Remestemcel-L

Identification

Name
Remestemcel-L
Accession Number
DB13973
Type
Biotech
Groups
Approved, Investigational
Description

Remestemcel-L is a third-party, off-the-shelf suspension of ex-vivo cultured adult human mesenchymal stem cells intended for intravenous infusion. The mesenchymal stem cells are derived from the bone marrow of unrelated and human leukocyte antigen (HLA)–unmatched healthy adult donors and have the ability to differentiate into different tissue cells. It was approved for use in Canada in May 2012 as Prochymal for the management of refractory acute Graft versus Host Disease (aGvHD) in children who are unresponsive to systemic steroid therapies, with the approval conditional upon further trials being conducted.

aGvHD is a T-cell mediated disease that occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues [A31822] developed by 30-80% of the recipients 1. aGvHD is often characterized by the presence of inflammatory cascades through signalling of activated T cells. While systemic corticosteroids and other immunosuppressive agents are commonly used as first-line treatments to manage aGvHD, about 30-50% of patients with aGvHD experience inadequately control of disease with first-line therapies, putting them in a risk for poor outcomes and creating a significant clinical challenge 1. It is estimated that the patients with the most severe forms of refractory aGvHD that do not respond to steroid therapy have expected one-year survival rates of only 5% to 30% 6. Human mesenchymal stem cells (hMSCs) serve to down-regulate inflammatory responses and produce anti-inflammatory cytokines and growth factors to promote tissue repair 1. In clinical studies, patients treated with remestemcel-L demonstrated an improvement in their aGvHD and improved survival rates at subsequent days following intravenous infusion 6. Based on its tolerability and safety profile, remestemcel-L is a promising alternative to second-line immunosuppressive agents 1.

Synonyms
  • Adult human mesenchymal stem cells
External IDs
MSC-100-IV
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ProchymalSolutionIntravenousMesoblast International SàrlNot applicableNot applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
Not Available
UNII
H57D26Z9YK
CAS number
Not Available

Pharmacology

Indication

Indicated for in the management of acute Graft versus Host Disease (aGvHD) in pediatric patients. Acute GvHD should be refractory to treatment with systemic corticosteroid therapy and/or other immunosuppressive agents. Remestemcel-L may be used for Grades C and D of the disease in any organ. Remestemcel-L may also be used in the management of Grade B aGvHD involving any visceral organ, including the GI tract and the liver, but excluding skin.6

Associated Conditions
Pharmacodynamics

Remestemcel-L exerts an immunomodulatory effects both in vivo and vitro by suppressing the proliferative activity of allogenic T lymphocytes. In vitro, there was evidence of tissue protection and tissue repair effects, through reduction of pro-inflammatory cytokines and secretion of factors. There were no signs of electrocardiogram disturbances, changes in hemoglobin saturation, heart rate, or respiration rate with intravenous administration of remestemcel-L.6

Mechanism of action

Pathogenesis of acute graft versus host disease: Acute graft versus host disease (aHvGD) occurs in recipients of allogenic stem cell transplantation and is characterized by differentiation and activation of alloreactive T lymphocytes. aGvHD is associated with tissue injury in various organs such as the liver, skin and intestinal mucosa 3. Acute GvHD can be summarized in a three-step process: conditioning phase, donor T-Cell activation, and cellular and inflammatory effector phase 2,3. The first phase involves the tissue damage induced by conditioning regimen (irradiation and chemotherapy) and production of inflammatory factors such as cytokines and adhesion molecules 2,3. The expression of MHC antigens and adhesion molecules is recognized by donor T cells. These donor T cells are activated in phase 2, resulting in subsequent proliferation, differentiation and secretion of cytokines including IL-2 and IFN-γ 2. These cytokines enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and facilitate the production of TNF-α and IL-1 by monocular phagocytes 2. Inflammatory cytokines promotes the production of inflammatory chemokines, thus recruits effector cells into target organs and initiates phase 3 of the disease 2,3. Phase 3 involves cascades of cell-mediated cytotoxicity and signalling of multiple inflammatory effectors 3, leading to amplification of local tissue injury and further promotion of an inflammatory response 2.

Mechanism of action of remestemcel-L: Human mesenchymal stem cells (hMSCs), or remestemcel-L, are derived from the bone marrow are capable of differentiation into cells derived from the mesoderm germ layer, such as osteocyte, adipocyte and chondrogenic cells 4. Once administered, they migrate to the site of inflammation to reduce the production of pro-inflammatory cytokines. It has been demonstrated that hMSCs secrete a wide range of bioactive molecules, such as growth factors, cytokines, and chemokines, that mediate regenerative and anti-apoptotic actions 5. Some molecules released by hMSCs include PGE2 and IL-10 for anti-inflammatory effects, or TGFβ1 and HLA-G5 for suppression of T cell proliferation 5. There is evidence that hMSCs interact with natural killers cells, monocytes, macrophages, effector T cells and regulatory T cells to shift their pro-inflammatory Th1 cytokine secretion profile to an anti-inflammatory Th2 cytokine profile 5. hMSCs also suppress NK cell proliferation and disrupts the migration, maturation, and antigen presentation of dendritic cells that differentiated from monocytes 5. In a mouse model of ischemia, remestemcel-L have been shown to stimulate the growth of new blood vessels, which is a process crucial to tissue repair, through secretion of factors such as VEGF.6 Overall, hMSCs exert immunomodulatory actions to inhibit inflammatory responses in aGvHD.

