Multiple Sclerosis Therapeutics Update. James Bowen, MD Multiple Sclerosis Center Swedish Neuroscience Institute

Transcription

1 Multiple Sclerosis Therapeutics Update. James Bowen, MD Multiple Sclerosis Center Swedish Neuroscience Institute 1

2 Current MS Treatments Interferons IFN 1-b Betaseron, Extavia IFN 1-a Intramuscular: Avonex Subcutaneous: Rebif, Plegridy Glatiramer acetate: Copaxone and Glatopa daily Copaxone tiw Mitoxantrone: Novantrone Natalizumab: Tysabri Fingolimod: Gilenya Teriflunomide: Aubagio Dimethyl fumarate: Tecfidera Alemtuzumab: Lemtrada Ocrelizumab: Ocrevus 2

3 Tysabri (natalizumab) Natalizumab 3

4 Natalizumab Side Effects Hypersensitivity reactions % Urticaria % Anaphylaxis/anaphylactoid 0.8% Others not statistically significant NEJM 2006;354:

5 Progressive Multifocal Leukoencephalopathy Multiple sclerosis 46 yo female, RRMS, after 37 doses of natalizumab (q 4 weeks) + interferon 1-a NEJM. 2005;353:

6 Natalizumab PML Risk Biogen communication 6/24/14 6

7 Natalizumab PML Risk 667 PML cases on natalizumab (6/16) 23% have died, about 10% mild disability Overall incidence 4.22/1000 treated (1:237) Shwab N. Neurology 2017;88: Medinfo.biogenidec.com 7

8 8

9 Recalculation of PML Risk Shwab N. Neurology 2017;88:

10 False Negative JCV Ab tests True false negative rate unknown. 2-3% convert to + at 1 year. How many ultimately convert: unknown. One case of PML with negative JCV antibody 2 weeks before (70 yo) Gagne M. Neurology 2016;86:

11 Stopping Natalizumab Dublin study- DC due to pt/md choice mean 19 months on Tx 8/29 (24%) relapsed within 6 months 27% new MRI lesions 9% large change in EDSS UCSF study planned Tx interuption 19/68 (27.9%) relapsed within 6 months 7/19 severe flairs (6-40 Gd+ lesions), mean EDSS 3 increased to 6 Kelly S, P01-197, AAN 2011 West TW. Ann Neuro 2010;68:395 11

12 3 ½ mos after stopping natalizumab 12

13 Fingolimod: Mechanism of action 13

14 Lymphocyte types Naïve never seen antigen. CCR7 targets to lymph nodes where they are presented antigens Central memory CCR7 targets to lymph nodes. Proliferate in lymph nodes in response to antigen Effector memory proliferate in peripheral tissue in response to second exposure to antigen Effector T cells interact with their targets on second exposure to antigen 14

15 Fingolimod: Bradycardia 0.6% vs 0.1% (placebo) Max 4-5 hrs after first dose, monitor 6 hrs Bradycardia not detectable after 2-4 weeks If stopped >2 weeks repeat first dose Cohen JA, et al. N Engl J Med. 2010; 362: Kappos L, NEJM 2010; 362:

16 Fingolimod: Macular Edema 0.4% DM or prior uveitis as high as 20% Usually by 3 months Cohen JA, et al. N Engl J Med. 2010; 362: Kappos L, NEJM 2010; 362:

17 Fingolimod: Immunosuppression Bronchitis/pneumonia: 8% vs 4% Zoster: 5.46/1000 pt yrs (similar to control) 1.2% of those CNS or visceral Cryptococcal meningitis: 1:20,000 Atypical mycobacteria Kaposi s sarcoma Lymphocyte counts not predictive: don t get them Cohen JA, et al. N Engl J Med. 2010; 362: Kappos L, NEJM 2010; 362:

18 Fingolimod: PML May 31, PML cases / 213K pts = 1 in 1:16K On fingolimod >2 yrs = 1 in 6,000 Risks 2/13 cancer or ulcerative colitis/immunosuppression 1 fingolimod 4.5 yrs, then PML on natalizumab X3mos Age Exposure months 18

19 Skin cancer: fingolimod Freedoms I (fingolimod vs placebo) Basal cell CA: 4 vs 3 cases Transforms (fingolimod vs IFN β1a IM) Basal cell CA: 3 vs 1 Freedoms II (fingolimod vs placebo) Basal cell CA: 10 vs 2 Each, plus all combined, not statistically significant 19

20 Fingolimod: monitoring Before treatment Baseline CBC and liver panel Cardiac history and ECG Baseline ophthalmological exam Varicella immune status First dose : 6-hour monitoring: ECG before/after On Treatment Monitoring Ophthalmology: 3-4 months and annually Check BP 20

