Biogen Research Articles

Distribution of F8 Gene Mutations in 81 Inhibitor-Free, Severe Hemophilia a Patients with Full Exposure to FVIII

Introduction: Factor (F) VIII genotype has been shown to be a risk factor for inhibitor development, where different mutation types are associated with different degrees of risk (Oldenburg J, et al.Haemophilia 2006;12 Suppl 6:15–22). However, it is not clear why some patients with a specific mutation develop inhibitors while others with the same mutation do not, including those with high-risk defects such as null mutations. Patients with severe hemophilia A (HA) with low-risk mutations are thought to produce some functional or non-functional FVIII that is sufficient to induce immune tolerance (Oldenburg J, et al.Haemophilia 2002;8 Suppl 2:23–29). In the present study, the distribution of F8 gene mutations in 81 patients fully exposed to FVIII with severe HA and no inhibitors is compared to data on mutation distribution among severe HA patients with/without inhibitors.Materials & Methods: Turoctocog alfa (NovoEight®) is a new recombinant FVIII product with a truncated B-domain. Previously treated patients (PTPs) with severe HA participated in the pivotal trials guardian™1 (n=150; 12–65 yrs) or guardian™3 (n=63; <12 yrs), in which they received turoctocog alfa as prophylaxis and to treat bleeds. The majority continued in an ongoing extension trial, guardian™2. All patients ≥12 yrs had a history of ≥150 exposure days (EDs) to FVIII products and patients <12 yrs had ≥50 EDs. No patients had inhibitors prior to or after turoctocog alfa treatment. Distribution of mutation types has previously been reported in populations with HA that consisted of or included patients with inhibitors (Salviato R, et al. Haemophilia 2007;13:361–372; Gouw SC, et al.Blood 2012;119:2922–2934). Here we report mutation distribution in a sample of guardian™ patients with severe HA who had long been previously treated with FVIII protein and remained inhibitor free, and compared this distribution with that from 2 published studies (Oldenburg J, et al. 2006; Salviato R, et al. 2007).Results: Eighty-one patients enrolled in the guardian™ trials had F8 gene mutation analyzed. For 52 patients <12 yrs old, genotype was analyzed during guardian™3. For 29 patients ≥12 yrs old, genotype analysis was done prior to enrollment and obtained from medical records. In 77/81 patients, the F8 gene defect was identifiable. Distribution of gene mutations in guardian™, in a population with severe HA with inhibitors, and in a population with severe HA with/without inhibitors are compared in table 1. It is interesting that the overall distribution of mutations among the populations appears quite similar, pointing toward the multifactorial nature of inhibitor development.Null mutations (inversions, nonsense mutations, and large deletions) were present in 66% and 75% of patients with severe HA and severe HA with inhibitors, respectively (table 1). In guardian™, 57% (46/81) of patients had null mutations despite never having developed an inhibitor. The difference in distribution of null mutations in the 3 populations is mainly accounted for by large deletions and nonsense mutations, while distribution of inversions was similar. It should be noted that in guardian™, 10/11 patients with missense mutations had these located outside the C1/C2 domain, which reportedly has a lower frequency of inhibitors compared with missense mutations at the C1/C2 domain (Oldenburg J, et al. 2006).Conclusions: Eighty-one patients in the guardian™ trial with severe hemophilia A had their genotype analyzed and all of them were inhibitor-free over their lifetime. Interestingly, the prevalence of high-risk mutation types does not seem to differ markedly from previously published data in patients with inhibitors, probably indicating the relevance of other factors in inhibitor development.Table 1Distribution of F8 gene mutation typesguardian™Additional studiesguardian™ patients (N)Distribution (%) in guardian™ patients (severe HA without inhibitors)Distribution (%) in patients with severe HA and inhibitors (Salviato R, et al. 2007)*Distribution (%) in patients with severe HA with/without inhibitors (Oldenburg J, et al. 2006)Total, N818176753Intron 22 inversion3340.744.745.0Intron 1 inversion33.71.32.5Nonsense89.918.413.5Large deletion22.510.55.0Missense1113.65.214.5Small del/ins/dupl1619.810.516.0Splice site44.95.23.5Unidentified/ not enough information44.93.90.0Total81100.0100.0100.0*Only patients with severe HA included. DisclosuresMatytsina:Novo Nordisk A/S: Employment. Arai:Novo Nordisk Pharma, Ltd: Employment. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Factor VIII Gene Variants and Inhibitor Risk in African American Hemophilia a Patients

