Presentation on theme: "Biogen Portfolio Update"— Presentation transcript:
1 Biogen Portfolio Update Biogen US MedicalMay 2015MU-US-0036a
2 Guidance for UseThis slide deck is intended to be used in response to an unsolicited request for information when received from a payer customer. This slide deck contains hyperlinks to enable the US Medical colleague (E.g., MSL) to navigate the slide deck with the intent of delivering a narrowly tailored response to a question. It is for reactive use only, and is not intended to be distributed in any format.Medical Guidance:When an MSL is asked a questionPlease ask why the question is being askedPlease ask what specific data is being requestedUtilize hyperlinks within the slide deck to tailor a response to the specific question.Please do not show the “Table of Contents” hyperlink slide to the customer.Ensure that the response is clear regarding approved vs investigational products/indicationsPlease note that the information contained within this slide deck was developed from referenced materials.
4 Biogen Biogen is the world's oldest independent biotechnology company Established 1978Biogen has >7,500 employees worldwide and >$9.7 billion USD in annual revenues (2014)Through cutting-edge science and medicine, we discover, develop and deliver to patients worldwide innovative therapies for serious neurodegenerative, hematologic and autoimmune diseasesFounded in 1978, we are the world’s oldest independent biotechnology company that today has a rapidly-expanding global footprint and employs approximately 7,000 people worldwideToday, Biogen Idec is one of the oldest independent biotechnology companies in the world.Biogen Idec is a Fortune 500 company and global technology leader that generates more than $6.9 billion in annual revenues. Our mission is to discover, develop, and deliver innovative therapies for the treatment of neurodegenerative diseases, hemophilia, and autoimmune disorders to patients worldwide through cutting-edge science and medicine. Our robust pipeline is supported by one of the industry’s leading capacities for biologics manufacturing, featuring nearly 200,000 liters of bioreactor capacity.In 2012, Research & Development is expected to be approximately 24% to 25% of total revenue.We have more than 7000 employees worldwide, a direct commercial presence in more than 29 markets, and a network of distribution partners in more than 70 additional markets, including emerging markets such as Central and Eastern Europe, Brazil, China, and India.To our patients, we are the trusted source of vital therapies for multiple sclerosis, such as AVONEX®, TYSABRI®, TECFIDERA®, PLEGRIDY®, and FAMPYRA®. We also discovered RITUXAN®, the world's most prescribed treatment for non-Hodgkin's lymphoma and an effective treatment for rheumatoid arthritis.To our employees, we are an exciting and invigorating place to work, an ambitious and nimble company where courageous innovation is encouraged and expected—not just of scientists but of every employee.To our partners and investors, we are a profitable company with a rich and diverse pipeline. We have the resources, financial strength, and vision to successfully discover, develop, manufacture, and commercialize new products.We now intend to continue our tradition in breakthrough therapies by delivering the next major innovation to the hemophilia community—long-lasting factors.ReferenceBiogen Idec. Available at*Pharmaceutical Industry Profile 2012, Washington DC, PhARMA, April 2012.Biogen. Available at
7 Daclizumab HYP* Multiple Sclerosis Daclizumab HYP is a SQ form of daclizumab that is being developed for once-monthly administration and is produced using a high-yield manufacturing process. DAC-HYP is the only form of daclizumab that has been developed for LT use in MS. Two registry trials SELECT and DECIDE to evaluate it in people with RRMS.Zenapax was another form of daclisumab that was indicated by the FDA for IV use for prophylaxis of acute organ rejection in pts receiving renal transplants. And was never studied in pts with MS.*Daclizumab HYP is an investigational candidate
8 Daclizumab HYPDaclizumab HYP is a humanized monoclonal antibody that binds to CD25, the alpha subunit of the high affinity IL-2 receptor that is expressed at high level on the T-cells thought to become abnormally activated in autoimmune conditions, such as MS1High-affinity IL-2 receptorIntermediate affinity IL-2 receptorIL-2 Signaling by Blocking the High-Affinity Receptor (CD25) PathwayIL-2 signaling is maintained via the intermediate - affinity IL-2 receptor in the presence of daclizumabFigure: Sheridan JP, et. al. (Poster P430) Presented at the 25th Congress of European Committee for Treatment and Research in Multiple Sclerosis; Düsseldorf, Germany, September 9-12, 20091. Rose JW et al. Amer Acad Neurology. 2007: 69;
9 Intermediate-affinity The IL-2 ReceptorHigh-affinityIL-2RIntermediate-affinityIL-2RThe high-affinity IL-2R is composed of IL-2Rα, IL-2Rβ, and γCIL-2Rα (CD25) has no known signaling functionIL-2Rβ and γC harbor all signaling capabilityThe intermediate-affinity IL-2R is composed of IL-2Rβ and γC but lacks the IL-2Rα1IL-2Rα(CD25)αIL-2IL-2γγIL-2 signaling is mediated via 2 IL-2 receptors:The high-affinity IL-2 receptor is composed of the IL-2R chain, the common chain and an chain also known as CD25.1CD25 has no known signaling function whereas the and chains harbor all signaling capability.The / chains are shared with IL-15R, whereas the chain is shared with IL-4R, IL-7R, IL-9R, and IL-21R.2The intermediate-affinity IL-2 receptor (IL-2R) is composed of the IL-2R chain and the common chain.The intermediate-affinity IL-2 receptor is present on resting and activated T cells1 whereas the high-affinity IL-2R is expressed when a T cell is activated.DAC HYP is a high-affinity monoclonal antibody that binds the subunit (CD25) of the IL-2 receptor and blocks its interaction with IL-2.References1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:2. Malek TR. Annu Rev Immunol. 2008;26:Wiendl and Gross 2013: p3/col1/para1-2βγC(CD132)IL-2Rβ(CD122)βγC(CD132)Malek TR. Annu Rev Immunol. 2008: p457/col1/para2.IL-2Rβ(CD122)DAC HYP=daclizumab high-yield process; IL=interleukin; R=receptor; γC=common gamma chain1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:Wiendl and Gross 2013: abstract
10 Daclizumab HYP Proposed Mechanism of Action High-affinityIL-2RβγIntermediate-affinityIL-2RIL-2Rβ(CD122)γC(CD132)IL-2Rα(CD25)DAC HYP binds the subunit (CD25) of the high-affinity IL-2R and blocks its interaction with IL-2DAC HYP does not block interaction between IL-2 and intermediate-affinity IL-2RαBy blocking the high-affinity IL-2R, DAC HYP modulates IL-2R signaling.This slide depicts the high-affinity and intermediate-affinity IL-2 receptors (IL-2R) and their role in DAC HYP’s mechanism of action.1DAC HYP selectively blocks the IL‑2 binding site of the high-affinity IL‑2 receptor by binding to CD25, thereby inhibiting assembly and signaling of the high-affinity IL‑2R. This results in:DAC HYP only blocking IL-2 interaction with the high-affinity IL-2 receptor AND NOT blocking interaction between IL-2 and the intermediate-affinity receptorThis further results in increase of available IL-2 levels which can then interact with intermediate-affinity receptors on many cell types including CD56 bright NK cells, and expanding their numbers. NK cells are thought to control autoimmune T cells. Thus, DAC HYP modulates but does not completely block all IL-2 biology.Key aspects of the DAC HYP’s mechanism of action:Impairs CD25-dependent IL-2 signalingReduces CD25-dependent T-cell survival, proliferation, and effector functionLeads to proliferation of immunomodulatory CD56bright NK cellsInhibits LTi cell development.LTi=lymphoid tissue inducer; NK=natural killerReference1. Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:γIL-2Rβ(CD122)βWiendl and Gross 2013: p1/col1/para2And p2 key pointsγC(CD132)DAC HYP=daclizumbab high-yield process; IL=interleukin; R=receptor; γC=γcommon.Wiendl H, Gross CC. Nat Rev Neurol. 2013;9:Wiendl and Gross 2013: p6/col2/para2 and figure 3Wiendl and Gross 2013: p2 key points
11 Daclizumab HYP Overview of Development1 20062007200820092010201120122013201420152016CHOICE (phase 2)DAC* add-on with IFNβSELECT (phase 2)DAC HYP vs placeboSELECTION (phase 2)DAC HYP blinded extension of SELECTSELECTED (phase 2)DAC HYP open-label extension of SELECTIONDECIDE (phase 3)DAC HYP vs IM IFNβ-1aEXTEND (phase 3)DAC HYP open-label extension of DECIDEN=230N=621N=517N=420N=1841N=1204*CHOICE used an investigational form of aclizumab different from daclizumab HYP1Status as of May 2015DAC=daclizumab; HYP=high-yield process; IFN=interferon; IM=intramuscular; RRMS=relapsing-remitting multiple sclerosis.
