Page 1. Multiple Sclerosis. I have no conflicts of interest. Team Menstrual Cycles Waves to Wine for MS. Overview.

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1 Multiple Sclerosis New Developments Jeffrey A. Tice, MD Professor of Medicine Division of General Internal Medicine University of California, San Francisco I have no conflicts of interest Team Menstrual Cycles Waves to Wine for MS Overview Background: Cost and Epidemiology Diagnosis Relapses Pregnancy Disease modifying therapy Relapsing MS Primary Progressive MS Page 1

2 Therapy for MS In 1996, the FDA approved 2 drugs for MS that cost about $8500 per year. How much is their annual cost now with 15 drugs approved and generic versions available? A: $4,000 B: $8,500 C: $20,000 D: $45,000 E: $60,000 National Multiple Sclerosis Society, 2016* Multiple sclerosis (MS) medications have transformed the treatment of relapsing MS over the last 20 years. Yet, many people living with MS cannot access the medications they need. Continually escalating prices are creating significant barriers to treatment, including higher costs, increased stress, and a greater burden for those who already live with a chronic, life-altering condition. People with MS report high and rapidly escalating medication prices, increasing out-of-pocket costs, confusing and inconsistent formularies, and complex approval processes that stand in the way of getting the treatments they need. It is time for change. * Topic in Context: DMTs and Cost $28 billion annually in US Interferon β-1a (Avonex) and GA (Copaxone) 1996: $8,500 per year 2013: $61,000 per year 35% annual increase in price Natalizumab 2004: $26,000 per year 2013: $64,000 per year 16% annual increase in price Source: Examination of Health Care Cost Trends and Cost Drivers Pursuant to G.L. c. 12C, Hartung et al, Neurology, 2015 Page 2

3 Background: Multiple Sclerosis (MS) Chronic, immune-mediated disease of CNS 400,000 Americans affected Diagnosis in 20 s and 30 s Progressive disability in prime years of productivity Women:men ~3:1 African Americans more rapid disease Relapsing-remitting MS ~ 85-90% at diagnosis Primary progressive MS ~10-15% at diagnosis No FDA approved medications Epidemiology Geographic variation Life expectancy essentially normal Total lifetime cost > $2,200,000 MS Signs and Symptoms Natural History of Multiple Sclerosis Fatigue Heat intolerance Visual symptoms Numbness, tingling, loss of sensation Weakness Imbalance Urinary and sexual dysfunction Cognitive deficits Relapses and impairment MRI activity (T2, T1+Gd) Axonal loss Measures of brain volume Preclinical Relapsing-remitting Secondary progressive Page 3

4 Natural History of RRMS and PPMS 15% PPMS 85% RRMS 5 years years 50% need a cane 50% SPMS and 50% need a cane 22 years from onset 50% bed bound 26 years from onset 90% SPMS 30 years from onset 83% need cane ~ 34% bed bound MS in Context: Patient Perspective Primary goal is to remain independent, balanced by risk for adverse events Some have strong preference for oral agents; others equally comfortable with injectable medications Their provider should be allowed to choose the best medication based on their individual disease history and personal characteristics without restriction Economic burdens are underappreciated: lost wages from missed work, transition to part-time work, high out of pocket costs of medications and medical equipment Weinshenker, 1989 MS Coalition Survey: Patients Perspective Decision-making Factor Important / Very Important Delay disability 94% Prevent relapse / MRI lesions 94% Continue working / usual 90% activities Doctor recommends therapy 86% Health plan restrictions 69% Risk of PML 68% Out of pocket costs 66% Dosing frequency 58% Monitoring / blood tests 44% CASE 1 30 yo Science Teacher Online Questionnaire: N=15,793 Page 4

5 CASE 1: 30 yo F science teacher 1year ago, 3 week history of urinary urgency & frequency, one episode of fecal incontinence and bilateral foot numbness with frequent tripping 6 months ago, 2 week history of clumsy gait and poor balance, tremors of the right hand 1 month history of blurry vision with right gaze only CASE 1 EXAM Hyper-reflexia of the bilateral legs Bilateral upgoing toes (+ Babinski) Absent vibration, poor proprioception in feet Mildly dysmetric finger-nose-finger and ataxic fine finger movements R>L + Romberg Ataxic gait CASE 1 Does she have MS? How do we diagnose MS? MS Diagnosis Dissemination in space and time Page 5

