Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. OBJECTIVE: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. METHODS: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. RESULTS: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). CONCLUSION: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Cognitive performance of patients with opioid use disorder transitioned to extended-release injectable naltrexone from buprenorphine: Post hoc analysis of exploratory results of a phase 3 randomized controlled trial.

BACKGROUND: Opioid use disorder (OUD) is associated with cognitive dysfunction. Understanding how pharmacotherapy may affect cognition is an important treatment consideration. METHODS: This was a hybrid residential-outpatient, randomized trial assessing transition regimens (naltrexone/buprenorphine [NTX/BUP] vs placebo-NTX/buprenorphine [PBO-N]/BUP) to extended-release naltrexone (XR-NTX) in patients with OUD seeking BUP discontinuation. Cognition was assessed at baseline, Day 22 (XR-NTX Day 14), and Day 36 (XR-NTX Day 28) using a range of measures (Brief Assessment of Cognition Symbol Coding test, Controlled Oral Word Association Task, Wechsler Memory Scale-III Spatial Span test, Continuous Performance Test, and Test of Attentional Performance). Pre-specified exploratory analyses compared treatment groups. Post hoc analyses were treatment-arm-independent analyses overall and by baseline BUP dose (<8 mg/day [low-dose] or 8 mg/day [higher-dose]). RESULTS: Baseline cognitive measures were similar between NTX/BUP and PBO-N/BUP groups and between BUP low-dose and higher-dose groups. There were improvements in several cognitive outcomes at Day 22 and Day 36 relative to baseline for the overall population, but no differences between NTX/BUP and PBO-N/BUP treatment groups were observed. Participants entering the study on low-dose BUP showed improvements at Day 36 relative to baseline in 5 of 7 cognitive outcomes; participants entering the study on higher-dose BUP generally did not show improvements in cognitive outcomes. CONCLUSIONS: Improvements in most cognitive domains were associated with the transition from BUP to XR-NTX, particularly in participants entering the study on low-dose (<8 mg/day) BUP. These improvements may be due to the discontinuation of BUP, the treatment with XR-NTX, or both.

Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile. OBJECTIVES: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis. METHODS: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. RESULTS: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%). CONCLUSIONS: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03093324).

Adherence and persistence among multiple sclerosis patients after one immunomodulatory therapy failure: retrospective claims analysis.

INTRODUCTION: There are no published data on patient adherence to, and persistence with, disease-modifying therapies (DMT) for multiple sclerosis (MS) after one immunomodulatory failure. The present study compares secondline DMT adherence and persistence among patients with MS. METHODS: Patients with MS initiating a second-line treatment with natalizumab, intramuscular interferon beta-1a (i.m.-IFNß-1a), subcutaneous (s.c.) IFNß-1a, interferon beta-1b (IFNß-1b), and glatiramer acetate (GA) from January 1, 2006 to October 4, 2008 were identified from a retrospective claims database associated with a large US health plan. Adherence was measured with medication possession ratio (MPR); adherence indicated MPR ≥ 0.80. Persistence was measured as time until a minimum 60-day gap in second-line therapy. Adherence and persistence were modeled with logistic and Cox proportional hazard regressions, respectively. RESULTS: The study population comprised 1381 patients. Multivariate analysis showed that the odds of adherence were significantly higher in the natalizumab cohort compared with all other second-line cohorts. The natalizumab cohort was more likely to be persistent compared with the i.m.-IFNß-1a and IFNß-1b cohorts. CONCLUSION: The natalizumab cohort was more adherent compared with the other second-line DMT cohorts, likely due in large part to active physician involvement and monitoring. Adherence to DMT, even after first-line failure, is critical to achieving optimal therapeutic benefit.

Comparison of adherence and persistence among multiple sclerosis patients treated with disease-modifying therapies: a retrospective administrative claims analysis.