12 SELECT: Design Overview 52-Week Treatment Period SELECT: MRI Substudy Design OverviewSELECT: Design OverviewSELECT: MRI Substudy Design Overview52-Week Treatment PeriodPlaceboRandomization307 patientsRandomizationn=621 patientsDAC HYP 150 mg SC q4wDAC HYP 300 mg SC every q4w481216202428323640444852Primary endpointAnnualized Relapse RateSecondary endpointsNew Gd+ lesions at weeks 8–24 (MRI substudy n=307)Tertiary endpointEDSS disability progression at week 52New T2 lesions at week 52Proportion of subjects relapsingChange in MSIS-29 physical score (quality of life measure)Gold R, et al; SELECT study investigators. Lancet. 2013;381:.
13 SELECT Results: Annualized Relapse Rate (Primary Endpoint) Adjusted ARR at end of trial (week 52)50% relativereductionvs placeboP=0.0002*54% relativereductionvs placeboP<0.0001*Gold et al Lancet 2013: Results p4/col2/para1 and table 2Gold et al Lancet 2013: Methodsp2/col2/para4 and p3/col1/p1DAC HYP treatment resulted in 50-54% reduction of ARR relative to placebo in 1 year.Results for the SELECT primary endpoint are presented in this slide.ARR at 52 weeks was lower for patients in the DAC HYP 150-mg (54% reduction; 95% CI, 33-68) or 300-mg groups (50% reduction; 95% CI, 28-65%) than for those given placebo.ReferenceGold R, et al; SELECT study investigators. Lancet. 2013;381:Gold et al Lancet 2013: Results p4/col2/para1Placebo (n=196)DAC HYP 150 mg (n=201)DAC HYP 300 mg (n=203)*Estimated from a negative binomial regression model adjusted for number of relapses in 1-year period before trial entry, baseline EDSS score (≤2.5 vs >2.5), and age (≤35 vs >35 years)ARR=annualized relapse rate; DAC HYP=daclizumab high-yield process; EDSS=Expanded Disability Status Scale. Gold R, et al; SELECT study investigators. Lancet. 2013;381:
14 SELECT Results: MRI Outcomes Mean number of new Gd+ lesions at week 52Adjusted mean number of new/ newly enlarging T2 lesions at week 5270% relative reduction vs placebo P<0.0001*79% relative reduction vs placebo P<0.0001*86% relative reduction vs placebo P<0.0001*79% relative reduction vs placebo P<0.0001*DAC HYP treatment was associated with a significant reduction in the accumulation of new Gd+ lesions and new/newly enlarging T2 lesions.MRI outcomes at week 52 are presented in this slide.DAC HYP treatment reduced new MS lesion activity vs placebo.Mean (SD) numbers of new Gd+ at week 52 were:Placebo: 1.4 (2.3)DAC HYP 150 mg: 0.3 (0.9); 79 % relative reduction vs placebo (P<0.0001)DAC HYP 300 mg: 0.2 (0.7); 86 % relative reduction vs placebo (P<0.0001).[Note: percent reduction not reported in paper, these data from slide deck]Adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions at week 52 were:Placebo: 8.1 ( )DAC HYP 150 mg: 2.4 ( ); 70% relative reduction vs placebo (P<0.0001)DAC HYP 300 mg: 1.7 ( ); 79% relative reduction vs placebo (P<0.0001).In addition, in a subset of patients who had monthly MRI scans between weeks 8 and 24 (secondary endpoint), DAC HYP reduced mean (95% CI) number of new Gd+ lesions at weeks 8-24:Placebo (n=104): 4.8 ( )DAC HYP 150 mg (n=101): 1.5 ( ); P<0.0001DAC HYP 300 mg (n=102): 1.0 ( ); P<Longitudinal analysis showed that Gd+ lesion activity was greater in the 150-mg group than in the 300-mg group during weeks 4-24, but was similar at week 52.ReferenceGold R, et al; SELECT study investigators. Lancet. 2013;381:Gold et al Lancet 2013:results p. 5/col1/para2-3 and table 2Placebo (n=195)DAC HYP 150 mg (n=199)DAC HYP 300 mg (n=200)Placebo (n=195)DAC HYP 150 mg (n=199)DAC HYP 300 mg (n=200)*Estimated from a proportional odds model adjusted for the baseline number of Gd+ lesions*Estimated from a negative binomial regression model adjusted for the baseline number of T2 lesionsDAC HYP=daclizumab high-yield process; Gd+=gadolinium-enhancing.Gold R, et al; SELECT study investigators. Lancet. 2013;381:Gold et al Lancet 2013:results p. 5/col1/para3
15 Confirmed Disability Progression at End of SELECT 0.000.050.100.151224364852Time on study (weeks)Proportion of patients with 12-week confirmed disability progression43%ReductionP=0.091*57%P=0.021*DAC HYP 150mgDAC HYP 300mgPlaceboPlaceboDAC HYP 150mgDAC HYP 300mgProportion with 3-month confirmed disability progression13.3%5.9%7.8%*Estimated from Cox-proportional hazards model adjusting for baseline EDSS (≤2.5 vs. >2.5), and age (≤35 vs. >35),Gold R, et al; SELECT study investigators. Lancet. 2013;381:.
