Progressive multifocal leukoencephalopathy with natalizumab extended or standard interval dosing in the United States and the rest of the world.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited. RESEARCH DESIGN AND METHODS: A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems. RESULTS: Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis. CONCLUSIONS: This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial.

BACKGROUND: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. METHODS: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. FINDINGS: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07-0·63) in the once every 6 weeks group and 0·05 (0·01-0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86-20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12-0·82) and 0·06 (0·01-0·31; mean lesion ratio 4·93 [95% CI 1·05-23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. INTERPRETATION: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. FUNDING: Biogen.

The 5-year Tysabri global observational program in safety (TYGRIS) study confirms the long-term safety profile of natalizumab treatment in multiple sclerosis.

BACKGROUND: Natalizumab is an effective treatment for multiple sclerosis (MS) and has a well-characterized safety profile, with more than 10 years of postmarketing experience. TYGRIS was a 5-year observational cohort study designed to obtain long-term safety data in natalizumab-treated MS patients. We examined the incidence and pattern of serious adverse events (SAEs) in this large postmarketing sample of natalizumab-treated patients. METHODS: Investigators reported SAEs in natalizumab-treated patients. Malignancy incidence rates were compared with rates in the general population using external databases. RESULTS: Of 6508 enrolled patients, 4938 (75.9%) completed the study. SAEs occurring in more than 0.5% of patients included urinary tract infection (n = 50; 0.8%), pneumonia (n = 46; 0.7%), progressive multifocal leukoencephalopathy (PML; n = 44; 0.7%), and immune reconstitution inflammatory syndrome (n = 44; 0.7%). Fifty-five patients (0.9%) experienced treatment-emergent serious opportunistic infections, 44 of which were PML. Two patients with PML died. The overall malignancy incidence rate was 449.0 per 100,000 patient-years (95% confidence interval [CI], 375.1-533.1). With few exceptions, incidence rates for individual malignancies had 95% CIs encompassing incidence rates in the general population. Hepatotoxic events occurred in 6 patients; 4 patients had evidence of alternative cause or confounders. Of 96 fatal events, investigators considered 81 unrelated or unlikely to be related to treatment and 5 related or possibly related; causality was not provided for 10. CONCLUSION: Data from this large, long-term study indicate that the nature, character, and frequency of SAEs in real-world settings are consistent with natalizumab's known safety profile. (Funded by Biogen; ClinicalTrials.gov identifiers: NCT00477113 and NCT00483847.).

Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.

OBJECTIVE: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, p < 0.001) and 0.12 (0.05-0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION: Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

The development of sarcoidosis in patients receiving daclizumab: A case series from multiple clinical trials.

INTRODUCTION: Several drugs have been associated with druginduced sarcoidosis-like reactions (DISRs) that are clinically indistinguishable from sarcoidosis. Daclizumab is a humanized monoclonal IgG1 antibody that binds to CD25 that has been studied for the treatment of multiple sclerosis (MS). During MS clinical trials of daclizumab, 12 subjects developed clinical conditions potentially consistent with sarcoidosis. Therefore, an independent adjudication committee of individuals with expertise in sarcoidosis was organized to determine the likelihood of these cases representing sarcoidosis. METHODS: The adjudication committee consisted of a pulmonologist, pathologist, and radiologist with clinical experience in sarcoidosis. The committee had access to the subjects' laboratory data, narratives of all suspect adverse reaction reports, radiographic imaging and histology from biopsies. A priori, a grading system was developed to determine criteria to establish the likelihood that the patient had developed sarcoidosis. RESULTS: The adjudication confirmed sarcoidosis in 11/12 subjects. The committee's decisions were unanimous in all cases. Biopsies were available in 7/11 of these. In the 4 subjects who did not have a biopsy, they all had presentations, clinical findings, and/or laboratory findings that were highly specific for sarcoidosis. Alternative causes for these clinical findings were reasonably excluded in all cases. The lung (8/11) and skin (6/11) were the most common organs involved. The mean daclizumab dose given when signs or symptoms of sarcoidosis occurred was 5413 ±â€¯2704 mg and the median time from first daclizumab dose was 996 days. The incidence rate of developing sarcoidosis in those participating in these daclizumab trials was 154/100,000 patient-years compared with incidence rates of sarcoidosis in the United States of 3.2-17.8/100,000/year. These data suggest that these sarcoidosis cases may have represented DISRs related to daclizumab therapy. CONCLUSIONS: Given the clinical presentation and subsequent evaluation of these 11 subjects, we suspect that they had DISRs from daclizumab.

