Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years.

BACKGROUND: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile. OBJECTIVE: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. METHODS: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. RESULTS: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. CONCLUSION: In patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab.

INTRODUCTION: The SARS-CoV-2 pandemic necessitated better understanding of the impact of disease-modifying therapies on COVID-19 outcomes and vaccination. We report characteristics of COVID-19 cases and vaccination status in ofatumumab-treated relapsing multiple sclerosis (RMS) patients. METHODS: COVID-19 data analyzed were from the ongoing, open-label, long-term extension phase 3b ALITHIOS study from December 2019 (pandemic start) and post-marketing cases from August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and breakthrough infection were evaluated. RESULTS: As of 25 September 2021, 245 of 1703 patients (14.4%) enrolled in ALITHIOS receiving ofatumumab (median exposure: 2.45 years) reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or moderate (46.5%) severity, but 9% had severe/life-threatening COVID-19. There were 24 serious cases (9.8%) with 23 patients hospitalized; 22 recovered and 2 died. At study cut-off, 241 patients (98.4%) had recovered or were recovering or had recovered with sequelae and 2 (0.8%) had not recovered. Ofatumumab was temporarily interrupted in 39 (15.9%) patients. Before COVID-19 onset, IgG levels were within the normal range in all COVID-19-affected patients, while IgM was < 0.4 g/l in 23 (9.4%) patients. No patient had a reinfection. Overall, 559 patients were vaccinated (full, 476; partial, 74; unspecified, 9). Breakthrough infection was reported in 1.5% (7/476) patients, and 11 reported COVID-19 after partial vaccination. As of 25 September 2021, the Novartis Safety Database (~ 4713 patient-treatment years) recorded 90 confirmed COVID-19 cases receiving ofatumumab. Most cases were non-serious (n = 80), and ten were serious (1 medically significant, 9 hospitalized, 0 deaths). Among 36 of 90 cases with outcomes reported, 30 recovered and 6 did not recover. CONCLUSION: COVID-19 in RMS patients on ofatumumab was primarily of mild/moderate severity and non-serious in these observational data. Most recovered from COVID-19 without treatment interruption. Two people died with COVID-19. Breakthrough COVID-19 despite being fully/partially vaccinated was uncommon.

BGG492 as an adjunctive treatment in patients with partial-onset seizures: A 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension.

OBJECTIVES: To evaluate dose-response relationship of BGG492 as add-on therapy to 1-3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study). RESULTS: Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose-response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7-10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] -18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events (AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]). SIGNIFICANCE: There was no significant dose-response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified.

A Randomized Trial of Iloperidone for Prevention of Relapse in Schizophrenia: The REPRIEVE Study.

BACKGROUND: The purpose of this study was to evaluate the safety and effectiveness of iloperidone for the prevention of relapse in schizophrenia. METHODS: Study subjects were adults with schizophrenia who started on oral open-label iloperidone titrated to an initial target dose of 12 mg/day (6 mg twice daily) and then stabilized on a flexible-dose iloperidone regimen (range 8-24 mg/day) for up to 24 weeks. Subjects meeting stabilization criteria then entered the relapse-prevention phase and were randomized 1:1 in a double-blind fashion to continue with iloperidone or placebo withdrawal for up to 26 weeks or until meeting relapse or other withdrawal criteria. RESULTS: A total of 303 subjects were randomized to the relapse-prevention phase; 153 continued to receive iloperidone, and 150 were withdrawn to placebo. The modal total daily dose for iloperidone in all phases of the study was 12 mg/day. The pre-defined unblinded interim analysis upon reaching 68 relapse events confirmed the hypothesis that iloperidone (n = 97) was more effective than placebo (n = 96) in preventing relapse events, and the trial was stopped early. The estimated relapse rates were 63.4 % (Kaplan-Meier [KM] estimate) for placebo compared with 20.4 % (KM estimate) for those continuing to receive iloperidone (log rank test: p < 0.0001). The mean time to relapse was 71 days for placebo and 139 days for iloperidone (hazard ratio 4.7; 95 % confidence interval 2.7-8.3; p < 0.0001). The safety profile observed in previous short-term studies was also reaffirmed in this maintenance treatment setting. The most common treatment-emergent adverse events (TEAEs) in the stabilization phase were dizziness (11.6 %), somnolence (8.3 %), and dry mouth (6.8 %). Rates of reported extrapyramidal disorder or akathisia during stabilization were 2.5 and 3.7 %, respectively. CONCLUSIONS: Flexible dosing of iloperidone for maintenance-phase therapy, with a modal dose of 12 mg/day was effective in preventing relapse in subjects previously stabilized on iloperidone. The adverse event profile for iloperidone was consistent with other studies, and the low extrapyramidal symptom and akathisia burden during stabilization was sustained during the course of the study. ClinicalTrials.gov identifier: NCT01291511.

Double-blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson's disease.

We performed a 39-week, randomized, double-blind, multicenter study to compare the efficacy, safety, and tolerability of levodopa/carbidopa/entacapone (LCE, Stalevo) with levodopa/carbidopa (LC, Sinemet IR) in patients with early Parkinson's disease (PD). Four hundred twenty-three patients with early PD warranting levodopa were randomly assigned to treatment with LCE 100/25/200 or LC 100/25 three-times daily. The adjusted mean difference in total Unified Parkinson's disease Rating Scale (UPDRS) Parts II and III between groups using the analysis of covariance model (prespecified primary outcome measure) was 1.7 (standard error = 0.84) points favoring LCE (P = 0.045). Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living (ADL) scores (P = 0.025), Schwab and England ADL scores (blinded rater, P = 0.003; subject, P = 0.006) and subject-reported Clinical Global Impression (CGI) scores (P = 0.047). There was no significant difference in UPDRS Part III or investigator-rated CGI scores. Wearing-off was observed in 29 (13.9%) subjects in the LCE group and 43 (20.0%) in the LC group (P = 0.099). Dyskinesia was observed in 11 (5.3%) subjects in the LCE group and 16 (7.4%) in the LC group (P = 0.367). Nausea and diarrhea were reported more frequently in the LCE group. LCE provided greater symptomatic benefit than LC and did not increase motor complications.

Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study.

OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.