16 SELECT: Adverse Events That Occurred in >5% of Patients During the Treatment Period AEPlacebo(n=204)DAC HYP 150 mg(n=208)DAC HYP 300 mg(n=209)MS relapse38%23%20%Nasopharyngitis15%14%Upper respiratory tract infection7%9%11%Headache10%Pharyngitis3%6%5%Gold R, et al; SELECT study investigators. Lancet. 2013;381:
17 SELECT: Adverse Events of Interest AEPlacebo(n=204)DAC HYP150 mg (n=208)300 mg (n=209)Infections44%50%54%Serious infections0%3%1%Cutaneous events*13%18%22%Injection site reaction, erythema, induration2%Serious cutaneous events<1%MalignancyDeath†1 (<1%)*Death: Patient recovering from serious cutaneous event died due to a complication of psoas abscess and ischemic colitis.*Cutaneous events are those treatment-emergent AEs whose preferred term contains the word dermatitis, rash, or erythema, or whose preferred term is one of the following: drug eruption, drug hypersensitivity, dyshidrosis, eczema, granuloma annulare, pityriasis rosea, psoriasis, skin exfoliation, toxic skin eruption, urticaria. †Patient recovering from serious cutaneous event died due to a complication of psoas abscess and ischemic colitis Gold R, et al; SELECT study investigators. Lancet. 2013;381:
18 SELECT: Incidence of ALT/AST Abnormalities Placebon=204DAC HYP150 mgn=208300 mgn=2091–3× ULN, n (%)64 (31)54 (26)62 (30)3–5× ULN, n (%)6 (3)7 (3)>5× ULN, n (%)1 (<1)9 (4)8 (4)Abnormalities of ALT/AST >5× ULNTypically occurred late in the treatment period (median onset day = 308)Median recovery time = 62 days7 patients resumed or continued therapy. None of these patients had a recurrence in the liver function test or abnormality in the next 5 months (the minimum period for which follow-up was available)ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Gold R, et al; SELECT study investigators. Lancet. 2013;381:
19 SELECT and SELECTION: Design Overview Double-Blind TreatmentDAC HYP 300 mg SC every 4 weeks (n=209)DAC HYP 150 mg SC every 4 weeks (n=208)Placebo (n=204)481216202428323640444852SELECT: N=621SELECTION: N=517DAC HYP 150 mg (n=86)DAC HYP 300 mg (n=84)24-week washout (n=86)DAC HYP 150 mgDAC HYP 150 mg (n=86)24-week washout (n=88)DAC HYP 300 mgDAC HYP 300 mg (n=87)481216202428323640444852Primary endpointAnnualised relapse ratePrimary endpointSafety and immunogenicityGold R et al. Lancet. 2013;381: ; Giovannoni G et al. Lancet Neurol. 2014;13:
20 SELECTION: Annualized Relapse Rate Year 1Placebo (n=163)Year 1DAC HYP (n=129)Year 2DAC HYP (n=129)DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.Giovannoni G et al. Lancet Neurol. 2014;13:
21 Confirmed Disability Progression Proportion of Patients with 3-Month SELECTION: Confirmed Disability Progression over 2 Years of DAC HYP TreatmentPlacebo year 1DAC HYP year 1DAC HYP continuousDAC HYP after placebo0.30.20.10.0Placebo patientsstart DAC HYP16%Confirmed Disability ProgressionProportion of Patients with 3-MonthDAC HYP13%12%K-M plot of time to sustained progression of disability for 3 months measured by an increase in EDSS score from baseline of SELECT over 2 years – ITT population.Sustained progression is defined as at least a 1.0 point increase on the EDSS from a SELECT baseline EDSS score >= 1.0 sustained for 3 months or at least a 1.5 point increase on the EDSS from a SELECT baseline EDSS score of 0 sustained for 3 months. A cutoff of 74 days was used to determine sustained progression for 3 months.PlaceboDAC HYP7%DAC HYP(Year 2)n=163DAC HYPTime on Study (months)DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.Giovannoni G et al. Lancet Neurol. 2014;13:
22 SELECTION: MRI Assessments After 2 Years New or Newly Enlarging T2 LesionsMean Number of New/Enlarging T2-Hyperintense LesionsYear 1Placebo (n=163)Year 1DAC HYP (n=129)Year 2DAC HYP (n=129)DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.Giovannoni G et al. Lancet Neurol. 2014;13:
23 SELECTION: After 24-Week Washout from DAC HYP, Gd+ Lesions were Below Pre-treatment Baseline End of 24 week washoutNumber New Gd+ Lesions (mean)End of 24 week washoutDAC HYP 150 mgDAC HYP 300 mgYear 1Year 2Year 1Year 2DAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.Giovannoni G et al. Lancet Neurol. 2014;13:
24 SELECTION: Adverse Events of Interest DAC HYP StartersYear 1 of DAC HYPDAC HYP ContinuousYear 2 of DAC HYPDAC HYP Washout / ReinitiationDAC HYP 150 mg(n=86)DAC HYP 300 mg(n=84)DAC HYP 150 mg(n=87)(n=88)Serious Infections, n (%)3 (3)1 (1)2 (2)Serious Cutaneous Events, n (%)ALT/AST > 5x ULN, n (%)4 (5)Malignancy, nDeath**One patient in the washout and re-initiation group died because of autoimmune hepatitis after re-initiation of 300 mg daclizumab HYP. Alanine aminotransferase was increased to 195 U/L about 8 weeks after re-initiation of daclizumab HYP and continued to rise in the following 3 months to 638 U/L in conjunction with an increase in serum bilirubin concentration to 1・5–2-times greater than the upper limit of normal before clinical symptoms of liver failure developed. The diagnosis of autoimmune hepatitis was made late in the disease course on the basis of an increased serum concentration of IgG and was confirmed with liver histology findings at autopsy. A contributory role of daclizumab HYP could not be excluded.ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal*One patient in the washout and re-initiation group died because of autoimmune hepatitis after re-initiation of 300 mg daclizumab HYPDAC HYP results are combined data for patients on continuous treatment with 150 mg or 300 mg.Giovannoni G et al. Lancet Neurol. 2014;13:
25 DECIDE: Study Design Overview 24-week follow-upweek treatment periodIM IFNβ-1a 30 μg every 1 week (n=922)Randomization(n=1841)Follow-upSC DAC HYP 150 mg every 4 weeks (n=919)481216202428323640444896-144CD56CD56bright NK cell count*CD56CD56CD56CD56CD56CD56CD56EDSS and MSFC-3assessments*EDSSRandomized double-blind, active-controlled study conducted to evaluate once-monthly DAC HYP as monotherapy as compared to INF-beta. Enrollement ended April (FYI US had 220 pts).DECIDE is one of the only trials in MS designed to show reduction in annualized relapse rate and disease progression over 2 yrs versus an active comparator.Avonex was selected as active comparator because it is an established trt for MS.Primary Endpoint: ARR with objective of testing the superiority of DAC HYP sc over IFN-beta-1a IM in preventing relapse in pts with RRMS.Secondary are disability progression and MRI efficacy measures (Gd+, T2)EXTEND study- designed to provide up to 3 additional yrs of efficacy and safety data from DECIDE and started to enroll in Feb EXTEND will include a 6 month AUTOinjector sub-study (N<100 pts) and will include sites from US and other countries. Pts will be eligible to participate in EXTEND AUTO-injector sub-study after 9 months (week 36) roll-over into EXTEND.EDSSEDSSEDSSEDSSEDSSEDSSBrain MRIAll subjects had a minimum of 2-years and maximum of 3-years of treatment Trial ended when last subject randomized completed 2-years* Also assessed at weeks 60, 72, 84, 108, 120, 132, 144EDSS, Expanded Disability Status Scale; DAC HYP=daclizumab high-yield process; IFN=interferon; IM=intramuscular; MSFC-3=Multiple Sclerosis Functional Composite; NK=natural killer; SC=subcutaneous;Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
26 DECIDE: Primary Endpoint Annualized Relapse Rate 45% Reduction (95% CI: 35.5%, 53.1%) p<0.0001ARRKappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
27 DECIDE: MRI Results 9.4 4.4 1.0 Mean number of lesions 4.3 2.1 0.4 *New/Newly Enlarging T2 Lesions54% ReductionP<0.00011.00.4†New Gd+ Lesions65% ReductionP<0.00014.42.1†New T1 Hypointense Lesions‘blackholes’52% ReductionP<0.0001Mean number of lesionsKey secondary endpoints:DAC 150 mg: 54% reduction in new and newly enlarging T2 lesions at week 96 (P<0.0001)DAC 150 mg: 16% reduction in 3-month confirmed disability progression confirmed disability progression (P=0.16)Assuming disability confirmation based on observed rate in trial, DAC reduced 3-month confirmed disability by 21% (P=0.047)n=841n=864n=909n=900n=908n=899IFN beta-1a 30 mcgDAC HYP 150 mg*2-year endpoint† Tertiary EndpointsKappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
