Anisha Keshavan. Roland Henry, PhD. Proportion of Patients (%) Rituximab 2000mg (n=66) Placebo (n=35)

Transcription

1 Two Faces of Multiple Sclerosis February 8, T H A N N U A L R E C E N T A D V A N C E S I N N E U R O L O G Y B CELL THERAPY FOR MULTIPLE SCLEROSIS: A NEW DAY? Inflammation Relapsing MS Anisha Keshavan Neurodegeneration Progressive MS Stephen L. Hauser, MD Department of Neurology University of California, San Francisco Roland Henry, PhD COI: Symbiotix, Annexon, Bionure, Neurona, Molecular Stethoscope 2 Rituximab in Relapsing Remitting MS Gadolinium-Enhancing Lesions from Baseline to Week 48 Rituximab in Primary Progressive MS Time to Confirmed Disease Progression Mean Number of Gd Lesions P =.78 P =.3 P =.1 P < Rituximab 2mg (n=66) (n=35) Proportion of Patients (%) All Intent-to-Treat Patients (n=439) HR (95% Cl):.77 (.55, 1.9); p-value=.1442 Rituximab * Missing values imputed by average of available data Hauser SL, et al. N Engl J Med 358:676 88, 28 3 Hawker et al, Ann Neurol 66:46,

2 in Relapsing Remitting MS: Reduction in Gd-Enhancing Lesions Maintained Through 144 OPERA I & II: Two Identical Studies of in Relapsing MS Mean No. T1 Gd-enhancing Lesions Primary end point: OCR vs placebo Patients with baseline MRI (n=54) 6mg (n=55) 1mg (n=55) IFN beta-1a (n=54) - Core Study' ( 96 weeks) - Follow-Up' ( weeks) a * RMS diagnosis yrs EDSS of clinical relapses within last 2 yrs or 1 relapse in last yr 1:1 Randomization OLE screening period OLE Safety follow-up 48 weeks from date of last infusion B-cell monitoring * for both OCR doses vs placebo, N (for primary analysis): =54, OCR 6 mg=51, OCR 1 mg=52, IFN-β1a=52 a Patients who withdrew during earlier treatment cycles were also included in the follow-up periods Hauser SL, et al. Presented at the American Academy of Neurology, March 13, Con nued 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. 6 MS Disease Histories and Characteristics Were Balanced Over 85% of Patients Completed the Studies OPERA I OPERA II OPERA I OPERA II 44 µg n=411 6 mg n=41 44 µg n=418 6 mg n= µg 6 mg 44 µg 6 mg Age, yr, mean (SD) 36.9 (9.3) 37.1 (9.3) 37.4 (9.) 37.2 (9.1) Female, n (%) 272 (66.2) 27 (65.9) 28 (67.) 271 (65.) Time since onset, yr, mean (SD) 6.3 (6.) 6.7 (6.4) 6.7 (6.1) 6.7 (6.1) ITT*, n Treated, n Time since diagnosis, yr, mean (SD) 3.7 (4.6) 3.8 (4.8) 4.1 (5.1) 4.2 (5.) Withdrawn, n (%) 69 (17) 42 (1) 97 (23) 57 (14) Relapses previous 12 months, mean (SD) 1.3 (.6) 1.3 (.7) 1.3 (.7) 1.3 (.7) Withdrawn due to AE, n (%) 25 (6.1) 13 (3.2) 25 (6.) 16 (3.8) Previously untreated*, n (%) 292 (71.4) 31 (73.8) 314 (75.3) 34 (72.9) Entered safety follow-up, n (%) 42 (61) 24 (57) 39 (4) 16 (28) 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.) Completed, n (%) Entered safety follow-up, n (%) 34 (83) 12 (4) 366 (89) 1 (3) 32 (77) 15 (5) 36 (86) 8 (2) Number Gd + T1 lesions, mean (SD) 1.9 (5.2) 1.7 (4.2) 2. (4.9) 1.8 (5.) Entered open-label extension, n (%) 326 (96) 352 (96) 297 (93) 35 (97) Number T2 lesions, mean (SD) 51.1 (39.9) 51. (39.) 51. (35.7) 49.3 (38.6) ITT *Untreated in 2 years prior to study entry. EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; SD, standard deviation; yr, year. *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

