Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

1. HALT-MSPhase II Clinical Trial of High Dose Immunosuppressive Therapy and AutoLogous Hematopoietic Stem Cell Transplantation for Active Relapsing-Remitting MSGeorge J. Hutton, MD

2. Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis • Aggressive therapeutic approach performed in several hundred (mostly progressive) MS patients worldwide. • Goal is to “reset” a patient’s immune system. • HSC is the progenitor of RBC, platelets, neutrophils, T lymphocytes, B lymphocytes, monocytes, and macrophages.

3. HSC Transplantation in MS • The problem: • Currently available MS treatments are unable to offer a sustained remission in most MS patients. • The immune attack is long lasting and the treatments have failed to eliminate the “memory” of the myelin attack.

4. HSC Transplantation in MS • Hypothesis: • Destroy or maximally suppress the immune compartment with high dose chemotherapy and/or radiotherapy and then infuse hematopoietic stem cells to allow maturation of new lymphocyte progenitors in an environment with no or minimal memory T cell influence. Muraro, J Exp Med, 2005.

6. HSC Transplantation in MS • Prior studies have demonstrated • Large decreases in number of enhancing lesions • Persistence of oligoclonal bands • Better outcomes for patients with baseline EDSS<6.0 • Probability of confirmed progression-free survival at 2-3 years is 50-85% Reviewed in: Mancardi, Saccardi, Lancet Neurology, 2008

7. Lessons Learned • Mobilization with G-CSF alone may lead to MS exacerbation • use Prednisone or CTX • Engraftment syndrome is common and may lead to neurological worsening • Prednisone post-HSCT • TBI-based regimens have unclear risk-benefit ratio • BEAM regimen • CD34 selection: Removing potentially autoreactive disease-causing lymphocytes from the infused graft may decrease risk of disease reactivation

8. HALT-MS: Objectives • To determine the five-year durability of disease stabilization in MS subjects after HDIT and autologous HSCT • To evaluate the safety and efficacy of the procedure • To evaluate myelin content and axonal integrity using MRI approaches in MS subjects undergoing the procedure. Immune reconstitution and mechanisms of disease following autologous HCT for MS will also be explored through a number of specific endpoints

9. HALT-MS: Endpoints • Primary endpoint is the time to treatment failure during the 5 years after transplant • Death due to any cause • Change in pre-transplant EDSS of >0.5 as compared to baseline (confirmed at 3 months) • Presence of at least 2 independent new MRI lesions (GD+ and/or new T2-W) • Clinical relapse (after day 56)

10. Reconstitution/mechanistic studies • Immunophenotyping of PBMC for major cell subsets • T cell repertoire analysis • Thymic function and output • Gene expression profiles in PBMC • Intracellular signaling in PBMC • EBV serology and viral load • T cell response to myelin antigens • B cell/antibody to myelin antigens • CSF studies: OCB, mechanistic studies

11. HALT-MS Eligibility • Age 18-60 • RRMS or PRMS • Poor response to standard DMT with residual disability • MS duration < 15 years • EDSS 3.0-5.5 (inclusive) • 2 or more relapses within last 18 months with EDSS increase ≥0.5 sustained for ≥4 weeks OR • 1 relapse within last 18 months with EDSS increase ≥1.5 for ≥4 weeks AND new Gd+/T2 MRI lesions separated from clinical relapse

12. BEAM: BCNU, etoposide, ARA-C (cytarabine), melphalan

13. Subjects Participants n=10 (6 female, 4 male) Age 32.5 years (median, range 26-46) Baseline EDSS 4.5 (median, range 3.0-5.0) Disease duration 3 years (median, range 1-11) Follow-up 12.2 months (median, range 0-27) CD34+ cells/kg 4.1x106 (median, purity 93.4%) Engraftment 11 days post AHSCT (median, range 11-13)

14. Enhancing MRI Lesions 38 40 37 AHSCT 20 # gd+ MRI lesions 0 0 0 0 0 Screening n=10 Baseline n=10 2 n=9 6 n=7 12 n=5 13 n=5 months

15. On DMT 20 No relapses No DMT 15 10 5 0 1-12 months FU 0-12 FU 6-12 12-24 >24 months prior AHSCT n=10 n=9 n=7 n=5 n=1 Relapses

16. EDSS Change from Baseline -2.5 -2.5 -2 improvement -1 median 0 median 0 0 1 worsening 1.0 6 months 12 months n=7 n=5

17. Post-HSCT Complications Engraftment syndrome n=1 Pseudo-Relapse n=1 Pseudo-GVHD n=1 Gallbladder obstruction n=1 Rehospitalization for leukopenia/fatigue n=1 Rehospitalization for IV line infection n=1 MRSA Infection n=1 Late leukopenia n=1

18. Results • Follow-up of up to 27 months (median 12 months) • No relapses since HSCT • 1 patient with worsened EDSS, others improved (up to 2.5 EDSS points) • No new Gd+ lesions • No patients have required DMT • Observed AEs were transient and mild.

19. Conclusions • HDIT and autologous HSCT can be performed safely in patients with treatment-refractory MS. • Initial results are encouraging. • HALT-MS is ongoing and open to enrollment. • Prospective trial with planned 5 year follow-up after last transplanted subject.

20. www.halt-ms.org • www.halt-ms.com • ClinicalTrials.gov Identifier: NCT00288626

21. University of Washington ●Richard A. Nash, MD Fred Hutchinson Cancer Research Center ●James D. Bowen, MD MS Center at Evergreen ●George H. Kraft, MD ●Annette Wundes, MD Houston, TX ● Uday Popat, MD University of Texas MD Anderson Cancer Center ●George J. Hutton, MD Baylor College of Medicine Ohio State University ● Michael K. Racke, MD ● Steven M. Devine, MD ●Linda Griffith, MD, PhD Medical Officer DAIT, NIAID, NIH ●Peter H. Sayre, MD, PhD Immune Tolerance Network San Francisco Consultants University of Texas Southwestern ●Elliott Frohman, MD, PhD ●Olaf Stuve, MD, PhD City of Hope ●Harry Openshaw, MD ●Stephen J. Forman, MD ●Paolo Muraro, MD, PhD Imperial College, London, UK ●Douglas L. Arnold, MD, FRCP(C) NeuroRx Research, Montreal ●Roland Martin, MD University Medical Center Eppendorf Hamburg, Germany ●Harry McFarland, MD NINDS/NIH, Bethesda HALT-MS Team IND Sponsor: Division of Allergy, Immunology and Transplantation (DAIT) National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH)