Remibrutinib Claims First BTKi RMS Win But Discloses No Efficacy or Liver Safety Data

Novartis Boosts Q3 Sales and Core Profit, Raises Full-Year Guidance

Novartis announced strong financial results for the third quarter of 2026, with net sales increasing by 4% (constant currency, kWk) to USD 14.5 billion and core operating income improving by 10% (kWk) to USD 6.0 billion. This performance was driven by significant growth from key brands such as Kisqali, Kesimpta, Scemblix, Leqvio, and Cosentyx. As a result of this robust performance, Novartis has raised its full-year 2026 guidance for core operating income, now expecting it to be stagnant to low single-digit percentage growth, an improvement from the previously projected low single-digit decline. The company also highlighted several pipeline advancements, including positive Phase III results for remibrutinib in relapsing multiple sclerosis (RMS) and new regulatory approvals for Rhapsido and Pluvicto.

• Novartis delivered robust financial performance in Q3 2026, with net sales reaching USD 14.5 billion (+4% kWk) and core operating income growing by 10% (kWk) to USD 6.0 billion, achieving a core operating margin of 41.6%. This strong financial momentum led the company to raise its full-year 2026 core operating income guidance, now anticipating stagnant to low single-digit growth, reflecting effective operational strategies and successful product commercialization.
• The quarter saw significant advancements in Novartis's pipeline and regulatory landscape. Positive Phase III results for remibrutinib in relapsing multiple sclerosis (RMS) demonstrated superiority over teriflunomide in reducing annualized relapse rate (ARR) and MRI lesions. Additionally, Rhapsido received FDA approval for symptomatic dermographism, and Pluvicto secured approvals in the US and China for PSMA-positive metastatic prostate cancer in mAPMN/S patients, expanding its approved indications.
• Strategic growth was fueled by strong sales from priority brands, including Kisqali (+37% kWk), Kesimpta (+22% kWk), Scemblix (+67% kWk), Leqvio (+63% kWk), and Cosentyx (+9% kWk), which collectively contributed 14 percentage points to volume growth. Novartis also strengthened its future pipeline through strategic transactions, completing the acquisition of Myricx Bio for antibody-drug conjugates and exercising an option to acquire Sironax's Brain Delivery Module platform for neuroscience.

Addressing Unmet Needs in Relapsing Multiple Sclerosis Treatment

Relapsing multiple sclerosis is a chronic inflammatory disease usually diagnosed at a young age, and most patients receive several disease-modifying therapies over time. Evidence-based guidelines to support treatment sequencing are limited, particularly for switches between high-efficacy DMTs, adding complexity to long-term management.

• Limited guidance for sequencing and switching between high-efficacy therapies: Switches may be triggered by lack of effectiveness or safety concerns, with change based on relapses, disability worsening, MRI activity, costs, and quality of life, yet optimal pathways remain undefined. Switching DMTs was associated with lower adherence and persistence, with patients who switched medications 2.4 times more likely to be non-persistent (95% CI: 1.3 - 4.5, p = 0.005), and the presence of a mental health disorder was associated with an increased hazard of discontinuing DMT (hazard ratio 1.22, 95% CI 1.03-1.44).

• Breakthrough activity and incomplete disease control: Breakthrough disease is defined as either clinical (relapse or disability progression) or radiological activity (new T2 lesion or gadolinium-enhancing lesions on MRI), or a combination of both. After one year, 29.2% of participants met NEDA-3 criteria, after two years, 30.8% of the cohort had NEDA, and progression independent of relapse activity represented the main disability accrual mechanism across phenotypes.

• Therapy-specific safety and monitoring burden: Fingolimod association with cardiovascular complications now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema, with first-dose bradycardia occurred in 13.7% and lymphopenia as the most frequent AE. Natalizumab carries risk of progressive multifocal leukoencephalopathy, with anti-JCV antibody testing every 6 months and annual MRI scans recommended as part of patient monitoring, while alemtuzumab carries significant risk of secondary autoimmunity and teriflunomide carries risk of teratogenicity.

• Rebound risk on withdrawal and challenges around de-escalation and family planning: Due to the possibility of rebound phenomena with certain medications (such as fingolimod and natalizumab), a bridging strategy could be applied in cases of family planning and drug-related adverse events. In patients who interrupted DMT to try to conceive, the ARR was 1.08, which was significantly higher than the ARR 1 year (0.44; p = 0.01) before DMT discontinuation, and patients who suffered relapses following DMT cessation before becoming pregnant had an 11-fold higher risk of relapse during pregnancy (relative risk [RR] = 11.1 [95%CI 1.6, 75], p = 0.002).

