CURRENT UNDERSTANDING OF PROGRESSIVE MS AND FUTURE DIRECTIONS

Transcription

1 CURRENT UNDERSTANDING OF PROGRESSIVE MS AND FUTURE DIRECTIONS Jeffrey A. Cohen, MD Director, Mellen MS Center Neurological Institute Cleveland Clinic 14 JUN 2014

2 Disclosures Jeffrey A. Cohen, MD reports for the last year: Personal compensation as a consultant: EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, Novartis, Vaccinex Research support paid to his institution: Biogen Idec, Consortium of MS Centers, Dept of Defense, Genzyme, NIH, National MS Society, Novartis, Receptos, Synthon, Teva, Vaccinex

3 Prototypic Course of MS Relapses and impairment MRI lesion activity Brain volume (atrophy) Secondary-Progressive Preclinical Relapsing-Remitting Disease Duration (Years)

4 MS Pathogenesis Early: multifocal CNS inflammatory lesions Lesions evolve and accumulate over time and produce demyelination and axonal damage Reflected in MRI lesions and relapses but much of the activity and accumulating damage may be subclinical Late degeneration Inflammatory lesion activity becomes less prominent and disability gradually worsens The pathogenesis of progression is uncertain: shift from adaptive to innate immune response, neurodegeneration, accelerated aging Some of these processes may be present at the early stages

5 Treatment Effects on GdE vs. Relapses R 2 = 0.71 Sormani. Lancet Neurol 12: , 2013

6 International Advisory Committee on Clinical Trials in MS Advisory group comprised of academic MS clinicians, clinical trialists, neuroradiologists, immunologists, statisticians Supported by the National MS Society and ECTRIMS Revise the Lublin & Reingold (1996) classification of MS clinical course Refine the definitions by incorporating recent relapse rate and MRI lesion activity Lublin et al. Neurology (in press)

7 MS Outcomes Assessments Consortium Collaboration of academic, industry, regulatory, and patientadvocacy representatives Supported by the US National MS Society Coordinated by the C-Path - a nonprofit, public-private partnership with the Food and Drug Administration (FDA), created in 2005 under the auspices of FDA's Critical Path Initiative. Mission: to develop, gain regulatory approval, and support adoption of a new clinician-reported outcome measure for use in future MS clinical trials Consortium Multiple Sclerosis Outcome Assessments (MSOAC)

8 Modified Multiple Sclerosis Functional Composite (MSFC) Dimension Measure Units Ambulation Timed 25-Foot Walk Seconds Arm function 9-Hole Peg Test Seconds Vision Sloan Low-Contrast Letter Acuity Number correct Cognition Symbol Digits Modality Test Number correct New component tests and scoring method Rudick 1997, Cutter 1999, Balcer 2003, Baier 2005, Wu 2007, Smith 1982, Rao 1991

9 Knowledge Program Software integrated into the Epic electronic medical record to facilitate systematic collection of clinical and imaging data at each encounter Combination of: Clinician- and patient-reported outcomes General items collection throughout the Cleveland Clinic Neurological Institute Program-specific items As of 12/11/13, since implementation at Mellen in 2007 data have been collected on 16,034 unique patients at 63,661 encounters

10 Knowledge Program: Clinician-Reported Outcomes Timed 25 foot walk (sec) and assistive device 9-hole peg test right (sec) 9-hole peg test left (sec) Number of falls in the last month

11 Knowledge Program: Patient Reported Outcomes European Quality of Life (EQ-5D) Patient Health Questionnaire (PHQ-9) MS Performance Scales: mobility, hand function, vision, sensation, cognition, bladder/bowel, spasticity, fatigue Neuro-QOL v1.0 Fatigue Sleep INFORMS-NQ Fatigue impact Sleep impact

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13 Multiple Sclerosis Performance Test Battery of quantitative neuroperformance assessments Administered using an ipad app Modeled after the MS Functional Composite approach but Additional data from the component tests Additional domains Supervised or self administration Raw data are transferred wirelessly to the cloud and scored instantaneously, enabling automatic entry into a research or clinical database.

