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: Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus interferon beta-1a in individuals with relapsing multiple sclerosis.
METHODS: We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18-55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0-5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, NCT02047734, and EudraCT, 2012-002714-40.
FINDINGS: Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to interferon beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14-0·21) with ozanimod 1·0 mg, 0·22 (0·18-0·26) with ozanimod 0·5 mg, and 0·28 (0·23-0·32) with interferon beta-1a, with rate ratios versus interferon beta-1a of 0·62 (95% CI 0·51-0·77; p<0·0001) for ozanimod 1·0 mg and 0·79 (0·65 to 0·96; p=0·0167) for ozanimod 0·5 mg. The incidence of treatment-emergent adverse events was higher in the interferon beta-1a group (365 [83·0%] of 440 participants) than in the ozanimod 1·0 mg group (324 [74·7%] of 434) or the ozanimod 0·5 mg group (326 [74·3%] of 439). More participants in the interferon beta-1a group had treatment-emergent adverse events leading to treatment discontinuation than in the ozanimod groups. Incidences of infections and serious treatment-emergent adverse events were similar across treatment groups. No cases of ozanimod-related symptomatic reduction in heart rate and no second-degree or third-degree cases of atrioventricular block were reported.
INTERPRETATION: In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular interferon beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis.
FUNDING: Celgene International II.
BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.
METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.
RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T
CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).
The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated.
BACKGROUND: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression.
OBJECTIVE: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNβ-1a).
METHODS: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNβ-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised.
RESULTS: Some 324 patients were randomised (IFNβ-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNβ-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings.
CONCLUSION: Effects on time to failure were comparable between teriflunomide and IFNβ-1a. There was no difference between teriflunomide 14 mg and IFNβ-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.
BACKGROUND: Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients.
METHODS: We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134.
FINDINGS: Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).
INTERPRETATION: Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis.
FUNDING: Novartis Pharma AG.
ANTECEDENTES: La actividad de la enfermedad alemtuzumab anticuerpo anti-CD52 monoclonal reducido en un ensayo de fase 2 de los pacientes no tratados previamente con esclerosis múltiple remitente-recurrente. El objetivo fue evaluar la eficacia y seguridad de alemtuzumab de primera línea en comparación con interferón beta-1a en un ensayo de fase 3.
MÉTODOS: En nuestro 2 años, enmascaradas calificadores, aleatorizado controlado ensayo de fase 3, que incluyeron adultos de 18 a 50 años con esclerosis múltiple remitente-recidivante tratados previamente. Los participantes elegibles fueron asignados aleatoriamente en una proporción de 2: 1 mediante un sistema de respuesta de voz interactiva, estratificada por sitio, para recibir por vía intravenosa alemtuzumab 12 mg por día o interferón beta 1a subcutáneo 44 mg. El interferón beta 1a fue dado tres veces por semana y alemtuzumab se administra una vez al día durante 5 días al inicio del estudio y una vez por día durante 3 días a 12 meses. Puntos finales coprimarios fueron la tasa y el tiempo de recaída en 6 meses sostenida acumulación de discapacidad en todos los pacientes que recibieron al menos una dosis del fármaco del estudio. Este estudio se ha registrado en ClinicalTrials.gov, número NCT00530348.
RESULTADOS: 187 (96%) de los 195 pacientes asignados al azar interferón beta 1a y 376 (97%) de los 386 pacientes aleatoriamente asignados alemtuzumab se incluyeron en los análisis primarios. 75 (40%) pacientes del grupo de interferón beta-1a en recaída (122 eventos), en comparación con 82 (22%) de los pacientes en el grupo de alemtuzumab (119 eventos; relación de tasa 0 · 45 [95% IC 0 · 32-0 · 63] ; p <0,0001), correspondiente a una mejora 54 · 9% con alemtuzumab. Sobre la base de las estimaciones de Kaplan-Meier, el 59% de los pacientes en el grupo de interferón beta 1a eran libre de recaída a los 2 años en comparación con el 78% de los pacientes en el grupo de alemtuzumab (p <0 · 0001). 20 (11%) de los pacientes en el grupo de interferón beta 1a habían sufrido acumulación de discapacidad en comparación con 30 (8%) en el grupo de alemtuzumab (razón de riesgo 0 · 70 [95% CI 0 · 40-1 · 23]; p = 0 · 22). 338 (90%) de los pacientes en el grupo de alemtuzumab tenía reacciones asociadas con la perfusión; 12 (3%) de los cuales fueron considerados como graves. Infecciones, predominantemente de intensidad leve o moderada, se produjo en 253 (67%) de los pacientes tratados con alemtuzumab frente a 85 (45%) de los pacientes tratados con interferón beta 1a. 62 (16%) de los pacientes tratados con alemtuzumab tenían infecciones por herpes (predominantemente cutánea) en comparación con los tres (2%) de los pacientes tratados con interferón beta 1a. A los 24 meses, 68 (18%) pacientes en el grupo de alemtuzumab habían acontecimientos adversos tiroideos asociada en comparación con 12 (6%) en el grupo de interferón beta 1a, y tres (1%) tuvieron trombocitopenia inmune en comparación con ninguno en el interferón beta grupo 1a. Dos pacientes en el grupo de alemtuzumab desarrollaron carcinoma papilar de tiroides.
INTERPRETACIÓN: perfil de seguridad consistente de alemtuzumab y el beneficio en términos de reducción de la recaída apoyan su uso en pacientes con esclerosis múltiple remitente-recidivante tratados previamente; Sin embargo, el beneficio en términos de criterios de valoración de discapacidad observadas en ensayos anteriores no se observó aquí.
FINANCIACIÓN: Genzyme (Sanofi) y Bayer Schering Pharma.
ANTECEDENTES: BG-12 (dimetilfumarato) está en desarrollo como tratamiento oral para la esclerosis múltiple remitente-recurrente, que se trata con agentes parenterales (interferón o acetato de glatiramer).
MÉTODOS: En esta fase 3, aleatorizado, se investigó la eficacia y seguridad de la vía oral BG-12, a una dosis de 240 mg dos o tres veces al día, en comparación con placebo en pacientes con esclerosis múltiple remitente-recurrente. Un agente activo, acetato de glatiramer, también se incluyó como un comparador de referencia. El criterio principal de valoración fue la tasa anual de recaídas en un período de 2 años. El estudio no fue diseñado para probar la superioridad o inferioridad de BG-12 en comparación con el acetato de glatiramer.
RESULTADOS: A los 2 años, la tasa anual de recaídas fue significativamente menor con BG-12 (0.22), BG-12 (0.20), y acetato de glatiramer dos veces al día tres veces al día (0,29) que con placebo (0,40) (reducciones relativas: dos veces al día BG-12, 44%, p <0,001; tres veces al día BG-12, 51%, p <0,001; glatiramer acetato, 29%; p = 0,01). Las reducciones en la progresión de la discapacidad con dos veces al día BG-12, tres veces al día BG-12, y el acetato de glatiramer versus placebo (21%, 24% y 7%, respectivamente) no fueron significativas. En comparación con el placebo, dos veces al día BG-12, tres veces al día de acetato BG-12, y de glatiramer redujo significativamente el número de T (2) lesiones hiperintensas ponderadas nuevas o ampliación (todos p <0,001) y la nueva T (1) lesiones hipointensas ponderadas (P <0,001, P <0,001 y P = 0,002, respectivamente). En las comparaciones post hoc de BG-12 en comparación con el acetato de glatiramer, las diferencias no fueron significativas a excepción de la tasa anual de recaídas (tres veces al día BG-12), nueva o ampliación de T (2) lesiones hiperintensas ponderadas (ambos de BG-12 dosis), y nueva T (1) lesiones hipointensas ponderadas (tres veces al día BG-12) (P nominal <0,05 para cada comparación). Los eventos adversos que ocurren con una incidencia más alta con un tratamiento activo que con placebo incluyeron enrojecimiento y eventos gastrointestinales (con BG-12) y los eventos relacionados con la inyección (con acetato de glatiramer). No hubo neoplasias malignas o infecciones oportunistas reportadas con BG-12. Recuento de linfocitos disminuyeron con BG-12.
Conclusiones: En los pacientes con esclerosis múltiple remitente-recurrente, BG-12 (en ambas dosis) y acetato de glatiramer redujeron significativamente las tasas de recaída y la mejora de los resultados neurorradiológico relación con el placebo. (Financiado por Biogen Idec; CONFIRMAR número ClinicalTrials.gov, NCT00451451.).
ANTECEDENTES: Dos prueba de concepto ensayos clínicos han aportado pruebas de que laquinimod reduce la actividad de la enfermedad en pacientes con esclerosis múltiple remitente-recurrente.
Métodos: Se realizó un estudio aleatorizado, doble ciego, de fase 3 estudio en 139 sitios en 24 países. Un total de 1.106 pacientes con esclerosis múltiple remitente-recidivante fueron asignados aleatoriamente en una proporción 1: 1 para recibir laquinimod oral en una dosis de 0,6 mg una vez al día o placebo durante 24 meses. El punto final primario fue la tasa anual de recaídas durante el período de 24 meses. Los objetivos secundarios fueron confirmados progresión de la discapacidad (que se define como un aumento en la puntuación en la Escala de Estado de Discapacidad Ampliado que se mantuvo durante al menos 3 meses) y el número acumulado de lesiones realzadas con gadolinio y lesiones nuevas o ampliación en T (2) - imágenes por resonancia magnética ponderada.