REMODEL-1 & -2: Remibrutinib's Efficacy and Safety Profile

In the active-comparator Phase 3 OPTIMUM study, 1133 patients were randomized 1:1 to 20 mg of ponesimod or 14 mg of teriflunomide once daily for 108 weeks. The relative rate reduction for ponesimod vs teriflunomide in the annualized relapse rate was 30.5% (0.202 vs 0.290; P < .001), with a mean difference in Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis of -3.57 (-0.01 vs 3.56; P < .001) and a relative risk reduction in combined unique active lesions per year of 56% (1.405 vs 3.164; P < .001). Reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates was 17% (10.1% vs 12.4%; P = .29) and 16% (8.1% vs 9.9; P = .37), respectively, while brain volume loss at week 108 was lower by 0.34% (-0.91% vs -1.25%; P < .001) and the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < .001). Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups, while treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). In the 240-week OPTIMUM long-term extension, 877 participants enrolled (ponesimod: 439; teriflunomide: 438), with 93.6% of participants in both groups experiencing ≥ 1 treatment-emergent adverse event, serious treatment-emergent adverse events experienced by 12.9% of participants (P20 mg/P20 mg: 12.8%; T14 mg/P20 mg: 13.0%) and events leading to discontinuation by 8.6% (P20 mg/P20 mg: 7.7%; T14 mg/P20 mg: 9.4%). Mean annualized relapse rate was 0.143 (95% CL: 0.123-0.167) for P20 mg/P20 mg and 0.184 (95% CL: 0.158-0.213) for T14 mg/P20 mg, with 44.3% and 49.5% experiencing relapse, and no evidence of disease activity-3 at end of long-term extension achieved by 17.5% vs 7.5%.

In ASCLEPIOS I and II, two double-blind, double-dummy, phase 3 trials, 946 patients were assigned to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) and 936 to receive oral teriflunomide (14 mg daily) for up to 30 months with median follow-up of 1.6 years. Annualized relapse rates were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In pooled trials, disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002), disability worsening confirmed at 6 months was 8.1% and 12.0% (hazard ratio, 0.68; P = 0.01), and disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09), with effects on gadolinium-enhancing lesions per T1-weighted scan, annualized rate of new or enlarging lesions on T2-weighted MRI, and serum neurofilament light chain levels at month 3 in the same direction as the primary end point but not change in brain volume. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group, and serious infections occurred in 2.5% and 1.8% of patients in the respective groups. Extended exposure in ALITHIOS included 1969 patients with 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched from teriflunomide (median time-at-risk 18.3 months, 986 patient-years), among whom 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events, with no opportunistic infections or progressive multifocal leukoencephalopathy events identified, risk of malignancies low, mean serum immunoglobulin G levels stable, mean immunoglobulin M levels decreased but remained above the lower limit of normal in most, serious infection incidence low, and decreased immunoglobulin levels not associated with serious infections.

Phase III randomized controlled trials ULTIMATE I and II compared ublituximab, an anti-CD20 monoclonal antibody, with teriflunomide and confirmed superior efficacy of ublituximab over teriflunomide, achieving substantial reductions in annualized relapse rates, near-complete suppression of gadolinium-enhancing T1 lesions and new/enlarging T2-hyperintense white matter lesions, as well as higher rates of no evidence of disease activity 3. Ublituximab was generally well tolerated, with mild, manageable infusion-related reactions as the most common adverse event, using maintenance doses administered in just 1 h twice a year. A systematic review and network meta-analysis of 15 randomized controlled trials of ublituximab, alemtuzumab, natalizumab, ocrelizumab, and ofatumumab found no statistically significant difference between ublituximab and other monoclonal antibodies for annualized relapse rate [ofatumumab (RR 1.02 (95% CI 0.64-1.62)), natalizumab (RR 0.99 (0.59-1.65)), alemtuzumab (RR 0.86 (0.51-1.46)), and ocrelizumab (RR 0.75 (0.44-1.28))], for confirmed disability progression at 6 months [ofatumumab (HR 0.97 (0.49-1.92)), natalizumab (HR 1.13 (0.53-2.40)), alemtuzumab (HR 1.25 (0.56-2.81)), and ocrelizumab (HR 1.29 (0.57-2.90))], or for all-cause treatment discontinuation rate except for alemtuzumab.

Remibrutinib's Place in the RMS Therapeutic Landscape

Remibrutinib is an oral small molecule Bruton's tyrosine kinase (BTK) inhibitor recommended for patients with antihistamine-refractory chronic spontaneous urticaria (CSU). Fenebrutinib, rilzabrutinib and TAS5315 are other BTK inhibitors reviewed in CSU, with fenebrutinib and rilzabrutinib evaluated in randomized, placebo-controlled phase 2 trials.