On April 17, 2023 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a pre-commercial-stage biopharmaceutical company focused on oncology, reported the publication of data from the Company’s GENESIS Phase 3 clinical trial in the peer-reviewed journal Nature Medicine (Press release, BioLineRx, APR 17, 2023, View Source [SID1234630138]). The international GENESIS trial evaluated the safety and efficacy of the Company’s lead investigational candidate motixafortide plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF for the mobilization of hematopoietic stem cells in patients with multiple myeloma prior to autologous stem cell transplantation (ASCT).
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Multiple myeloma is the second most common hematologic malignancy and ASCT has been shown to improve survival and plays a central role in the treatment of these patients. A meaningful number of patients, however, are unable to collect a desired number of peripheral blood CD34+ hematopoietic stem and progenitor cells (HSPC) with current treatment modalities.
The primary objective of the study was to demonstrate that one dose of motixafortide with G-CSF, compared to placebo with G-CSF, allowed more patients to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight, in up to two apheresis sessions. A secondary objective of the study was to demonstrate that one dose of motixafortide with G-CSF was superior to placebo with G-CSF in its ability to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight in just one apheresis session. The clinical trial found that all primary and secondary endpoints were achieved with a statistical significance of p<0.0001.
"Despite improvements in survival that ASCT offers patients with multiple myeloma, there has not been significant innovation in stem cell mobilization treatments in over a decade," said John DiPersio, MD, PhD, Professor of Medicine and Director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine in St. Louis, and principal investigator of the GENESIS study. "With today’s increased use of multiple drug induction therapies and transplants in increasingly older patients, there is a corresponding increased need for new treatment options. These data highlight the potential of motixafortide plus G-CSF, if approved, to enhance the treatment options for clinicians and patients with multiple myeloma undergoing ASCT."
"This first peer-reviewed publication of results from the Phase 3 GENESIS trial is an important validation of the potential of motixafortide to address critical clinical challenges and the evolving needs of today’s ASCT treatment landscape in appropriate multiple myeloma patients," said Tami Rachmilewitz, MD, Chief Medical Officer at BioLineRx. "We look forward to continuing the development of motixafortide with the aim of advancing care for patients with multiple myeloma."
Additional GENESIS clinical trial objectives included time to engraftment of neutrophils and platelets and durability of engraftment. The motixafortide-plus-G-CSF regimen resulted in rapid and durable engraftment[i] of HSPCs following transplantation, and the regimen was also shown to have a favorable safety-profile and that it was generally well-tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions.[ii]
The study included patients that are representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with ~70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy. Increased age, as well as increased exposure to lenalidomide-containing induction regimens, including four-drug combination regimens, have been associated with impaired HSPC mobilization.[iii]
The study authors also performed parallel comparative FACS and single-cell transcriptional profile analyses, using GENESIS data and data from trial cohorts with other mobilization regimens, to better understand the types of cells mobilized.
The FACS analysis, as described by the study authors in Nature, found that motixafortide plus G-CSF resulted in a 10.5-fold increase in primitive HSPCs collected versus placebo plus G-CSF (p<0.0001); and significantly greater numbers of early stem and progenitor cells versus both placebo plus G-CSF (p<0.0001) and plerixafor plus G-CSF (p=0.0327). Primitive HSPCs and early stem and progenitor cells may be associated with enhanced self-renewal and regeneration.[iv] "The cohort analyses were not designed to understand potential clinical outcomes; nevertheless, we believe the findings are of interest and a compelling area for further research," said Dr. DiPersio.
A New Drug Application (NDA) for motixafortide in stem cell mobilization for autologous transplantation in multiple myeloma patients is currently under review with the U.S. Food and Drug Administration (FDA), with an assigned PDUFA date of September 9, 2023.
About the GENESIS Trial
The GENESIS trial (NCT03246529) was initiated in December 2017. GENESIS was an international, randomized, double-blind, placebo-controlled, multicenter study, evaluating the safety and efficacy of motixafortide and G-CSF, compared to placebo and G-CSF, for the mobilization of hematopoietic stem-cells for autologous transplantation in multiple myeloma patients. The primary objective of the study was to demonstrate that one dose of motixafortide with G-CSF, compared to placebo with G-CSF, allowed more patients to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight, in up to two apheresis sessions. A secondary objective of the study was to demonstrate that one dose of motixafortide with G-CSF was superior to placebo with G-CSF in its ability to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight in just one apheresis session. