Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223.

BACKGROUND: In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients with relapsing-remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656). METHODS: In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies. RESULTS: Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7-12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases. CONCLUSIONS: Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials.

Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab.

OBJECTIVE: To examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS. METHODS: Patients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity. RESULTS: Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes. CONCLUSIONS: Repopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.

Comparative effectiveness of dimethyl fumarate versus fingolimod and teriflunomide among MS patients switching from first-generation platform therapies in the US.

BACKGROUND: Previous real-world comparative research of MS disease modifying therapies (DMTs) in the overall population has suggested dimethyl fumarate (DMF) to be comparable to fingolimod (FTY) and more efficacious than teriflunomide (TERI) in reducing relapses. However, there is limited comparative evidence in patients switching from platform DMTs in the US. The objective of the study was to compare the annualized relapse rate (ARR) and risk of relapse in MS patients who have switched from a platform therapy to DMF, FTY, or TERI. METHODS: MS patients (18-65 years old) initiating an oral DMT from June 2013 to March 2015 were identified from the Truven MarketScan® Commercial Claims Database. The index date was the date of first oral DMT fill. Patients were required to have: continuous enrollment in the database for 12 months pre-index date and ≥3 months post-index date; ≥1 MS diagnosis over the pre-index period; discontinuation of a platform DMT with no evidence of oral or infusion DMTs over the pre-index period; and adherence to the index drug for ≥90 days. DMF patients were propensity-score matched (PSM) 3:1 to FTY and to TERI based on age, gender, region, a claims-based MS severity measure, ARR, and number of hospitalizations over the pre-index period. Patients were censored when they dropped out of the database or at the end of the study period (March 31, 2016). Post-index relapses were annualized. RESULTS: The database included 20,311 oral DMT users. After applying the study criteria, the PSM yielded 1602:534 switch patients for the DMF-FTY matched cohort. DMF-FTY patients were well-matched on all covariates: age (mean = 44 for both), gender (28% vs. 26% male, respectively), MS severity measure (0.99 vs. 1.08), and baseline ARR (0.40 vs. 0.44). PSM yielded 833:279 switch patients for the DMF-TERI match. DMF-TERI patients were well-matched on all covariates: age (mean = 50), gender (24% vs. 25% male), MS severity measure (0.86 vs. 0.99), and baseline ARR (0.23 vs. 0.30). The standardized differences confirmed balance across all covariates for matched cohorts. The matched DMF-FTY cohorts had comparable post-index ARR (Rate Ratio [RR] = 1.07 [95% Cl: 0.861, 1.328]) and risk of relapse (Hazard Ratio [HR ]= 0.996 [95% CI: 0.803, 1.236]). Post-index ARR was significantly lower with DMF in comparison to TERI (RR = 0.667 [0.486, 0.914]). The risk of relapse was also significantly lower when switching to DMF than TERI (HR = 0.679 [0.503, 0.917]). CONCLUSION: In this analysis, the effectiveness profiles for those oral DMT users specifically switching from platform therapies are consistent with findings from previous research conducted among all oral DMT users, regardless of prior therapy.