28 DECIDE: Results Confirmed Disability Progression DAC 150 mg: 16% reduction in 3-month confirmed disability progression confirmed disability progression (P=0.16)Assuming disability confirmation based on observed rate in trial, DAC reduced 3-month confirmed disability by 21% (P=0.047)*3-month confirmed: Patients censored after tentative progression (n-67) analyzed per primary method in the statistical analysis plan; secondary endpoint; all imputed as non-progressors;†6-month confirmed: Patients censored after tentative progression (n=108) imputed per observed rate in trial; tertiary endpoint. Estimated proportions are the average over imputed datasets. For both endpoints risk reduction based on Cox proportional hazards model adjusted for baseline EDSS, history of prior IFN use, and age.Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
29 DECIDE: Overview of Safety Deaths: 4 in AVONEX group, 1 in DAC; all considered not related to drugSimilar safety results for risk of infections and cutaneous events as in SELECTSerious infections: DAC 4% AVONEX 2%Serious cutaneous reactions: DAC 2% AVONEX <1%Transaminases > 5 x ULN: DAC 6% AVONEX 3%* All deaths were considered unrelated to treatment. The death in the DAC HYP group was due to aspiration pneumonia in a patient who had a MS relapse involving the brain stem and after withdrawing from the study. Deaths in the IFN beta-1a group were due to myocardial infarction, completed suicide, metastatic pancreatic cancer and peritonitis. AE, adverse event; SAE, serious adverse eventKappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
30 DECIDE: Common Adverse Events ≥10% of patients in any treatment group Deaths: 4 in AVONEX group, 1 in DAC; all considered not related to drugSimilar safety results for risk of infections and cutaneous events as in SELECTSerious infections: DAC 4% AVONEX 2%Serious cutaneous reactions: DAC 2% AVONEX <1%Transaminases > 5 x ULN: DAC 6% AVONEX 3%Selmaj K, et al. Safety and tolerability of daclizumab HYP treatment in relapsing-remitting multiple scleorosis: Results of the DECIDE study. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
31 DECIDE: Adverse Events of Interest Deaths: 4 in AVONEX group, 1 in DAC; all considered not related to drugSimilar safety results for risk of infections and cutaneous events as in SELECTSerious infections: DAC 4% AVONEX 2%Serious cutaneous reactions: DAC 2% AVONEX <1%Transaminases > 5 x ULN: DAC 6% AVONEX 3%*Clinical assessment of causality based on structured approach (Rockey et al Hepatology 51:2117). One case in each group with causality score of “probable” or higher. ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; ULN, upper limit of normal.Kappos L, Selmaj K, Arnold D, et al. Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. interferon β-1a in RRMS patients. Presented at: Joint ACTRIMS-ECTRIMS Meeting. September 10-13, Boston, MA
32 Anti-LINGO-1* Multiple Sclerosis (MS) & Acute Optic Neuritis (AON) LINGO - “Leucine-rich repeat and Ig domain containing Nogo Receptor-interacting protein1LINGO-1Transmembrane protein that is selectively expressed in the brain and spinal cord1, 2Expressed in neurons and oligodendrocyte precursor cells1, 2Appears to inhibit oligodendrocyte precursor cell1, 2 differentiationAntagonism of LINGO-1 leads to enhanced oligodendrocyte maturation and myelin production31Mi S, et al. Nature Neurosci. 2004;7:1-8, 2Mi S, et al. Int J Biochem Cell Biol. 2008;40: , 3Mi S, et al. Nature Neurosci. 2005;8:*Anti-LINGO is an investigational candidate
33 Anti-LINGO-1 Multiple Sclerosis (MS) and Acute Optic Neuritis (AON) Current treatments focus on targeting the immunological responseAnti-LINGO-1 (BIIB033) is the first drug candidate that targets CNS repair in MS through remyelination1LINGO-1 is a CNS-specific, leucine-rich repeat (LRR) and lg-domain, membrane-associated glycoprotein2Hypothesized that blocking the action of LINGO-1 may allow neuronal repair and remyelination following CNS injury1Data on File. Biogen.1. Rudick R et al. Expert Opin. Biol. Ther. 2008; 8(10):2. Mi S, et al. Nature. 2004: 7;
34 Anti-LINGO-1 Mature oligodendrocyte Lingo-1 protein prevents oligodendrocyte maturationLINGO-1, allrlyAnti-LINGO-1 antibody binds LINGO-1, allowing oligodendrocytes to mature and function properlyLINGO-1, allrlyLINGO-1, allrlyOligodendrocytes are brain cells that provide support and protection to neurons by myelinating their axonsIn MS, oligodendrocytes are damaged and do not fully mature and, therefore, do not function properlyLINGO-1 a protein found in oligodendrocytes that suppresses their differentiationANTI-LINGO-1 is a monoclonal antibody that inhibits LINGO-1, allowing the oligodendrocytes to mature and provide myelination to neuronal axonsMyelinatingoligodentrocytesImmature oligodentrocytesNdubaku U, deBellard ME. Acta Histochem. 2008;100:Adapted from Jackman N et al. Physiology. 2009;24: ; Zhang SC. Nat Rev Neurosci. 2001;2:
35 LINGO-1 Blockade Resulted in Oligodendrocyte Differentiation P<0.001510152025Control RNAiMature Oligodendrocytes(% Total)Lentivirus carry LINGO-1 specific RNAi infected oligodendrocytes shows that reduction of LINGO-1 resulted in more highly differentiated, mature (MBP+) oligodendrocytes compared to control infected cells asevident by increases in the length of cell processes and the presence of abundant myelin sheet-like structures, white arrow.In LINGO-1 RNAi expressing cells there were 3 times as many mature oligodendrocytes as in control cultures (bar graph).LINGO-1 expression was reduced by infection with LINGO-1 RNAilentivirus, and confirmed by RT-PCR (agarose gel).LINGO-1 RNAiNo RNAiControl RNAiLINGO-1 RNAiRNAi=ribonucleic acid interference.Mi S et al. Nat Neurosci. 2005;8:
36 Anti-LINGO-1 Antibody Resulted in Remyelination in Animal Models of Demyelination ControlAnti-LINGO-1Cuprizone model(1 µg/local)Lysolecithin model(1 mg/kg/IP)Experimental autoimmune encephalitis (EAE)(3 mg/kg/IP)*Anti-LINGO-1 dose originally given but not confirmed from paperCurizone model: 1 µg/localLysolecithin model: 1 mg/kg/IPEAE model: 3 mg/kg/IP****Adapted from Mi S et al. Ann Neurol. 2009;65: ; Mi S et al. Presented at ECTRIMS; October 13–16, 2010; Gothenburg, Sweden. P731.**Demyelinated AxonsRemyelinated Axons
37 Anti-LINGO-1 Phase 1 Studies: Safety in Humans Completed Single Ascending Dose (IV And SC) Study in Healthy Volunteers and a Multiple Ascending Dose (2 IV Doses 2 Weeks Apart) in MS Subjects (RRMS and SPMS)In the multiple ascending dose study, common adverse events for anti-LINGO-1 at doses ranging from 0.3 mg/kg–100 mg/kg (combined) vs placebo wereUrinary tract infection (16% vs 13%)Headache (16% vs 13%)Upper respiratory tract infection (9% vs 20%)PK was linear with a T1/2 typical of a mAb (≈2–3 weeks)CSF penetration was low (≈0.1% of serum levels), but concentrations reached levels ≥EC90* values at 10 mg/kg doseFindings supported advancing into phase 2 studies*90% effective concentration. SC=subcutaneous; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS; PK=pharmacokinetics; T1/2=half life.Tran J et al, Neurology Neuroimmunology (N2 Journal) 2014; 1 (18)
38 Anti-LINGO-1 Phase 2 Studies RENEWAcute Optic NeuritisPlacebo-controlled proof of biologySubjects with recent first episode of acute optic neuritisDose: 100 mg/kg q4wks×6Endpoints:Visual evoked potential (VEP)/multifocal VEP (latency delay)Optical coherence tomography (retinal nerve fiber and ganglion cell layer loss)Visual function (low contrast letter acuity, visual quality of life)SYNERGYRelapsing Forms of MSPlacebo-controlled proof of concept and dose rangingSubjects with RRMS and relapsing SPMS receiving IM IFNβ-1aDose: 3, 10, 30, 100 mg/kg q4wks×18Physical and cognitive endpoints:EDSS/T25FW/9HPT/PASAT compositePrimary=improvementKey secondary=delayed progressionMS-COG (information processing and learning and memory)MRI (MTR, DTI, black holes, atrophy)IM=intramuscular; IFNβ=interferon beta; EDSS=Expanded Disability Status Scale; T25FW=Timed 25-Foot Walking Test; 9HPT=9-Hole Peg Test; PASAT=Paced Auditory Serial Addition Test; DTI=diffusion tensor imaging.Cadavid D et al. Presented at AAN; April 26–May 3, 2014; Philadelphia, PA USA. RENEW: P2.262; SYNERGY: P3.154.
