Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study.

BACKGROUND: Patients with multiple sclerosis (MS) or Crohn's disease (CD) being treated with natalizumab (Tysabri®, Biogen) who are planning to become pregnant or discover they are pregnant after exposure to natalizumab are currently advised to balance the potential benefits and potential risks of exposure when considering treatment options. This study was undertaken to evaluate pregnancy outcomes of women with MS or CD who were exposed to natalizumab at any time within 3 months prior to conception or during pregnancy. A pregnancy registry was created to better understand the effect of natalizumab exposure on pregnancy outcomes. METHODS: The Tysabri Pregnancy Exposure Registry was a global, observational exposure registration and follow-up study. Evaluations included spontaneous abortions (<22 weeks gestational age), fetal losses (≥22 weeks gestational age), ectopic pregnancies, elective or therapeutic terminations, stillbirths, birth defects, and live births. Birth defects were reviewed and coded in accordance with the Metropolitan Atlanta Congenital Defects Program (MACDP) classification of birth defects. RESULTS: A total of 369 patients with MS and 7 patients with CD were enrolled prospectively, of whom 355 patients (99.4 %; 349 MS and 6 CD) had known pregnancy outcomes (including 8 twin sets). The spontaneous abortion rate was 9.0 % (n = 32; 95 % confidence interval [C. I.], 6.3-12.5 %). An independent advisory committee review determined the major birth defect rate to be 5.05 % (16 of 316 live births + 1 elective abortion; 95 % C. I., 2.9-8.1 %). The mean gestational age of the live-born infants was 38.3 weeks, and the mean birth weight was 3158.3 g. CONCLUSIONS: Although the overall rate of birth defects was higher than that observed by the MACDP, these registry outcomes showed no specific pattern of malformations that would suggest a drug effect, and the spontaneous abortion rate was consistent with that of the general population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00472992 (11 May 2007).

Risk of natalizumab-associated progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. We quantified the risk of PML in patients with multiple sclerosis, according to the presence or absence of three risk factors: positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increasing duration of natalizumab treatment. METHODS: We used data from postmarketing sources, clinical studies, and an independent Swedish registry to estimate the incidence of PML among natalizumab-treated patients with multiple sclerosis, according to positive or negative status with respect to anti-JC virus antibodies, prior or no prior use of immunosuppressants, and duration of treatment (1 to 24 months vs. 25 to 48 months). Blood samples were available for anti-JC virus antibody testing from 5896 patients with multiple sclerosis and from 54 patients with multiple sclerosis who were treated with natalizumab and in whom PML later developed. RESULTS: As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti-JC virus antibodies. When the risk of PML was stratified according to three risk factors, the risk of PML was lowest among the patients who were negative for anti-JC virus antibodies, with the incidence estimated to be 0.09 cases or less per 1000 patients (95% confidence interval [CI], 0 to 0.48). Patients who were positive for anti-JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1000 patients [95% CI, 8.3 to 14.5]). CONCLUSIONS: Positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were associated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis. (Funded by Biogen Idec and Elan Pharmaceuticals.).

Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy.

Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML.

Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy.

OBJECTIVE: The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti-JC virus (JCV) antibodies. We analyzed whether anti-JCV antibody levels, measured as index, may further define PML risk in seropositive patients. METHODS: The association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JCV antibody-positive multiple sclerosis (MS) patients from natalizumab clinical studies and postmarketing sources. For PML and non-PML patients, the probabilities of having an index below and above a range of anti-JCV antibody index thresholds were calculated using all available data and applied to the PML risk stratification algorithm. Longitudinal stability of anti-JCV antibody index was also evaluated. RESULTS: Anti-JCV antibody index data were available for serum/plasma samples collected >6 months prior to PML diagnosis from 71 natalizumab-treated PML patients and 2,522 non-PML anti-JCV antibody-positive patients. In patients with no prior immunosuppressant use, anti-JCV antibody index distribution was significantly higher in PML patients than in non-PML patients (p < 0.0001). Among patients who were anti-JCV antibody negative at baseline in the AFFIRM and STRATIFY-1 trials, 97% remained consistently negative or below an index threshold of 1.5 over 18 months. Retrospective analyses of pre-PML samples collected longitudinally from PML patients displayed sustained higher anti-JCV antibody index over time. INTERPRETATION: Anti-JCV antibody levels in serum/plasma, measured as index, may differentiate PML risk in anti-JCV antibody-positive MS patients with no prior immunosuppressant use. Continued evaluation of anti-JCV antibody index and PML risk is warranted.

Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1.

OBJECTIVE: A study was undertaken to define the prevalence of anti-JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false-negative rate of a 2-step anti-JC virus antibody assay. METHODS: STRATIFY-1 is an ongoing, longitudinal, observational study of relapsing MS patients in the United States who are being treated or considering treatment with natalizumab. Baseline serum and plasma samples were collected for anti-JC virus antibody detection using an analytically validated, 2-step, virus-like particle-based enzyme-linked immunosorbent assay. Urine was collected for JC virus DNA detection. RESULTS: At baseline (n = 1,096), overall anti-JC virus antibody prevalence was 56.0% (95% confidence interval [CI], 53.0-59.0) in STRATIFY-1 patients, with an assay false-negative rate of 2.7% (95% CI, 0.9-6.2). Prevalence was significantly lower in females (53.4%; 95% CI, 49.9-56.8) than males (64.3%; 95% CI, 58.2-70.0) and increased with age, p = 0.0019 and p = 0.0001, respectively. Prevalence was similar in patients regardless of natalizumab exposure or prior immunosuppressant use, p = 0.9709 and p = 0.6632, respectively. STRATIFY-1 results were generally consistent with those observed in another large North American cohort, TYGRIS-US (n = 1,480). INTERPRETATION: Baseline results from STRATIFY-1 are consistent with other studies utilizing this assay that demonstrate a 50 to 60% prevalence of anti-JC virus antibodies, a low false-negative rate, and an association of increasing age and male gender with increasing anti-JC virus antibody prevalence. Neither natalizumab exposure nor prior immunosuppressant use appear to affect prevalence. Longitudinal data from STRATIFY-1 will confirm the stability of anti-JC virus antibody prevalence over time.

Evaluation of Opioid Overdose Reports in Patients Treated with Extended-Release Naltrexone: Postmarketing Data from 2006 to 2018.

INTRODUCTION: After treatment with naltrexone extended-release injectable suspension (XR-NTX), a µ-opioid receptor antagonist, opioid tolerance is reduced from pretreatment baseline. Patients may be vulnerable to opioid overdose if they attempt to override the blockade during treatment, at the end of a dosing interval, after missing a dose, or after discontinuing treatment. OBJECTIVE: We analyzed postmarketing data to characterize reporting rates of opioid overdose during treatment with and after discontinuation of XR-NTX. METHODS: Postmarketing adverse event reports within the XR-NTX safety database, received 2006-2018, for patients treated with XR-NTX for any indication were reviewed for opioid overdose cases. Assessable cases were categorized by timing of the event from the last dose of XR-NTX (latency): ≤28 days (on treatment), 29-56 days, and >56 days from last dose of XR-NTX. Within each latency group, cases were further classified as serious and, of those, cases that had a fatal outcome. RESULTS: During the 12-year period, an estimated 495,602 patients received XR-NTX. Opioid overdose was reported in 161 cases; of these, 66 contained sufficient information to determine latency. Reporting rates of opioid overdose per 10,000 patients treated were similar among latency groups: 0.54 for ≤28 days (0.24 fatal), 0.34 for 29-56 days (0.16 fatal), and 0.44 for >56 days (0.40 fatal) from the last dose of XR-NTX. CONCLUSIONS: Over the 12-year period, the reporting rates of opioid overdose were similar during treatment with or after discontinuation of XR-NTX and <10/10,000 patients exposed. Our findings are limited by the nature of spontaneously reported safety data.

Outcome and survival of asymptomatic PML in natalizumab-treated MS patients.

