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Two Faces of Multiple Sclerosis February 8, 2017 Inflammation Neurodegeneration Relapsing MS Progressive MS 5 0 T H A N N U A L R E C E N T A D VA N C E S I N N E U R O L O G Y B CELL THERAPY FOR MULTIPLE SCLEROSIS: A NEW DAY? Anisha

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Stephen L. Hauser, MD

Department of Neurology University of California, San Francisco COI: Symbiotix, Annexon, Bionure, Neurona, Molecular Stethoscope

B CELL THERAPY FOR MULTIPLE SCLEROSIS: A NEW DAY?

5 0 T H A N N U A L R E C E N T A D VA N C E S I N N E U R O L O G Y February 8, 2017

Inflammation

Relapsing MS

Neurodegeneration

Progressive MS

Two Faces of Multiple Sclerosis

Anisha Keshavan Roland Henry, PhD 3

Rituximab in Relapsing Remitting MS

Gadolinium-Enhancing Lesions from Baseline to Week 48

Hauser SL, et al. N Engl J Med 358:676–88, 2008

Weeks Mean Number of Gd Lesions 0.5 1 1.5 2 2.5 4 8 12 16 20 24 28 32 40 36 44 48

* Missing values imputed by average of available data

P = 0.78 P = 0.003 P = 0.001 P < 0.001 Rituximab 2000mg (n=66) Placebo (n=35) 4

Rituximab in Primary Progressive MS

Time to Confirmed Disease Progression

Hawker et al, Ann Neurol 66:460, 2009

All Intent-to-Treat Patients (n=439)

Weeks Proportion of Patients (%) 12 24 36 48 60 72 84 108

HR (95% Cl): 0.77 (0.55, 1.09); p-value=0.1442

10 20 30 40 96 Rituximab Placebo 50 60

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* *

Ocrelizumab in Relapsing Remitting MS:

Reduction in Gd-Enhancing Lesions Maintained Through 144 Weeks

Hauser SL, et al. Presented at the American Academy of Neurology, March 13, 2013 Placebo (n=54) Ocrelizumab600mg (n=55) Ocrelizumab1000mg (n=55) IFN beta-1a (n=54) Patients with baseline MRI

‘Core Study' (0–96 weeks)
‘Follow-Up' (97–144 weeks)a

Weeks 4 8 12 16 20 24 48 72 96 120 144 Mean No. T1 Gd-enhancing Lesions 1.0 2.0 3.0 4.0

Primary end point: OCR vs placebo

*p<0.0001 for both OCR doses vs placebo, N (for primary analysis): Placebo=54, OCR 600 mg=51, OCR 1000 mg=52, IFN-β1a=52 a Patients who withdrew during earlier treatment cycles were also included in the follow-up periods 6

OPERA I & II: Two Identical Studies of Ocrelizumab in Relapsing MS

RMS diagnosis
18–55 yrs
EDSS of 0.0–5.5
≥2 clinical

relapses within last 2 yrs or 1 relapse in last yr

1:1 Randomization

OLE OLE screening period

Safety follow-up ≈48 weeks from date of last infusion

B-cell monitoring‡

‡Connued monitoring occurs if B cells are not repleted. EDSS, Expanded Disability Status Scale; IFN, interferon; i.v., intravenous; OLE, open-label extension; RMS, relapsing multiple sclerosis; s.c., subcutaneous.

