Presentation Overview

Transcription

1 Best Practices in the Treatment and Management of Multiple Sclerosis The Payer s Perspective Gary M. Owens, MD NAMCP April 22, Presentation Overview MS background and disease state review Diagnosing and managing MS MS therapeutic options Safety and Efficacy o A review of first generation therapy (ABCR drugs) o A review of newer MS therapy options o Targeting T and B cells Where are we on prognostic indicators and biomarkers? Promoting adherence and compliance with MS therapies MS therapies on the horizon 2 1

2 4/8/2016 MS Disease State Review 3 0.1% 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 Multiple Sclerosis Overview Neurodegenerative disorder of CNS Presumed to be autoimmune Women = 1/200; Men = 1/400 5 Overview of MS Subtypes 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 Natural History of RRMS Clinical and MRI Measures Relapses/Disability MRI Activity MRI T2 Burden of Disease Axonal Loss Secondary Progressive MS Disability Preclinical * Relapsing Remitting MS CIS Trapp BD, et al. Neuroscientist. 1999;5:48 57, Time 7 MRI Changes T1 & hypo intensity T2 & hyper intensity 8 4

5 MS Pathophysiology We are learning more about the cellular mechanisms of the disease 9 T Cell Pathophysiology Blood-brain barrier breakdown The BBB prevents 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. 10 5

6 Inflammatory Phase of MS: T cells Cross the BBB 11 T Cell Pathophysiology Auto- Immunology and Inflammation The immune system attacks the nervous system, forming plaques or lesions. Destroys oligodendrocytes- causing demyelination Re-myelination occurs in early phase but not completely. T-cells attacks on myelin triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. 12 6

7 B Cells in MS Source: Medscape; Ther Adv Neurol Disorders. 2013;6(3): B Cell Pathophysiology 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 B cells may contribute to the development and progression of CNS autoimmune disease as APCs for activation of T cells Source: Medscape; Ther Adv Neurol Disorders. 2013;6(3):

8 4/8/2016 MS Treatment Landscape is Changing 15 MS Drug Treatment Timeline: Not to Scale! Tecfidera Avonex Lemtrada Aubagio Tysabri Betaseron Plegridy Extavia Gilenya Copaxone Rebif Novantrone First Generation Therapies Next Generation Therapies 16 8

9 First Generation MS Agents The ABCR Drugs Interferon beta-1a (Avonex, Rebif) Interferon beta-1b (Betaseron Extavia) Glatiramer acetate (Copaxone) All have years of patient experience for MS and still have a large number of users and new starts 17 Interferon Beta 1b & 1a Beta Interferon was the first class of medications approved by the US FDA for MS Administered by self injection Injection site necrosis and flulike symptoms are potentially limiting adverse events Neutralizing antibodies may reduce the bioavailability of interferon IFN-β diminishes the ability of activated T cells to cross the blood-brain barrier and enter the central nervous system parenchyma Source: beta and multiple sclerosis 18 9

10 Glatiramer Acetate 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 may be adverse events No laboratory monitoring is necessary Only agent with pregnancy category B 19 Mitoxantrone 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 Minimal current use in MS 20 10

11 Natalizumab Given by monthly infusion 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 Integrin α4 blockade Stops circulating lymphocytes entering the CNS 21 MOA of Natalizumab : Humanized mouse antibody (-zumab) Binds to α4 integrins Selewski et al. (2010). American Journal of Neuroradiology, 31,

12 Fingolimod Sphingosine-1-phosphate receptor modulator Induces rapid and reversible sequestration of lymphocytes in lymph nodes o 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: Fingolimod 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 24 12

13 Teriflunomide: Aubagio Leflunomide parent compound used in treatment of rheumatoid arthritis Inhibits pyrimidine synthesis o Binds dihydroorotate dehydrogenase, the fourth enzyme in de- novo pyrimidine synthesis Inhibits T-cell division OH O F F F H 3 C N H Zeyda M, et al. Arthritis Rheum. 2005;52: N 25 Dimethyl Fumarate: Tecfidera Dimethyl Fumarate Fumarate Dimethyl Fumarate (DMF) Fumarate is a naturally occurring molecule that is essential for cellular oxidative respiration (Citric Acid Cycle) Dimethyl fumarate was formulated into entericcoated oral microtablets contained in a capsule DMF is rapidly converted to MMF after absorption Monomethyl Fumarate (MMF) 26 13

