INTERVENTION: Trade Name: Arzerra Product Name: ofatumumab Product Code: OMB157G Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: OFATUMUMAB CAS Number: 679818‐59‐8 Current Sponsor code: OMB157 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Aubagio Product Name: Teriflunomide Pharmaceutical Form: Capsule, hard INN or Proposed INN: TERIFLUNOMIDE CAS Number: 108605‐62‐5 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 14‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use CONDITION: multiple sclerosis ; MedDRA version: 20.0 Level: PT Classification code 10048393 Term: Multiple sclerosis relapse System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: Demonstrate that ofatumumab 20 mg sc once every 4 (q4) weeks is superior to teriflunomide 14 mg po once daily in reducing the frequency of confirmed relapses as evaluated by the annualized relapse rate (ARR) in patients with relapsing MS. Primary end point(s): Demonstrate that ofatumumab 20 mg sc once every 4 (q4) weeks is superior to teriflunomide 14 mg po once daily in reducing the frequency of confirmed relapses as evaluated by the annualized relapse rate (ARR) in patients with relapsing MS. Secondary Objective: Key secondary objectives; ; To evaluate if ofatumumab is superior to teriflunomide on:; 1. Time to disability worsening as measured by 3‐month confirmed worsening (3mCDW) on EDSS ; 2. Number of T1 GdE lesions per MRI scan ; 3. Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate); 4. Time to disability worsening as measured by 6‐month confirmed worsening (6mCDW) on EDSS; 5. Rate of brain volume loss (BVL) based on assessments of percentage brain volume change from baseline; 6. Time to disability improvement, as measured by 6‐month confirmed improvement (6mCDI) on EDSS; 7. Neurofilament light chain (NfL) concentration in serum ; ; See protocol for complete list of secondary objectives. Timepoint(s) of evaluation of this end point: Up to 30 months SECONDARY OUTCOME: Secondary end point(s): ‐Time to disability worsening as measured by 3‐month confirmed worsening (3mCDW) on The Expanded Disability Status Scale (EDSS). ; ‐Time to disability worsening as measured by 6‐month confirmed worsening (6mCDW) on EDSS. ; ‐Time to disability improvement as measured by 6‐month confirmed improvement (6mCDI) on EDSS. ; ‐Number of T1 Gd‐enhancing lesions per MRI scan. ; ‐Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate). ; ‐Rate of brain volume loss (BVL) based on assessments of percentage brain volume change from baseline. ; ‐Neurofilament light chain (NfL) concentration in serum Timepoint(s) of evaluation of this end point: Up to 30 months INCLUSION CRITERIA: •Male or female patients aged 18 to 55 years (inclusive) at screening •Diagnosis of MS according to the 2010 Revised McDonald criteria •Relapsing form of MS: relapsing‐remitting course (RRMS), or secondary progressive course with disease activity (relapsing SPMS) •Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive) •Neurologically stable within 1 month prior to randomization •At least 1 documented relapse during the previous 1 year OR at least 2 documented relapses during the previous 2 years OR a positive GdE MRI scan during the year prior to randomization and including screening. Please see protocol for complete detailed list of inclusion criteria Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 900 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
To compare the efficacy and safety of ofatumumab administered subcutaneously (sc) every 4 weeks versus teriflunomide administered orally once daily in patients with relapsing multiple sclerosis
Abstract Background Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. Methods In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. Results Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups 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 the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. Conclusions Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.)
BACKGROUND: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide.
OBJECTIVES: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS.
METHODS: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events.
RESULTS: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population.
CONCLUSION: The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).
Trade Name: Arzerra Product Name: ofatumumab Product Code: OMB157G Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed
INN:
OFATUMUMAB CAS Number: 679818‐59‐8 Current Sponsor code: OMB157 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Aubagio Product Name: Teriflunomide Pharmaceutical Form: Capsule, hard INN or Proposed
INN:
TERIFLUNOMIDE CAS Number: 108605‐62‐5 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 14‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use
CONDITION:
multiple sclerosis ; MedDRA version: 20.0 Level: PT Classification code 10048393 Term: Multiple sclerosis relapse System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10]
PRIMARY OUTCOME:
Main Objective: Demonstrate that ofatumumab 20 mg sc once every 4 (q4) weeks is superior to teriflunomide 14 mg po once daily in reducing the frequency of confirmed relapses as evaluated by the annualized relapse rate (ARR) in patients with relapsing MS. Primary end point(s): Demonstrate that ofatumumab 20 mg sc once every 4 (q4) weeks is superior to teriflunomide 14 mg po once daily in reducing the frequency of confirmed relapses as evaluated by the annualized relapse rate (ARR) in patients with relapsing MS. Secondary Objective: Key secondary objectives; ; To evaluate if ofatumumab is superior to teriflunomide on:; 1. Time to disability worsening as measured by 3‐month confirmed worsening (3mCDW) on EDSS ; 2. Number of T1 GdE lesions per MRI scan ; 3. Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate); 4. Time to disability worsening as measured by 6‐month confirmed worsening (6mCDW) on EDSS; 5. Rate of brain volume loss (BVL) based on assessments of percentage brain volume change from baseline; 6. Time to disability improvement, as measured by 6‐month confirmed improvement (6mCDI) on EDSS; 7. Neurofilament light chain (NfL) concentration in serum ; ; See protocol for complete list of secondary objectives. Timepoint(s) of evaluation of this end point: Up to 30 months
SECONDARY OUTCOME:
Secondary end point(s): ‐Time to disability worsening as measured by 3‐month confirmed worsening (3mCDW) on The Expanded Disability Status Scale (EDSS). ; ‐Time to disability worsening as measured by 6‐month confirmed worsening (6mCDW) on EDSS. ; ‐Time to disability improvement as measured by 6‐month confirmed improvement (6mCDI) on EDSS. ; ‐Number of T1 Gd‐enhancing lesions per MRI scan. ; ‐Number of new or enlarging T2 lesions on MRI per year (annualized T2 lesion rate). ; ‐Rate of brain volume loss (BVL) based on assessments of percentage brain volume change from baseline. ; ‐Neurofilament light chain (NfL) concentration in serum Timepoint(s) of evaluation of this end point: Up to 30 months
INCLUSION CRITERIA:
•Male or female patients aged 18 to 55 years (inclusive) at screening •Diagnosis of MS according to the 2010 Revised McDonald criteria •Relapsing form of MS.: relapsing‐remitting course (RRMS), or secondary progressive course with disease activity (relapsing SPMS) •Disability status at Screening with an EDSS score of 0 to 5.5 (inclusive) •Neurologically stable within 1 month prior to randomization •At least 1 documented relapse during the previous 1 year OR at least 2 documented relapses during the previous 2 years OR a positive GdE MRI scan during the year prior to randomization and including screening. Please see protocol for complete detailed list of inclusion criteria Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 900 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