MS Disease Histories and Characteristics Were Balanced

7 ITT *Untreated in 2 years prior to study entry. EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; SD, standard deviation; yr, year. OPERA I OPERA II IFN β-1a 44 µg n=411 Ocrelizumab 600 mg n=410 IFN β-1a 44 µg n=418 Ocrelizumab 600 mg n=417 Age, yr, mean (SD) 36.9 (9.3) 37.1 (9.3) 37.4 (9.0) 37.2 (9.1) Female, n (%) 272 (66.2) 270 (65.9) 280 (67.0) 271 (65.0) Time since onset, yr, mean (SD) 6.3 (6.0) 6.7 (6.4) 6.7 (6.1) 6.7 (6.1) Time since diagnosis, yr, mean (SD) 3.7 (4.6) 3.8 (4.8) 4.1 (5.1) 4.2 (5.0) Relapses previous 12 months, mean (SD) 1.3 (0.6) 1.3 (0.7) 1.3 (0.7) 1.3 (0.7) Previously untreated*, n (%) 292 (71.4) 301 (73.8) 314 (75.3) 304 (72.9) EDSS, mean (SD) 2.8 (1.3) 2.9 (1.2) 2.8 (1.4) 2.8 (1.3) Gd+ lesions, n (%) 155 (38.1) 172 (42.5) 172 (41.4) 161 (39.0) Number Gd+ T1 lesions, mean (SD) 1.9 (5.2) 1.7 (4.2) 2.0 (4.9) 1.8 (5.0) Number T2 lesions, mean (SD) 51.1 (39.9) 51.0 (39.0) 51.0 (35.7) 49.3 (38.6)

Over 85% of Ocrelizumab Patients Completed the Studies

8 *All randomized patients will be included in the ITT population. Patients prematurely withdrawing from the study for any reason and for whom an assessment was not performed for whatever reason will still be included in the ITT analysis. AE, adverse event; IFN, interferon; ITT, intent to treat. OPERA I OPERA II IFN β-1a 44 µg Ocrelizumab 600 mg IFN β-1a 44 µg Ocrelizumab 600 mg ITT*, n 411 410 418 417 Treated, n 409 408 417 417 Withdrawn, n (%) Withdrawn due to AE, n (%) Entered safety follow-up, n (%) 69 (17) 25 (6.1) 42 (61) 42 (10) 13 (3.2) 24 (57) 97 (23) 25 (6.0) 39 (40) 57 (14) 16 (3.8) 16 (28) Completed, n (%) Entered safety follow-up, n (%) Entered open-label extension, n (%) 340 (83) 12 (4) 326 (96) 366 (89) 10 (3) 352 (96) 320 (77) 15 (5) 297 (93) 360 (86) 8 (2) 350 (97)

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Ocrelizumab in Relapsing MS

9 ITT *Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs ≥4.0), and geographic region (US vs ROW). ARR, annualised relapse rate; EDSS, Expanded Disability Status Scale; IFN, interferon; ROW, rest of the world.

46%

ARR reduction vs IFN β-1a p<0.0001

OPERA I OPERA II

47%

ARR reduction vs IFN β-1a p<0.0001

Reduction in Annualized Relapse Rate Compared With IFNβ-1a

Ocrelizumab in Relapsing MS

10 ITT *Adjusted by means calculated by negative binomial regression and adjusted for baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW). EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world.

Reduction in Mean Gadolinium-Enhancing Lesions Compared With IFNβ-1a OPERA I OPERA II

95%

p<0.0001

98%

p<0.0001

91%

p<0.0001

92%

p<0.0001

96%

p<0.0001

97%

p<0.0001

Reduction in Pre-specified Pooled Analysis of Confirmed Disability Progression (CDP)

11 ITT CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab.

Time to CDP for ≥12 weeks Time to CDP for ≥24 weeks

Risk reduction: 40%

HR (95% CI): 0.60 (0.45, 0.81); p=0.0006

Risk reduction: 40%

HR (95% CI): 0.60 (0.43, 0.84); p=0.0025

15.2 9.8 12.0 7.6

Higher Proportion of Patients With Improvement in Brain Volume Loss Compared With IFNβ-1a

12 ITT Exploratory endpoints: *24% improvement vs IFN β-1a; p<0.0001; †24% improvement vs IFN β-1a; p=0.0001; ‡Compared using the Cochran–Mantel–Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4.0 vs. ≥4.0).

Percentage Change in Brain Volume from Baseline to Week 96* Week

OPERA I

Percentage Change in Brain Volume from Baseline to Week 96† Week

OPERA II

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n (%) IFN β-1a 44 μg (n=826) Ocrelizumab 600 mg (n=825)

Total number of patients with ≥1 AE 688 (83.3) 687 (83.3) Total number of patients with ≥1 AE occurring at relative frequency ≥5% 539 (65.3) 544 (65.9) Injury, Poisoning and Procedural Complications Infusion-related reaction General Disorders and Administration-site Conditions Influenza-like illness Injection-site erythema Fatigue Injection-site reaction Infections and Infestations Upper respiratory tract infection Nasopharyngitis Urinary tract infection Sinusitis Bronchitis Nervous System Disorders Headache Psychiatric Disorders Depression Insomnia Musculoskeletal and Connective Tissue Disorders Back pain Arthralgia 80 (9.7) 177 (21.4) 127 (15.4) 64 (7.7) 45 (5.4) 87 (10.5) 84 (10.2) 100 (12.1) 45 (5.4) 29 (3.5) 124 (15.0) 54 (6.5) 38 (4.6) 37 (4.5) 51 (6.2) 283 (34.3) 38 (4.6) 1 (0.1) 64 (7.8) 2 (0.2) 125 (15.2) 122 (14.8) 96 (11.6) 46 (5.6) 42 (5.1) 93 (11.3) 64 (7.8) 46 (5.6) 53 (6.4) 46 (5.6)

Adverse Events Were Similar

13 Table includes only AEs occurring in ≥5% of patients in at least one treatment group. AE, adverse event; IFN, interferon.

Total Serious Adverse Events Were Low and Similar

14 Table includes only AEs occurring in ≥5% of patients in at least one treatment group. AE, adverse event; IFN, interferon.

n (%) IFNβ-1a 44 μg (n=826) Ocrelizumab 600 mg (n=825) Overall patients with ≥1 SAE 72 (8.7) 57 (6.9) Infections and infestations 24 (2.9) 11 (1.3) Nervous system disorders 11 (1.3) 8 (1.0) Injury, poisoning, and procedural complications 10 (1.2) 6 (0.7) During OPERA I and OPERA II, three deaths occurred

IFN β-1a 44 μg arm: completed suicide, mechanical ileus
Ocrelizumab 600 mg arm: completed suicide

Six malignancies were reported:

IFN β-1a 44 μg arm: mantle cell lymphoma and squamous cell carcinoma
Ocrelizumab 600 mg arm: renal cancer, melanoma and two breast cancers

Ocrelizumab Is Effective in Relapsing MS and Has A Favorable Safety Profile

Compared with IFN-β-1a, ocrelizumab significantly reduced:
ARR
12- and 24-week CDP
T1 Gd+ lesions
New and/or enlarging T2 lesions
There were no new or unexpected safety findings associated with ocrelizumab in OPERA I and

OPERA II over the 96-week controlled period

The consistency of effect and magnitude of treatment effect size seen in OPERA I and OPERA

II indicate that targeting CD20+ B cells with ocrelizumab is highly effective in relapsing MS

CDP, confirmed disability progression; Gd+, gadolinium enhancing; IFN, interferon. 16

ORATORIO: Phase 3 Study of Ocrelizumab in Primary Progressive MS

*Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. †The blinded treatment period may be extended unl database lock. #2:1 randomisation stratified by age (≤45 vs >45) and region (US vs ROW). ‡Connued monitoring occurs if B cells are not repleted. BL, baseline; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; i.v., intravenous; MRI, magnetic resonance imaging.

Diagnosis of PPMS

(2005 revised McDonald criteria)1

Age 18–55 years
EDSS 3.0–6.5
CSF: elevated IgG

index or >1

ligoclonal bands
No history of RRMS,

SPMS, or PRMS

No treatment with
ther MS DMTs at

screening

2:1 Randomization#

1 Polman CH, et al. Ann Neurol 2005;58:840–6.

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17 *No disease-modifying treatments in the previous 2 years. EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging; MS, multiple sclerosis; SD, standard deviation.

ORATORIO: MS Disease History and Baseline characteristics

Placebo n=244 Ocrelizumab n=488 Age, yrs, mean (SD) 44.4 (8.3) 44.7 (7.9) Female, n (%) 124 (50.8) 237 (48.6) Time since MS symptom onset, yrs, mean (SD) 6.1 (3.6) 6.7 (4.0) Time since MS diagnosis, yrs, mean (SD) 2.8 (3.3) 2.9 (3.2) MS disease-modifying treatment naïve,* n (%) 214 (87.7) 433 (88.7) EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2) MRI Patients with T1 Gd+ lesions, n (%) Number of T1 Gd+ lesions, mean (SD) Brain T2 hyperintense lesion volume, cm3, mean (SD) Normalized brain volume, cm3, mean (SD) 60 (24.7) 0.6 (1.6) 10.9 (13.0) 1469.9 (88.7) 133 (27.5) 1.2 (5.1) 12.7 (15.1) 1462.9 (83.9)