OBJECTIVE: As of 3 September 2013, 399 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab-treated MS patients who were asymptomatic at PML diagnosis. METHODS: Analyses included data available as of 5 June 2013. Asymptomatic patients diagnosed with PML by magnetic resonance imaging (MRI) findings and JC virus DNA detection in the central nervous system were compared with patients presenting with symptoms at diagnosis. Demographics, MRI, and survival over 12 months were analyzed. Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were recorded pre-PML, at diagnosis, and at 6 and 12 months post-diagnosis. RESULTS: A total of 372 PML cases were analyzed; 30 patients were asymptomatic and 342 were symptomatic at PML diagnosis. Classifications of PML lesions on MRI in asymptomatic versus symptomatic patients were unilobar in 68% versus 37%, multilobar in 21% versus 24%, and widespread in 11% versus 40%. In both groups with unilobar lesions, frontal lobe lesions predominated. Prior to PML, mean EDSS and KPS scores were similar for asymptomatic and symptomatic patients. At diagnosis, mean EDSS score was significantly lower for asymptomatic patients (4.1; n = 11) than for symptomatic patients (5.4; n = 193; P = 0.038). Six months after PML diagnosis, asymptomatic patients had less functional disability than symptomatic patients. As of 5 June 2013, 96.7% of asymptomatic patients and 75.4% of symptomatic patients were alive. INTERPRETATION: PML patients asymptomatic at diagnosis had better survival and less functional disability than those who were symptomatic at diagnosis.

Assessment of malignancy risk in patients with multiple sclerosis treated with intramuscular interferon beta-1a: retrospective evaluation using a health insurance claims database and postmarketing surveillance data.

BACKGROUND: Intramuscular interferon beta-1a (IFNß-1a), a multiple sclerosis (MS) therapy that has been commercially available for over a decade, provides a unique opportunity to retrospectively assess postmarketing data for evidence of malignancy risk, compared with relatively limited data available for more recently approved therapies. Postmarketing and claims data were analyzed to determine the risk of malignancy in MS patients treated with intramuscular IFNß-1a. MATERIALS AND METHODS: The cumulative reporting rates of suspected adverse drug reactions coded to malignancy in the intramuscular IFNß-1a global safety database were compared with malignancy incidence rates in the World Health Organization GLOBOCAN database. In addition, using data from a large US claims database, the cumulative prevalence of malignancy in MS patients treated with intramuscular IFNß-1a was compared with non-MS population controls, MS patients without intramuscular IFNß-1a use, and untreated MS patients. Mean follow-up was approximately 3 years for all groups, ie, 3.1 years for the intramuscular IFNß-1a group (range 0.02-6.0 years), 2.6 years for non-MS population controls (range 0-6.0 years), 2.6 years for the intramuscular IFNß-1a nonuse group (range 0.01-6.0 years), and 2.4 years for the untreated MS group (range 0.01-6.0 years). RESULTS: An estimated 402,250 patients received intramuscular IFNß-1a during the postmarketing period. Cumulative reporting rates of malignancy in this population were consistent with GLOBOCAN incidence rates observed within the general population. The claims database included 12,894 MS patients who received intramuscular IFNß-1a. No significant difference in malignancy prevalence was observed in intramuscular IFNß-1a users compared with other groups. CONCLUSION: Results from this evaluation provide no evidence of an increased risk of malignancy with intramuscular IFNß-1a use.

Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study.

OBJECTIVE: The objective of this study was to assess the risk of acute pancreatitis in patients with type 2 diabetes compared with that in patients without diabetes. We also examined the risk of biliary disease (defined as occurrence of cholelithiasis, acute cholecystitis, or cholecystectomy), which is a major cause of pancreatitis. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using a large, geographically diverse U.S. health care claims database. Eligible patients (>or=18 years) were enrolled for at least 12 continuous months (1999-2005), with no incident events of pancreatitis or biliary disease during that 1 year baseline period. ICD-9 codes and prescription data were used to identify patients with type 2 diabetes; ICD-9 codes were also used to identify cases of pancreatitis and biliary disease. Overall, 337,067 patients with type 2 diabetes were matched on age and sex with 337,067 patients without diabetes. Incidence rates of disease and 95% CI were calculated per 100,000 person-years of exposure. RESULTS: The type 2 diabetic cohort had a 2.83-fold (95% CI 2.61-3.06) greater risk of pancreatitis and 1.91-fold (1.84-1.99) greater risk of biliary disease compared with the nondiabetic cohort. Relative to patients of corresponding age without diabetes, younger type 2 diabetic patients had the highest risk of pancreatitis (<45 years: incidence rate ratio [IRR] 5.26 [95% CI 4.31-6.42]; >or=45 years: 2.44 [2.23-2.66]). CONCLUSIONS: These data suggest that patients with type 2 diabetes may have an increased risk of acute pancreatitis and biliary disease.