39 Anti-LINGO-1 Phase 2 AON Study (RENEW) Completed Subjects with first episode of acute optic neuritisN=82 subjects randomized, 2 arms, 33 sitesEvaluating efficacy after onset of inflammatory CNS demyelination in a clinically eloquent area (the optic nerve)The visual system affords an opportunity to study the functional consequences of CNS remyelinationNeurophysiology (VEP/mfVEP)Survival of retinal ganglion cells (OCT)Clinical benefit (contrast acuity)Top line results revealed evidence of proof of biology for remyelination34% improvement in average FF-VEP latency recovery at 24wks (p )VEP=visual evoked potential; mfVEP=multifocal VEP; OCT=optical coherence tomography.
40 Anti-LINGO-1 Phase 2 MS Study (SYNERGY) Fully-enrolled and ongoing* Active relapsing forms of MS418 patients enrolled, 5 arms, 72 sites, 12 countriesActive relapsing MS patients will receive IM IFN beta-1a plus anti-LINGO-1 (4 doses) or IM IFN beta-1a plus placebo18-months treatment duration allows study of clinical benefitAllows the study of efficacy in preventive mode (with drug on board before new lesions develop) but also on pre-existing lesionsAdvanced MRI methodology to study the morphological features of CNS repair*As of May 2015
41 TYSABRI® (natalizumab)* Secondary Progressive MS (SPMS) *Though approved for some indications, TYSABRI is an investigational candidate for SPMS
42 Secondary Progressive MS (SPMS) PrevalenceMajority of patients with relapse remitting multiple sclerosis (RRMS) eventually develop secondary progressive multiple sclerosis (SPMS)50% at 10 years; 90% at 25 yearsAt any given time, 30-40% of MS patients suffer from progressive disease1SPMS PathologyIntrathecal chronic inflammation drives secondary neurodegeneration via soluble toxic mediators in the CSF241% of brain autopsy specimens have ectopic meningeal lymphoid tissues31. Protocol 101MS326 Biogen Idec. 2. UK MS Brain Tissue Bank Data. 3. Magliozzi R et al, 2007.
43 Natural History of MS: Clinical and MRI Measures Relapses/DisabilityMRI T2 lesion loadMRI ActivitySecondary Progressive MSBrain VolumePreclinicalRelapsing-Remitting MSDisabilityGiven variability in how disability is expressed from patient to patient and over time, what is the preferable outcome measure in MS?MOTORSENSORYBALANCE COGNITIONVISUALEtc. etc.TimeData on File. Biogen
44 RRMS SPMS: Moving from an Acute, Focal Inflammatory Process to Chronic, Compartmentalized Global InflammationMeningeal lymphoid germinal-like centersPerivascular white matter infiltratesModified from Uccelli et alTrends Immunol. 26:RRMS ExacerbationMajor InflammationVery high chemokine levelsEarly Progressive MSLess InflammationModerate-low chemokine levelsCIS, RRMSInflammationModerate chemokine levelsLate Progressive MSLow, but significant chemokine levelsAcute Gd+ Lesions(White Matter)Meningeal Foci(Grey Matter)“Chronic lesions”Cortical PathologyIllustration by Diego Cadavid and Jeff Browning. Biogen
45 Clinical Features of Progressive MS Phenotypes Motor impairmentProgressive spastic paraparesis (weakness in the legs)1Presenting symptom in majority of patients with progressive forms of MS (80%)Involves impaired mobility with weakness, stiffness, clumsiness, dragging of legsImpacts ability to walk long distances without restProgressive ataxic syndrome with cerebellar and brainstem involvementSecond most common presentation (15%)1-3Upper limb dysfunction and impairment in activities that require manual dexterity4Bladder and bowel dysfunctionUrgency and incontinence1Predominant spinal cord involvement5,6Cognitive symptomsProgressive cognitive deficits are infrequentLess common in PPMS than SPMS7MS, multiple sclerosis; PPMS, primary progressive MS; SPMS, secondary progressive MS.1. Miller DM, Leary SM. Lancet Neurol. 2007;6: ; 2. Tremlett H et al. J Neurol. 2009;256: ; 3. Harding KE et al. J Neurol Neurosurg Psychiatry. 2014;Jun 4. [Epub ahead of print]; 4. Holper L et al. J Neurol. 2010;257: ; 5. Thompson AJ et al. Brain. 1997;120: ; 6. Comi G. Mult Scler. 2013;19: ; 7. Comi G et al. J Neurol Sci. 1995;132:
46 Rationale for Natalizumab Treatment in SPMS It is believed to prevent trafficking of lymphocytes across blood vessels and into the brain and spinal cordMay also suppress inflammation within the CNS1Possible reduction in CXCL13 levels in the CSF of patients with active and progressive MSPossible reduction in intrethecal levels of osteopontin, another molecule that has been implicated in MS progression at the experimental levelPost-hoc analyses of relapsing and non-relapsing SPMS studies suggest that natalizumab may be beneficial (T25FW, 9HPT)2Speculative MoA: Peripheral effects, known, relevant to RRMSCentral effects?Inhibition of binding of α4-positive lymphocytes with osteopontin/fibronectin. Thus, natalizumab may act to suppress existing inflammatory activity present within CNSChristensen JR et al. Neurology. 2014;82;Sellebjerg et al. Multiple Sclerosis (S4):
47 Ongoing Development & Research ASCEND Trial OverviewAn investigation of whether TYSABRI treatment slows the accumulation of disability not related to relapses in patients with SPMSPrimary endpoint: the proportion of subjects experiencing confirmed progression of disability as measured by a composite endpointFDA special protocol assessment (SPA) obtained with accepted regulatory endpointStudy fully enrolled in May 2013 (N=889)Data readout expected 2015SCR=screening; R=randomization; IV=intravenous; q4w=once every 4 weeks.Data on File. Biogen.
