Is Mesoblast’s acute Graft versus Host Disease product poised to fulfil the promise of mesenchymal stem cells?

The therapeutic use of mesenchymal stem cells or MSCs was first investigated in humans in 1995, generating a great deal of early enthusiasm about their promise as easily manufactured allogeneic cellular medicines. Since 1995, MSCs have become one of the most clinically studied experimental cell therapy platforms in the world. After more than 20 years of MSC clinical research, which has not yet resulted in an FDA-approved therapy, many people have questioned whether they can fulfil their therapeutic promise.

However, an MSC product developed by Mesoblast, a world leader in the development of cellular medicines, could be poised to be the first MSC therapy approved in the United States. Recently released Phase 3 results for remestemcel-L demonstrated a 100-day survival rate of 75% in pediatric patients with acute Graft versus Host Disease (GVHD) that have failed to respond to steroids. Patients with this disease typically have extremely poor outcomes, with overall survival as low as 20%.  As a first-line or salvage therapy, remestemcel-L has the potential to change the standard of care for steroid-refractory acute GVHD.


About remestemcel-L


Remestemcel-L comprises a population of MSCs, which are rare cells found around blood vessels that respond to signals associated with tissue damage. These cells secrete mediators and growth factors which promote tissue repair and modulate immune/inflammatory responses. MSCs are immune privileged, meaning that they do not need to be tissue-matched to individual patients.


Mesoblast extracts mesenchymal lineage precursor cells (MPCs), and their progeny MSCs, from the bone marrow of healthy adults. Through a proprietary process, these cells are isolated and highly purified before being industrially expanded to produce multiple doses from each donor that meet stringent criteria regarding release and lot-to-lot consistency.


In preclinical studies, remestemcel-L has demonstrated immunomodulatory properties that regulate T-cell mediated inflammatory responses such as those occurring in acute GVHD. MSCs inhibit T-cell proliferation and down-regulate the production of the pro-inflammatory cytokines, including tumor necrosis factor-alpha and interferon gamma.


What is Graft versus Host Disease?


GVHD is a serious and life-threatening complication of a bone marrow transplant which occurs when the donor cells attack the recipient’s healthy tissues and organs. This can impair the tissue or organ’s function or may cause them to fail altogether. The donor cells trigger secretion of tumor necrosis factor alpha and interferon gamma, which results in activation of pro-inflammatory T-cells and the often-fatal tissue damage to the skin, gut and liver.


Approximately 50% of patients will develop acute GVHD of the estimated 30,000 allogeneic bone marrow transplants occurring every year. Around 20% of all bone marrow transplants occur in children. About 50% of patients respond to steroid therapy to treat acute GVHD, but those patients who are refractory to steroids have very poor outcomes with overall survival as low as 20%.


Currently, there are no approved therapies for patients with steroid-refractory acute GVHD in the United States.


In Japan, Mesoblast’s licensee JCR Pharmaceuticals Co. Ltd., is marketing TEMCELL® HS Inj. for children and adults with acute GVHD. TEMCELL was the first allogeneic cellular medicine to receive full regulatory approval in Japan.


Bringing remestemcel-L to the US market

Following the announcement of positive 28-day and 100-day results from its Phase 3 trial in the first half of 2018, Mesoblast is poised to be first to market in the United States with an allogeneic regenerative medicine candidate for acute GVHD.


The Phase 3 open-label clinical trial assessed the safety and efficacy of remestemcel-L in pediatric patients with acute GVHD who have failed systemic corticosteroid therapy. The study enrolled 55 children aged between six months and 17 years in 32 sites across the United States, with 89% of these patients having severe (grade C/D) acute GVHD.


In February this year, the Phase 3 trial met the primary endpoint of Day 28 overall response. The overall Day 28 response rate was 69%, a statistically significant increase compared to the protocol-defined historical control rate of 45%(p=0.0003).


The 100-day secondary endpoint results showed that patients had an overall survival rate of 75%. The survival rate for patients who showed a response at day 28 was 87%. The typical mortality rates for steroid-refractory acute GVHD are around 70%. The multi-dose regimen of remestemcel-L infusions was well tolerated.


These results were consistent with the overall response, safety, and survival in previous use of remestemcel-L in a 241 subject expanded access protocol of pediatric subjects with steroid refractory acute GVHD who failed to respond to steroids as well as to multiple additional therapies.


Given the serious and life-threatening nature of steroid-refractory acute GVHD and the lack of any approved treatments, the FDA granted Mesoblast Fast Track designation for investigation of remestemcel-L for the treatment of children with steroid refractory acute GVHD.


Based on interactions with the FDA, Mesoblast believes that the successful results from the completed Phase 3 trial through Day 100, combined with 180-day safety and quality of life follow-up in these patients, may provide sufficient clinical evidence for filing for remestemcel-L in the United States under an accelerated approval pathway.


Mesoblast hopes to be able to bring remestemcel-L to the United States market itself. If marketing approval is gained for use of remestemcel-L in children, the company plans to seek label extension for high-risk adult patients with steroid-refractory acute GVHD.  


Mesoblast is developing its mesenchymal lineage cell technology for use in multiple other disease areas, including chronic heart failure and chronic lower back pain due to disc degeneration. Its extensive intellectual property estate covers the extraction of mesenchymal lineage cells from healthy volunteers, the expansion of these cells, the development of particular products for specific diseases and the administration of the therapy to the patient.


This robust pipeline of late-stage cellular medicines for serious and life-threatening conditions, recognition by the FDA of their importance, a burgeoning portfolio of earlier stage therapy candidates, and very comprehensive intellectual property puts Mesoblast in a strong position going forward to make novel therapies based on mesenchymal lineage cells available worldwide.


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