African American hemophilia A (HA) patients experience a higher incidence of neutralizing antibodies (“inhibitors”) against factor VIII (FVIII) vis-à-vis Caucasian patients. Non-HA-causing non-synonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-484H, FVIII-1241E and FVIII-2238V are more prevalent in African Americans than in Caucasians. Currently available recombinant FVIII products have FVIII-R484, FVIII-D1241 or E1241, and FVIII-M2238. Therefore a number of HA patients are infused with FVIII products (plasma-derived or recombinant) having amino acid sequences that differ from the sequence encoded by their hemophilic F8 gene. This study tested the hypothesis that immune responses to sequences encoded by these ns-SNPs are a significant risk factor for inhibitor development in the African American HA community.As part of the Personalized Approaches to Therapies for Hemophilia (PATH) Study, blood samples were obtained from 175 African American and 198 Caucasian severe HA subjects, including several subjects with an intron-22 inversion mutation but moderate bleeding disorder. Questionnaires indicated which subjects had an inhibitor history, defined as ≥1 inhibitor titer measurements of >0.6 Bethesda units/ml. The F8 gene sequences at the three ns-SNPs and HLA-DRB1 genotypes were determined and PBMCs isolated from blood samples.To determine which HLA-DRB1 proteins are capable of presenting the sequences encoded by these F8 ns-SNPs, synthetic 20-mer peptides with these polymorphic sequences were synthesized and quantitative peptide-HLA-DRB1 binding assays carried out. Binding to the HLA-DRB1 peptide-binding groove is a prerequisite for presentation of potentially immunogenic sequences on antigen-presenting cells. These assays identified several HLA-DRB1 that bound with moderate to high affinity to each of the polymorphic sequences, however none of the peptides showed promiscuous HLA-DRB1 binding. Most of the 11 HLA-DRB1 proteins tested, which together comprise ~40% of HLA-DRB1 alleles in the African American population, did not bind to the polymorphic FVIII sequences.CD4 T cells from 1 (the only), 7 and 20 HA subjects who had been infused with FVIII products that were mismatched with sequences encoded by their endogenous F8 gene at FVIII-484, -1241 or -2238, respectively, and whose HLA-DRB1 proteins bound these sequences, were cultured with FVIII peptides containing both versions of these polymorphic sequences, in an attempt to identify HLA-restricted T-cell responses to “sequence-mismatched” FVIII. Positive control cultures consisted of parallel cultures of CD4 T cells with peptides corresponding to validated HLA-restricted epitopes in tetanus toxoid (TT) protein. Flow cytometry experiments then quantified the number of CD4 T cells that bound fluorescent HLA-DRB1 tetramers loaded with FVIII or TT peptides. Tetramer-positive cells were then sorted and cultured in attempts to isolate T-cell clones and polyclonal lines recognizing these sequences, as these would constitute unambiguous confirmation of T-cell responses to the peptide sequences. TT-specific clones were obtained routinely, as expected. The few cells positive for FVIII peptide-loaded tetramers did not produce T-cell clones or polyclonal T-cell lines, indicating the marginal tetramer-positive staining had been nonspecific.Among the 373 HA subjects, inhibitor risks associated with the most common F8 ns-SNPs in African Americans, FVIII-E1241 and FVIII-V2238, were: E1241/D1241, OR=1.3(0.8-2.0, p=0.3); V2238/M2238, OR=1.1(0.5-2.4, p=0.84); 95%CI). Interestingly, African Americans with a F8 intron-22 inversion mutation showed a significantly higher inhibitor incidence compared to Caucasians with the same mutation, OR=2.9(2.4 – 5.8, p=0.004), but this did not correlate with any of the 3 ns-SNPs.We conclude that immune responses to FVIII products mismatched with the FVIII sequences encoded by these three ns-SNPs are unlikely to contribute appreciably to the overall inhibitor incidence in African Americans with severe HA, but we emphasize that the at-risk population should be better defined through additional immunological investigations. The higher inhibitor incidence in African Americans with an intron-22 inversion mutation clearly warrants further investigation.On behalf of the PATH Study Investigators (NIH 1RC2 HL101851) DisclosuresFletcher:Biogen Idec: Research Funding. Pratt:Pfizer ASPIRE hemophilia research award: Research Funding; Grifols, Inc: Research Funding.