3 in Relapsing MS Reduction in Annualized Relapse Rate Compared With IFNβ-1a OPERA I OPERA II in Relapsing MS Reduction in Mean Gadolinium-Enhancing Lesions Compared With IFNβ-1a OPERA I OPERA II 46% ARR reduction vs 47% ARR reduction vs 97% 95% 92% 96% 91% 98% ITT *Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4. vs 4.), and geographic region (US vs ROW). ARR, annualised relapse rate; EDSS, Expanded Disability Status Scale; IFN, interferon; ROW, rest of the world. ITT *Adjusted by means calculated by negative binomial regression and adjusted for baseline T1 Gd lesion (present or not), baseline EDSS (<4. vs 4.) 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. 9 1 Reduction in Pre-specified Pooled Analysis of Confirmed Disability Progression (CDP) Higher Proportion of Patients With Improvement in Brain Volume Loss Compared With IFNβ-1a OPERA I OPERA II Time to CDP for 12 weeks Time to CDP for 24 weeks Percentage Change in Brain Volume from Baseline to Week 96 * Percentage Change in Brain Volume from Baseline to Week 96 Week Week Risk reduction: 4% HR (95% CI):.6 (.45,.81); p=.6 Risk reduction: 4% HR (95% CI):.6 (.43,.84); p=.25 ITT CI, confidence interval; HR, hazard ratio; IFN, interferon; OCR, ocrelizumab. ITT Exploratory endpoints: *24% improvement vs ; ; 24% improvement vs ; p=.1; Compared using the Cochran Mantel Haenszel test stratified by geographic region (US vs ROW) and baseline EDSS score (<4. vs. 4.)

4 Adverse Events Were Similar n (%) 44 μg (n=826) 6 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 Table includes only AEs occurring in 5% of patients in at least one treatment group. AE, adverse event; IFN, interferon. 8 (9.7) 177 (21.4) 127 (15.4) 64 (7.7) 45 (5.4) 87 (1.5) 84 (1.2) 1 (12.1) 45 (5.4) 29 (3.5) 124 (15.) 54 (6.5) 38 (4.6) 37 (4.5) 51 (6.2) 283 (34.3) 38 (4.6) 1 (.1) 64 (7.8) 2 (.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) Total Serious Adverse Events Were Low and Similar n (%) Table includes only AEs occurring in 5% of patients in at least one treatment group. AE, adverse event; IFN, interferon. IFNβ-1a 44 μg (n=826) 6 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.) Injury, poisoning, and procedural complications 1 (1.2) 6 (.7) During OPERA I and OPERA II, three deaths occurred 44 μg arm: completed suicide, mechanical ileus 6 mg arm: completed suicide Six malignancies were reported: 44 μg arm: mantle cell lymphoma and squamous cell carcinoma 6 mg arm: renal cancer, melanoma and two breast cancers Is Effective in Relapsing MS and Has A Favorable Safety Profile ORATORIO: Phase 3 Study of in Primary Progressive MS 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 Diagnosis of PPMS (25 revised McDonald criteria) 1 Age years EDSS CSF: elevated IgG index or >1 oligoclonal bands No history of RRMS, SPMS, or PRMS No treatment with other MS DMTs at screening 2:1 Randomization # The consistency of effect and magnitude of treatment effect size seen in OPERA I and OPERA II indicate that targeting CD2 + B cells with ocrelizumab is highly effective in relapsing MS CDP, confirmed disability progression; Gd+, gadolinium enhancing; IFN, interferon. 15 *Patients received methylprednisolone prior to each ocrelizumab infusion or placebo infusion. The blinded treatment period may be extended un l database lock. #2:1 randomisation stratified by age ( 45 vs >45) and region (US vs ROW). Con nued 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. 1 Polman CH, et al. Ann Neurol 25;58:

5 ORATORIO: MS Disease History and Baseline characteristics *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. 17 n=244 n=488 Age, yrs, mean (SD) 44.4 (8.3) 44.7 (7.9) Female, n (%) 124 (5.8) 237 (48.6) Time since MS symptom onset, yrs, mean (SD) 6.1 (3.6) 6.7 (4.) 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, cm 3, mean (SD) Normalized brain volume, cm 3, mean (SD) 6 (24.7).6 (1.6) 1.9 (13.) (88.7) 133 (27.5) 1.2 (5.1) 12.7 (15.1) (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 () in Progressive MS Time to 12-week Confirmed Disability Progression 7 (6mg) Proportion of Patients (%) % reduction in risk of CDP HR (95% CI):.76 (.59,.98); p= Montalban X, Hauser SL, Kappos L, et al. NEJM Secondary Endpoint: Significant Reduction In the Progression Rate of Walking Time Change in Brain T2 Hyperintense Lesion Volume From Baseline to Week 12 Percent Change in Timed 25-Foot Walk From Baseline to Week 12 29% reduction vs placebo p=.44* % Change from Baseline Walking Time % Change From Baseline T2 Lesion Volume % Change From Baseline T2 Lesion Volume n=39 n= % with placebo vs 3.4% with ocrelizumab * n=183 n=4 % Change From Baseline T2 Lesion Volume n=144 n=291 *Analysis based on ITT population; p-value based on ranked ANCOVA at 12-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 logtransformed 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. *Analysis based on ITT population; p-value based on ranked ANCOVA at 12-week visit adjusted for baseline T2 lesion volume, geographic region and age with missing values imputed by LOCF. Point estimates and 95% CIs based on MMRM analysis on logtransformed 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

6 Change of Whole Brain Volume From Week 24 to Week 12 % Change in Whole Brain Volume From Week % relative reduction p=.26* n=15 n=325 SAEs by System Organ Class Reported by 1% of Patients in Either Treatment Arm Until Clinical Cut-Off Date n (%) (n=239) 6mg (n=486) Overall patients with 1 SAE 53 (22.2) 99 (2.4) Infections and Infestations 14 (5.9) 3 (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) % Change in Whole Brain Volume From Week 24 n=31 n=83 % Change in Whole Brain Volume From Week 24 *Analysis based on ITT population with Week 24 and at least one post-week 24 assessment; p-value based on MMRM at 12-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. n=119 n=241 SAE, serious adverse event. Gastrointestinal Disorders 3 (1.3) 1 (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.) Five deaths were reported: 1 (.4%) in the placebo arm: road traffic accident 4 (.8%) in the ocrelizumab arm: pulmonary embolism, pneumonia, pancreas carcinoma, pneumonia aspiration Thirteen malignancies were reported: 2 (.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, Was Effective in PPMS and Had an Overall Safety Profile Similar to How Does Work? 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 AE, adverse event; CDP, confirmed disability progression; PPMS, primary progressive multiple sclerosis; SAE, serious adverse event

