Acute Graft Versus Host Disease

remestemcel-L is being developed for the treatment of acute graft versus host disease (aGVHD) following an allogeneic bone marrow transplant (BMT). 

Disease Indication and Patient Population

In patients who have received a BMT, donor cells may attack the recipient (the person receiving the transplant), causing aGVHD. The donor T-cell mediated inflammatory response involves secretion of TNF-alpha and INF-gamma, resulting in activation of pro-inflammatory T-cells and tissue damage in the skin, gut and liver which is often fatal.

According to the Center for International Blood and Marrow Transplant Research, there are approximately 30,0001 allogeneic BMTs globally per year for diseases including hematological cancers, with 25%2 of all cases in the pediatric population. Nearly 50% of all allogeneic BMT patients develop aGVHD3. Liver or gastrointestinal involvement occur in up to 40%4 of all patients with aGVHD and are associated with the greatest risk of death, with mortality rates of up to 85%5.

Currently, there are no products currently approved in the United States for treatment of steroid-refractory aGVHD in children under 12, and off-label options have demonstrated mixed efficacy with high toxicity. We believe there is a significant need for effective treatment with a favorable risk/benefit profile.


remestemcel-L is a Tier 1 intravenously delivered product candidate comprising 100 million mesenchymal stem cells (MSCs)/unit dose under investigation for the treatment of steroid refractory acute graft versus host diseases (aGVHD) following an allogeneic BMT.

Mechanism of Action

remestemcel-L has demonstrated immunomodulatory properties to regulate T-cell mediated inflammatory responses by inhibiting T-cell proliferation and down-regulating the production of the pro-inflammatory cytokines, including tumor necrosis factor-alpha, or TNF-alpha, and interferon gamma.

Regulatory Approval and Clinical Trials

Product Registration - Japan

Our licensee in Japan for aGVHD, JCR Pharmaceuticals Co. Ltd., is marketing its MSC-based product for children and adults with aGVHD. TEMCELL® HS Inj.6 is the first allogeneic cellular medicine to receive full regulatory approval in Japan.

Expanded Access Program (EAP)

More than 240 pediatric patients suffering from steroid-refractory aGVHD have been treated with remestemcel-L under an EAP in the United States, Canada and several European countries.

Phase 3 Trial

Mesoblast’s open-label Phase 3 trial enrolled 55 children with steroid-refractory aGVHD (aged between six months and 17 years) at 32 sites across the United States, with the vast majority (89%) suffering from the most severe form of aGVHD (Grade C/D).

This Phase 3 trial successfully met its primary endpoint of Day 28 Overall Response (OR) to remestemcel-L treatment, with 69% of patients achieving this endpoint compared to the protocol-defined historical control rate of 45% (p=0.0003). In patients who had a positive OR to treatment with remestemcel-L at Day 28, survival was 87% at Day 100. At Day 180, survival in these patients was 79% (p=0.001 by Kaplan-Meier survival estimates compared to non-responders). Overall Day 180 survival for the entire remestemcel-L treated group was 69%. Historical survival rates in patients with Grade C/D disease and failure to respond to steroids have been only 10-30%7-10.

These Phase 3 outcomes are consistent with previous results in 241 children with steroid-refractory aGVHD who failed to respond to multiple biologic agents and were treated under an expanded access program (EAP) that followed outcomes through 100 days. The multi-infusion regimen in both the EAP11 and the Phase 3 trial was well tolerated12. In discussions with the Company, the United States Food and Drug Administration (FDA) advised that a successful Phase 3 trial should achieve both the primary endpoint of Day 28 OR and also demonstrate overall survival benefits through 180 days. Mesoblast is now working towards a pre-BLA meeting with the FDA in the next few months. Existing Fast Track designation from the FDA allows eligibility for priority review and a rolling BLA review process.


1CIBMTR, Decision resources GVHD Epi Nov 2012

2Number of hematopoietic stem cell transplants registered with the CIBMTR by US centers, 2008 – 2012, by year of transplant

3Decision resources Niche Markets and Rare diseases: GVHD Nov 2012

4Jacobsohn, David A and Vogelsang, Georgia B. Acute graft versus host disease. Orphanet J Rare Dis. 2007; 2: 35.

5Westin, Jason R. et al. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Advances in Hematology

6TEMCELL® HS Inj. is the registered trademark of JCR Pharmaceuticals Co. Ltd.

7MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment trials. Blood. 2010; 115 (26): 5412-5417.

8MacMillan ML, Couriel D, Weisdorf DJ, et al. A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease. Blood. 2007; 109 (6): 2657-2662.

9Pidala J, Kim J, Field T, et al. Infliximab for managing steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009; 15 (9): 1116-1121.

10Arai S et al, Poor outcome in steroid refractory graft versus host disease with anti-thymocyte globulin treatment. Biol Blood Marrow Transplant. 2002; 8: 155-160

11Kurtzberg J. et al. Effect of Human Mesenchymal Stem Cells (remestemcel-L) on Clinical Response and Survival Confirmed in a Large Cohort of Pediatric Patients with Severe High-Risk Steroid-Refractory Acute Graft Versus Host Disease. BBMT. 2016; 22.

12Data on file from Protocol 280 Clinical Study Reports