Safety, Efficacy and Pharmacokinetics of Nonacog Beta Pegol (N9-GP) in Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Pediatric Hemophilia B Patients

▪Background: Primary prophylaxis in severe hemophilia patients has been shown to improve patient outcomes and quality of life by decreasing the number of joint bleeds, lowering the subsequent risk of developing hemophilic arthropathy (Blanchette et al.Haemophilia 2010 (Suppl. 5); Ljung R. Blood Rev 2009) and by reducing the incidence of other bleeds including intracranial hemorrhages. Currently licensed factor concentrates have a relatively short half-life, and require frequent infusions for effectiveness. The intensity of this prophylaxis is difficult for most patients (particularly young children) and contributes to reduced compliance and quality of life.Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a prolonged half-life (up to 111 h in adolescent and adult patients) as compared to currently available standard plasma-derived and rFIX products (18-19 h). N9-GP is therefore expected to be effective in preventing bleeds when given less frequently than currently available FIX products. It is hoped that this will improve patient compliance, clinical outcomes and quality of life. Until now only adolescents and adults have received N9-GP. Given this experience a trial (paradigm™5) was undertaken to evaluate the safety and effectiveness of N9-GP in children ≤12 years of age.Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP in previously treated pediatric (≤12 years of age) hemophilia B patients (FIX≤2%) with no history of inhibitors and at least 50 exposures days (ED) to other FIX products. Key secondary objectives were to evaluate efficacy, pharmacokinetic (PK) properties and general safety of N9-GP in this group of patients.Methods: paradigm™5 was a multicenter, single arm, open label trial investigating the safety, efficacy and PK of N9-GP in this group of patients. A total of 20 children allocated to two age cohorts ≤6 years and 7-12 years (minimum 10 patients per age cohort) were required to be dosed with a prophylactic regimen of 40 U/kg N9-GP once weekly for at least 50 exposures (as per EMA guidelines), with treatment of breakthrough bleeds with 40 U/kg N9-GP (80 U/kg N9-GP for severe bleeding episodes).Results: 25 patients were enrolled and treated in the trial: 12 in the younger (0-6 years) and 13 in the older (7-12 years) age group. No patients developed inhibitors during the trial, and no safety concerns were observed in standard safety parameters and clinical evaluation.Among patients on prophylaxis prior to inclusion (N=22), the median (range) number of bleeds in the 12 months prior to inclusion was 2.0 (0–9). The median (range) annualized bleeding rate during the trial was 1.0 (0.0–6.5); 5 of the 12 younger patients (41.7%) and 10 of the 13 older patients (76.9%) reported bleeds. 72.7% of these bleeds in the younger cohort were reported as traumatic vs. 54.8% in the older age cohort. All bleeding episodes were treated with 40 U/kg N9-GP: 92.9% were successfully treated; 85.7% were treated with a single injection.PK analysis showed 1) an incremental recovery (IR) of N9-GP of 0.016 (U/mL)/(U/kg) with no difference between the 2 age groups; 2) a geometric mean single-dose half-life of 69.6 (0-6 years) and 76.3 hours (7-12 years) and 3) a faster clearance in the younger vs. older age group (0.758 and 0.650 mL/h/kg, respectively). Geometric mean FIX trough levels after the first dose of N9-GP was 0.084 U/ml in the 0-6 year age group and 0.109 U/ml in the 7-12 year age group. Estimated mean steady state trough levels (95% CI) for the younger age group was 0.154 U/ml (0.127; 0.186), as compared to 0.190 U/ml (0.159; 0.228) in the older age group. Steady state trough levels were reached after approximately 4 weeks of treatment.Conclusion: In this trial, N9-GP appeared to have a safe and well-tolerated profile. Prophylactic protection and treatment of bleeds with N9-GP in previously treated pediatric hemophilia B patients was confirmed. The PK profile of N9-GP confirmed an extended half-life and high trough levels with 40 U/kg once weekly injections in the pediatric population. As with other FIX products younger patients show lower IR, shorter half-lives and higher clearance than what is observed in adolescents and adults. DisclosuresCarcao:Baxter, Bayer, Biogen, Novo Nordisk, Pfizer, CSL Behring, Octapharma: Honoraria, Research Funding, Speakers Bureau. Off Label Use: N9-GP is not yet FDA approved. Information provided will discuss phase 3 pediatric clinical trial data.. Zak:Novo Nordisk A/S: Employment. Hanabusa:Baxter Healthcare, Novo Nordisk, Bayer, Pfizer, Biogen Idec and KaketsuKen: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Persson:Novo Nordisk A/S: Employment. Rangarajan:Baxter, Biotest, Grifols, Pfizer: Honoraria, Research Funding, Speakers Bureau. Santagostino:Pfizer, Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, Biotest: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

