Gary M. Owens, MD NAMCP April 23, 2015

Transcription

1 4/27/2015 Gary M. Owens, MD NAMCP April 23, MS Background and disease state review The evolution of MS therapeutic options T and B cell roles in MS A review of first generation therapy (ABCR drugs) A review of the next generation MS therapy options MS therapies on the horizon and how the landscape may change Payer approaches to MS therapy 2 1

2 4/27/ % Worldwide incidence 400,000 people in US have MS The ratio is increasing now > worse prognosis Predominant age: % risk of MS among 1st-degree relatives Highly variable and unpredictable Higher incidence in Northern European descent and in temperate climate, but the latitude gradient is decreasing 4 2

3 Neurodegenerative disorder of CNS Presumed to be autoimmune Women = 1/200; Men = 1/400 5 PRMS Progressive Relapsing MS Steady decline since onset with super-imposed attacks. SPMS Secondary Progressive MS Initial RRMS that suddenly begins to decline without periods of remission and relapses. PPMS Primary Progressive MS Gradual progression of the disease from its onset with no relapses or remissions RRMS Relapsing/ Remitting MS Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission 6 3

4 Relapses/Disability MRI Activity MRI T2 Burden of Disease Axonal Loss Secondary Progressive MS Disability Preclinical * CIS Relapsing Remitting MS Trapp BD, et al. Neuroscientist. 1999;5:48 57, Time 7 T1 & hypo intensity T2 & hyper intensity 4

5 4/27/2015 It s getting complicated! Circulation Rolling Extravasation Adhesion B L O O D F L O W B cell Activated T cell LUMEN OF 4 Integrin VCAM VENULE B A S A L Proteases L A M I N A BRAIN TISSUE astrocytes Cytokines and chemokines IL 1, IL 12, chemokines Antigen presenting cell Activated microglia/macro phages Activated Macrophage T CELL REACTIVATION (Astrocyte or Microglial cell) Proteases TNF- O2 NO AXONAL DAMAGE oligodendrocyte Autoantibodies Complement MYELIN Courtesy of Sergio Baranzini, PhD. 5

6 Reactive T lymphocytes cross BBB Trigger inflammation Axon demyelination Ultimately results in nerve damage Adhesion Extravasation VCAM: Vascular Cell Adhesion Molecule; MadCAM: Muccosal adressin Cell Adhesion Molecule Source: Medscape; Ther Adv Neurol Disorders. 2013;6(3):

7 Blood-brain barrier breakdown Autoimmunology Inflammation The BBB prevent entrance of T cells into the nervous system. The blood brain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctions. When the blood brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain. The immune system attacks the nervous system, forming plaques or lesions. Commonly involves white matter. Destroys oligodendrocytes- causing demyelination Remyelination occurs in early phase but not completely. Repeated attacks lead to fewer remyelination. T-cells attacks on myelin triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Leaks form in the BBB cause swelling, activation of macrophages, and more activation of cytokines and other destructive proteins CNS lesions in MS patients contain B cells, plasma cells and antibodies. The level of B cell involvement may vary in MS patients. The most frequently found pattern of lesion pathology is characterized by significant antibody deposits and complement activation, suggesting that the locally produced antibody response may indeed contribute to CNS demyelination Besides differentiating into antibody secreting plasma cells, B cells may contribute to the development and progression of CNS autoimmune disease as APCs for activation of T cells 7

8 4/27/2015 MS Drug Treatment Timeline: Not to Scale! Tecfidera AVONEX Lemtrada Aubagio TYSABRI Betaseron Plegridy Extavia Gilenya Copaxone Rebif Novantrone First Generation Therapies Recently Approved 8

9 Interferon beta 1a (Avonex, Rebif) Interferon beta 1b (Betaseron Extavia) Glatiramer acetate (Copaxone) All well known agents that large experience in the MS population Beta Interferon was the first class of medications approved by the US FDA for MS Administered by self injection Injection site necrosis and Flu like symptoms Neutralizing antibodies can reduce the bioavailability of interferon 9

10 Polymers of four amino acids compete with APC to T cell Inducer of specific T helper 2 type suppressor cells Injection site reactions, chest pain, flushing, dyspnea, palpitations No laboratory monitoring is necessary Only one with pregnancy category B Originally suggested for highly active RRMS and possibly early progression 50% reduction in relapse rate Cardiotoxicity, less common with newer regimes Potential risk of leukemia particularly Promyelocytic leukemia 10

11 Integrin α4 blockade Stops circulating lymphocytes entering the CNS Well tolerated monthly infusions Effective relapse suppression (68% vs. placebo) Risk of PML can be assessed with JC virus testing Risk of PML appears to increase with time on treatment: Very low in first year Increases after 2 or more years Risk of rebound disease activity when stopped Humanized mouse antibody ( zumab) Binds to α4 integrins Selewski et al. (2010). American Journal of Neuroradiology, 31,