PURPOSE: To compare adherence and persistence among patients with multiple sclerosis (MS) initiated on disease-modifying therapy (DMTs), including intramuscular (IM) interferon beta-1a (IFNß-1a), subcutaneous (SC) IFNß-1a, IFNß-1b, or glatiramer acetate (GA). METHODS: MS patients initiated on IM-IFNß-1a, SC-IFNß-1a, IFNß-1b, or GA between January 1, 2000 and January 2, 2008 were identified from a retrospective claims database study associated with a large US health plan. The date of DMT initiation was the index date; patients were observed for 6 months before and 12-36 months after the index date. Adherence to the index DMT was measured with a medication possession ratio (MPR), the proportion of days patients possessed their index DMTs; MPR ≥ 0.80 was considered adherent. Persistence was time in days from index date until the earlier of a minimum 60-day gap in DMT therapy or the last DMT claim during follow-up. Adherence and persistence were modeled with logistic and Cox proportional hazard regressions, respectively. RESULTS: The study population comprised 6,680 patients in the DMT cohorts: IM-IFNß-1a (N = 2,305, 34.5%); IFNß-1b (N = 894, 13.4%); GA (N = 2,270, 34.0%); and SC-IFNß-1a (N = 1,211, 18.1%). The IM-IFNß-1a cohort had significantly higher regression-adjusted odds of adherence relative to the other cohorts: 52.4% higher odds versus the IFNß-1b cohort (OR = 0.656, CI = 0.561-0.768); 33.5% higher odds versus the GA cohort (OR = 0.749, CI = 0.665-0.844); and 20.6% higher odds versus the SC-IFNß-1a cohort (OR = 0.829, CI = 0.719-0.957). There were no consistent differences in persistence between the cohorts. CONCLUSION: IM-IFNß-1a patients had significantly higher odds of adherence compared with other DMT cohorts, possibly attributable to IM-IFNß-1a's less frequent dosing schedule. The benefits of adherence may include better quality of life, lower risk of relapse, and fewer hospitalizations and emergency visits, making adherence a critical component of MS management.

Medical chart validation of an algorithm for identifying multiple sclerosis relapse in healthcare claims.

OBJECTIVE: Relapse is a common measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objective of this study was to test the content validity of an operational algorithm for detecting relapse in claims data. METHODS: A claims-based relapse detection algorithm was tested by comparing its detection rate over a 1-year period with relapses identified based on medical chart review. According to the algorithm, MS patients in a US healthcare claims database who had either (1) a primary claim for MS during hospitalization or (2) a corticosteroid claim following a MS-related outpatient visit were designated as having a relapse. Patient charts were examined for explicit indication of relapse or care suggestive of relapse. Positive and negative predictive values were calculated. RESULTS: Medical charts were reviewed for 300 MS patients, half of whom had a relapse according to the algorithm. The claims-based criteria correctly classified 67.3% of patients with relapses (positive predictive value) and 70.0% of patients without relapses (negative predictive value; kappa 0.373: p < 0.001). Alternative algorithms did not improve on the predictive value of the operational algorithm. Limitations of the algorithm include lack of differentiation between relapsing-remitting MS and other types, and that it does not incorporate measures of function and disability. CONCLUSIONS: The claims-based algorithm appeared to successfully detect moderate-to-severe MS relapse. This validated definition can be applied to future claims-based MS studies.

Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a.

Immunologic response was assessed prospectively using influenza vaccine in 86 patients with multiple sclerosis (MS) who were taking interferon beta-1a and 77 patients who were not taking interferon. Blood samples were assayed for hemagglutination inhibition (HI) titers 0, 21, and 28 days after immunization. The two groups were similar in the proportion of patients achieving an HI titer of 40 or greater, the prespecified primary end point and on all secondary indicators of immune response.

The relationship between depression and interferon beta-1a therapy in patients with multiple sclerosis.

It has been suggested that interferons (IFN) may cause depression de novo or worsen pre-existing depression. Depression data collected using validated instruments from individual clinical trials in multiple sclerosis, however, have consistently failed to identify an association. In this study, pooled data from 6 controlled studies and 17 noncontrolled clinical trials of subcutaneous IFN beta-1a were assessed to determine the relationship between IFN therapy with physician reports of depression and suicide. In distinction to the negative findings for depressive symptom ratings, pooling of physician-reported side effect data from these clinical trials identified a statistically significant association between depression and IFN use during the first six months of treatment There was an association between these reported episodes of depression and discontinuation of IFN therapy, but IFN treatment was not associated with suicide attempts. IFN beta-1a may induce a constellation of symptoms, particularly early in therapy, that may be labelled as depression by physicians. However, the lack of an increase in depression-rating scale scores and the lack of association with suicide risk suggests that the syndrome may be an atypical one.