A Complementary Role of High Throughput Sequencing and Multiparameter Cytometry for Minimal Residual Disease (MRD) Detection in Chronic Lymphocytic Leukemia (CLL):an European Research Initiative (ERIC) Study

BACKGROUND. The detection of minimal residual disease (MRD) at the level of 0.01%/10-4 or above is a strong independent predictor of reduced progression-free (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy. Although newer agents such as B-cell receptor pathway inhibitors can result in prolonged survival without achieving complete response, there remains a important role for MRD analysis in assessing therapeutic strategies aimed at disease eradication and cure. This is particularly important in front-line trials for fit patients which now require at least five years of follow-up if PFS is used as an endpoint. The feasibility of using MRD as a surrogate or intermediate endpoint for accelerated approval of new treatments is under review by regulatory agencies but further prospective validation is required. At the same time technology is rapidly evolving and high-throughput sequencing (HTS) technologies now detect MRD at the 0.0001%/10-6 level. It is therefore important to determine the most effective approaches for quantifying MRD that are compatible with previous studies but sufficiently sensitive for current treatments.AIMS. This collaborative project had two objectives. First, to identify the simplest and most flexible flow cytometry panel capable of detecting MRD at the 0.01%/10-4 or lower, that is compatible with published data and independent of instrument/reagent manufacturer. Second, to compare the flow cytometry approach with HTS analysis using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA).METHODS AND RESULTS. A core panel of antibodies for MRD detection was identified by testing an 8-marker combination in 52 samples (27 post-treatment and 25 dilution study) and re-analysing data with serial exclusion of single markers to determine redundancy. A 1-tube core panel of CD19, CD20, CD5, CD43, CD79b, and CD81 was identified and validated against the previously published 2-tube 6-marker and 4-tube 4-marker ERIC panels in 76 samples (19 post-treatment and 57 dilution study). The results showed good concordance (for log-transformed data above the LoQ, linearity=0.977, Pearson correlation co-efficient=0.983, average difference=0.026 log, 95% limit of agreement 0.20log) and a limit of detection of 0.001%/10-5 for the 1-tube core panel. Inter-operator variation was similar to CML MRD monitoring with both experienced operators, or inexperienced cytometrists after ~1 hour of specific education, achieving a 95% limit of agreement less than 0.3log in samples with MRD levels ranging from 0.0001 – 100%.The flow cytometry approach was compared with the ClonoSEQ HTS assay in 109 samples (21 dilution study and 88 post-treatment samples, complete data currently available on 13/88). The assay was applicable to the vast majority CLL patients, often with two clonal markers. There was 94% concordance at the 0.01% (10-4) threshold (15 samples with ≥0.01% CLL by both methods, 14 samples with <0.01% by both methods, 1 sample with 0.03% CLL by HTS and <0.003% CLL by flow cytometry, and 1 sample with 0.005% CLL by HTS and 0.012% by flow cytometry. HTS detected CLL IGH sequences in 22% (7/31) samples with no detectable CLL cells by flow cytometry (i.e. CLL level 0.0001-0.001%, 3/13 patient samples and 4/18 dilution samples). HTS demonstrated a relatively high variability in quantification, as seen in previous studies, but with a clear superiority in the limit of detection and good linearity (linearity=0.905, Pearson correlation co-efficient=0.870, average difference=0.078 log, 95% limit of agreement 1.5 log).CONCLUSIONS. The 1-tube 6-marker flow cytometry core panel is compatible with published studies, manufacturer-independent and flexible, providing directly quantitative results to 0.001%/10-5 without requiring a pre-treatment sample. HTS requires further work to standardise the quantitative analysis and prospective validation but the ClonoSEQ assay is applicable to >95% of CLL patients, does not require viable cells and is extremely sensitive, detecting residual disease in a significant proportion of cases with <0.01% CLL. The results indicate that flow cytometry and HTS are complementary technologies with a combined approach offering the most reliable way of quantifying CLL at the 0.01%/10-4 threshold while allowing higher sensitivity in clinical trials aimed at disease eradication. DisclosuresRawstron:Roche: Honoraria; Biogen Idec: Consultancy; Gilead: Consultancy, Honoraria; Abbvie: Honoraria; BD Biosciences: Intrasure reagent Patents & Royalties; Celgene: Honoraria; GSK: Honoraria. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sanders:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Hallek:Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Gilead: Honoraria. Hillmen:Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.

Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (ADEM)

Case of autoantibodies against N‐methyl‐D‐aspartate receptor+/antibodies against myelin‐oligodendrocyte glycoprotein+ multiphasic acute disseminated encephalomyelitis (<scp>ADEM</scp>)

The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes.

Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-to-severe psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [(3)H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor-α (TNFα), interleukin-6, and interleukin-1α as well as the production of TNFα. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent.

Clinical Benefit of Adalimumab Dose Adjustment for Patients With Moderately to Severely Active Crohn’s Disease in EXTEND

Clinical Benefit of Adalimumab Dose Adjustment for Patients With Moderately to Severely Active Crohn’s Disease in EXTEND

NATALIZUMAB FOR RELAPSING-REMITTING MS IN THE UK TOP COHORT

Introduction The TYSABRI® Observational Program (TOP) is a global, open-label study of natalizumab for relapsing-remitting multiple sclerosis (RRMS) in clinical practice. Methods Baseline characteristics were summarised. On-therapy annualised relapse rates (ARRs) were compared with baseline. Results As of 01 May 2013, 122 patients were enrolled in the United Kingdom (UK) and 5122 patients were enrolled globally. Median duration of RRMS was 5.4 years in the UK and 7.3 years globally. Mean numbers of relapses in the 2 years prior to natalizumab treatment were 3.22 in the UK and 2.85 globally. Mean baseline Expanded Disability Status Scale (EDSS) scores were 4.2 in the UK and 3.5 globally. Median Multiple Sclerosis Severity Scores (MSSS) were 6.2 in the UK versus 4.9 globally (p Conclusions The UK Cohort appears to have more aggressive disease, as evidenced by higher MSS score and higher ARR history. Despite this similar significant reductions in ARR were observed in the UK-specific and global cohorts. Supported by Biogen Idec Ltd. RN: grant support and support for travel to conferences from Biogen Idec Ltd. JH: employee of Biogen Idec Ltd.

▼Dimethyl fumarate for relapsing-remitting multiple sclerosis

For many years the only drugs licensed for the treatment of multiple sclerosis (MS) were administered by injection (interferon beta, glatiramer and ▼natalizumab). Recently, three oral drugs have become available....

FRI0439 Urinary Collagen Fragments Are Reduced in Lupus Nephritis Subjects with Renal Dysfunction

BackgroundInterstitial fibrosis is a key component of chronic kidney injury in lupus nephritis (LN) and a critical determinant of the disease progression as it leads to the reduction of functioning...

INSIDE INDUSTRY

Sanaria® PfSPZ malaria vaccine wins 2014 Vaccine Industry Excellence Award for “Best Prophylactic Vaccine”. Analytik Jena AG planning merger by absorption of CyBio AG. Sanguine to begin work with Mayo Clinic Bioservices to accelerate individualized medicine research and development. Thermo Fisher Scientific and the National University of Singapore Sign MOU to create strategic alliance to accelerate life science research in Singapore. Sun Pharma to acquire Ranbaxy in a US$ 4 billion landmark transaction. Meda and Valeant terminates joint ventures. Crown Bioscience enters Japanese market via strategic partnership with Shin Nippon Biomedical Laboratories. Quintiles and Biogen Idec enter comprehensive clinical development partnership. Registration opened for Oxford Global's Drug Discovery USA Congress. Speakers for Oxford Global's Microbiology &amp; Infectious Diseases Congress released. Daiichi Sankyo and UC San Francisco announce collaboration in drug discovery research for neurodegenerative diseases. Funding crunch hits neglected diseases plan. Coca-Cola partners with A*STAR to expand technology presence in Singapore. DaVita expands kidney care services in Malaysia acquires Sinar Indentiti clinics in Seremban.

Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11

Published data for the epidemiology of idiopathic pulmonary fibrosis in the USA are scarce. We sought to estimate the incidence, prevalence, and mortality risk of idiopathic pulmonary fibrosis among US Medicare beneficiaries. We used administrative claims from a 5% random sample of Medicare beneficiaries (aged 65 years and older) from the years 2000-11 as a data source. Idiopathic pulmonary fibrosis was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. We estimated annual incidence and cumulative prevalence of idiopathic pulmonary fibrosis, median survival time of patients, and potential risk factors for diagnosis of idiopathic pulmonary fibrosis and death between 2001 and 2011. We also estimated incidence and prevalence using more restrictive algorithms for diagnosis. The annual incidence of idiopathic pulmonary fibrosis in the Medicare population remained stable between 2001 and 2011, with an overall estimate of 93.7 cases per 100000 person-years (95% CI 91.9-95.4) across the study period. The annual cumulative prevalence increased steadily from 202.2 cases per 100000 people in 2001 to 494.5 cases per 100000 people in 2011. Among newly diagnosed patients with Medicare (mean age 79.4 years [SD 7.2], 54% female, 91% white), the median survival time was 3.8 years (95% CI 3.5-3.8). Older age and male sex were associated with a higher incidence of disease and shorter survival time after diagnosis. Mortality risk was lower in patients diagnosed in more recent years (median survival time 3.3 years [95% CI 3.0-3.8] in 2001 vs 4.0 years [3.8-4.5] in 2007). The incidence and prevalence of idiopathic pulmonary fibrosis in people aged 65 years and older in the USA are substantially higher than previously reported, and prevalence is increasing annually, even in the subgroups based on more restrictive algorithms for diagnosis. Patients with idiopathic pulmonary fibrosis aged 65 years and older were living longer in 2011 than they were 10 years before, which could partly account for the steady increase in prevalence. Biogen Idec.

Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study

Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. Biogen Idec.

