Multiple Sclerosis Update

Transcription

1 Multiple Sclerosis Update Amanda Stahnke, PharmD, BCACP University of Missouri-Kansas City School of Pharmacy Kansas City Veterans Affairs Honor Annex Kelsey Morris, PharmD University of Kansas Health-System Disclosure and Conflict of Interest Pharmacist and Technician Objectives Amanda Stahnke and Kelsey Morris declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings and honoraria. At the conclusion of this program, the pharmacist and technician will be able to: 1. Discuss the basic etiology, pathophysiology, and diagnosis of multiple sclerosis (MS) 2. Discuss recently approved disease modifying therapies (DMTs) 3. Identify potential candidates for newly approved DMTs 1

2 Pre-Test Questions 1. The Criteria is utilized in practice to determine the diagnosis of MS. a) Summer b) McDonald c) Sclerosis d) Farmer Pre-Test Questions 2. Which of the following therapies is contraindicated in pregnancy and requires completion of an elimination protocol if pregnancy occurs? a) Ocrelizumab b) Fingolimod c) Dimethyl fumarate d) Teriflunomide Pre-Test Questions 3. Which of the following disease modifying therapies (DMTs) carries a Black Box Warning for progressive multifocal leukoencephalopathy (PML)? Background a) Natalizumab b) Teriflunomide c) Glatiramer acetate d) Peginterferon 2

3 Etiology/Risk factors Pathophysiology Environmental Epstein-Barr Virus (EBV) Cytomegalovirus (CMV) Negative risk factor Geography Vitamin D deficiency Genetics Smoking REFERENCES: Pharmacotherapy, 9 th Ed. 2014; Porth s Pathophysiology, 9 th Ed. 2014; REFERENCES: J Rehabil Res Dev 2006;43(1): Pathophysiology Pathophysiology T-cells: Expression of alpha-4 integrin (adhesion molecule) Cytokine and nitric oxide production Matrix metalloproteinase production B-cells: Antigen presentation Autoantibody production Cytokine regulation Formation of ectopic lymphoid aggregates in the meninges REFERENCES: Pharmacotherapy, 9 th Ed. 2014; Rehabil Res Dev 2006;43(1): Neurodegener Dis Manag. 2016;6(1): N Engl J Med, 2017;376: REFERENCES: Nat Rev Clin Oncol. 2014;11: Nature Clinical Practice Neurology. 2008;4:

4 Diagnosis Diagnosis History Birthplace, Family history (FHx), Travel, Past medical history (PMH), Signs and symptoms- acute exacerbation Laboratory tests Neurological Exam Cognitive Exam MRI = magnetic resonance imaging Lumbar puncture Oligoclonal bands REFERENCES: Diagnosis 2010 McDonald Criteria Acute exacerbation history MRI history Additional data needed 2 exacerbations 2 lesions None 2 exacerbations 1 lesion DIS or wait for additional exacerbation 1 exacerbation 2 lesions DIT or wait for additional exacerbation 1 exacerbation 1 lesion DIS and DIT or wait for additional exacerbation Continuous progression of disease over 1 year 2 of the 3: 1. DIS (non-spinal cord lesions) 2. DIS (2 or more T2 lesions on spinal cord) 3. Oligoclonal bands and/or elevated IgG index present in CSF Classification Phenotypes: Clinically isolated syndrome (CIS) Radiographically isolated syndrome (RIS)* Relapsing remitting MS (RRMS) Secondary progressive MS (SPMS) Primary progressive MS (PPMS) Modifiers: Active or Not active Progressing or Not progressing MRI = magnetic resonance imaging, DIS = dissemination in space (1 or more T2 lesion in 2 of 4 regions of the CNS typical of MS (periventricular, juxtacortical, infratentorial, or spinal cord), DIT = dissemination in time (presence of gadolinium-enhancing and non-enhancing lesions simultaneously or new lesions on a repeat MRI (T2 or gadolinium-enhancing), CSF = cerebrospinal fluid REFERENCES: Ann Neurol. 2011;69(2): RRMS- Active PPMS- Not active, Progressing PPMS or SPMS - Active, Progressing REFERENCES: Neurology. 2014;83:1-9. 4