14 ipad Apps and Analogous Technician- Administered Neuroperformance Tests ipad App Technician-Administered Walking Speed Test (WST) Timed 25-Foot Walk (T25FW) Upper Extremity Function Test (UEFT) 9-Hole Peg Test (9HPT) Low Contrast Visual Acuity (LCVA) Sloan Low Contrast Acuity (SLCVA) Processing Speed Test (PST) Symbol Digits Modality Test (SDMT) Spatial Memory Test (SMT) Visuo-spatial episodic memory Balance Assessment Balance Error Scoring System, Tetrax

15 Walking Speed Test Based on T25FW ipad is attached at sacrum level on subject with purpose-built belt Accelerometer and Gyrometer in ipad collect motion data at 100 Hz Gait is objectively analyzed from motion data

16 Upper Extremity Function Test Based on 9-Hole Peg Test Physical board overlays on ipad screen with actual pegs Two configurations for more detailed analysis Ability to measure individual peg insertion and removal times

17 Low Contrast Visual Acuity Test Based on SLCVA Variable contrast ratio at 100%, 10%, 5%, 2.5% and 1.25% Randomly selected letter combinations of equal difficulty Screen brightness controlled

18 Processing Speed Test Analogous to SDMT Data provided: Time to complete Total # correct Total # incorrect Inter-stimulus response time

19 Spatial Memory Test

20 Spatial Memory Test

21 Medial-Lateral (ML) Anterior-Posterior (AP) Balance Assessment Two 30 second trials Hands on hips, feet together Eyes open, then eyes closed ipad os attached at sacrum level on subject with purpose-built belt Accelerometer and Gyrometer in ipad collect motion data at 100 Hz Measures patient center of gravity movement to quantify postural stability

22 MSPT Summary Relative to the technician administered counterparts, MSPT ipad apps demonstrate comparable or superior performance with regard to: Reliability Concurrent Validity Practice Effects Sensitivity ipad apps can provide metrics that are not possible with technician administered tests ipad apps are well-tolerated by MS patients Currently collecting normative database consisting of 240 healthy adults, allowing clinical interpretations of MSPT scores in individual MS patients.

23 International Progressive MS Alliance Previously known as the International Progressive MS Collaborative Supported by: MS International Federation, National MS Society (US), Italian MS Society, MS Society (UK) Five key areas of unmet need: 1. Experimental models 2. Identify potential therapies, including pathway identification and drug repurposing 3. Proof-of-concept trial design 4. Clinical outcome measures 5. Symptom management and rehabilitation Fox RJ et al. Mult Scler J 2012

24 Progressive MS Trials ASCEND natalizumab in SPMS (Phase III) INFORMS fingolimod in SPMS (Phase III) ORATORIO ocrelizumab (anti-cd20) in PPMS (Phase III) EXPAND siponimod (selective S1PR modulator) in SPMS (Phase III) PROXIMUS Trial - oxcarbazepine in SPMS (Phase II) MS Smart riluzole, amiloride, ibudilast in SPMS (Phase II) SPRINT-MS ibudilast in PPMS/SPMS (Phase II) Phenytoin, mastitinib, lipoic acid, erythropoietin, hydroxyurea, idebenone, rehabilitation

25 Bone Marrow Stem Cell Lineages MSCs comprise % of BM cells

26 MSC Properties Facilitating Isolation Plastic adherence High proliferative rate in culture Methods to confirm purity: Characteristic fusiform, spindle-shaped morphology Surface markers Methods to confirm functional capacity: Mesodermal differentiation Immunomodulatory effects

27 Adult MSCs Promote Repair in Several Ways In addition, MSCs can traffic from blood into inflamed or injured tissue Trzaska. Molec Med Reports 1:307, 2008

28 MSC Treatment of Multiple Sclerosis Reference Indication Patients MSC Source Connick 2012 SPMS 10 Karussis 2010 RR, SP, PP MS 15 Liang 2009 PP MS 1 Mohyeddin Bonad 2007 Treatment-refractory MS 10 Autologous culture-expanded BM MSCs administered IV Autologous culture-expanded BM MSCs administered IV and IT Allogeneic umbilical cord MSCs administered IV and IT after CTX Autologous culture-expanded BM MSCs administered IT Rice 2010 Chronic MS 6 Fresh BM cells enriched for MSCs Riordan 2009 Treatment-refractory MS 3 Yamout 2010 SPMS 10 Autologous non-expanded adipose MSCs Autologous culture-expanded BM MSCs administered IT

29 Safety Considerations with MSC Transplantation Infusion-related adverse effects Embolic phenomena Immunogenicity including anti-fbs Ab Bradycardia, MI, encephalopathy, stroke from DMSO Infection Contamination Immunosuppression Neoplasia Ectopic tissue formation MS related: allergic phenomena, autoimmunity, disease activation

30 Implications of Pilot Studies MSCs may have both anti-inflammatory and proinflammatory effects on MS-relevant immune responses MSC phenotype depends on their history and microenvironment These results support the rationale of conducting safety studies with comprehensive clinical, imaging, and immunologic monitoring Darlington. Ann Neurol 68:540, 2010

31 Goals of the Trial Assess and document feasibility and safety Create a foundation for future studies IND Standardized procedures for marrow harvest, cellexpansion, infusion, follow-up, etc. with SOPs where appropriate Regulatory-compliant electronic data capture, database, and site monitoring Trial infrastructure e.g. Steering Committee, Medical Monitor, DSMC, central labs

32 Goals of the Trial Develop efficacy endpoints for a Phase 2 trial focusing on neurodegeneration and repair Feasibility and measurement properties of outcomes Preliminary assessment of benefit on those outcomes Generate mechanistic data re: MSC biology in MS Scientific interest Related to trial design

33 Phase 1 Trial of Adult MSC Transplantation in MS Study Population 24 patients RR or SP MS (approx 12 each) EDSS History or evidence of prior optic neuritis Treatment Follow-up Single IV infusion of 1-2 x 10 6 /kg autologous MSCs Isolated from bone marrow, culture expanded, cryopreserved, thawed, infused 2 months pre- and 6 months post-treatment 1 o outcome Feasibility, and infusion-related safety and tolerability over 1 month 2 o outcomes Safety and tolerability over 6 months GdE MRI lesions at Month 1

34 Phase 1 Trial of Autologous MSC Transplantation in MS Exploratory outcomes Pre- vs. post transplant: Self-reported overall status Relapses, EDSS, MSFC MRI: GdE, N/E T2, T2-vol, T1-vol, whole brain and GM atrophy, DTI, MTI Visual pathways: SLCLA, VEP, OCT Immunologic mechanistic studies

35 Study Status Enrollment and Follow-up 24 of planned 24 participants were infused All completed the study (LPLV JAN 2014) Feasibility 1 culture failure; participant was replaced All the other participants received the target dose of cells All planned assessments were performed (except 1 blood test at 1 visit)

36 Study Status Safety No treatment-related severe (CTCAE grade 3+) or serious adverse events No autoimmune phenomena No evidence of paradoxical disease activation Efficacy No clearcut impact on disease activity or severity Exploratory efficacy analyses are in progress

37 Baseline Characteristics (infused) Characteristic Participants (n=24) Age, yr mean ± SD 46.5 ± 5.4 Sex Disease course 16 F / 8 M 10 RR / 14 SP Disease duration, yr mean ± SD 13.8 ± 9.0 EDSS mean ± SD median (range) Disease treatment 5.2 ± ( ) 6 IFNβ, 6 GA Participants with Gd-enhancing lesions 6 (25%) T2 lesion volume, ml mean ± SD 20.3 ± 12.3 Brain parenchymal fraction mean ± SD 0.78 ± 0.04

38 Culture Kinetics and Yield Parameter Percoll Yield (x10 6 ) Final Yield (x10 6 ) Culture Duration (days) Dose (x10 6 /kg) N Mean ± SD ± ± ± ± 0.2 Minimum Maximum culture terminated at 28 days All other cultures were successful and cell products fulfilled the release criteria Variable BMA yield of nucleated cells, MSC growth rate, and final yield No obvious correlation with demographics, other medical diagnoses, MS clinical features, or medications Updated 12 AUG 2013

39 Expanded Disability Status Scale M -2 M -1 M 0 M 1 M 2 M 3 M 6 N Mean SD Median Min Max Update this slide Updated 08 DEC 2013

40 Gadolinium-Enhancing Lesion Number M -2 M -1 M 0 M 1 M 2 M 3 M 6 N Mean SD Median Range N Active % Active 25% 33% 50% 38% 33% 29% 33% Participants were not selected for active MRI Overall MRI lesion activity has been modest in most participants No clearcut disease activation or inhibition post-transplant