Psoriatic arthritis screening tools: study design and methodological challenges

Funding sources: No external funding. Conflicts of interest: A.A.Q. has licensed the PASE questionnaire to Merck and Pfizer, has received a grant from Amgen, and is a consultant for Jansen, Novartis and Abbott. J.F.M. is a consultant for Biogen IDEC, an investigator for Amgen and has served on an advisory board for Amgen. M.E.H. has licensed the PASE questionnaire as above, and has also acted as a consultant for UCB, Amgen, Novartis, Bristol Myers Squibb and Abbott. Dear Editor, In their study ‘Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study)’, Coates et al.1 compared three published, validated screening tools for psoriatic arthritis (PsA), the Psoriasis Epidemiology Screening project (PEST), the Toronto Psoriatic Arthritis Screen (ToPAS) and the Psoriatic Arthritis Screening and Evaluation (PASE) tools.1 2 3 4 5 We would like to address how PASE was not adequately or appropriately compared in this setting.

Med Check

Med Check

Eisai and Biogen Idec Partner to Advance Alzheimer’s Disease Drug Candidates

Biogen Idec and Eisai have joined forces to co-develop and co-commercialise drug candidates that address multiple mechanisms in Alzheimer’s disease (AD), beginning with two clinical-stage drugs from Eisai’s pipeline: the BACE (β-site amyloid precursor protein cleaving enzyme) inhibitor E2609; and BAN2401, an anti-amyloid beta (Aβ) monoclonal antibody. As part of the deal, Eisai also has an option to develop and commercialise jointly two of Biogen’s AD drug candidates, the Phase Ib Aβ antibody BIIB037 and an unspecified anti-tau monoclonal antibody. Currently, only symptomatic therapies are available for AD.

EYE ON CHINA

Sirona Biochem completes exclusive licensing agreement with leading anti-diabetic company in China, Wanbang Biopharmaceuticals. Actavis signs agreement with Zhejiang Chiral Medicine Chemicals Co., Ltd to divest Actavis Foshan, China. Showa Denko ups high-purity ammonia production capacity in China. Biogen Idec and UCB enter agreements to develop and commercialize multiple sclerosis and hemophilia therapies in China and other parts of Asia. China-U.S. lab dedicated to enhance mussel conservation, pearl production. Sagent Pharmaceuticals launches national research center in Chengdu, China. 3M enters partnership with U.S.-China Clean Energy Research Center Building Energy Efficiency consortium. Innovative technique creates large skin flaps for full-face resurfacing. NCKU stem cell research team discovers drug to rejuvenate aged hearts Biotech.

Tecfidera ® : an Approach for Repurposing

As a case study of patent coverage for a repurposed drug, Biogen Idec's approach for Tecfidera(®), an oral formulation of dimethyl fumarate, was analyzed. While mixtures of fumarates have been used for over 50 years to treat psoriasis, Tecifidera is approved for the treatment of relapsing-remitting multiple sclerosis. Biogen pursued claims to pharmaceutical formulations and useful doses for treating multiple sclerosis, an approach that is relevant to pharmaceutical lifecycle management in general. A survey of recent US, EP, and PCT patent applications indicate other companies are developing competing fumarate formulations. While it is possible to pursue secondary patents for compounds without composition of matter coverage, regulatory data exclusivity provides additional protection to delay competitors.

2013 William Allan Award: My Multifactorial Journey

I wish to sincerely acknowledge the support, efforts, and hard work of numerous trainees and collaborators whose work I have described, as well as the patients and their families who lent themselves to our investigations. Importantly, I acknowledge the numerous contributions of the members of the International Hirschsprung Disease Consortium, particularly the junior leaders, Jeanne Amiel, Merce Garcia-Barcelo, Raquel Fernandez, Francesca Lantieri, and Yunia Sribudiani. Finally, I remain deeply indebted to the National Institutes of Health, which, despite my frequent complaints, have steadfastly and consistently supported my diverse research ideas since 1984. I am a paid member of the Scientific Advisory Boards of Affymetrix and Biogen Idec. These potential conflicts of interest are managed by the policies of Johns Hopkins University School of Medicine.

Tyrosine kinases: the molecular switch for inflammasome activation

Tyrosine kinases: the molecular switch for inflammasome activation