HALT-MSPhase II Clinical Trial of High Dose

Immunosuppressive Therapy and AutoLogous Hematopoietic Stem Cell Transplantation for

Active Relapsing-Remitting MS

George J. Hutton, MD

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.

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.

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.

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

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

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

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)

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

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 weeksOR

1 relapse within last 18 months with EDSS increase ≥1.5 for ≥4 weeks AND new Gd+/T2 MRI lesions separated from clinical relapse

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

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)

Subjects

Enhancing MRI Lesions

37 38

0 0 0 00

20

40

Screening

n=10

Baseline

n=10

2

n=9

6

n=7

12

n=5

13

n=5

monthsAH

SC

T

# g

d+

MR

I le

sions

Relapses

0

5

10

15

20

1-12 monthsprior AHSCT

n=10

FU 0-12

n=9

FU 6-12

n=7

12-24

n=5

>24 months

n=1

On DMT

No relapsesNo DMT

median 0 median 0

1

0

-1

-2

6 months 12 monthsn=7 n=5

imp

rovem

en

tw

ors

en

ing

-2.5 -2.5

1.0

EDSS Change from Baseline

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

Post-HSCT Complications

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.

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.

www.halt-ms.org www.halt-ms.com ClinicalTrials.gov Identifier:

NCT00288626

HALT-MS Team

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 TexasMD Anderson Cancer Center

●George J. Hutton, MDBaylor College of Medicine

Ohio State University● Michael K. Racke, MD● Steven M. Devine, MD

●Linda Griffith, MD, PhDMedical OfficerDAIT, NIAID, NIH

●Peter H. Sayre, MD, PhDImmune Tolerance NetworkSan 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, PhDImperial College, London, UK

●Douglas L. Arnold, MD, FRCP(C)NeuroRx Research, Montreal

●Roland Martin, MDUniversity Medical Center EppendorfHamburg, Germany

●Harry McFarland, MDNINDS/NIH, Bethesda

IND Sponsor: Division of Allergy, Immunology and Transplantation (DAIT) National Institute of Allergy and Infectious Diseases (NIAID)

National Institutes of Health (NIH)