Evaluation of efficacy in patient subgroups with and without T1 gadolinium-enhancing lesions at baseline is a key area of interest

B cell Therapy (Ocrelizumab) in Progressive MS

Time to 12-week Confirmed Disability Progression

Weeks Proportion of Patients (%) 216 60 12 10 20 30 40 60

Montalban X, Hauser SL, Kappos L, et al. NEJM 2016

70 Ocrelizumab (600mg) Placebo 50 24 36 48 72 84 96 108 120 132 144 156 168 180 192 204

24% reduction in risk of CDP

H R ( 9 5 % C I ) : . 7 6 ( . 5 9 , . 9 8 ) ; p = . 3 2 1 19

*Analysis based on ITT population; p-value based on ranked ANCOVA at 120-week visit adjusted for baseline timed 25-foot walk, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on log- transformed data adjusted for baseline timed 25-foot walk, geographic region and age. CI, confidence interval; HR, hazard ratio; ITT, intent to treat; LOCF, last observation carried forward.

Secondary Endpoint: Significant Reduction In the Progression Rate of Walking Time

% Change from Baseline Walking Time (Mean, 95% CI)

Percent Change in Timed 25-Foot Walk From Baseline to Week 120

29%

reduction vs placebo p=0.0404*

20 *Analysis based on ITT population; p-value based on ranked ANCOVA at 120-week visit adjusted for baseline T2 lesion volume, geographicregion and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRManalysis on log- transformed data adjusted for baseline T2 lesion volume, geographic region and age. CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; LOCF, last observation carried forward; MMRM; mixed-effect model repeated measure.

Change in Brain T2 Hyperintense Lesion Volume From Baseline to Week 120

% Change From Baseline T2 Lesion Volume (Mean, 95% CI) Placebo n=144 Ocrelizumab n=291 % Change From Baseline T2 Lesion Volume (Mean, 95% CI) Placebo n=39 Ocrelizumab n=107 % Change From Baseline T2 Lesion Volume (Mean, 95% CI)

+7.4% with placebo

−3.4% with ocrelizumab

p<0.0001* Placebo n=183 Ocrelizumab n=400

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21 *Analysis based on ITT population with Week 24 and at least one post-Week 24 assessment; p-value based on MMRM at 120-week visit adjusted for Week 24 brain volume, geographic region and age. CI, confidence interval; Gd+, gadolinium-enhancing; ITT, intent to treat; MMRM; mixed-effect model repeated measure.

Change of Whole Brain Volume From Week 24 to Week 120

% Change in Whole Brain Volume From Week 24 (Mean, 95% CI)

17.5%

relative reduction p=0.0206* Placebo n=150 Ocrelizumab n=325 % Change in Whole Brain Volume From Week 24 (Mean, 95% CI) Placebo n=31 Ocrelizumab n=83 % Change in Whole Brain Volume From Week 24 (Mean, 95% CI) Placebo n=119 Ocrelizumab n=241

22 SAE, serious adverse event.

SAEs by System Organ Class Reported by ≥1% of Patients in Either Treatment Arm Until Clinical Cut-Off Date

n (%) Placebo (n=239) Ocrelizumab 600mg (n=486)

Overall patients with ≥1 SAE 53 (22.2) 99 (20.4) Infections and Infestations 14 (5.9) 30 (6.2) Injury, Poisoning, and Procedural Complications 11 (4.6) 19 (3.9) Nervous System Disorders 9 (3.8) 18 (3.7) Neoplasms Benign, Malignant and Unspecified (including cysts and polyps) 7 (2.9) 8 (1.6) Gastrointestinal Disorders 3 (1.3) 10 (2.1) Musculoskeletal and Connective Tissue Disorders 6 (2.5) 6 (1.2) General Disorders and Administration-site Conditions 3 (1.3) 6 (1.2) Renal and Urinary Disorders 3 (1.3) 5 (1.0)

