Cellerant's most advanced program, CLT-008 (romyelocel-L), is an allogeneic myeloid progenitor cell (MPC) therapy under development for the treatment of severe neutropenia following myelosuppressive chemotherapy or radiation exposure. Currently, CLT-008 is in phase 2 development for the treatment of severe neutropenia associated with induction chemotherapy for acute myeloid leukemia (AML).
CLT-008 is a universal 'off-the-shelf' human allogeneic MPC product that is cryopreserved. The CLT-008 product is manufactured from pooled hematopoietic stem cells (HSCs) isolated from screened and tested healthy donors. HSCs are cultured ex vivo under conditions that promote their expansion and differentiation into MPCs. The CLT-008 MPC product is comprised of Multipotent Progenitors (MPP: CD34+CD90+), Common Myeloid Progenitors (CMP), Granulocyte Macrophage Progenitors (GMP), and Megakaryocyte Erythroid Progenitors (MEP), but importantly, contains few or undetectable levels of T or B lymphocytes. The figure below highlights the progenitor cell population targeted by the CLT-008 product. As a population of MPCs, CLT-008 has the capacity to produce granulocytes (including neutrophils), monocytes, macrophages, red blood cells and platelets, but lacks the ability to permanently engraft in the bone marrow and has little potential to produce lymphoid cells.
CLT-008 is intended to engraft transiently and produce mature myeloid cells that migrate to tissues damaged by chemotherapy or radiation to mitigate the risk of bacterial or fungal infection for weeks following myelosuppressive chemotherapy or radiation. In preclinical models, fully allogeneic MPCs can be infused and the myeloid effector cells derived from them function to prevent infection and bridge myelopoiesis following high-dose radiation exposure (Singh 2012; Bitmansour 2002; Bitmansour 2005; Arber 2005). Similarly, in the clinical setting, the interaction of neutrophils with their target is not HLA restricted and the product can be infused without HLA matching.
Neutropenia is a condition that exists when the blood contains an abnormally low number of neutrophils. Neutrophils are mature white blood cells that are responsible for removing foreign organisms that cause bacterial and fungal infections. A healthy person will have at least 1.5 million neutrophils per milliliter of blood. Chemotherapy and radiation therapy for cancer preferentially kill cells that are actively dividing, including not only the targeted cancer cells but also many types of normal cells. Blood stem and progenitor cells in the bone marrow are continuously dividing under normal conditions in order to replenish the bloodstream and they are particularly sensitive to chemotherapy and radiation damage because they are dividing cells. As a result, many chemo- and radiation therapies for the treatment of cancer, as well as exposure to radiation from a nuclear accident or terrorist act, can cause a condition known as severe neutropenia, in which there are fewer than 0.5 million neutrophils per milliliter of blood. A prolonged period of severe neutropenia makes the patient very susceptible to infections, often leading to serious infections that can result in death even when excellent medical care and antimicrobials are given.
Granulocyte colony stimulating factor (G-CSF), also known as Neupogen® or filgrastim, is a growth factor that stimulates myeloid progenitor cells to divide and to differentiate into neutrophils, and it has been shown to be effective in decreasing the duration of severe neutropenia in several chemo- and radiotherapy settings. However, there remains an unmet medical need in patients receiving myelosuppressive chemotherapy or radiation therapy where, despite the use of G-CSF, the duration of severe neutropenia remains prolonged and the risk of developing a serious infection is high.
Cellerant has successfully completed the initial phase 1 safety testing of CLT 008 in a total of 75 patients receiving treatment for a hematologic malignancy, one study in patients receiving chemotherapy and radiation conditioning for an umbilical cord blood transplant (see clinicaltrials.gov; NCT00891137), and the other in patients with leukemia receiving consolidation or induction chemotherapy (see clinicaltrials.gov; NCT01297543). A phase 2 safety and efficacy study of CLT-008 in elderly patients receiving induction chemotherapy for de novo AML is in progress (see clinicaltrials.gov; NCT02282215) to evaluate safety and to explore efficacy in reducing infection-related complications in this setting. In the event of an accident or event involving radiation exposure, CLT-008 may also be evaluated in subjects who receive acute radiation injury at a dose level resulting in severe neutropenia.
The CLT 008 program is funded by a contract from the Biomedical Advanced Research and Development Authority (BARDA) in the U.S. Department of Health and Human Services to develop a medical countermeasure for use in a public health emergency to treat the effects of the Acute Radiation Syndrome (ARS) on the blood system for a total contract value of $188 million.