Absorption

Following intravenous infusion, distribution of remestemcel-L to the lungs within minutes of infusion was observed in several in vivo biodistribution studies of healthy animals. Based on findings of total body irradiation studies of animals, remestemcel-L will preferentially distribute to sites of inflammation and tissue damage such as the bone marrow, GI tract, and skin, the organs that have sustained the most tissue damage.6

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

The metabolism of cellular components (nucleic acids, amino acids, lipids, etc) in the normal course of cell turnover in the body is well understood. It is expected that the infused cells will be metabolized the same way; therefore these studies were not conducted.6

Route of elimination

The excretion of cellular components (nucleic acids, amino acids, lipids, etc) in the normal course of cell turnover in the body is well understood. It is expected that the infused cells will be metabolized the same way; therefore these studies were not conducted.6

Half life
Not Available
Clearance
Not Available
Toxicity

In a single-dose toxicology study in rats, the no-observed adverse effect level (NOAEL) following IV administration was 40x106 MSC/kg and the maximum tolerated dose (MTD) was 65x106 MSCs/kg. The NOAEL was a cumulative dose of 80x106 MSC/kg when dosing twice per week in a repeat-dose study in rats, with no effects on host immune cell quantities or immune system functionality. There was no evidence of alloantibody formation.6

In a 6-week tumorigenicity study in mice, there was no evidence of tumor formation attributed to human mesenchymal stem cells. Standard genotoxicity and carcinogenicity studies, as well as animal reproduction and developmental toxicology studies were not conducted with remestmecel-L as they were not relevant for the aGvHD patient population.6

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

References

General References
  1. Kurtzberg J, Prockop S, Teira P, Bittencourt H, Lewis V, Chan KW, Horn B, Yu L, Talano JA, Nemecek E, Mills CR, Chaudhury S: Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant. 2014 Feb;20(2):229-35. doi: 10.1016/j.bbmt.2013.11.001. Epub 2013 Nov 8. [PubMed:24216185]
  2. Reddy P: Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 2003 Dec;21(4):149-61. doi: 10.1002/hon.716. [PubMed:14735553]
  3. Jaksch M, Mattsson J: The pathophysiology of acute graft-versus-host disease. Scand J Immunol. 2005 May;61(5):398-409. doi: 10.1111/j.1365-3083.2005.01595.x. [PubMed:15882431]
  4. Tobin LM, Healy ME, English K, Mahon BP: Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 2013 May;172(2):333-48. doi: 10.1111/cei.12056. [PubMed:23574329]
  5. Amorin B, Alegretti AP, Valim V, Pezzi A, Laureano AM, da Silva MA, Wieck A, Silla L: Mesenchymal stem cell therapy and acute graft-versus-host disease: a review. Hum Cell. 2014 Oct;27(4):137-50. doi: 10.1007/s13577-014-0095-x. Epub 2014 Jun 6. [PubMed:24903975]
  6. Health Canada Product Monograph: Remestemcel-L adult mesenchymal stem cells [Link]
External Links
Wikipedia
Prochymal

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAtopic Dermatitis (AD)1
1CompletedTreatmentIdiopathic Pulmonary Fibrosis (IPF)1
2CompletedTreatmentChronic Bronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Pulmonary Emphysema1
2CompletedTreatmentChronic Ischemic Left Ventricular Dysfunction / Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction / Myocardial Infarction1
2CompletedTreatmentCrohn's Disease (CD)1
2CompletedTreatmentDiabetes Mellitus, Insulin-Dependent / Type 1 Diabetes Mellitus1
2CompletedTreatmentGraft Versus Host Disease (GVHD)2
2CompletedTreatmentMyocardial Infarction1
3CompletedOtherGrade B Acute Graft Versus Host Disease / Grade C Acute Graft Versus Host Disease / Grade D Acute Graft Versus Host Disease1
3CompletedTreatmentCrohn's Disease (CD)3
3CompletedTreatmentGrade B aGVHD / Grade C aGVHD / Grade D aGVHD / Grades B-D aGVHD1
3CompletedTreatmentGraft Versus Host Disease (GVHD)2
3RecruitingTreatmentAcute Respiratory Distress Syndrome (ARDS) / COVID / Mesenchymal Stromal Cells / Novel Coronavirus Infectious Disease (COVID-19) / Remestemcel-L1
Not AvailableNo Longer AvailableNot AvailableCrohn's Disease (CD)1
Not AvailableNo Longer AvailableNot AvailableGraft Versus Host Disease (GVHD)2
Not AvailableNo Longer AvailableNot AvailableModerate to Severe Acute Respiratory Distress Syndrome Associated With COVID-19 / Novel Coronavirus Infectious Disease (COVID-19)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntravenous
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Drug created on January 17, 2018 15:39 / Updated on June 12, 2020 10:53

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