Five deaths were reported:

1 (0.4%) in the placebo arm: road traffic accident
4 (0.8%) in the ocrelizumab arm: pulmonary embolism, pneumonia, pancreas carcinoma, pneumonia aspiration

Thirteen malignancies were reported:

2 (0.8%) in the placebo arm: one cervix adenocarcinoma in situ and one basal cell carcinoma
11 (2.3%) in the ocrelizumab arm: four breast cancers, one endometrial adenocarcinoma, one anaplastic

lymphoma, one histiocytoma, one metastatic pancreas cancer, and three basal cell carcinomas

In ORATORIO, Ocrelizumab Was Effective in PPMS and Had an Overall Safety Profile Similar to Placebo

AE, adverse event; CDP, confirmed disability progression; PPMS, primary progressive multiple sclerosis; SAE, serious adverse event.

ORATORIO data show that B cells may play a role in PPMS pathophysiology
Initial analysis showed that, compared with placebo, ocrelizumab significantly reduced:
12- and 24-week CDP
Change in timed 25-foot walk
Change in T2 lesion volume
Brain volume loss
Throughout the mean treatment duration of approximately 3 years, ocrelizumab showed a favorable

safety profile:

Overall, the proportion of patients experiencing AEs and SAEs associated with ocrelizumab, including serious infections, was similar

to placebo

Most common adverse events were mild-to-moderate infusion-related reactions
Complete safety analyses are ongoing, including investigation of imbalance in malignancies

How Does Ocrelizumab Work?

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Targeting CD20+ B cells Can Preserve B cell Reconstitution and Long-Term Immune Memory

B CELLS PLASMA CELLS CD20

B cell Reconstitution Preserved1-3 Long-term Immune Memory Preserved1,2,4

Rituximab (chimeric), ocrelizumab (humanised), and ofatumumab (human) are monoclonal antibodies that selectively deplete CD20+ B cells

Image adapted from Krumbholz M, et al. Nat Rev Neurol 8:613–23, 2012; 1. Hauser SL. Mult Scler 21:8–21, 2015; 2. Pescovitz MD. Am J Transplant 6:859–66, 2006; 3. Leandro MJ, et al. Arthritis Rheum 54613–20, 2006; 4. DiLillo DJ, et al. J Immunol 180:361–71, 2008 26

Many MS Drugs in Development Target B cell Mechanisms

Mode of Action Drug Target Trial Status MS NMO (SD) Lytic Rituximab 1 CD20 Off Label Off Label Ocrelizumab Phase 3 – Ofatumumab Phase 3 Ublituzumab 2 – Phase 2 MEDI-551 2 CD19 Phase 2 Signaling Solouble Atacicept (Taci-Fc) 3 BAFF & APRIL Phase 2 Tabalumab BAFF Phase 2 – Cell Surface Aquaporumab 4 AQP-4 – Phase 2 Alemtuzumab CD52 Approved VAY736 BAFF-R Phase 2 – Tocilizumab IL-6R Off Label Off Label SA237 Phase 2 Effector Eculizumab C5a – Phase 3 NPB-01 (IVIg) Diverse – Phase 2

1 Two studies with intrathecal application; 2 Glyco-engineeered: binding to FcgammaR indepentdent of haplotype; 3 Studies halted: disease exacerbation; 4 Blocks antigen access

MS Therapies Have Consistent Effects on B cells

Effect on B cells*

Interferon Beta Glatiramer acetate Fingolimod Dimethyl fumarate Teriflunomide Mitoxantrone Natalizumab Alemtuzumab Anti-CD20 RTX, OCR, OFA

Modulation

Differentiation
Activation
Migration
Depletion
*In humans and experimental models

Therapy

Rituximab vs. Ocrelizumab

Are Differences in Anti-CD20 MAbs Clinically Meaningful?

