinium-enhancing T1-lesions atWeek 12 (W12) in parti cipants with relapsing multi ple sclerosis (RMS). Eligible participants were randomized to receive either high- (n=52) or low-dose frexalimab (n=51),or matching placebos (n=12 and=14, respectively) for 12 weeks. The Multiple Sclerosis Impact Scale 29 version 2 (MSIS-29v2) yields physical and psychological impact scores, with higher scores showing greater disability. Patient-Reported Outcomes Measurement Information System Short Form-Fatigue-Multiple Sclerosis 8a (PROMIS-Fati gue-MS-8a) is an 8-item patient questionnaire; higher T-scores indicate increased fatigue. Changes from baseline to W12 in scores were compared post hoc between groups using analyses of covariance. P-values were nominal. At baseline, the pooled arms mean score (SD) for MSIS-29v2 physical and psychological impact subscales was 25.05 (23.05) and 34.55 (24.62), respectively, and PROMIS-Fatigue T-score was 52.68(10.68).At W12, least-squares (LS) mean change (SE) in physical impact score was -1.52 (1.95) in high-dose, 0.43 (1.95) in low-dose, and 6.40 (2.79) in placebo, with high-dose showing significant improvement versus placebo (LS mean difference [95% CI]: -7.92 [-14.66, -1.18], P=0.021), and a numerical improvement in low-dose (-5.97 [-12.71, 0.77],P =0.082). The psychological impact scores between frexalimab and placebo groups showed no significant difference. PROMIS-Fatigue T-score, compared to placebo (LS mean change [SE]: 2.32 [1.37]), showed a significant improvement with both high-dose (LS mean change [SE]: -1.24 [0.96]; LS mean difference versus placebo [95% CI]:-3.55 [-6.86, -0.25],P =0.035) and low-dose (-1.41 [0.96]; -3.73 [-7.03, -0.43],P=0.027) frexalimab. These preliminary findings suggest that frexalimab may improve physical impact and fatigue in people with RMS. [ABSTRACT FROM AUTHOR]

Frexalimab is a second-generation anti-CD40L antibody that blocks the costimulatory CD40/CD40L pathway, which is important in regulating adaptive and innate immunity. In the double-blind period (DBP) of the phase 2 trial in participants with relapsing multiple sclerosis (RMS; NCT04879628), frexalimab treatment was well-tolerated and efficacious at reducing disease activity. Frexalimab 1200 mg intravenous (IV) every 4 weeks (q4w) decreased new gadolinium-enhancing (Gd+) T1 lesions by 89% vs placebo at W12. The treatment effect was sustained over 48 weeks in the open-label extension (OLE). In the DBP, participants were randomized (4:4:1:1) to receive either 1200 mg IV q4w or 300 mg subcutaneous (SC) q2w doses of frexalimab or matching placebo for 12 weeks. After W12, participants receiving placebo switched to respective frexalimab arms and entered the OLE. During the OLE, the SC dose was increased to 1800 mg q4w (first high-dose administered on 21 Aug 2023) which resulted in a similar exposure as with the 1200 mg q4w IV dose. 7/57 participants in the SC arms had their W72 magnetic resonance imaging (MRI) assessments after receiving high-dose frexalimab. Key endpoints were safety and efficacy outcomes (number of Gd+ T1 lesions and new/enlarging T2 lesions). 125/129 participants completed DBP and entered OLE. Of these, 111 (89%) participants completed W72 and had ongoing treatment as of 2 Feb 2024. At W72, the number of Gd+ T1 lesions (mean±SD) remained low in participants who continued on frexalimab and in those who switched from placebo to frexalimab at W12 (frexalimabIV, 0.1±0.4; frexalimabSC, 0.4±0.9; placeboIV/frexalimabIV, 0.0±0.0; placeboSC/frexalimabSC, 0.2±0.4). New/enlarging T2 lesion count and T2 lesion volume change remained low through W72. No new safety signals were observed over 72 weeks of frexalimab treatment. The most common adverse events (in ≥10% of participants) observed during the OLE from baseline until the cut-off at W72 were nasopharyngitis (13%), COVID-19 (12%) and headache (11%). Frexalimab continues to show favourable safety and sustained reduction in disease activity in participants with RMS as assessed by MRI outcomes through 18 months. These findings support further development of frexalimab in phase 3 MS trials as a high-efficacy, non-lymphocyte-depleting therapy. [ABSTRACT FROM AUTHOR]

Frexalimab is a second-generation anti-CD40L monoclonal antibody that blocks the costimulatory CD40/CD40L pathway, which is important for activation and function of adaptive and innate immunity. In the phase 2 trial (NCT04879628) in participants with relapsing MS (RMS),frexalimab was well-tolerated and showed an 89% reduction in new gadolinium-enhancing (Gd+)T1 lesions in the high-dose arm vs placebo at week 12. In the ongoing open-label extension, 96%of participants in the high-dose arm were free of Gd+ T1 lesions at week 48. FREXALT (comprising two trials, FREXALT-1 and FREXALT-2) is a double-dummy,active-controlled, event-driven (6-month composite confirmed disability worsening [cCDW] pooled across studies) trial with variable treatment duration of approximately 20‒40 months in RMS participants. Planned enrollment is 1400 participants randomly assigned 1:1 to frexalimab or teriflunomide. Key eligibility criteria include RMS diagnosis, Expanded Disability Status Scale (EDSS) ≤5.5, and ≥1 relapse within 1 year or ≥2 relapses within 2 years or ≥1 Gd+ lesion within 1year. Primary endpoint is adjudicated annualized relapse rate, and key secondary endpoint is timeto onset of 6-month cCDW (as assessed by the composite of EDSS, timed 25-foot walk and 9-hole peg tests). FREVIVA is a placebo-controlled, event-driven (6-month composite confirmed disability progression [cCDP]) trial with variable treatment duration of approximately 27‒51months in nrSPMS participants. Planned enrollment is 858 participants randomly Enrollment has started in December 2023. These phase 3 trials will assess the efficacy and safety of frexalimab in RMS andnrSPMS, which is a population with no approved therapeutic options. [ABSTRACT FROM AUTHOR]

• We assessed the efficacy/safety of teriflunomide (TFM) extended treatment in TOPIC. • Early TFM 14 mg treatment reduced CDMS conversion risk by 47.1% vs delayed treatment. • Low MRI activity was maintained in the extension with early TFM treatment. • No new safety signals were seen with TFM extended treatment. • Results support the importance of early/continuous treatment on the disease course. In the phase 3 TOPIC study, teriflunomide significantly reduced the risk of relapse determining conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome, versus placebo. We assessed clinical and safety outcomes associated with extended teriflunomide treatment in the TOPIC extension study. Patients who completed the TOPIC core study (including those still on study at early termination) or converted to CDMS after at least 24 weeks in the core study were eligible to participate in the extension. The primary efficacy endpoint in the extension was time to conversion to CDMS. Risk of relapse determining conversion to CDMS was 47.1% lower in patients treated with teriflunomide 14 mg during the core and extension studies compared with patients treated with placebo during the core study and teriflunomide 14 mg during the extension. The incidence of adverse events was 75.8% and 81.9% for 7 and 14 mg teriflunomide, respectively. Reduced risk of relapse determining conversion to CDMS in patients with early MS receiving teriflunomide 14 mg in the core study remained throughout the extension supporting the benefits of early treatment. No new safety signals were observed for teriflunomide 7 or 14 mg. [ABSTRACT FROM AUTHOR]

Highlights • Efficacy and safety of teriflunomide in Asian patients with relapsing MS were comparable to the overall TOWER population. • No new or unexpected safety findings were observed. • This analysis provides evidence of the clinical benefits of teriflunomide in a diverse patient population with relapsing MS. Abstract In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS. [ABSTRACT FROM AUTHOR]

Background Teriflunomide, a once-daily oral immunomodulator for the treatment of relapsing-remitting multiple sclerosis, has demonstrated consistent efficacy on clinical and MRI parameters in clinical trials. Objective To summarize the safety and tolerability profile of teriflunomide based on data from four placebo-controlled trials. Methods Safety and tolerability were assessed using two teriflunomide clinical program data pools. Pool 1 contained 3044 patients randomized to teriflunomide (14 mg or 7 mg) or placebo in the core studies of one phase 2 trial and three phase 3 trials, with cumulative treatment exposure >1500 patient-years per group. Pool 2 comprised 2338 patients who received teriflunomide treatment in the above trials, including those continuing in extension studies, with a duration of treatment up to 12 years, representing >6800 patient-years. Safety assessments included adverse events, laboratory parameters, and physical examinations. Results In Pool 1, the number of patients experiencing adverse events and serious adverse events was similar in the three treatment groups. Common events occurring in ≥10% of patients in either teriflunomide group, and with an incidence ≥2% compared with placebo, were alanine aminotransferase (ALT) increase, headache, diarrhea, hair thinning, and nausea. Overall, the nature of events observed in Pool 2 was similar to Pool 1. The majority of events in both pools were of mild-to-moderate intensity, were self-limiting, and infrequently resulted in discontinuation of therapy. The most common reason for treatment discontinuation in all treatment groups was ALT elevation, reflecting the protocol requirement to discontinue treatment on confirmation of ALT>3×the upper limit of normal. Conclusions No new or unexpected safety signals beyond those detected in individual trials were identified in this pooled analysis with treatment duration exceeding 12 years and a cumulative exposure to teriflunomide exceeding 6800 patient-years. Overall, both doses of teriflunomide had consistent and manageable safety profiles. [ABSTRACT FROM AUTHOR]