12 Anti natalizumab antibodies (5%) Hypersensitivity reaction (4%) Progressive Multifocal Leukoencephalopathy (0.1%) JC (John Cunningham) Virus associated loss of oligodendrocytes fatal Horga & Tintore (2011). Neurologia, 26(6), Sphingosine 1 phosphate receptor modulator Induces rapid and reversible sequestration of lymphocytes in lymph nodes Prevents activated and auto reactive cells from migrating to target organs Lymphocytes remain functional and may still be activated as part of an immune response Crosses blood brain barrier and may have neuroprotective properties Brinkmann V, et al. J Biol Chem. 2002;277: ; Pinschewer DD, et al. J Immunol. 2000;164: ; Chiba K, et al. J Immunol. 1998;160:

13 Daily oral tablet, first dose given in hospital due to potential for bradycardia and AV block Relapse reduction 55% Potential for macular edema Ophthalmic monitoring Hypertension possible Leflunomide parent compound used in treatment of rheumatoid arthritis Inhibits pyrimidine synthesis Binds dihydroorotate dehydrogenase, the fourth enzyme in de novo pyrimidine synthesis F F OH O F Inhibits T cell division Zeyda M, et al. Arthritis Rheum. 2005;52: H 3 C N N H 13

14 Fumarate Fumarate is a naturally occurring molecule that is essential for cellular oxidative respiration (Citric Acid Cycle) Dimethyl fumarate was formulated into enteric-coated oral microtablets contained in a capsule Dimethyl Fumarate Dimethyl Fumarate (DMF) DMF is rapidly converted to MMF after absorption Monomethyl Fumarate (MMF) Activated macrophages and microglia produce excess reactive oxygen and nitrogen species (ROS, RNS) Endogenous ROS detoxified by homeostatic mechanisms ROS & RNS permeate into neurons, cause mitochondrial dysfunction, DNA, protein and lipid damage, causing significant cellular stress Adopted from Craner and Fugger Nat Med 17:

15 DMF or MMF Nrf2 Keap1 Nrf2 Nrf2 Proteasome Nrf2 Nrf2 Cytoplasm ARE Nucleus Phase 2 Antioxidant Response Target Gene Function Direct antioxidants Free radical metabolism Normalization of energy metabolism Inhibition of inflammation Repair/degradation of damaged proteins and DNA ARE=antioxidant response element; Keap1=kelch-like ECH-associated protein 1; Nrf2=Nuclear factor (erythroid-derived 2)-like 2 CONFIRM 1 (Change vs placebo at 2 yrs) BG-12 BID n=359 44% ARR* P< Proportion of 34% patients relapsed P<0.003 Disability Progression (12 wk) 21% P=NS BG-12 TID n=345 51% P< % P< % P=NS GA n=350 29% P< % P<0.01 7% P=NS Adverse events seen in CONFIRM were similar to those seen in DEFINE. The most common AEs in the BG 12 groups were flushing and GI events. New enlarging T2- hyperintense 71% P< % P< % P< New T1-hypointense 57% P< % P< % P<

16 Recombinant humanized mab 1,2 Targets CD52 antigen 1,2 Causes rapid and prolonged immune cell depletion, particularly for T cells 1,3 Established treatment for B-cell chronic lymphocytic leukemia 4 Black box warnings exist around hematologic toxicity, infusion reactions and opportunistic infection Anti-infective prophylaxis recommended Recommended maximum dose of 90 mg/week to avoid risk of pancytopenia Pregnancy category C mab=monoclonal antibody; CDR=complementarity-determining region; Ig=immunoglobulin. 1. Xia MQ et al. Biochem J. 1993;293: ; 2. Coles AJ et al. Ann Neurol. 1999;46: ; 3. Klotz L et al. Clin Immunol Apr [Epub ahead of print]; 4. Alemtuzumab [prescribing information]. Cambridge, MA: Genzyme; Natural killer (NK) cell Hematopoietic stem cell Lymphoid progenitor cell X X X T lymphocytes B lymphocyte Neutrophil Basophil X X X Eosinophil Monocyte/Macrophage/DC Multipotential stem cell Myeloid progenitor cell Platelets Red blood cells 1. Accessed December 23, 2011; 2. Domagala and Kurpisz. Med Sci Monit. 2001;7:

17 4/27/2015 Daclizumab (Zinbryta): Anti CD 25 Currently used in transplants Selective antagonism of activated T cell responses Expansion of immunoregulatory CD56bright NK cells which have been shown to selectively decrease the number of activated T cells Reduction in lymphoid tissue inducer cells which are associated with cortical inflammation and demyelination 17

18 Ofatumumab (Arzerra): Currently used for CLL Depletes B cells via antibody dependent cellmediated toxicity and complement dependent cytotoxicity Antibody is directed against the small 7 mer loop of CD20 and binds in close proximity to the plasma membrane Plans for a Phase III trial for testing the subcutaneous formulation in RRMS, beginning in 2015, have been announced by Genmab after a decision was made by its partner GlaxoSmithKline. Ocrelizumab: Humanized anti CD20 monoclonal antibody Targets mature B lymphocytes and hence is an immunosuppressive drug Demonstrated a statistically significant reduction in disease activity as measured by brain lesions (measured by MRI scans) and relapse rate compared to placebo 18