48 TYSABRI® (natalizumab)* Acute Ischemic Stroke *Though approved for some indications, TYSABRI is an investigational candidate for acute ischemic stroke
49 TYSABRI in Ischemic Stroke PrevalenceThere are nearly 800,000 strokes of all types per year in the USIschemic stroke accounts for approximately 80%TreatmentRecombinant tissue plasminogen activator (rtPA) only approved pharmacological therapy for acute ischemic stroke. Must be used within 3 hours of stroke onset (US Guidelines)TYSABRI could be used as an adjunctive therapy with TPABlocking the α4β1 integrin with natalizumab is expected to reduce peri-stroke inflammation and thereby reduce the expansion of the infarct due to inflammationPotential to be the first disease-modifying, anti-inflammatory therapeutic for stroke, with better efficacy and safety than TPAAs a result of acute dosing, PML is not expected to be an observed AE in stroke.Data On File. John WalshRoger 2011 (From Protocol 101SK201)Data On File. Biogen.Roger 2011 (From Protocol 101SK201)
50 Etiology of Acute Ischemic Stroke (AIS) Obstructed blood flow in the brain leads to ischemiaBlockageIschemic tissueIschemic PenumbraCore ischemic zoneInfarctionPenumbraThrombusADDITIONAL MATERIAL FOR INTERNAL USE ONLYThis slide shows the etiology of AIS. It should be noted in this slide that stroke can only grow to the size of tissue bed which is left unperfused. The penumbra of ischemic tissue will eventually infarct if left alone and it is this area of ischemic tissue which we are trying to target with natalizumab.Formation of a blood clot1When a blood vessel is injured, the body uses platelets and fibrin to form blood clots which prevents blood loss; even when a blood vessels is not injured, blood clots can form in the body under certain conditions. The formation of a blood clot inside a blood vessel obstructing the flow of blood is called thrombosis. A blood clot that forms in a vessel and remains there is called a thrombus.Other causes of AIS1Carotid artery dissection – caused by a tear in one of the carotid arteries of the neck, which allows blood under arterial pressure to enter the wall of the artery and split its layers, which results in either an intramural hematoma or an aneurysmal dilatationVasoconstriction – caused primarily by blood vessel spasm (vasospasm)Atherosclerosis – caused by artery walls thickening as a result of the accumulation of calcium and fatty materials such as cholesterol and triglyceride which reduces their elasticity and allows less blood to travel through themThe Internet Stroke Center. Ischemic Stroke. Available at: Accessed: Feb 2014AbbreviationsAIS=acute ischemic strokeClot within artery blocks normal flow to the brainLoss of blood supply results in ischemiaTwo major zones of injury:● Core ischemic zone● Ischemic penumbraIschemia = restriction in blood supply to tissuesCore ischemic zone = area of severe ischemia (blood flow <10–25%)Ischemic penumbra = rim of mildly-to-moderately ischemic tissueSaver JL. Stroke 2006;37:263–6
51 Etiology of Acute Ischemic Stroke (AIS) Ischemia leads to infarction (neuronal death)Minutes after blockage, an ischemic cascade is initiated, leading to neuronal death (infarct) at the core zoneUnless blood flow is promptly restored, the penumbra also infarcts, resulting in a larger total infarct volume1Golden treatment window during which pharmacologic or mechanical interventions are most likelyto be effectiveADDITIONAL MATERIAL FOR INTERNAL USE ONLYThis slide shows the etiology of acute ischemic stroke.Pathophysiology1Ischemia is a condition in which there is insufficient blood flow to the brain to meet metabolic demand, which results in poor oxygen supply and thus death of brain tissue (infarction). During a typical untreated AIS, 32,000 neurons are lost every second. Within an hour 120 million neurons are lost. Within 10 hours 1.2 billion neurons are lost, which ages the brain by 35 years. Therefore, the longer a stroke goes without medical attention, the greater the chance of permanent neurologic damage. It follows that the earlier a treatment is administered – the greater the chance that the infarct volume will be reduced. It should be noted that the window for intervention in ischemic penumbra is poorly defined and is dependent on the location of the ischemia and the patient’s collateral blood flow. It is, therefore, difficult to define a “golden hour” of treatment.Process of ischemia (ischemic cascade)2 The process of ischemia is started by a series of biochemical reactions (ischemic cascade) that are initiated in the brain seconds after ischemia. The ischemic cascade is not always linear, in some cases it can be circular as one event can cause or be caused by multiple events. Also, cells receiving different amounts of blood June go through different chemical processes. Generally the ischemic cascade is characterized by an initial lack of oxygen which causes the neurons normal process for making ATP for energy to fail. This in turn halts ion transport pumps which results in an excess of calcium with in the cell and causes the production of cytotoxic chemicals which eventually results in cell necrosis.Saunders et al. study3Saunders et al. studied the reproducibility and accuracy of measurements of infarct volume using MRI and correlated the measurements with the patients’ functional outcomes. Patients (n=23) with cortical MCA territory infarcts were studied up to 72 hours after of stroke onset in a study which lasted over 2 years. Infarct volume was measured on T2 weighted FLAIR MRI.It was found that measurements of infarct volume were highly accurate and reproducible. The Scandinavian Stroke Scale was used to calculate a prognostic score, and clinical outcomes were assessed at 3 months.Infarct volume was found to significantly predict outcome. Mean infarct volume in the independent patients was 35.7±29.7cm3 compared with 88.3±71.3cm3 in dependent patients and 166.5±65.9cm3 in dead patients (p<0.001). The study concluded that measuring the size of middle cerebral artery infarction with MRI is a useful tool in assessing the prognosis and has a valuable role is assessing new therapeutic agents.1. Saver JL et al. Stroke 2006;37:263–62. Idadecola C et al. Nature Medicine 2011;17:796–8083. Saunders DE et al. Stroke 1995;26:2272–6AbbreviationsAIS=acute ischemic strokeATP=Adenosine triphosphateFLAIR=Fluid attenuated inversion recoveryMCA=Middle cerebral artery strokeMRI=Magnetic resonance imagingThe larger the infarct volume, the worse theclinical outcomes for AIS patients21. The Internet Stroke Center. The Ischemic Penumbra. Available at: Accessed: Jan 2014; 2. Saunders DE et al. Stroke 1995;26:2272–6
52 Common long term outcomes Acute and long-term functional outcomes in AIS Type and degree of long-term disability depend upon area of brain affected and extent of damageADDITIONAL MATERIAL FOR INTERNAL USE ONLYThis slide shows the acute and long-term functional outcomes of AIS patients using the mRS. The data on this slide come from a study by Petty et al.1 who studied all residents of Rochester, Minnesota, with a first ischemic stroke from 1985– mRS was used to assess functional outcome at the time of stroke, 3 months and 1 year later. A neurologist and a nurse abstractor abstracted the medical record of each patient and recorded on standardized forms information regarding stroke risk factors and functional status before or at the time of first cerebral infarction and diagnostic studies, treatment, and dates of last follow-up and death after the stroke before January 1, 1993.Maximal deficit is defined as the maximal severity of neurological deficits within the first 7 day after stroke measured by the mRS.Outcomes in the study focussed on functional outcomes, rather than specific deficits as it can be difficult to assess a stroke patient’s outcome solely by describing their disabilities post-stroke. For example, some patients with hemiplegia (paralysis on one side of the body) can function well in everyday tasks and even return to work despite having half their body paralysed, whereas other patients would require supervision 24 hours a day.1) Petty GW et al. Stroke 2000;31:1062–8Abbreviations:AIS=acute ischemic strokemRS=modified Rankin ScaleCommon long term outcomesparalysis/problems controlling movementproblems using or understanding languagesensory disturbancesproblems with thinking and memoryemotional disturbances*p= AIS=acute ischemic stroke; mRS=modified Rankin ScalePetty GW et al. Stroke 2000;31:1062–8No significant or slight disability: Rankin score of I or II; Moderately severe or severe disability: Rankin score of IV, V or dead
53 Natalizumab as AIS Therapy Natalizumab is believed to block the migration of lymphocytes that are thought to mediate post-AIS inflammatory responses that increase infarct volume1. Natalizumab, an a α4β1 integrin antibody ( ), binds to α4β1 integrin receptors on all human leukocytes (except polymorphonuclear leukocytes)1α4β1integrin2. Natalizumab binding blocks CNS α4β1 integrin from interacting with its ligand, vascular cell adhesion molecule-1 (VCAM-1), on the endothelial wall1VCAM-1ADDITIONAL MATERIAL FOR INTERNAL USE ONLYThis slide shows the hypothesized mechanism of action of natalizumab. Adhesion molecules are involved in the inflammatory demyelination process in the CNS. Adhesion molecules and ligands expressed on endothelial cells and leukocytes mediate the entry of activated T- and B-lymphocytes and monocytes into the CNS. The glycoprotein α4β1 integrin is one of these adhesion molecules and is expressed on lymphocytes, monocytes, mast cells, macrophages, basophils and eosinophils but not neutrophils. The expression of the α4β1 integrin increases after T-cell activation.Natalizumab’s mechanism of action1Natalizumab binds to α4β1 integrin on the surface of activated T-cells and other mononuclear leukocytes, preventing cellular adhesion between the T-cell and the endothelial cell – this disruption of the cell adhesion molecule’s interactions results in the prevention of mononuclear leukocyte migration across the endothelium and into the parenchyma, with a subsequent reduction in proinflammatory cytokines. A further mechanism of natalizumab June be the suppression of ongoing inflammatory reactions in diseased tissues by inhibiting the binding of α4-positive leukocytes with osteopontin and fibronectin. There are three potential modes of action:Blockade of migration by blocking adhesion to endothelial cells and interaction with extracellular matric proteinsBlockade of priming by interaction with osteopontin and VCAM expressed on microglial cells and monocytes in situInduction of apoptosis by blocking interaction of α4-integrin bearing leukocytes with extracellular matrix proteinsTherefore, natalizumab June have dual anti-inflammatory effects: inhibition of recruitment of immune cells into inflamed tissue and suppression of existing inflammatory activity at the disease site.Rudick RA et al. NEJM 2006;354:911–23Abbreviations:CNS=central nervous systemVCAM=endothelial vascular adhesion molecule 13. Blocking entry of leukocytes into the brain suppresses the inflammatory activity thought to cause post-AIS increases in infarct volume2CNS=central nervous system,1. Rudick RA et al. NEJM 2006;354:911–23; 2. Protocol 101SK201. Data on file. Biogen, Jun 2013
54 ACTION Phase II Study Primary objective: Effect of a single dose of natalizumab infarct volume in AIS patients who have either already received, or are ineligible for, IV rt-PA treatmentPrimary objective:To assess the effect of natalizumab on infarct volume over first 5 days after strokeSecondary objectives – to assess:The effect of natalizumab on infarct growth at multiple time points after ischemic strokeThe effect of natalizumab on disability and neurological function (BI, mRS, NIHSS etc)The safety of natalizumab via physical and neurological examinations:vital sign measurementshematology and blood chemistryanti-natalizumab antibodiesmonitoring of AEs and SAEsBaseline5 daysADDITIONAL MATERIAL FOR INTERNAL USE ONLYEffect of Natalizumab on Infarct Volume in Acute Ischemic Stroke (ACTION)MRI scansThis slide shows the phase II study objectives. At the baseline the infarct will be measured using DWI MRI which is the most sensitive MRI method which can be used to identify acute cerebral infarction within the first few hours. As time progresses and the infarct evolves and ischemia results in cell death and disintegration, the once bright DWI MRI image appears dark. Therefore at day 5, FLAIR MRI is used to image patients as it offers the most sensitive method of imaging lesions 24 hours after LKN (by depicting areas of tissue T2 prolongation while suppressing CSF signal)1.Xavier AR et al. Southern medical journal 2003;96:367–79Abbreviations:CSF=cerebrospinal fluidDWI=diffusion weighted imagingFLAIR=fluid attenuated inversion recoveryLKN=last known normalMRI=magnetic resonance imagingDay 5AIS=acute ischemic stroke; AE=adverse event; BI=Barthel index; mRS=modified Rankin Scale;NIHSS=National Institute of Health Stroke Scale; SAE=serious adverse eventProtocol 101SK201. Data on file. Biogen, Jun 2013; Clinicaltrials.gov NCT , accessed April
55 Anti-TWEAK (BIIB023)* Lupus Nephritis *Anti-TWEAK is an investigational candidate. Efficacy and safety have not been established.