7 Targeting CD2+ B cells Can Preserve B cell Reconstitution and Long-Term Immune Memory B CELLS B cell Reconstitution Preserved 1-3 CD2 PLASMA CELLS Long-term Immune Memory Preserved 1,2,4 Rituximab (chimeric), ocrelizumab (humanised), and ofatumumab (human) are monoclonal antibodies that selectively deplete CD2 + B cells Many MS Drugs in Development Target B cell Mechanisms Mode of Action Drug Target Signaling Rituximab 1 MS Off Label Trial Status NMO (SD) Off Label Phase 3 CD2 Lytic Ofatumumab Phase 3 Ublituzumab 2 Phase 2 MEDI CD19 Phase 2 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 Off Label Off Label IL-6R SA237 Phase 2 Eculizumab C5a Phase 3 Effector NPB-1 (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 Image adapted from Krumbholz M, et al. Nat Rev Neurol 8:613 23, 212; 1. Hauser SL. Mult Scler 21:8 21, 215; 2. Pescovitz MD. Am J 25 Transplant 6:859 66, 26; 3. Leandro MJ, et al. Arthritis Rheum , 26; 4. DiLillo DJ, et al. J Immunol 18:361 71, MS Therapies Have Consistent Effects on B cells Effect on B cells* Interferon Beta Glatiramer acetate Fingolimod Therapy Dimethyl fumarate Modulation Differentiation Teriflunomide Mitoxantrone Natalizumab Alemtuzumab Anti-CD2 RTX, OCR, OFA Are Differences in Anti-CD2 MAbs Clinically Meaningful? Rituximab vs. Activation Migration Depletion *In humans and experimental models

8 Superior Efficacy and Tolerability of Rituximab c/w Fingolimod Following Switch From Natalizumab Due to JCV+ Serology.2 A Retrospective Observational Study of RTX in MS Incidence of drug discontinuation Disease Breakthrough Fingolimod Rituximab Adverse Events Fingolimod Rituximab Days 5 Alping P, et al. Ann Neurol 79:95, Salzer J, et al. Neurology 87:274 81, Rituximab vs. in Relapsing MS: Phase 2 Studies Primary Endpoints Compared With Rituximab vs. in Progressive MS Time to 12-week Confirmed Disability Progression Mean No. T1 Gd+ Lesions Rituximab (RTX) RTX Study (OCR) OCR Study Adjusted AAR at Proportion of Patients (%) Rituximab (RTX) RTX Study (OCR) OCR Study OCR RTX Hauser SL, et al. N Engl J Med 358:676 88, 28; Kappos L, et al. Lancet 378: , Hawker et al, Ann Neurol 66:46, 29; Montalban X, Hauser SL, Kappos L, et al. NEJM

9 The B cell Experience in MS Clinical Implications 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-cd2 Targeting plasma cells may now be possible: Monoclonal Abs: Anti-CD38 (Daratumumab) Anti-CD19 (Blinatumomab) Novel BCR signaling pathway inhibitors: BTK (Ibrutinib); PI3Kd (Idelalisib); 2S Proteosome (Carflizomib); B cell CLL/lymphoma 2 (BCL-2); (Kyprolis) Follicle inhibitors: Anti-LT a ( Pateclizumab); Anti LT b (Baminercept) The anti-cd2 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 217: Relapsing MS Therapeutic Decision Making 217: Relapsing MS Alemtuzumab Natalizumab Natalizumab JC Virus + JC Virus - Third Line Second Line Oral Parenteral E Bone Marrow Transplantation Alemtuzumab Natalizumab Natalizumab JC Virus + JC Virus - Third Line Second Line E E Oral Parenteral Emerging EFFICACY Mitoxantrone Daclizumab Fingolimod Dimethyl Fumarate First Line EFFICACY Mitoxantrone Daclizumab Fingolimod Dimethyl Fumarate First Line Teriflunomide Glatiramer Acetate Interferons (Avonex, Betaseron, Rebif) Teriflunomide Glatiramer Acetate Interferons (Avonex, Betaseron, Rebif) LOWER SAFETY LOWER SAFETY

10 Therapeutic Decision Making 217: Progressive MS Therapeutic Decision Making 217: Progressive MS Oral Parenteral Oral Parenteral SPMS SPMS PPMS PPMS EFFICACY O Off-label EFFICACY O E Off-label Emerging E LOWER SAFETY O LOWER SAFETY O Thank You! 39 1