DAA Therapies: What Do The Data Show?

New and Emerging Therapies in MS: Is It Time to Change the Status Quo?

Anne H. Cross, MD Professor of NeurologyWashington University School of MedicineSt. Louis, Missouri

#OutlineHow have our goals been altered by the new MS therapies?Balancing efficacy with safetyThe old guard medications vs newer agents3 newest FDA-approved disease-modifying therapies Natalizumab Fingolimod TeriflunomideDrugs in late-phase trialsDimethyl fumarate, alemtuzumab, daclizumab, laquinimod, and ocrelizumabCombination therapies: teriflunomide + IFN-, CombiRx trialIndividualizing therapyThe role of MRI and other biomarkers in guiding therapies

#9 FDA-Approved MS Disease-Modifying Therapies DrugApprovedType of MS1st/2nd LineInterferon -1b (2 products) SQ QOD 1993, 2009Relapsing MS, CIS1st Glatiramer acetate SQ QD1996RRMS, CIS1st Interferon -1a IM weekly 1996Relapsing MS, CIS1st Mitoxantrone IV q3mo (dose limit) 2000Worsening RRMS, SPMS, progressive relapsing MS2nd

IFN -1a SQ TWI2002RRMS1st Natalizumab IV q4wk 2004/2006Relapsing MS2ndFingolimod oral QD2010Relapsing MS1st Teriflunomide oral QD2012Relapsing MS1st Abbreviations: CIS, clinically isolated syndrome; MS, multiple sclerosis; RRMS, relapsing-remitting MS; SPMS, secondary-progressive MS. Graphic courtesy of Anne H. Cross, MD.

#More Treatments Are Good, But It Makes Treatment Choices More Difficult!

Treatment AMaybeSwitch treatments??Treatment BTreatment CNoYesGraphic courtesy of Anne H. Cross, MD.#Treatment DecisionsA Balancing ActImpactDisease courseDisability outcomesToleranceConvenienceShort-term safetyLong-term safety PregnancyFinancial costs

BenefitsRisksGraphic courtesy of Anne H. Cross, MD.#5Role of MRI in Guiding Initial Medication DecisionsImproves diagnostic certaintySpinal cord MRIHelps to gauge the aggressiveness of the MSNumber and extent of T2 lesions on early MRIInfratentorial lesionsDegree of cerebral atrophy requires careful measurementHelps to gauge MS activity Number of contrast-enhancing lesionsAlthough correlation of Gd+ lesions with future disability not clear#6Advantages of The Old Guard Interferon-s and Glatiramer Acetate Highly efficacious in a sizeable proportion of relapsing-remitting MS patientsKnown safety profiles years, decadesNo immunosuppressionGlatiramer acetate (GA) is Pregnancy Category B No blood monitoring needed for GA

#Disadvantages of The Old Guard IFN-s and GAPartial efficacy against relapsesEffect on long-term disability less clearImmediate IM IFN -1a at time of clinically isolated syndrome reduced relapse rate over 10 years but did not improve disability outcomes1Neutralizing antibody formation with IFNsInjections: site reactions, lipoatrophy, infectionsFlu-like illness with IFN-sNonadherence in up to 40%50%2,3Blood monitoring needed for IFN-sIFN-s are Pregnancy Category C

1. Kinkel RP, et al. Arch Neurol. 2012;69:183-190. 2. Klauer T, et al. J Neurol. 2008;255:87-92. 3. Wong J, et al. Can J Neurol Sci. 2011;38:429-433. #8Long-Term Outcome Considerations

Age of patient and expected lifespan?How aggressive does the disease appear?How long can the patient be on the medication?Future and present childbearing potential?Concomitant illnesses?Does the medication increase risk of future neoplasm?

#Newer Drugs#Natalizumab #ChemokineInside the CNSICAM-1, VCAM-1(Ig superfamily)

MMPs

VLA-4, LFA-1, Mac-1, (integrins)ChemokinesAddressinsChemokine RLymphocyteStep 1 (rolling)Step 2Step 3LectinsBloodTransmigration of Inflammatory CellsGraphic courtesy of Anne H. Cross, MD.#Natalizumab for Relapsing MSHumanized monoclonal antibody to 4-integrins (part of VLA-4)1Blocks interactions of 41 and 47 on leukocyte surface with VCAM-1 on endothelium and fibronectin in extracellular matrix1Suppressing cell transmigration through the bloodbrain barrier and trafficking into tissuesInitially approved 2004, generally recommended for patients who have had an inadequate response to, or unable to tolerate, an alternate MS therapy2Available only through the TOUCH program2

1. Engelhardt B, et al. Neurodegener Dis. 2008;5:16-22. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. #13NatalizumabBoxed Warning[Natalizumab] increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability1As of October 3, 2012, 298 cases of PML with 104,300 exposures to natalizumab worldwide2 3 risk factors for PML1Longer treatment duration, particularly >2 yearsPrior immunosuppressant treatmentPresence of anti-JCV antibodies1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Biogen Idec. Tysabri Update. October 18, 2012.#14PMLBiomarkers to Stratify Risks with Natalizumab Antibodies to JCV indicate prior JCV exposure and risk of PMLAbsence of anti-JCV antibodies indicates low, but not 0, riskExamples of prior immunosuppressants include mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetilNatalizumab ExposureAnti-JCV Antibody Positive +Prior Immunosuppressant UseNoYes124 months 80% recovery before disease-modifying therapyStarted IFN -1a SC 44 ug TIW about 2 years after diagnosisHas taken it since, with few neurologic problems Complained at visit earlier this year about injection-site reactionsAdmitted missing about 25% of injections#Case 3MRI FindingsMRI was compatible with MSMild to moderate lesion burdenNo enhancing lesionsNo black holesGraphic courtesy of Anne H. Cross, MD.

#Case 3Evaluation and Switching TherapyLaboratory testsCMP with liver function tests normalCBC with differential normalPregnancy test negativeTB skin test negativeBlood pressure 112/70 Initiated teriflunomide at 14 mg/dayNo wash-out from interferon-

#Case 3Follow-UpVery happy taking it after 2 monthsAlthough concerned about possible hair lossMonitoring planLiver function tests every month for 6 months then every 23 monthsCBC every 23 monthsBlood pressure check every 23 monthsMRI brain yearly# Whats in the Pipeline?

Graphic courtesy of http://opsweb.phmsa.dot.gov/pipelineforum/facts-and-stats/index.html.#MS PipelineAgentMechanisms of Action*Dimethyl fumarate (BG-12), oral1Activates Nrf2, prevents oxidative stress*Alemtuzumab, IV1 (SC under evaluation2)Anti-CD52 (depletes T- and B-cells and monocytes)Laquinimod, oral1Th2 shift Daclizumab, IV1Anti-CD25 (increases CD56+ natural killer cells)Ocrelizumab, IV1Anti-CD20 (depletes B-cells)*Under review by FDA. Abbreviation: Nrf2, nuclear factor erythroid 2-related factor. 1. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137. 2. Perumal JS, et al. Mult Scler. 2012;18:1197-1199. Graphic courtesy of Anne H. Cross, MD.#Dimethyl Fumarate (BG-12)Overview

240 mg BID or TID, oralActivates nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway1Nrf2 antioxidant response pathway regulates phase 2 detoxifying enzymes crucial to countering oxidative stress1Not considered immunosuppressive1. Linker RA, et al. Brain. 2011;134:678-692.#

60N = 1234 DEFINEBG-12 BID and TIDvs Placebo for 2 YearsProportion of Relapsers, Primary Endpoint Gold R, et al. N Engl J Med. 2012;367:1098-1107. P