56 Lupus Nephritis Prevalence Treatment Lupus Nephritis (LN) is present in up to 60% of Systemic Lupus Erythematosus (SLE) patients.1 (SLE occurs in approximately 20 to 70 cases per 100,000)2TreatmentNo indicated therapiesTreatment regimens include combination Mycophenolate mofetil with prednisone or cyclophosphamide with methypredinisoloneSuppress the immune system to treat the acute inflammatory injury3Limited efficacy with increasing toxicities over time4ATK Anti Tweak Background and ATLAS Study Design Slides Nov 2013Cameron J. J of Amer Society of Nephrology. 1999; 10(2):Pons-Estel GJ et al. Seminars in Arthritis and Rheumatism. 2010; 39(4):Ortega L et al. Lupus. 2010; 19:Waldman M and Appel GB. Kidney International. 2006; 70:
57 Anti-TWEAK (BIIB023)TWEAK is a proinflammatory cytokine expressed by WBCs and functions as a soluble cytokine through the fibroblast growth factor (FGF)-inducible molecule 14 (Fn14)Fn14 is highly induced in disease target tissues and implicated in the pathogenesis of LNAnti-TWEAK is thought to target Fn14 and is designed to inhibit glomerular and tubular pathologies1Phase II study ongoing and expected to be completed in 20192Sanz AB et al. Kidney International. 2011; 80:NCTData on File. Biogen.
58 BIIB023 Study DesignProtocol 211LE201 Data on File. Biogen
59 Neublastin (BG00010)* Neuropathic Pain *Neublastin is an investigational candidate. Efficacy and safety have not been established.
60 Neuropathic Pain Prevalence Estimated 1-2% of population experiences neuropathic pain. Possibly underestimated due to undiagnosed chronic pain1Associated with physical injury to a nerve, systemic diseases (e.g. diabetes), autoimmune disorders, infections, etc.2TreatmentCurrent therapies: LYRICA® (pregabalin), NEURONTIN® (gabapentin), CYMBALTA® (duloxetine)Poor control of pain with increased side effects3LYRICA® and NEURONTIN® are a registered trademarks of Pfizer Inc.; CYMBALTA® is a registered trademark of Eli Lilly and Company1. Smith BH and Torrance N. Curr Pain Headache Rep2. NINDS.NIH.gov3. Investigator Brochure V7; Biogen.
61 Neublastin (NBN)NBN is a potent cell survival and growth factor which signals through receptor GFRα3 highly expressed on pain-sensing neurons1Possible targeted alleviation of pain and minimal CNS side effects were shown in animal studiesNBN is being investigated as a first-in-class, potentially restorative treatment for neuropathic pain and neuropathy associated with nerve damage2Phase 2 study expected to be completed 20153GFRα3 = GDNF family receptor alpha-3GDNF = Glial cell-derived neurotrophic factorGardell L et al. Nature. 2003; 9:Data on File. Biogen.NCT
62 Neublastin – Program Development Phase 1 SAD and MAD studies completePhase 2 POC Study in lumbar radiculopathy on-goingMulti-center, double-blinded, placebo‑controlled study, multi-dose study (~ 168 patients)Neublastin (50, 150, 400, 800, and 1200 µg/kg) vs placebo IV three times a week for approximately 13 weeksPrimary endpoint: Change from baseline in the mean 24-h average general pain intensity score (AGPI) at the end of the treatment week using an 11‑point Numeric Rating Scale (NRS)Protocol 103NS201 v6
63 ISIS-SMNRX* Spinal Muscular Atrophy *ISIS-SMNRX is an investigational candidate. Efficacy and safety have not been established.
64 Spinal Muscular Atrophy (SMA) SMA is an autosomal recessive neuromuscular disease. It results in the degeneration of alpha motor neurons in the spinal cord leading to proximal muscle weakness and paralysis.PrevalenceApproximate incidence is 1 in 6,000 to 1 in 10,000 live births1Though classified into three major types, the disorder demonstrates a continuous range of severity and overlap2TypeOther NamesAge at OnsetLife SpanHighest Function AchievedSMA IAcute spinal muscular atrophy; Werdnig Hoffmann disease0-6 months<2 yearsNever sit independentlySMA IIChronic spinal muscular atrophy; Dubowitz disease7-18 monthsVaries from 2 years to the third decade of lifeSit independently, never standSMA IIIJuvenile spinal muscular atrophy; Kugelberg-Welander disease>18 monthsNormalStand and walk alone1. D’Amico A et al. Orphanet Journal of Rare Diseases. 2011; 6 (71);2. Mitchell LR et al, Lancet. 2008; ;
65 Spinal Muscular Atrophy (SMA) Current Treatments:No indicated therapies for SMA. Treatment centers around the management of symptoms and preventing complications of SMASMA caused by genetic defects in the SMN1 gene that result in the lack of functional SMN proteinIntervention: Antisense oligonucleotide (ASO) to insert missing exon in “backup” geneISIS-SMNRX is believed to increase production of fully functional SMN protein in model systemsUniformly 2’-0-methoxyethyl modified (MOE) antisense drug1Chiriboga, C et al. Results of an Open-Label, Escalating Dose Study to Assess the Safety, Tolerability, and Dose Range Finding of a Single Intrathecal Dose of ISIS-SMNRX in Patients with Spinal Muscular Atrophy. Presented at AAN 2013
66 ISIS-SMNRXISIS-SMNRX is currently in Phase 3 trials; estimated to be completed in 20172Granted Orphan Drug Status in US & EU and Fast Track in the US1ISIS-SMNRX is a joint collaboration with ISIS Pharmaceuticals1. Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 20142. NCTData on File. Biogen.
