ABSTRACT
BACKGROUND: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. OBJECTIVES: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. METHODS: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). RESULTS: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. CONCLUSIONS: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.
Subject(s)
Abnormalities, Drug-Induced/epidemiology , Clinical Trials as Topic , Crotonates/adverse effects , Hydroxybutyrates/adverse effects , Immunosuppressive Agents/adverse effects , Multiple Sclerosis/drug therapy , Nitriles/adverse effects , Pregnancy Complications/chemically induced , Pregnancy Complications/epidemiology , Pregnancy Outcome/epidemiology , Product Surveillance, Postmarketing , Toluidines/adverse effects , Adult , Female , Humans , Infant, Newborn , Pregnancy , Prospective Studies , Retrospective StudiesABSTRACT
OBJECTIVE: Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or urine of natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal leukoencephalopathy (PML). METHODS: A total of 12,850 blood and urine samples from nearly 1,400 patients participating in natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH). RESULTS: At the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive patients developed PML. In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in 224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of natalizumab, treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients before or after natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at any time point before symptoms first occurred. INTERPRETATION: Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for predicting PML risk in natalizumab-treated MS patients.
Subject(s)
Antibodies, Viral , DNA, Viral/immunology , JC Virus/immunology , Leukoencephalopathy, Progressive Multifocal , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Viral/blood , Antibodies, Viral/therapeutic use , Antibodies, Viral/urine , Confidence Intervals , DNA, Viral/blood , DNA, Viral/urine , Enzyme-Linked Immunosorbent Assay/methods , Female , Follow-Up Studies , Humans , Leukoencephalopathy, Progressive Multifocal/blood , Leukoencephalopathy, Progressive Multifocal/therapy , Leukoencephalopathy, Progressive Multifocal/urine , Male , Natalizumab , Statistics, NonparametricABSTRACT
BACKGROUND: There is an unmet need for disease-modifying therapies to improve ambulatory function in disabled subjects with multiple sclerosis. OBJECTIVES: Assess the effects of natalizumab on ambulatory function in disabled subjects with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS). METHODS: We retrospectively reviewed ambulatory function as measured by timed 25-foot walk (T25FW) in clinical trial subjects with an Expanded Disability Status Scale score ≥3.5, including RRMS subjects from the phase 3 AFFIRM and SENTINEL trials, relapsing SPMS subjects from the phase 2 MS231 study, and nonrelapsing SPMS subjects from the phase 1b DELIVER study. For comparison, SPMS subjects from the intramuscular interferon beta-1a (IM IFNß-1a) IMPACT study were also analyzed. Improvement in ambulation was measured using T25FW responder status; response was defined as faster walking times over shorter (6-9-month) or longer (24-30-month) treatment periods relative to subjects' best predose walking times. RESULTS: There were two to four times more T25FW responders among disabled MS subjects in the natalizumab arms than in the placebo or IM IFNß-1a arms. Responders walked 25 feet an average of 24%-45% faster than nonresponders. CONCLUSION: Natalizumab improves ambulatory function in disabled RRMS subjects and may have efficacy in disabled SPMS subjects. Confirmation of the latter finding in a prospective SPMS study is warranted.