41 Issues Under Discussion for Phase 2 Safety monitoring Less intense Efficacy monitoring Placebo-controlled, delayed start, crossover Prioritize the efficacy endpoints Eligibility criteria Follow-up duration Sample size Single- or multi-center

42 Issues Under Discussion for Phase 2 Cell product Culture protocol xeno-free defined medium Dose Dosing (i.e. multiple doses) Fresh vs. thawed Other manipulations to improve potency Potency assay(s) Autologous vs. allogeneic (non-ms)

43 Impact of Co-Morbidities on MS 8,983 patients with MS in the NARCOMS database surveyed for coexisting medical conditions 77% had one or more coexisting condition e.g. hyperlipidemia (37%), hypertension (30%), diabetes (6%) Presence of coexisting medical conditions, particularly vascular co-morbidities (DM, HTN, CAD, hyperlipidemia, PVD): Increased delay from symptom onset to diagnosis Increased disability at diagnosis Increased rate of disability accrual Marrie. Neurology 72:117, 2009, Neurology 74:1041, 2010

44 Gait Impairment Develops Earlier With Any Vascular Comorbidity at Diagnosis Disability endpoint Unaffected Affected Difference (years) Early gait disability 16.1 ( ) 11.0 ( ) 5.1 Unilateral assistance 18.8 ( ) 12.8 ( ) 6.0 Bilateral assistance 23.2 ( ) 17.3 ( ) 5.9 Unadjusted median (95% CI) time from diagnosis to gait impairment Marrie. Neurology 74:1041, 2010

45 Vascular Comorbidity at Any Point in the Disease Increases the Risk of Disability Progression Vascular comorbidity Early gait disability Unilateral assistance Bilateral assistance N=7342 N=7342 N=5439 HR 95% CI HR 95% CI HR 95% CI Diabetes Heart dis Hypertension Cholesterol PVD HR adjusted for sex, year of symptom onset, age at symptom onset, income, health insurance status, race, and region of residence Marrie. Neurology 74:1041, 2010

46 Rationale for Statins to Treat MS Beneficial immunoregulatory effects Potential neuroprotective effects Direct Indirect via treatment of vascular comorbidity Oral bioavailability Extensive experience Excellent record for patient tolerance Limited risk of toxicity

47 MS-STAT Simvastatin 80 mg/d vs. placebo over 2 years in SPMS Slowed brain volume loss Reduced disability (EDSS) worsening No difference in relapse rate, MRI T2 lesion activity, or PBMC cytokine profile Chataway. Lancet published online 19 Mar 2014

48 MS-STAT Chataway. Lancet published online 19 Mar 2014

49 Sodium Chloride and MS Increased local [NaCl] drives induction of pathogenic T h 17 cells in vivo a Modest [NaCl] SGK I IL-23R b IL-23 has a critical role in stabilizing and reinforcing the T h 17 phenotype High salt diet severity of murine EAE a Whether dietary salt affects MS risk or disease course is unknown a Kleinewietfeld. Nature 496:518, 2013 b Wu. Nature 496:513, 2013

50 Vitamin D and MS In addition to a role in Ca/bone metabolism, Vitamin D regulates a wide range of cellular processes, including both immunomodulatory and neurotrophic effects Epidemiologic studies implicate low Vitamin D as a risk factor for MS either directly or as a mediator of UV exposure a Vitamin D levels correlate inversely with relapse rate, EDSS, and MRI lesion activity b Preliminary studies support the safety of Vitamin D supplementation in MS c Ongoing studies are investigating benefit of Vitamin D supplementation in RR and SP MS a Munger. JAMA 296:2832, 2006; Simpson. Ann Neurol 68:193, 2010 b Mowry. Ann Neurol 72:234, 2012; Runia. Neurology 79:261, 2012 c Burton. Neurology 74:1852, 2010; Stein. Neurology 77:1611, 2011

51 Management of Progressive MS Assess (reassess) for other treatable conditions that may be contributing to manifestations Collect quantitative neuroperformance data A trial of approved disease therapies is reasonable Particularly with recent inflammatory disease activity Acknowledgement of decreased likelihood of benefit and potential risk Plan to discontinue if no benefit after a reasonable trial Address comorbidities Treat symptoms and other sequelae Refer for participation in clinical trials