67 Phase 2 Multiple-Ascending Dose, Open-Label Study in Medically Stable SMA Patients 2-15 Years of Age Study CompleteObjectivesEvaluate the safety and tolerability of multiple intrathecal doses of ISIS-SMNRxEvaluate CSF, plasma PK, and clinical outcomes related to SMA (including HMFSE)Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014
68 Dose and Time Dependent Increases in HFMSE Scores after Multiple Doses of ISIS-SMNR* In multi-dose study, SMN protein increase of 115% (p=0.004,n=9) observed at 3 months In single-dose study, SMN protein increase of 160% (p=0.09,n=6) observed at ~ 1 yearDarras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014*Study is now complete; data presented above is for first 3 cohorts, 12 mg data cohort not yet available (as of May 2015)
69 ISIS-SMNRx Phase 3 Study (ENDEAR)* A Phase 3, randomized, double-blind, sham-procedure controlled study in infants with SMAGlobal study in ~110 SMA infants ≤ 7 months old with 2 copies of SMN213 month study durationEvaluate the efficacy and safety of ISIS-SMNRxPrimary efficacy endpoint is time to death/permanent ventilationAdditional efficacy endpoints include CHOP INTEND and motor milestonesInitiated - August 2014Darras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014*Link to study details at https://clinicaltrials.gov/ct2/show/NCT ?term=ENDEAR&rank=1
70 ISIS-SMNRx Phase 3 Study (CHERISH)* A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study in Children with SMAGlobal study in ~120 SMA children with SMA15 month study durationDetermine the efficacy and safety of ISIS-SMNRxPrimary endpoint is change in Hammersmith motor function scoreInitiatedDarras, B et al. Interim Results of a Phase 2 Study of ISIS-SMNRx in Children with Spinal Muscular Atrophy. Presented at AAN 2014*Link to study details at https://clinicaltrials.gov/ct2/show/NCT ?term=CHERISH&rank=2
71 Aducanumab (BIIB037)* Alzheimer’s Disease *BIIB037 is an investigational candidate. Efficacy and safety have not been established.
72 Alzheimer’s Disease (AD) PrevalenceAlzheimer’s disease (AD) is the most common cause of dementia, accounting for 60% to 80% of all cases1Estimated that 5.2 million Americans suffer from dementia caused by AD in the US1 and million people living with dementia worldwide2Estimated to increase to million worldwide by 20502Current Approved Treatments*Mild to Moderate AD - ARICEPT® (Donepezil), EXELON® (Rivastigmine), RAZADYNE® (Galantamine)Moderate to Severe AD - ARICEPT ® (Donepezil), NAMENDA® (Memantine)Current treatments regulate neurotransmitters in the brain which may help to improve thinking, memory, and speaking skills.However, current therapies do not modify the underlying disease process and may not be effective for all patients affected by AD22014 Alzheimer’s Disease Facts and Figures. 2. Alzheimer’s Disease International*All trademarks for drugs mentioned are the property of their respective owners
73 Aducanumab (BIIB037)AD is defined by the presence of extracellular neuritic plaques (NPs) containing amyloid beta (Aβ) peptide and intraneuronal neurofibrillary tangles (NFTs) composed of tau protein in the brain1BIIB037 is a human monoclonal antibody that targets aggregated forms of beta amyloidTherapeutic rationale: Clearance of aggregated Aβ in the brain will attenuate the neurodegenerative process and slow the clinical progression of AD21. Hardy and Selkoe. Science. 2002; 197(5580): , 2 Data on File. Biogen.
74 Aducanumab (BIIB037)*Recently completed a pre-specified interim analysis of Phase 1bPhase 1b study is a randomized blinded placebo controlled ascending dose study in prodromal and mild AD patients who are also amyloid positive in the brain at baselineInterim analysis indicated that BIIB037 reduced amyloid levels in a dose and time dependent fashion. Other preliminary findings:Statistically significant effect on cognition at 54 weeksMost significant safety findings have been amyloid-related imaging abnormalities (ARIAs). These events appear to be both dose and ApoE4 dependent, largely mild to moderate and self-resolvingContinuing the current Phase 1b study in a blinded fashionPreparing to implement Phase 3 program*As of May 2015Data on File. Biogen
75 Aducanumab (BIIB037) Interim Phase 1B Analysis Effect on Mini Mental State Examination (MMSE) Sevigny J, et al. Randomized, Double-blind, Placebo-controlled, Phase 1b Study of Aducanumab (BIIB037), an Anti-Aβ Monoclonal Antibody, in Patients With Prodromal or Mild Alzheimer’s Disease: Interim Results by Disease Stage and ApoE ε4 Status. Presented at 2015 AAN Congress, Washington, DC.
76 Aducanumab (BIIB037) Interim Phase 1B Analysis Safety Results Summary Sevigny J, et al. Randomized, Double-blind, Placebo-controlled, Phase 1b Study of Aducanumab (BIIB037), an Anti-Aβ Monoclonal Antibody, in Patients With Prodromal or Mild Alzheimer’s Disease: Interim Results by Disease Stage and ApoE ε4 Status. Presented at 2015 AAN Congress, Washington, DC.
77 BAN2401* Alzheimer’s Disease *BAN2401 is an investigational candidate. Efficacy and safety have not been established.
78 BAN2401Suggested that amyloid beta (Aβ) protofibril, an intermediate in the aggregation process of the amyloid-β peptide, initiates and drives the neurodegenerative process in Alzheimer’s diseaseBAN2401 is a humanized monoclonal antibody that specifically targets the protofibrillar form of Aβ1Currently in phase 2 expected to be completed by 20162Collaboration with Eisai Co.NCTData on File. Biogen
79 BG00011* Idiopathic Pulmonary Fibrosis (IPF) *BG00011 is an investigational candidate. Efficacy and safety have not been established.
80 Idiopathic Pulmonary Fibrosis (IPF) PrevalenceApproximately 100,000 people in the United States have IPFMost people diagnosed with IPF only live 3 to 5 years after diagnosis. Most common cause of death is respiratory failure1United States National Library of Medicine website. “Idiopathic Pulmonary Fibrosis” Accessed October 7, 2014med-cor b.htmFigure: National Heart, Lung, and Blood Institute website. “How the Lungs Work”1. United States National Library of Medicine website. “Idiopathic Pulmonary Fibrosis”
81 Idiopathic Pulmonary Fibrosis (IPF) Two therapies recently approved for the treatment of IPFESBRIET® (pirfenidone) was approved in the US on October 15, 2014The mechanism of action is unknown1OFEV® (nintedanib) was approved in the US on October 16th, 2014Nintedanib is a tyrosine kinase inhibitor (TKI) that targets growth factor receptors involved in the mechanisms by which pulmonary fibrosis occurs. It inhibits the platelet-derived growth factor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR)2Sequential therapy might represent the best use of current therapies but it does not provide a long-term solution to the problem; pirfenidone and nintedanib are not miracle drugs. Idiopathic pulmonary disease continues to progress, albeit more slowly, and whether either drug is efficacious as a second-line drug is not yet known. The search for better outcomes now faces an essential divide between so called personalised medicine and combination therapies.United States National Library of Medicine website. “Idiopathic Pulmonary Fibrosis” Accessed October 7, 2014med-cor b.htmESBRIET® is a registered trademark of Intermune. OFEV® is a registered trademark of Boehringer ingelheim1.2.
82 BG00011 (anti-αvβ6 mAb)αvβ6 integrin is expressed in low levels on alveolar epithelial cells in normal healthy adults and is tightly regulated by transforming growth factor-β (TGF-β); αvβ6 is upregulated with tissue injuryαvβ6 blockade provides a mechanism for injury- specific attenuation of TGF-β activation, inhibiting fibrogenesisαvβ6 blockade provides a mechanism for injury- specific attenuation of TGF-β activity1BG00011 is a humanized monoclonal antibody targeting integrin αvβ6.BG00011, preclinically, exhibits anti-fibrotic activity in models of lung, kidney and liver disease. 2Phase 2 studying patients with IPF; estimated completion 201531.2. BI1IB Press Release3. wwwl.clinicaltrials.gov NCT