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Superior Efficacy and Tolerability of Rituximab c/w Fingolimod Following Switch From Natalizumab Due to JCV+ Serology

Days Incidence of drug discontinuation 400 300 200 0.15

Alping P, et al. Ann Neurol 79:950, 2016

500 100 0.20 0.10 0.05 0.00 Fingolimod Rituximab Disease Breakthrough Fingolimod Rituximab Adverse Events

A Retrospective Observational Study of RTX in MS

Salzer J, et al. Neurology 87:2074–81, 2016 31

Rituximab vs. Ocrelizumab in Relapsing MS: Phase 2 Studies

Primary Endpoints Compared With Placebo

Hauser SL, et al. N Engl J Med 358:676–88, 2008; Kappos L, et al. Lancet 378:1779–87, 2011

Weeks 4 8 12 20 24 Mean No. T1 Gd+ Lesions 1.0 2.0 3.0 4.0 16

Ocrelizumab (OCR) Placebo – OCR Study Rituximab (RTX) Placebo – RTX Study

OCR Adjusted AAR at 24 Weeks 0.0 0.2 0.4 0.6 1.0 0.8 RTX

Placebo Placebo 32

Rituximab vs. Ocrelizumab in Progressive MS

Time to 12-week Confirmed Disability Progression

Weeks Proportion of Patients (%) 216 60 12 10 20 30 40 60

Hawker et al, Ann Neurol 66:460, 2009; Montalban X, Hauser SL, Kappos L, et al. NEJM 2016

Ocrelizumab (OCR) Placebo – OCR Study Rituximab (RTX) Placebo – RTX Study

50 24 36 48 72 84 96 108 120 132 144 156 168 180 192 204

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The B cell Experience in MS – Clinical Implications

Ocrelizumab represents an extremely effective, well-tolerated therapy for RRMS
Effect size is unprecedented.
Anticipate significant early adoption by the MS community
Fueled by failure of “treat-to-target” approach; lack of “rebound” when D/C’d
Long-term safety surveillance and best practice strategies need to be developed
Safety concerns in patients with chronic infections, including hepatitis
Administer immunizations prior to beginning treatment
Avoid live vaccines (zoster, typhoid) in B cell depleted patients
Switch rules are empirically-based at this time
Unclear risks from legacy treatments
JCV monitoring unnecessary
Ideal duration of therapy also uncertain
For primary progressive MS, at long-last an effective therapy is available
Effect is quite partial, as measured by EDSS
Trends for responses in both Gad+ and Gad- patients

The B cell Experience in MS – Disease Implications

Opportunity to understand MS behavior when inflammation is shut down at onset
Is late neurodegeneration/progression prevented or mitigated?
Even more selective B cell based approaches are now feasible
Target restricted subpopulations of B cells or even culprit B cell clones
For progressive MS, much more needs to be done
Are meningeal B cells and plasma cells the culprit?
Plasma cells are long-lived, resistant to RT, most chemotherapies, anti-CD20
Targeting plasma cells may now be possible:
Monoclonal Abs: Anti-CD38 (Daratumumab) Anti-CD19 (Blinatumomab)
Novel BCR signaling pathway inhibitors: BTK (Ibrutinib); PI3Kd (Idelalisib); 20S Proteosome (Carflizomib); B cell

CLL/lymphoma 2 (BCL-2); (Kyprolis)

Follicle inhibitors: Anti-LT a ( Pateclizumab); Anti LT b (Baminercept)
The anti-CD20 trials have revealed profound insights into the biology of MS
B cells are central players in pathogenesis, but so many questions remain!

Therapeutic Decision Making 2017: Relapsing MS

EFFICACY SAFETY

HIGHER HIGHER LOWER

Oral Parenteral

(Avonex, Betaseron, Rebif) Daclizumab Dimethyl Fumarate Mitoxantrone Glatiramer Acetate Natalizumab Interferons Fingolimod Teriflunomide Natalizumab

First Line Second Line Third Line

JC Virus + JC Virus -

Alemtuzumab

Therapeutic Decision Making 2017: Relapsing MS

EFFICACY SAFETY

HIGHER HIGHER LOWER

Emerging Oral Parenteral

(Avonex, Betaseron, Rebif) Daclizumab

Ocrelizumab

Dimethyl Fumarate Mitoxantrone Glatiramer Acetate Natalizumab Interferons Fingolimod Teriflunomide Natalizumab

First Line Second Line Third Line

JC Virus + JC Virus -

Alemtuzumab

Bone Marrow Transplantation

E E

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