19 4/27/2015 Firategrast: Anti α4β integrin small molecule Similar mechanism of action to natalizumab (α4 integrin blocker), but its faster elimination could improve safety profile Ibudilast: Selective PDE4 inhibitor Trials ongoing in both primary and secondary progressive MS BIIB033: Human aglycosyl IgG1 monoclonal antibody LINGO 1 (leucine rich repeat and immunoglobulin like domain containing, Nogo receptor interacting protein) 19

20 There is currently insufficient class I evidence for a detailed MS treatment algorithm The lack of definitive clinical evidence to guide MS treatment decisions has become increasingly important as the number of therapeutic options continues to increase annually Payers struggle with which drug is right for which patient Payers must balance cost, outcomes and access 20

21 4/27/2015 Importance of Various Types of Information on Formulary Evaluation Most Important Least Important Number of ratings of very important ; max=46 Xcenda Managed Care Network Survey (n=46), 2010 Clinical Practice Guidelines1 Recommendations informed by a systematic review of evidence Developed by a panel of experts and representatives from key groups Provide ratings of the quality and strength of the recommendations Treatment Algorithms2 vs Schematic models commonly developed based on information in a clinical guideline and used to aid in clinical diagnosis Permit the modeling and testing required to explore the impact of changing various assumptions (eg, outcomes and costs) 1. National Research Council. "1 Introduction." Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press, Margolis CZ. Methodology Matters VII Clinical Practice Guidelines: Methodological Considerations. International Journal for Quality in Health Care. 1997;9(4);

22 Cost Effectiveness Evidence based Medicine (EBM) A type of economic evaluation used to determine the best use of resources by comparing different kinds of interventions with similar, but not Comparative identical, effects on the basis of the Effectiveness cost per unit achieved Research (CER) Cost effectiveness analysis is increasingly being used as a tool to address issues of efficiency and resource allocation as it compares relative costs and gains of various Health health Technology interventions Assessment (HTA) VS Comparative Effectiveness Research (CER) CER includes both evidence generation and evidence synthesis It is concerned with the comparative assessment of interventions in routine practice settings The outputs of CER activities are useful for clinical guideline development, evidence based medicine, and the broader social and economic assessment of health technologies (i.e., HTA) Hutubessy, R. Chisholm, D. et al. Generalized cost effectiveness analysis for national level priority setting in the health sector Abstract of Focus: New versus Old: Long Term Comparative Effectiveness Research Projections for Disease Modifying Therapies in Relapse Remitting Multiple Sclerosis Campbell et al Objectives To estimate the long term comparative effectiveness research (CER) of first line treatment with glatiramer acetate (GA), fingolimod, or natalizumab, for relapse remitting multiple sclerosis (RRMS). Methods Simulation model to estimate the average 20 year comparative effectiveness of GA, fingolimod, and natalizumab for a cohort of 30 year olds with RRMS Outputs were DMT specific longterm harm (PML risk) and benefits (average relapse rate and time to disability (EDSS 7)) and qualityadjusted life years (QALYs) Courtesy of Campbell et al, University of Colorado, AAN 2012 Abstract. GN US 0164a For Internal Use Only; Do not modify, copy, or 22

23 Simulation model of 30 year olds with RRMS over 20 year period Measure (average per person) Natalizumab Fingolimod Glatiramer acetate Relapse Time (years) to Disability (EDSS 7) QALY Compared to GA, fingolimod resulted in 2.9 fewer relapses, 0.5 more years of disability free time, and an incremental 0.7 QALYs Compared to GA, natalizumab resulted in 4.6 fewer relapses, 0.6 more years of disability free time, more cases of PML per treated patient, and an incremental 1.0 QALYs gained CER models like this can be used to compare all DMTs to provide projections about long term harms and benefits. QALY Quality Adjusted Life Years, 1 QALY = I year of perfect health, composite measure that includes benefits and harms Courtesy of Campbell et al, University of Colorado, AAN 2012 Abstract. 2 rounds of web based questionnaires First round largely open ended Second round largely closed ended Live consensus meeting 14 panel members (including the chair) who are experts in managed care were involved in all 3 phases of the Delphi process 8 pharmacy directors and 6 medical directors from 12 US health plans,1 specialty pharmacy, and 1 consulting company All were presently or previously involved in the formulary decision making process at their organization Consensus was defined as a mean response of at least 3.3 or 100% of responses either agree or strongly agree A 4 item Likert scale (1 = strongly disagree, 2 = disagree, 3 = agree, 4 = strongly agree) was utilized Miller et al, JMCP 2012;18(1):

24 DMT therapy initiation for patients with CIS is a provider decision, but patients with CDMS should be treated with a DMT Patients with MS should have preferred access to platform therapies Access to natalizumab should be limited to use for the FDA approved indication Access to fingolimod should be managed by payers until additional safety information is available Payers identify the need for patient compliance and support while on DMTs Miller et al, JMCP 2012;18(1): More effective, with limited burden More effective, but increased burden Efficacy Less effective, but limited burden Less effective, with increased burden Burden of Therapy Factors affecting burden of therapy include convenience, monitoring, tolerability, and safety. MS=multiple sclerosis. 24

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