RESULTADOS: El tratamiento con laquinimod en comparación con el placebo se asoció con una reducción moderada de la media (± SE) la tasa anual de recaídas (0,30 ± 0,02 vs. 0,39 ± 0,03, p = 0,002) y con una reducción en el riesgo de progresión de la discapacidad confirmada (11,1% vs. 15,7%; razón de riesgo, 0,64; intervalo de confianza del 95%, ,45-0,91; P = 0,01). Las cifras acumuladas medias de lesiones realzadas con gadolinio y lesiones nuevas o ampliación de T (2) imágenes ponderadas fueron menores para los pacientes que recibieron laquinimod que para aquellos que recibieron placebo (1,33 ± 0,14 vs. 2,12 ± 0,22 y 5,03 ± 0,08 vs. 7,14 ± 0,07, respectivamente, p <0,001 para ambas comparaciones). Elevaciones transitorias de los niveles de alanina aminotransferasa que superen en más de tres veces el límite superior del rango normal se observaron en 24 pacientes que recibieron laquinimod (5%) y 8 que recibieron placebo (2%).
Conclusiones: En este estudio de fase 3, laquinimod oral administrada una vez al día redujo la progresión de la discapacidad y la reducción de la tasa de recaída en pacientes con esclerosis múltiple remitente-recurrente. (Financiado por Teva Pharmaceutical Industries;. Número ClinicalTrials.gov, NCT00509145).
ANTECEDENTES: El alemtuzumab anticuerpo monoclonal anti-CD52 reduce la actividad de la enfermedad en pacientes no tratados previamente con esclerosis múltiple remitente-recurrente. El objetivo fue evaluar la eficacia y seguridad de alemtuzumab en comparación con interferón beta-1a en pacientes que han recaído a pesar del tratamiento de primera línea.
MÉTODOS: En nuestro 2 años, evaluador-ciego, ensayo controlado aleatorio de fase 3, que incluyeron adultos de 18 a 55 años con esclerosis múltiple remitente-recurrente y al menos una recaída de interferón beta o glatiramer. Los participantes elegibles fueron asignados aleatoriamente en una proporción 1: 2: 2 ratio por un sistema de respuesta de voz interactiva, estratificada por sitio, para recibir interferón beta 1a subcutáneo 44 mg, alemtuzumab intravenosa 12 mg por día, o intravenosa alemtuzumab 24 mg por día. El interferón beta 1a fue dado tres veces por semana y alemtuzumab se administra una vez al día durante 5 días al inicio del estudio y durante 3 días a 12 meses. Los 24 mg por grupo día se suspendió para ayudar a la contratación, pero los datos se incluyen para las evaluaciones de seguridad. Puntos finales coprimarios fueron la tasa y el tiempo de recaída en 6 meses sostenida acumulación de la discapacidad, la comparación de alemtuzumab 12 mg y el interferón beta 1a en todos los pacientes que recibieron al menos una dosis del fármaco del estudio. Este estudio se ha registrado en ClinicalTrials.gov, número NCT00548405.
RESULTADOS: 202 (87%) de los 231 pacientes asignados al azar interferón beta 1a y 426 (98%) de los 436 pacientes asignados al azar alemtuzumab 12 mg se incluyeron en los análisis primarios. 104 (51%) pacientes del grupo de interferón beta-1a en recaída (201 eventos), en comparación con 147 (35%) de los pacientes en el grupo de alemtuzumab (236 eventos; relación de tasa 0 · 51 [95% IC 0 · 39-0 · 65] ; p <0 · 0001), correspondiente a una mejora 49 · 4% con alemtuzumab. 94 (47%) pacientes en el grupo de interferón beta 1a eran libre de recaída a los 2 años en comparación con 278 (65%) pacientes en el grupo de alemtuzumab (p <0 · 0001). 40 (20%) de los pacientes en el grupo de interferón beta 1a habían sufrido la acumulación de la discapacidad en comparación con 54 (13%) en el grupo de alemtuzumab (razón de riesgo 0 · 58 [IC 95% 0 · 38-0 · 87]; p = 0 · 008), correspondiente a un 42% de mejora en el grupo de alemtuzumab. Para 435 pacientes asignados alemtuzumab 12 mg, 393 (90%) tuvieron reacciones asociadas con la perfusión, 334 (77%) tenían infecciones (en comparación con 134 [66%] de 202 pacientes en el grupo de interferón beta-1a) que eran en su mayoría leves-moderados con ninguno fatal, 69 (16%) tenían trastornos de la tiroides, y tres (1%) tuvieron trombocitopenia inmune.
INTERPRETACIÓN: Para los pacientes con tratamiento de primera línea refractaria de recaída-remisión de esclerosis múltiple, alemtuzumab se podría utilizar para reducir las tasas de recaída y la acumulación sostenida de la discapacidad. Las estrategias de gestión de riesgos adecuados permiten la identificación temprana de principal efecto adverso de alemtuzumab de la autoinmunidad secundaria.
FINANCIACIÓN: Genzyme (Sanofi) y Bayer Schering Pharma.
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.)