21 Metabolite of leflunomide Teriflunomide Blocks de novo pyrimidine synthesis/ dihydroorotate dehydrogenase DNA synthesis in rapidly dividing tissues Salvage pathway recycles pyrimidine from breakdown of DNA/RNA Preserves tissues with slower rates of proliferation (hematopoietic cells, lymphocytes, skin, hair) Teriflunomide Blasting lymphocyte De novo pathway DHO-DH Pyrimidine pools DHO-DH, dihydroorotate dehydrogenase; Salvage pathway CTP-, UTP-sugars Nucleotides CDP lipids Glycoproteins, Glycolipids RNA, DNA Phospholipids Cell-cell contact Adhesion and diapedesis Proliferation Ig secretion Resting lymphocyte Cell membranes Second messengers Nonlymphoid cells 21

22 Teriflunomide: side effects Peripheral neuropathy: % (0.4% Placebo) Stevens-Johnson, Toxic epidermal necrolysis WBC by 15%, platelets by 10% Interstitial lung dz with leflunomide Placebo 7mg/d 14mg/d Diarrhea 9% 15% 18% Nausea 9% 9% 14% Alopecia 3% 10% 13% Presentation 153 ECTRIMS,

23 Teriflunomide: side effects Infections 1.6% Placebo, 2.5% in 7mg/d, 2.2% in 14mg/d Opportunistic infections Gram neg bacteremia Bacterial pneumonia Klebsiella sepsis Intestinal tuberculosis Presentation 153 ECTRIMS,

24 Teriflunomide Half life days May cause major birth defects. If pregnancy planned or occurs unplanned, rapidly remove by: Cholestyramine 8gm q8hr X11 d or 50g activated charcoal q12 hr X11d Measure plasma levels <0.02 to confirm elimination Applies to men as well as women Liver failure with leflunomide Avoid if baseline ALT > 2X normal Monitor ALT monthly X 6. DC if > 3X normal Transient acute renal failure 24

25 Before starting Teriflunomide PPD/QuantiFERON-TB Gold CBC, CMP LFTs within 6 months prior to starting After starting LFT monthly X 6 months 25

26 Dimethyl Fumarate Keap1/Cullin cause ubiquitination/destruction of Nrf2 (T 1/2 20 min) Transcription factors MMF dissociates Keap1/Cullin from Nrf2 In nucleus, MMF acts as upstream regulator of transcription factors MMF Cullin 3 Keap1 Nrf2 DMF to MMF: T ½ 12 minutes. Enters citric acid cycle: T ½ 36 hours MMF = monomethyl fumarate Keap1 =Kelch like-ech-associated protein 1 Cullin 3 Nrf2 = Nuclear factor (erythroid-derived 2)-like 2 26

27 Dimethyl Fumarate proinflammatory cytokines: IL-6, IL-1, TNFα Increase anti-inflammatory cytokines: IL-10, IL-4, and IL-6 Decreased lymphocyte levels, especially CD4 and Th 1 Antioxidant 27

28 Dimethyl Fumarate: Side effects GI (Nausea, abdominal pain, diarrhea): 20% Taper dose Take with high fat meal Montelukast (Singulair) 10mg/d Antiemetics (Pepto-Bismol, antacids, omeprazole, ranitidine, metoclopramide, domperidone, pantoprazole, prochlorperazine) Loperamide, Pepto-bismol (bismuth subsalicylate), Lomotil Improves over 6-8 weeks Meltzer L, et al. AAN abstract P01.164,

29 Dimethyl Fumarate: Side effects Flushing: 40% Similar to niacin flush, prostaglandin mediated. Take ASA Take with food, max blood level by 40% Decreases over several months Sheikh SI, et al. CMSC/ACTRIMS poster DX74,

30 Dimethyl Fumarate: Side effects Lymphopenia: Ave 30% Slowly over 6 months 6% ALC <500, 1% <200 ½ of these single events Longbrake EE Multiple Sclerosis 2015;21:796 30

31 Dimethyl Fumarate: PML 5 cases / 230K 1:30K 4 cases had ALC <500 1 case did not Rosenkranz T. N Engl J Med 2015;372:1476 Lehmann-Horn Neuro 2016;87:

32 Before starting CBC, CMP After starting Dimethyl Fumarate CBC at 6 months, every 6-12 months thereafter Stop medication of ALC persists <500 32

33 Anti-CD52 Alemtuzumab Cell surface glycoprotein found on B cells, T lymphocytes, NK cells, monocytes, and macrophages Given as 4 hour infusion of 12mg X 5d. Repeat 3 doses at 12 months. Failed 2 or more other treatments first 33

34 Alemtuzumab: side effects Autoimmune diseases Thyroid disorders (34%), Graves ophthalmopathy (1%) Immune thrombocytopenia (ITP) (2%) Glomerular nephropathy (0.3%) membranous glomerulonephritis, anti-gbm disease Autoimmune hemolytic anemia, autoimmune pancytopenia, undifferentiated connective tissue disorder, antifactor VIII antibodies (0.2% each) RA, Type I DM, vitiligo, retinal pigment epitheliopathy (0.1% each) Guillain-Barre, chronic inflammatory demyelinating polyradiculoneuropathy, 34