6 Diagnostic Criteria Summarized Diagnostic Criteria Dawson criteria: 1916 Schumacher criteria: 1965 Poser criteria: 1983 McDonald criteria: 2001 Revised McDonald criteria: 2005; 2010 All criteria require dissemination in time and space 1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS 2. Dissemination in Time: Onset of neurological deficits separated by at least one month 3. Rule out other explanations! August November New Diagnostic Criteria DIAGNOSTIC WORK UP Incorporate use of MRI Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time = Earlier MS Diagnosis DIS DIT August November History & Physical Exam Brain and Spinal Cord MRI Labs: rule out mimics of MS Connective tissue diseases, infections, metabolic disorders Cerebrospinal Fluid (when clinical and MRI evidence inconclusive) Evoked Potentials: Identify damage to visual, auditory, & touch perception systems Less sensitive than MRI or cerebrospinal fluid Page 6

7 Differential Diagnosis CASE 1: New RRMS Metabolic: SCD (B12 def), Adrenomyeloneuropathy Connective Tissue Diseases: Sjogren s, SLE Infectious: HIV, HTLV1, Lyme disease, Syphillis Structural: Chiari malformation, spinal cord compression Genetic: ataxias, paraplegias, mitochondrial Neoplastic: CNS lyphoma, paraneoplastic Other: Neurosarcoidosis, CNS vasculitis Psychiatric > 2 historical events with objective findings on examination MRI consistent with MS Normal rule out labs CXR normal CASE 2 CASE 2 26yo IRS agent 26 yo LH WF with RRMS diagnosed 2 yrs ago 3 day history of difficulty writing, clumsy and numb left hand No signs/symptoms of infection No prior history of similar symptoms Page 7

8 CASE 2: Acute relapse Strength 4/5 interosseus muscles of left hand Hyper reflexia of left arm Ataxic & dysmetric FNF on left Decreased LT on left face, arm, leg Expanded Disability Status Scale CASE 2 EDSS=0 last 3 visits Expanded Disability Status Scale Current EDSS=3 Acute MS Relapse CASE 2 HOW TO IDENTIFY A RELAPSE? CRITICAL: compare with previous examinations (history and examination), when ever possible Relapses can be precipitated by infections and fever Check U/A for occult UTI Page 8

9 TREATMENT OF RELAPSE INPATIENT Severe deficits Risk of fall or other injury Poor social support TREATMENT OF RELAPSE: IV Solumedrol one gram daily for 5 days Severe cases: up to 2 grams qd x 7d Plasmapheresis when not responding OUTPATIENT All other relapses CASE 3: SPMS CASE 3 45 yo Automotive Executive 45yo RH M with 13 yr history of MS DMT with Glatiramer Acetate Last MS relapse 7 years ago Ambulation: Cane 4 years ago Walker 3 years ago Wheelchair 1 year ago Page 9

10 Predictors of more rapid progression Treating SPMS Frequent relapses in first 5 years Spinal cord involvement Volume and number of T2-weighted lesions on MRI African ancestry No treatment has been shown to be helpful UNLESS the patient still has superimposed relapses What is the natural history of MS during pregnancy? A. It gets better B. It stays the same C. It gets worse D. We don t know CASE 4 36 yo Physician Page 10

11 CASE 4 36yo WF with 4yr history of RRMS Betaseron for past 3.5 years Last MS relapse 1 year ago EDSS 2, unchanged for past year Wants to become pregnant Pre-pregnancy Counseling No differences in Prenatal Care MS has no known effect on fertility High Risk should be determined on obstetrical status and disease activity Little evidence to support increased risk of relapse with anesthesia administration Closely monitor for urinary tract infections MS not worsened by pregnancy Pregnancy not worsened by MS Pre-pregnancy Counseling Lifetime Risk of MS (%) General population F 0.5 ; M 0.3 Child of MS patient 3-5 Sibling of MS patient 3 Monozygotic twin of MS patient Only 10-15% of MS is familial Pregnancy and Relapse Rate 1.4 Pregnancy P1 P2 P Trimesters Pre-Pregnancy Post Partum PRIMS, n=254 Annualized Relapse Rate Page 11

