Multiple sclerosis onset in youth is increasingly recognized. A systematic review was conducted to assess incidence and prevalence of pediatric-onset multiple sclerosis, focusing on occurrence by age subgroups and disease course. A literature search for the period 1965-2018 was carried out, selecting population-based studies of multiple sclerosis in individuals aged 19 years and younger. Nineteen studies met inclusion criteria. One pediatric neurologist extracted the data. Overall incidence ranged from 0.05 (95% confidence interval 0.03-0.08) to 2.85 (95% confidence interval 2.83-2.86) per 100 000 children and overall prevalence from 0.69 (95% confidence interval 0.58-0.80) to 26.92 (95% confidence interval 26.61-27.23) per 100 000 children. Incidence increased with age. The female-male ratio increased from 1.2:1 in children <12 years old to 2.8:1 in children ≥12 years old. Ten studies (n=521 children) reported disease course. Seven studies found only relapsing-remitting disease and 3 studies found primary-progressive disease in 3.0% to 6.7%. Two secondary-progressive disease cases were identified. Epidemiologic data aid in understanding the magnitude of multiple sclerosis and its clinical phenotypes, for planning for new disease-modifying therapies in the pediatric population.

Background: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study. Methods: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors. Results: The total safety population ( N = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years. Conclusion: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting.

IntroductionMultiple sclerosis (MS) is more common in women and can occur during childbearing years; thus, information on outcomes following exposure to MS therapy during pregnancy is important. No formal studies of daclizumab have been conducted in pregnant women. Here, we report available nonclinical and clinical data on pregnancy outcomes from the daclizumab clinical study program.MethodsReproductive and developmental toxicity studies were conducted in cynomolgus monkeys. Reports of pregnancies that occurred during the daclizumab clinical study program through March 9, 2015 were collated and summarized. In the event of pregnancy, daclizumab was discontinued and safety monitoring continued.ResultsStudies in cynomolgus monkeys showed no daclizumab-related effects on maternal well-being, embryo–fetal development, indirect fertility end points, and pre- and postnatal development and growth. Across the clinical study program, 38 pregnancies were reported in 36 daclizumab-exposed women (on treatment ≤6 months from last dose); 20 resulted in live births and four (11%) in spontaneous abortions or miscarriages. One congenital heart defect (complex transposition of great vessels) occurred in one live birth (considered unrelated to daclizumab); daclizumab had been discontinued and intramuscular interferon beta-1a and lisinopril were used at conception. Eight women had an elective termination, two had an ectopic pregnancy, and two were lost to follow-up; two pregnancy outcomes are pending. Six additional pregnancies occurred in five women >6 months after their last daclizumab dose; in one additional pregnancy, exposure was unknown.ConclusionSpontaneous abortion rate in daclizumab-exposed women was consistent with early pregnancy loss in the general population (12%–26%). Data on pregnancies exposed to daclizumab do not suggest an increased risk of adverse fetal or maternal outcomes, although the numbers are too small for definitive conclusions.ClinicalTrials.gov identifiersNCT00390221, NCT01064401, NCT01462318, NCT00870740, NCT01051349, and NCT01797965.FundingBiogen and AbbVie Biotherapeutics Inc.

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Introduction: Trisenox®(arsenic trioxide) injection was approved in the United States in Sept 2000 and in the EU in March 2002 for the treatment of patients (pts) with relapsed or refractory acute promyelocytic leukemia (APL). Aim: The aim of this analysis is to assess the safety profile of Trisenox®. Methods: Safety information was gathered from monitored clinical trials and from spontaneous postmarketing reports. Results: As of June 2004, approximately 3600 pts had received commercial drug for a variety of hematologic and nonhematologic cancers. In clinical trials or compassionate programs since the beginning of the Trisenox® development program, 808 pts [with APL (265), multiple myeloma (103), MDS (188), and other hematologic cancers or solid tumors (252)] have been treated. The overall safety experience for Trisenox® is therefore based on exposure of approximately 4400 pts. Postmarketing Experience: As of May 2004, 380 spontaneous postmarketing adverse event (AE) reports were received by CTI; 123 of these were serious AEs (SAEs), with 13 deaths, most due to disease progression or complications of the disease being treated. Trisenox® may have contributed to a death due to possible tumor lysis syndrome in a pt with MM, and 1 AML pt died with no cause reported. Most reported AEs are expected events that are listed in the Trisenox® product labeling. AEs reported for >15 pts were cytopenia (anemia, leukopenia, neutropenia, thrombocytopenia), pyrexia, prolonged QT interval, dyspnea, edema/wt gain, pain, hypotension, leukocytosis, rash, differentiation syndrome, nausea, asthenia/fatigue. Clinical Trial Experience: SAEs considered related to Trisenox® have been reported for 120 of 305 pts enrolled in clinical trials since US approval. This larger proportion of pts with SAEs likely reflects the monitored data in clinical trials compared to spontaneous postmarketing reports. Most of these SAEs are events listed in the Trisenox® label. AEs considered by investigators to be related to Trisenox® in 20% or more of the 233 pts with data received by CTI since US approval are pain (51%), nausea/vomiting (47%/23%), edema (43%), diarrhea (43%), fatigue/asthenia (37%/21%), pyrexia (36%), rash (34%), dyspnea (33%), gastrointestinal disorder (32%), headache (30%), cough (30%), upper respiratory symptoms (27%), abdominal pain (26%), anorexia (23%), lower respiratory disorders (22%), any cardiac arrhythmia (21%), hemorrhage (21%), viral infection (21%). As disease symptoms diminish, adverse events generally decrease in incidence and severity with continued use of Trisenox®. Few pts require interruption of therapy. A recent report of transient arrhythmias in pts continuously monitored during treatment with a non-Trisenox® formulation of arsenic trioxide (Unnikrishnan, Br J Haematol2004;124:610–7) does not reflect the safety experience in pts treated with Trisenox® and managed in accordance with the product labeling. Conclusion: With >4400 pts exposed to Trisenox®, the postmarketing AEs reported are generally similar to those observed in clinical trials and listed in the product labeling. The risk/benefit profile of Trisenox® when pts are managed in accordance with the product label remains acceptable.