Improving Patient Outcomes with Novel Treatment Strategies in the Management of Multiple Sclerosis. Gary M. Owens, MD April 27, 2017

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1 Improving Patient Outcomes with Novel Treatment Strategies in the Management of Multiple Sclerosis Gary M. Owens, MD April 27, Discussion Outline Brief MS background and disease state review Diagnosing MS earlier diagnosis and impact on outcomes MS pathophysiology may determine future selection of MS treatments MS therapeutic options are expanding, creating a need for changing management strategies Categorizing MS treatments in 2017 Payer management strategies for MS What is on the MS treatment horizon management of the class will continue to change Summary and questions 2 1

2 MS Overview and Epidemiology 3 MS Prevalence MS Prevalence: >400,000 cases in United States 1 and 2.3 million worldwide 8,500 to 10,000 new cases annually Most cases occur between ages 15 and 45 Women outnumber men 3:1 85% present with relapsing-remitting MS (RRMS) Without treatment, 50% of these patients develop secondaryprogressive MS (SPMS), with significant disability within 10 years 1. Prayson R. Neuropathology Review. 2nd ed. Totawa, NJ: Humana Press; (map) map of multiple scleros 1329/ 4 2

3 Basic Pathology Neurodegenerative disorder of CNS Presumed to be autoimmune-and we are learning more all of the time 5 MS Subtypes 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 Diagnosing MS 8 4

5 Diagnosing MS McDonald Criteria first released in 2001, last revision Typical MRI Changes 10 5

6 Diagnosing MS Other diagnostic tools include: o CSF analysis for oligoclonal bands o Evoked potentials o Anti-myelin antibodies [oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)] not shown to be useful Consider other diagnoses if there is: o Family history of neurologic disease other than MS o A well demarcated spinal level in the absence of disease above the foramen magnum o Prominent back pain that persists o Symptoms and signs that can be attributed to one anatomical site o Patients who are over 60 years of age or less than 15 years at the onset of disease o Rapidly progressive disease o Symptoms of systemic disease such as weight loss, fever, etc. 11 Clinically Isolated Syndrome Clinically Isolated Syndrome (CIS) most often presents with: o Long tract symptoms/signs, o Optic neuritis, o Brainstem, cerebellar, or spinal cord syndrome, While CIS is by definition isolated to a single attack in time, it is not necessarily isolated in space o Approximately one-quarter of patients present with multifocal abnormalities. Radiologically Isolated Syndrome (RIS): o Characterized by incidental brain MRI findings highly suggestive of multiple sclerosis in the absence of signs or symptoms of the disease 12 6

7 MS Pathophysiology Our understanding of the pathophysiology is changing and is essential to future management by payers 13 Immune Cells in MS Drugs (2014) 74:

8 Immune Cells In MS T cells are stimulated to proliferate when they encounter antigen-presenting cells in the lymph node. Circulating T cells and B cells can traffic from the circulation across the blood brain barrier. T cells encounter CNS antigens presented by dendritic cells. Macrophages and activated T cells can attack components of the CNS and activate other cell types, including B cells. B cells mature into antibody-producing plasma cells. Drugs (2014) 74: T-Cell Role in MS 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. 16 8

9 T-Cell Action on the CNS 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 17 B-Cell Role in MS Source: Medscape; Ther Adv Neurol Disorders. 2013;6(3):

10 4/14/2017 B-Cell Role in MS 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): MS Treatment Landscape is Changing 20 10

11 Avonex Betaseron Copaxone MS Drug Timeline: Not to Scale! Tysabri Extavia Gilenya Aubagio Tecfidera Plegridy Lemtrada Ocrevus Zinbryta Rebif Novantrone First Generation Therapies Second Generation Therapies 21 MS Drug Pipeline: All dates and approvals speculative! Firategrast Ofatumumab Opicinumab Ameselimod Ozainmod Ibudilast Siponimod Potential New Therapies 22 11

12 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 23 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 24 12

13 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 25 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 26 13

14 Natalizumab Integrin α4 blockade 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 Stops circulating lymphocytes entering the CNS Selewski et al. (2010). American Journal of Neuroradiology, 31, 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:

15 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 29 Teriflunomide 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 30 15

16 Dimethyl Fumarate 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 enteric-coated oral microtablets contained in a capsule The compound (and its metabolite, monomethyl fumarate) activates the nuclear (Nrf2) pathway and has been identified as a nicotinic acid receptor agonist in vitro. Precise MOA is unknown Monomethyl Fumarate (MMF) 31 Recombinant humanized mab 1,2 Targets CD52 antigen 1,2 Alemtuzumab 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 o 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;