5 Expanded Disability Status Scale (EDSS) Disease Management 10.0 = Death due to MS = Completely dependent = Confined to bed/chair; self-care with help = Confined to wheelchair = Walking assistance is needed = Increasing limitation in ability to walk = Impairment is relatively severe = Impairment is mild to moderate = Impairment is minimal = No impairment 0 = Normal neurologic exam REFERENCES: Neurology. 1983;33: Acute exacerbation treatment Steroids Methylprednisolone mg/day IV or mg PO for 3-5 days Other therapy- IVIG, plasmaphoresis, ACTH (Acthar ) Disease modifying therapies Mainstay of management Symptom management Depression, fatigue, bowel/bladder dysfunction, gait abnormalities, IVIG = intravenous immunoglobulin, ACTH = Adrenocorticotropic hormone REFERENCES: Lancet. 2015;386: NICE nice.org.uk/guidance/cg186. Disease Management Goals Decrease attack/exacerbation rate Decrease annualized relapse rate (ARR) Slow progression of disease Disability, MRI findings, Cognition Prevent/limit ADRs Effectively manage symptoms Interferons o β-1a o β-1b o All require titration ARR = Annualized Relapse Rate Disease Modifying Therapies (DMTs) Therapy Maintenance Dosing ARR o Avonex 30mcg IM qweek o Rebif 22 or 44mcg subcut three times per week o Peginterferon (Plegridy ) 125mcg subcut q2weeks o Betaseron or Extavia 0.25mg subcut every other day Glatiramer acetate (Copaxone ) 20mg subcut daily [generic available (Glatopa )] 40mg subcut three times weekly 18% 33.2% 36% 34% 29% 34% Mitoxantrone (Novantrone ) 12mg/m 2 IV q3months 66% Natalizumab (Tysabri ) 300mg IV q4weeks 68% Fingolimod (Gilenya ) 0.5mg PO daily 48-54% Teriflunomide (Aubagio ) 7 or 14mg PO daily ~31% Dimethyl fumarate (Tecfidera ) 240mg PO BID, requires titration 44-49% Alemtuzumab (Lemtrada ) 12mg IV for 5 days, repeated in 1 year for 3 days 49-55% Daclizumab (Zinbryta ) Ocrelizumab (Ocrevus ) REFERENCES: Multiple Sclerosis Coalition

6 New Multiple Sclerosis Therapies Daclizumab Daclizumab (Zinbryta ) FDA approved: May 2016 Indication: Relapsing forms of multiple sclerosis SELECT MOA: humanized monoclonal antibody which binds to the CD25 subunit of the high-affinity interleukin-2 (IL-2) receptor Prevents signaling at the high-affinity IL-2 receptor Allows for increased IL-2 availability for signaling at the intermediate-affinity IL-2 receptor REFERENCES: Lancet. 2013;381:

7 SELECT: Treatment Groups and Study Design SELECT: Primary Endpoint daclizumab 150mg group: 54% reduction in ARR daclizumab 300mg group: 50% reduction in ARR REFERENCES: Lancet. 2013;381: REFERENCES: Lancet. 2013;381: SELECT: Secondary Endpoints More patients relapse free at 52 weeks Significantly fewer new Gd+-enhancing lesions at 52 weeks Gd+ = gadolinium REFERENCES: Lancet. 2013;381: SELECT: Adverse Events Placebo (N = 204) Daclizumab HYP 150mg (N = 208) Adverse events of interest Number of patients (%) Daclizumab HYP 300mg (N = 209) Infections 89 (44) 104 (50) 112 (54) Serious infections 0 6 (3) 3 (1) Cutaneous events 27 (13) 38 (18) 45 (22) Serious cutaneous events 0 2 (<1) 3 (<1) Death 0 1 (<1) 0 Incidence of ALT or AST abnormalities Number of patients (%) 1-3 x ULN 64 (31) 54 (26) 62 (30) 3-5 x ULN 6 (3) 7 (3) 6 (3) >5 x ULN 1 (<1) 9 (4) 8 (4) Injection-site reactionm erythema 3 (1) 4 (2) 4 (2) Malignancy 1 (<1) 1 (<1) 2 (<1) REFERENCES: Lancet. 2013;381:

8 DECIDE: Treatment Groups and Study Design DECIDE REFERENCES: N Engl J Med. 2015;373: DECIDE: Primary and Secondary Endpoints DECIDE: Adverse Events 45% reduction in ARR with daclizumab vs. INF beta-1a Daclizumab HYP (N = 919) Interferon Beta- 1a (N = 922) Event Number of patients (%) Infection Nasopharyngitis Upper respiratory tract infection Urinary tract infection Serious infection 595 (65) 226 (25) 149 (16) 96 (10) 40 (4) 523 (57) 197 (21) 124 (13) 98 (11) 15 (2) Cutaneous events 344 (37) 176 (19) REFERENCES: N Engl J Med. 2015;373: REFERENCES: N Engl J Med. 2015;373:

9 DECIDE: Adverse Events Event Daclizumab HYP (N = 919) Interferon Beta 1-a (N = 922) Hepatic laboratory abnormality Number of patients (%) ALT or AST >3 x ULN 96 (10) 80 (9) ALT or AST >5 x ULN 59 (6) 31 (3) Ocrelizumab ALT or AST >3 x ULN and total bilirubin >2x ULN 7 (1) 1 (<1) EMA = European Medicines Agency REFERENCES: N Engl J Med. 2015;373: Ocrelizumab (Ocrevus ) FDA approved: March 2017 Indication: relapsing or primary progressive forms of multiple sclerosis OPERA I & OPERA II MOA: ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells CD20 is a cell-surface antigen that is express on Pre-B cells Mature B cells Memory B cells REFERENCES: N Engl J Med. 2017;376:

10 OPERA I & OPERA II: Treatment Groups OPERA I & OPERA II: Primary and Secondary Endpoints Gd+ = gadolinium OPERA I: 46% lower ARR with ocrelizumab vs. INF beta-1a OPERA II: 47% lower ARR with ocrelizumab vs. INF beta-1a Significantly fewer Gd+ enhancing lesions at 96 weeks REFERENCES: N Engl J Med. 2017;376: REFERENCES: N Engl J Med. 2017;376: OPERA I & OPERA II: Adverse Events ORATORIO REFERENCES: N Engl J Med. 2017;376:

11 ORATORIO: Treatment Groups ORATORIO: Primary Endpoint 6.4% fewer patients experienced disease progression at 12 weeks vs. placebo REFERENCES: N Engl J Med. 2017;376: REFERENCES: N Engl J Med. 2017;376: ORATORIO: Secondary Endpoint ORATORIO: Adverse Events Ocrelizumab (N = 486) Placebo (N =239) 6.1% fewer patients experienced disease progression at 24 weeks vs. placebo REFERENCES: N Engl J Med. 2017;376: Event Number of patients (%) >1 infusion-related reaction (mild-severe) 194 (39.9) 61 (25.5) Serious infection 30 (6.2) 14 (5.9) Neoplasms Breast Basal-cell Adenocarcinoma of cervix Anaplastic large-cell lymphoma Endometrial adenocarcinoma Malignancy fibrous histiocytoma Metastatic pancreatic carcinoma 11 (2.3) 4 (0.8) 3 (0.6) 0 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.8) 0 1 (0.4) 1 (0.4) Death 4 (0.8) 1 (0.4) REFERENCES: N Engl J Med. 2017;376:

12 Ocrelizumab: Post-Marketing Updates Post Test: Question #1 KS is a 52 year old white female diagnosed with MS 20 years ago. At the time of diagnosis her MRI showed multiple Gd+ enhancing and non-enhancing lesions in the infratentorial and along her spinal cord and her lumbar puncture was (+) for oligoclonal bands. KS continues to experiences relapses at least yearly and her most recent MRI demonstrated new Gd+ enhancing lesions in the juxtacortical and periventricular regions of her brain. She does not experience worsening of disease outside of relapses. 1. How would you classify KS s disease course? a) Secondary-progressive MS- active, not progressing b) Relapsing-remitting MS- active c) Clinically Isolated Syndrome d) Primary-progressive MS- not active, progressing Post Test: Question #2 Post Test: Question #3 KS has now failed the oral option you selected for her previously (totaling 4 failed therapies). Labs were completed to assist in further therapy selection. Na 141 meq/l 2. Based on clinical trial data and recent FDA post-marketing reports, which of the following therapies would you avoid in KS? a) Ocrelizumab b) Daclizumab K Cl CO2 SCr BUN GLU Ca AST ALT Vit D 3.6 meq/l 106 meq/l 24 meq/l 0.74 mg/dl 14 mg/dl 88 mg/dl 9.5 mg/dl 130 U/L 154 U/L 18 ng/ml 3. To date no reports of progressive multifocal leukoencephalopathy (PML) have been reported with either daclizumab or ocrelizumab. a) True b) False 12

13 Take Home Points The exact cause of MS is still unknown, but multiple risk factors have been identified and several new therapies have been developed within the last few years, specifically daclizumab and ocrelizumab. The choice of therapy is based upon many factors, including patient and provider preference, disease course and severity, patient specific factors, and medication adverse effects. Resources & References Bainbridge JL, Miravalle A, Corboy JR. Pharmacotherapy, 9th Ed. 2014; Porth s Pathophysiology, 9th Ed. 2014; Cudrici C, et al. J Rehabil Res Dev 2006;43(1): Gasperi C, Stüve O, Hemmer B. Neurodegener Dis Manag. 2016;6(1): Hauser SL, Bar-Or A, Comi G, et al. N Engl J Med. 2017;376: Choi SW, Reddy P. Nat Rev Clin Oncol. 2014;11: Dalakas MC. Nature Clinical Practice Neurology. 2008;4: Polman CH, Reingold SC, Banwell B, et al. Ann Neurol 2011;69(2): Lublin FD, Reingold SC, Cohen JH, et al. Neurology. 2014;83:1-9. Kurtzke JF. Neurology. 1983;33: Management. LePage E, Veillard D, Laplaud DA, et al. Lancet. 2015;386: NICE nice.org.uk/guidance/cg186. Costello K, Halper J, Kalb R, et al. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence Gold R, Giovannoni G, Selmaj K, et al. Lancet. 2013;381: Kappos L, Wiendl H, Selmaj K, et al. N Engl J Med. 2015;373: Montalban X, Hauser SL, Kappos L, et al. N Engl J Med. 2017;376: Speaker Contact Information Amanda Stahnke, PharmD, BCACP University of Missouri-Kansas City Department of Pharmacy Practice and Administration- Clinical Assistant Professor Kansas City Veterans Affairs Medical Center Honor Annex Patient-Aligned Care Team Pharmacist in Primary Care stahnkea@umkc.edu Kelsey Morris, PharmD University of Kansas Healthcare System Clinical Ambulatory Care Pharmacist: Neurology-Multiple Sclerosis kmorris8@kumc.edu 13