35 Alemtuzumab: side effects Infusion reactions 92% (rash, headaches, pyrexia, nausea) Serious reactions 3% Anaphylaxis Pneumonitis (0.5%) hypersensitivity pneumonitis, pneumonitis with fibrosis 35

36 Alemtuzumab: side effects Malignancies Thyroid Cancer: (0.3%) Melanoma (0.3%) Lymphoproliferative disorders Lymphoma 36

37 Alemtuzumab: side effects Infections 71% vs 53% in IFN group Serious infections 3% vs 1% Appendicitis, gastroenteritis, pneumonia, zoster, oral infections. Herpes 16% vs 3% Oral 8.8%, zoster 4.2%, HSVI 1.8%, HSVII 1.3% HSVI meningitis 0.1% Cervical HPV 2% Active/latent TB 0.3% Candidiasis, listeria meningitis Avoid live vaccines 37

38 Alemtuzumab: Prior testing Prior to starting PPD/ VZV titer CBC (diff), TSH, CMP, urinalysis with cell counts All vaccinations 6 wks prior to treatment Skin examination 38

39 Alemtuzumab: administration Premedicate Methylprednisolone 1000mg IV before each of first 3 days of series Antihistamine (Cetirizine 10mg po + diphenhydramine 50mg IV) Antipyretic pre-infusion (acetaminophen 500mg) Administer over 4 hours, monitor 2 hours after Acyclovir mg po bid on day 1 39

40 Monitoring Monthly: CBC with diff, creatinine, UA + micro until 48 months after last dose. Every 3 months: TFTs (TSH) until 48 mos after last dose. Monitor for thyroid nodules Annually Dermatology Human papilloma virus (pap smear) in women Antiherpetic medication starting first dose each course, for 2 months or CD4+ 200, whichever is longer (acyclovir mg po bid) 40

41 Daclizumab Monoclonal antibody, (90% human) Targets IL2 receptor α subunit (CD25) Monthly subcutaneous injection Actions Interupts IL2 mediated expansion of T lymphs Increase CD56 (bright) natural killer cells (decreases survival of activated T cells) Inhibit CD40 ligand expression (CD154) on T cell macrophage activation B cell activation by follicular helper T cells (T FH ) Decreased T reg # and function 41

42 Daclizumab Rash 18% (>1/3 require steroid creams) Longterm 77% (mod-severe 19%) Infection (65% vs 57% on IFN) Serious infections (4% vs 2% on IFN) Fatal psoas abscess Autoimmune disease Autoimmune hepatitis: 5/17 fatal fulminant case, onset 25 fatal 38 days after last dose Renal CNS vasculitis (1 case) LFT elevations Cortese I. Neurology 2016;86:

43 Daclizumab Before starting treatment Hepatic function tests Evaluate high-risk patients for TB Hepatitis B and C screening After initiating treatment Liver function tests monthly until 6 months after last dose 43

44 Ocrelizumab Monoclonal antibody fully humanized Targets CD20 (B cells marker) IV infusion every 6 months (600mg) First dose split 300mg X2, 2 weeks apart 44

45 Ocrelizumab: side effects Injection site reactions 34-40% 2 nd infusion: 11.1% vs 3.8% Most B-cell lysis syndrome rather than allergic Systemic inflammatory response with diffuse intravascular coagulation: 1 case (? Sepsis) Possible opportunistic infection (complicated by RA, SLE and NHL populations, non-us cases) Pneumocystis, disseminated herpes, mycobacterium, reactivated hepatitis B, systemic candidiasis, cryptococcal meningitis, CMV, histoplasmosis. 45

46 Ocrelizumab: infections URI: 40 vs 33% (IFN tiw) or 49 vs 43 (placebo) LRI: 8 vs 5% (IFN) or 10 vs 9 (placebo) Herpes Zoster: 2.1 vs 1% (IFN) Oral: 3 vs 2.2% (IFN) Genital: 0.1 vs 0% (IFN) PML: No cases thus far. Hep B reactivation: No cases thus far 46

47 Ocrelizumab: Malignancies Overall: vs (IFN tiw) vs 0.008% (placebo) Breast cancers: 6 cases vs none in controls 6 within expected #, 0 not within expected # 47

48 Ocrelizumab Prior to starting Hep B serology Probably wise: CBC, CMP, VZV serology, QuantiFERON-TB Gold, JCV antibody, IgG Premedicate Methylprednisolone 100mg IV Diphenhydramine 25-50mg IV Acetaminophen mg po 48

49 Overview Medication Efficacy Safety Interferon Glatiramer acetate Fingolimod Teriflunomide Dimethyl fumarate Natalizumab Alemtuzumab Daclizumab Ocrelizumab 49