17 Hematopoietic stem cell Immune Cell Populations Depleted by Alemtuzumab Natural killer (NK) 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: Daclizumab First approved for prevention of renal allograft rejection by FDA (1997) Humanized MAb vs. CD25 Mouse (~10%) Human (~90%) Biological activity Binds to IL-2R α-chain, blocking IL-2 binding and signaling Inhibits T-cell and B-cell activation by IL-2 Expansion of CD56bright regulatory NK cells Approved to treat relapsing forms of MS in 2016 Waldmann. JCI 27:1, 200, 34 17

18 Ocrelizumab o FDA approved March 28, 2017 o Humanized anti- CD20 monoclonal antibody o Approved for both PPMS and RRMS o Targets mature B lymphocytes Roche pharma day 2015.html 35 Ocrelizumab Roche pharma day 2015.html 36 18

19 Payer Management of MS Therapy 37 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 (now at 14!) Payers struggle with which drug is right for which patient Payers must balance cost, outcomes and access 38 19

20 One Approach by Payers From 2012 Useful, but now dated! 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) as 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):

21 Categorizing MS Drugs Current Method Platform Therapies (ABCR) Oral Agents Infusion Agents Proposed Method Immunomodulators Inhibitors of cell replication Cell depletion agents Altered cell trafficking 41 Ensure Access to All Categories for Appropriate Patients Drug Category Agent(s) Comments Immunomodulators Interferon beta, glatiramer acetate, dimethyl fumarate, daclizumab All generally considered first line except daclizumab Inhibitors of Cell Replication mitoxantrone, teriflunomide Mitoxantrone rarely used in 2017 Cell depletion agents Altered Cell Trafficking alemtuzumab, ocrelizumab natalizumab, fingolimod Act on T and B cell lines More agents in the pipeline More agents in the pipeline 42 21

22 General Principles for MS Management There are still no approved guidelines that can be used (unlike areas like NCCN for cancer) o Therefore plans must conduct their own assessments of literature and data o Consider the newer agents and their roles in therapy o Work with physicians to assess the role(s) of newer therapeutic agents Consider establishing quality metrics to improve outcomes Use patient education and support programs Actively manage medication adherence 43 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:

23 Site of Service Management A retrospective analysis on the impact of site of care on utilization adherence and cost in 4 geographic areas. o HOPD administration was more expensive than physician office administration o HOPD administration accounted for 40% of claims but 50% of cost o Home infusion accounted for 10% of claims and 8% of cost o Physician office accounted for 50% of claims and 43% of cost o Virtually no differences in the 4 regions. Conclusion: Managing site of service of this infused agent can have substantial cost impact. *Lord, Hassan and Lopes: Poster presentation at AMCP, April 2015, San Diego, CA 45 Adherence to Therapy Retrospective analysis of 2,407 natalizumab patients retrospectively assessed 4 patterns emerged: o Persistent and remained persistent (PP) o Non-persistent, but became persistent (NP) o Persistent, but became non-persistent (PN) o Non-persistent and remained non-persistent (NN) Findings: Category Relapse Rate I Yr Relapse Cost PP.28/yr $1289 NP.47/yr $2062 PN.45/yr* $2645* NN.67/yr* $3816* McQueen et al; JMCP; 2015; 21 (3 * Statistically significant compared to PP group 46 23

24 Evolving Treatment Strategies May Impact Payer Management Borrowing from ACR: Treat to target Shared, explicit goal of therapy: To maximize long term outcomes such as neurologic function and healthrelated quality of life through effective prevention of MSrelated CNS tissue damage. Selection and/or adjustment of therapy based on ongoing measurement of disease activity and severity. Suggests need for formal treatment algorithms something payers have wanted for a long time! 47 No Evidence of Disease Activity (NEDA) Complete absence of detectable disease activity while on a disease therapy Criteria: o No MRI lesion activity (Gd-enhancing lesions, new/enlarged T2 lesions) o No clinical relapses o No disability worsening Increasingly reported in clinical trials and beginning to be used at MS centers 48 24

25 4/14/2017 Selected MS Pipeline Agents 49 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 Phase III trial for underway for the subcutaneous formulation in RRMS

26 4/14/2017 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 Opicinumab: o Human aglycosyl IgG1 monoclonal antibody o LINGO-1 (leucine-rich repeat and immunoglobulin-like domain containing, Nogo receptor interacting protein) 51 Questions? 52 26