12 Planned Pregnancy Pre-Pregnancy Planning Discontinue DMT 1-2 menstrual cycles before planned conception Brain MRI Scan Unplanned Pregnancy First Trimester: Discontinue DMT Second Trimester: Review safety data Post-Partum Management Post-Partum DMT Resume soon after delivery or after breastfeeding Breastfeeding Not contraindicated But DMT pass into breast-milk May decrease relapse rate Best Shaved Ice: Kailua Kona DMTs for MS Drug Route Mechanism Year approved Interferons, SC Immune modulation GA Natalizumab IV Anti-integrin α4β1/ α4β7 mab 2004 Fingolimod PO Sphingosine 1 receptor modulator 2010 Teriflunomide PO Pyrimidine synthesis inhibitor 2012 Dimethyl PO Multifactorial 2013 fumarate Alemtuzumab IV Anti-CD52 mab 2014 PegInterferon SC Immune modulation 2014 Daclizumab IV Anti-CD25 mab 2016 Ocrelizumab IV Anti-CD20 mab 2017 Rituximab IV Anti-CD20 mab? Page 12

13 Key Outcomes MS Relapses Confirmed disability progression (CDP) Change in Expanded Disability Status Score (EDSS) MRI findings Patient-reported outcomes Fatigue Mood disorders / depression Quality of life (QOL) Function Network Meta-Analysis (NMA) for RRMS Network Diagram for Relapse Rates Results: Annualized Relapse Rate Page 13

14 Results: Annualized Relapse Rate Results: Annualized Relapse Rate Results: Annualized Relapse Rate NMA for Confirmed Disability Progression Page 14

15 Disability Progression Harms of the DMTs The most effective DMTs have highest risk of lifethreatening adverse events Natalizumab PML incidence: 11/1000 for JC virus + Alemtuzumab Autoimmune disease: up to 50% at 6 years Black Box Warnings: natalizumab, alemtuzumab, dimethyl fumarate, daclizumab, rituximab, teriflunomide REMS: natalizumab, alemtuzumab, daclizumab Ocrelizumab: unknown as just FDA approved Limitations of the Evidence Figure: Safety and Effectiveness of DMTs Trials too short: minimum of 5 years recommended to evaluate disability progression Preferred outcome (CDP confirmed at 24 weeks) not always reported MRI technology evolving: no standard measure used across trials Patient reported outcomes insufficient No standard measure Not consistently measured / reported Goal: NEDA No evidence of disease activity Page 15

16 Placebo-controlled Trials in PPMS PPMS OLYMPUS: Rituximab. Good-quality study Significant reduction in T2 lesion volume (primary endpoint) No significant reduction in disability progression ORATORIO: Ocrelizumab. Good-quality study. Significant reduction in disability progression HR 0.75, 95% CI Also significant reductions in T2 lesion volume, brain volume loss, but not QOL (SF-36) Summary Questions? Diagnosis: new neurologic symptoms Separated in space and time Pregnancy No increased risk for pregnancy or MS Stop DMTs DMTs Expensive: $60,000 to $75,000 per year Trend towards early aggressive therapy Page 16

17 Drug Costs Real World Estimates We estimated net prices by comparing the four-quarter (i.e., 4Q15 3Q16) rolling averages of both net prices* and list (WAC) prices per unit to arrive at an average discount from WAC, by drug. Annual Net Acquisition Cost Discount Drug Name and Labeled Dose WAC Package Cost Applied to Subsequent Year 1 WAC years Interferon β-1a 30 mcg (Avonex) $6,287 / 4EA 20% $65,654 $65,654 Interferon β-1b 250 mcg (Betaseron) $6,648/ 14EA 35% $60,958 $56,328 Interferon β-1b 250 mcg (Extavia) $5,947 / 15EA 35% $50,899 $47,033 Glatiramer Acetate 20 mg (Copaxone) $7,114 / 30EA 15% $73,571 $73,571 Glatiramer Acetate 20 mg (Glatopa) $5,194 / 30EA 35% $41,075 $41,075 Interferon β-1a 22/44 mcg (Rebif) $6,629 / 0.5ml 12EA 15% $73,454 $73,454 Peginterferon β-1a 125 mcg (Plegridy) $6,287 / 1ml 10% $73,760 $73,760 Daclizumab 150 mg (Zinbryta) $6,833 / 1ml 5% $77,900 $77,900 Fingolimod 0.5 mg (Gilenya) $6743 / 30EA 10% $73,839 $73,839 Teriflunomide 7/14 mg (Aubagio) $5,877 / 28EA 10% $68,951 $68,951 Dimethyl Fumarate 240 mg (Tecfidera) $6,820 / 60EA 10% $74,679 $74,679 Natalizumab 20 mg (Tysabri) $6,000 / 15ml 5% $74,304 $74,304 5% *Source: $98,562 SSR Health, $59,137 LLC Alemtuzumab 12 mg (Lemtrada) $20,749 /1.2ml Page 17