Risk of pure red cell aplasia in patients with hepatitis C receiving antiviral therapy and an erythropoiesis-stimulating agent.

Antibody-mediated pure red cell aplasia (PRCA) has been primarily observed in patients with chronic kidney disease treated with an erythropoiesis-stimulating agent (ESA); only a few anecdotal cases have been reported in other patient populations. We searched the Amgen Global Safety Adverse Event Database and identified 14 patients with hepatitis C who developed severe anemia, anti-erythropoietin antibodies, and bone marrow biopsy-proven PRCA, while receiving interferon therapy (with or without ribavirin) and an ESA. During the follow-up period and after ESA treatment stopped, 11 patients no longer required transfusions and 3 did. Analysis of antibody isotypes showed that, contrary to reports of patients with chronic kidney disease, immunoglobulin G1 was the predominant isotype rather than immunoglobulin G4 (immunoglobulin G4 was detected in only 1 of 6 patients). Epitope mapping showed the anti-erythropoietin antibodies bound domains required for receptor binding. Therefore, the potential benefits of ESA therapy must be weighed against the risk for PRCA in patients with hepatitis C who are receiving treatment with interferon and ribavirin.

Postpartum diabetes screening in women with a history of gestational diabetes.

OBJECTIVE: Women with a history of gestational diabetes mellitus (GDM) are at high risk for developing type 2 diabetes (diabetes mellitus, DM). The American Diabetes Association recommends regular postpartum diabetes screening for women with a history of GDM, but the American College of Obstetricians and Gynecologists (ACOG) is not as directive. We sought to examine postpartum glycemic testing in women diagnosed with GDM. METHODS: We conducted an observational cohort study of women diagnosed with GDM at one of two large academic medical centers between 2000 and 2001. Kaplan-Meier estimates of the time from delivery to the first postpartum DM screening tests were determined, and predictors of postpartum DM screening were examined using Cox proportional hazards testing. RESULTS: Only 37% of eligible women underwent the postpartum diabetes screening tests recommended by the American Diabetes Association (fasting glucose or oral glucose tolerance test [OGTT]), with a median time from delivery to the first such testing of 428 days. By comparison, 94% of women underwent postpartum cervical cancer screening using a Papanicolaou (Pap) test, with a median time from delivery to Pap testing of 49 days. Even when random glucose testing was included in a broad definition of postpartum DM screening (random or fasting glucose, glycosylated hemoglobin, or OGTT), only two thirds of women (67%) received a postpartum glycemic assessment. CONCLUSION: In the population studied, only 37% of women with a history of GDM were screened for postpartum DM according to guidelines published by the American Diabetes Association. Efforts to improve postpartum DM screening in this high-risk group are warranted.

Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies.

Preeclampsia is far more common in women's first pregnancy but the mechanism of this association is unknown. Altered angiogenesis, marked by increased levels of circulating soluble fms-like tyrosine kinase (sFlt-1), an inhibitor of placental growth factor (PlGF) and vascular endothelial growth factor, has been implicated in the pathogenesis of preeclampsia. We tested the hypothesis that nulliparous women demonstrate increased sFlt-1 levels compared with multiparous women, suggesting an overall increase in relative antiangiogenesis during first pregnancies. We measured sFlt-1 and PlGF levels in early pregnancy serum samples from the first 2 completed pregnancies of 97 women who participated in the MOMS cohort study. Repeated measures analyses demonstrated that sFlt-1 levels were significantly increased in first compared with second pregnancies (877+/-598 pg/mL vs 728+/-399 pg/mL; P=.01) but there was no significant difference in PlGF levels (45.3+/-40.7 pg/mL vs 40.1+/-31.9 pg/mL; P=.14). After adjusting for age, gestational age, blood pressure, body mass index, smoking, and the interpregnancy time interval, the residual decrease in sFlt-1 levels from the first to the second pregnancy remained significant at 107 pg/mL (P=.04). Significant interaction between ethnicity and pregnancy order on sFlt-1 levels was observed such that Hispanic women demonstrated greater sFlt-1 levels than white women during their first pregnancy but lower levels in their second pregnancies. Increased sFlt-1 secretion in first versus second pregnancies may account in part for the increased risk of preeclampsia among nulliparous women. Additional studies are needed to verify these findings and to further examine ethnic differences in angiogenesis factors and their potential impact on the incidence of preeclampsia.

Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia.

Altered angiogenesis and insulin resistance, which are intimately related at a molecular level, characterize preeclampsia. To test if an epidemiological interaction exists between these two alterations, we performed a nested case-control study of 28 women who developed preeclampsia and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed preeclampsia had lower serum levels of SHBG (208+/-116 versus 256+/-101 nmol/L, P=0.05) and PlGF (16+/-14 versus 67+/-150 pg/mL, P<0.001), and in multivariable analysis, women with serum levels of PlGF < or =20 pg/mL had an increased risk of developing preeclampsia (odds ratio [OR] 7.6, 95% CI 1.4 to 38.4). Stratified by levels of serum SHBG (< or =175 versus >175 mg/dL), women with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia (P=0.10), compared with 1.8 (P=0.38) among women with high levels of SHBG and low levels of PlGF. Formal testing for interaction (PlGFxSHBG) was significant (P=0.02). In a model with 3 (n-1) interaction terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as follows: low PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin resistance are additive insults that lead to preeclampsia.

First-trimester C-reactive protein and subsequent gestational diabetes.

OBJECTIVE: Systemic inflammation is associated with the development of type 2 diabetes. We tested the hypothesis that increased inflammation, measured early in pregnancy, is associated with the subsequent development of gestational diabetes mellitus (GDM), a precursor of type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a prospective nested case-control study in a pregnancy cohort. First-trimester C-reactive protein (CRP) levels were measured using a high-resolution assay in 43 women who subsequently developed GDM and in a random sample of 94 women who remained euglycemic throughout pregnancy. Median CRP levels were compared using Wilcoxon's rank-sum test. Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among CRP tertiles. RESULTS: First-trimester CRP levels were significantly increased among women who subsequently developed GDM compared with control subjects (3.1 vs. 2.1 mg/l, P < 0.01). The risk of developing GDM among women in the highest CRP tertile compared with the lowest tertile was 3.2 (95% CI 1.2-8.8). After adjusting for age, race/ethnicity, smoking, parity, blood pressure, and gestational age at CRP sampling, the risk of developing GDM among women in the highest compared with the lowest tertile was 3.6 (95% CI 1.2-11.4). When BMI was included in the model, however, the association between increased CRP and GDM was attenuated (odds ratio for the highest compared with lowest tertile 1.5 [95% CI 0.4-5.5]). CONCLUSIONS: In women who develop GDM, there is evidence of increased inflammation during the first trimester. This association is mediated in part by increased BMI. Larger studies are needed to verify these results.

Role of hydration in the binding of lac repressor to DNA.

The osmotic stress technique was used to measure changes in macromolecular hydration that accompany binding of wild-type Escherichia coli lactose (lac) repressor to its regulatory site (operator O1) in the lac promoter and its transfer from site O1 to nonspecific DNA. Binding at O1 is accompanied by the net release of 260 +/- 32 water molecules. If all are released from macromolecular surfaces, this result is consistent with a net reduction of solvent-accessible surface area of 2370 +/- 550 A. This area is only slightly smaller than the macromolecular interface calculated for a crystalline repressor dimer-O1 complex but is significantly smaller than that for the corresponding complex with the symmetrical optimized O(sym) operator. The transfer of repressor from site O1 to nonspecific DNA is accompanied by the net uptake of 93 +/- 10 water molecules. Together these results imply that formation of a nonspecific complex is accompanied by the net release of 165 +/- 43 water molecules. The enhanced stabilities of repressor-DNA complexes with increasing osmolality may contribute to the ability of Escherichia coli cells to tolerate dehydration and/or high external salt concentrations.