Update in Multiple Sclerosis

Transcription

1 Update in Multiple Sclerosis Kyle Smoot, MD Providence MS Center Portland, OR 1

2 Disclosures Research funds from Biogen. Consulting fees from Acorda, Biogen, EMDSerono, Genzyme, Novartis, and Teva. 2

3 Outline Review current medication options for relapsing multiple sclerosis Natalizumab and Risk of Progressive Multifocal Encephalopathy (PML) Daclizumab Ocrelizumab Concept of No Evidence of Disease Activity (NEDA) Future Research 3

4 Case Presentation 54 y.o female who was diagnosed with MS in August 2000 after presenting with sensory disturbance in the right lower extremity which progressed to involve her torso. Previously, in 1998, she did have an episode of left optic neuritis. Started on interferon-β1a (Avonex) in The patient is on a β-blocker for SVT. 4

5 Case Presentation Patient was stable on interferon-β1a until Summer Attended her daughter s wedding in June shortly after the wedding, she developed shingles involving the left leg. Several weeks later, she developed sensory disturbance on the right from the neck down. This resulted in incoordination and some urinary urgency. 5

6 Case presentation 6

7 Case Presentation Do you consider this a treatment failure? If so, what medications would you consider transitioning her to? If not, what would be your long-term plan? Any other testing that would be helpful before making a decision? 7

8 Disease Modifying Therapy Efficacy and Safety 8

9 Disease Modifying Therapy Efficacy and Tolerability 9

10 Case Presentation 42 y.o female with relapsing MS on natalizumab Previous medication trials have included interferon-β and dimethyl fumarate. Medications were discontinued secondary to disease progression Patient has received 26 doses of natalizumab, and she has been relapse free. She had been JCV negative, but her recent test was positive with an index of What do you recommend? If you decide to continue natalizumab, what monitoring would you recommend? 10

11 Natalizumab Initially approved in Shortly after approval, 3 cases of PML reported. Removed from the market, and re-established in 2006 after surveillance program established. AFFIRM - N Engl J Med 2006; 354: SENTINEL - N Engl J Med 2006; 354: MOA Inhibition of migration of immune cells into CNS binds to the α4 subunit of α4β1 and α4β7 integrins and blocks binding to their endothelial receptors (VCAM-1 and mucosal addressin-cell adhesion molecule 1, respectively) Stabilization of BBB Inhibition of APC turnover in the CNS Reduction in Relapses by 68% at 2 years verses placebo. MRI 83% reduction in T2 lesions vs. Placebo 92% reduction in Gd+ lesions vs. Placebo 11

12 Natalizumab Disability Data NTZ reduced the risk of sustained disability progression over 2 years by 42% compared to placebo. 12

13 Natalizumab - PML Antibodies to the JC virus Present in 60 to 70% of the population 2-3% risk of a false positive PML risk estimates per 1000 anti-jcv antibody positive patients by NTZ treatment duration in patients with no prior IS use 99% have been positive 6 months prior to developing PML. 2-3% sero-conversion rate per year Higher risk of PML in patients with previous exposure to immunosuppression. Early detection = Better prognosis Mortality rate of 22% Overall PML incidence as of 4.22 per Kuesters et al AAN 2015 P

14 PML Case NTZ treated patient April 2012 July

15 Managing Patients on Natalizumab Anti-JCV negative Within in the first 2 years, check JCV status every 6 months and repeat MRI of the brain yearly. After 2 years, check JCV status every 3 months and repeat MRI of the brain every 6 months. Anti-JCV positive Within in the first year, check JCV status every 6 months and repeat MRI of the brain yearly. After 1 year, check JCV status every 3 months and repeat MRI of the brain every 6 months. The decision to continue depends on the patient and their provider. 15

16 Daclizumab First humanized mab Initially designed for HTLV-1 induced T-cell leukemia First approved in 1997 for prevention of allograft rejection in patients undergoing renal transplant Approved in July 2016 Subq injection given monthly MOA Prevents activation of the high-affinity IL-2 receptor Increases Natural Killer (NK) cells. Regulate self-tolerance and play a role in the adaptive immune system. Lancet Neurology 2013;12:

17 Daclizumab DECIDE TRIAL NEJM 2015; 373: Clinical Results Daclizumab (N 919) Interferonβ-1a (N 922) P-Value Annualized Relapse Rate < Relative Reduction 45% Proportion Relapse Free 67% 51% Confirmed Disability Progression MRI Results 16% 20% 0.16 New T2 lesions < % 17

18 Daclizumab - Safety Cutaneous Events 37% in the DAC group Rash, Eczema, Dermatitis, Erythema Liver Dysfunction ALT/AST values >5 times the upper range of normal 6% vs. 3% Interferon elevation typically occurs within the first month. FDA recommendation = monitor LFTs monthly while on the medication Serious Infection 4% vs. 2% SELECT Trial one death secondary to a psoas abscess. No cases of PML reported to date. 18

19 Ocrelizumab - a humanized monoclonal antibody that selectively depletes CD20+ B cells 19

20 Ocrelizumab Studied in relapsing MS and primary progressive MS Under FDA review decision is expected in December Dosing: Two IV infusions two weeks apart Subsequent doses every 6 months 20

21 Ocrelizumab OPERA I and II Clinical Data Clinical Results Ocrelizumab (N 827) Interferonβ-1a (N 829) P-Value Annualized Relapse Rate < Relative Reduction 46% Confirmed Disability Progression (24 weeks) MRI Results 7.6% 12% New Gd+ lesions 0.016/ /0.416 < Relative Reduction 94%/95% New T2 lesions 0.323/ /1.904 < Relative Reduction 77%/83% 21

22 Ocrelizumab ORATORIO (PPMS) MS disease history and baseline characteristics Placebo n=244 Ocrelizumab 600 mg n=488 Age,yr, mean (SD) 44.4 (8.3) 44.7 (7.9) Female, n (%) 124 (50.8) 237 (48.6) Time since symptom onset, yr, mean (SD) 6.1 (3.6) 6.7 (4.0) Time since diagnosis, yr, mean (SD) 2.8 (3.3) 2.9 (3.2) MS disease-modifying treatment naive, n (%) 214 (87.7) 433 (88.7) EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2) MRI Patients with Gd + lesions, n (%) Number of Gd + T1 lesions, mean (SD) T2 lesion volume, cm 3, mean (SD) Normalised brain volume, cm 3, mean (SD) 60 (24.7) 0.6 (1.6) 10.9 (13.0) (88.7) 133 (27.5) 1.2 (5.1) 12.7 (15.1) (83.9) Montalban et al. Presentation 228. Presented at ECTRIMS; October 10, 2015; Barcelona, Spain.. 22

23 ORATORIO (PPMS) 23

24 ORATORIO - PPMS 25-foot walk 29% relative reduction T2 lesion volume 3.4% reduction OCRE vs. 7.4% increase placebo Brain volume 17.5% relative reduction 24

25 No Evidence of Disease Activity (NEDA) Relapse-free No EDSS change Lack of radiographic progression New or enlarging T2 and Gd+ lesions What about atrophy, cognition, and quality of life measures? How attainable is this goal? 25

26 Treat Early! 26

27 Disease Activity After 1 Year of Treatment May Predict Disability Progression L. Prosperini European Journal of Neurology 2009, 16: J. Rio Nat Rev Neurol 2009, 10: Percentage of patients defined as responders (white) and poor responders (grey). 27

28 From: Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort JAMA Neurol. 2015;72(2): doi: /jamaneurol

29 From: Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort JAMA Neurol. 2015;72(2): doi: /jamaneurol

30 Current Research Hot Topics Autologous Hematopoietic Cell Transplantation Rebooting HALT-MS 25 patients; no control group EDSS 4.5 Event-free survival 69.2% at 5 years 3 deaths thought not to be related Mesenchymal Cell Transplantation Isolated from bone marrow or adipose tissue Promote Neurotrophic Factors Traffic from Blood/CSF to injured tissue Re-myelination Clemastine Fumarate (Data Presented at AAN 2016) Anti-LINGO Over 40 agents being evaluated Diet/Microbiome 30

31 Case Presentation 54 y.o on interferon-β1a who had an episode of transverse myelitis. This was her first relapse in 16 years. Do you consider this a treatment failure? If so, what medication would you transition her to? If not, what would be your long-term plan? Any other testing that would be helpful before making a decision? 31

32 Questions? Thank you! 32