14 Proposed MOA Dimethyl Fumarate DMF or MMF Nrf2 Keap1 Nrf2 Nrf2 Proteasome Nrf2 Nrf2 Cytoplasm 27 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 27 Alemtuzumab: 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 o Anti-infective prophylaxis recommended o 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;

15 4/8/2016 Immune Cell Populations Depleted by Alemtuzumab Natural killer (NK) cell Hematopoietic stem cell X X Lymphoid progenitor cell Neutrophil T lymphocytes X Basophil XX X Eosinophil B lymphocyte 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: Biomarkers and MS 30 15

16 Biomarkers: A Work in Progress Establishing satisfactory biomarkers for multiple sclerosis has been proven to be very difficult, due to the clinical and pathophysiological complexities of the disease Potential new biomarkers are divided into three subgroups, genetic-immunogenetic, laboratorial, and imaging. The ultimate goal would be better predictors for: o Prognosis o Drug selection o Disability progression o Adverse event prediction 31 Biomarkers: Potential Classes of potential biomarkers (examples) o Chemokine and cytokine measurements o Adhesion molecules o Genetic markers o Vitamin D o T and B-cell characteristic markers o NKS Markers o Markers of blood-brain barrier disruption o Myelin basic proteins o Many more... Katsavos, Biomarkers in MS-An up-to-date Overview

17 4/8/2016 Payer Management of MS Therapy 33 An MS Treatment Algorithm? 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 34 17

18 One Approach by Payers 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-type scale (1 = strongly disagree, 2 = disagree, 3 = agree, 4 = strongly agree) was utilized Miller et al, JMCP 2012;18(1): Payer Delphi Panel Recommendations 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 FDAapproved 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):

19 Adherence to Therapy is Important Payers make a large lifetime investment in MS treatments. Adherence to therapy in MS (like all chronic diseases) can be an issue. Why do MS patients stop their medications:* o I m not feeling any better o The side effects make me feel worse than the disease o I have taken my medication but I had an exacerbation anyway o Maybe something else would work better for me o My insurance stopped covering the medication I was taking o I can no longer afford the co-payments for my medication * National MS Society: 37 Adherence to Therapy Factors that can influence adherence to disease-modifying therapies (DMTs) include o Medication tolerability, o Patient physical and cognitive decline, o Frequency and complexity of the dosing regimen o Duration of disease and treatment, o Patient perceptions of medication benefits and risks, o Economic burden associated with medication. Interventions aimed at optimizing medication adherence by the patient with MS need to incorporate new and creative approaches that take individual patient needs and lifestyle into account. When considering a DMT, it is important to evaluate the safety and tolerability profile of the drug, the individual patient's needs and lifestyle, and how the specific requirements and characteristics of the drug intersect with the individual patient's profile. *Remington et al., Int J MS Care Spring; 15(1):

20 4/8/2016 Selected MS Pipeline Agents 39 MS Pipeline Daclizumab : Anti CD-25 o Currently used in transplants o Selective antagonism of activated T-cell responses o Expansion of immunoregulatory CD56bright NK cells which have been shown to selectively decrease the number of activated T-cells o Reduction in lymphoid tissue inducer cells which are associated with cortical inflammation and demyelination 40 20

21 MS Pipeline Ofatumumab: o Currently used for CLL o Depletes B cells via antibody-dependent cell-mediated toxicity and complement-dependent cytotoxicity o Antibody is directed against the small 7-mer loop of CD20 and binds in close proximity to the plasma membrane o 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. 41 MS Pipeline Ocrelizumab: o Humanized anti-cd20 monoclonal antibody o Targets mature B lymphocytes and hence is an immunosuppressive drug o Demonstrated a statistically significant reduction in disease activity as measured by brain lesions (measured by MRI scans) and relapse rate compared to placebo 42 21

22 4/8/2016 MS Pipeline Firategrast: o Anti-α4β-integrin small molecule o Similar mechanism of action to natalizumab (α4-integrin blocker), but its faster elimination could improve safety profile Ibudilast: o Selective PDE4 inhibitor o Trials ongoing in both primary and secondary progressive MS BIIB033: o Human aglycosyl IgG1 monoclonal antibody o LINGO-1 (leucine-rich repeat and immunoglobulin-like domain containing, Nogo receptor interacting protein) 43 Questions? 44 22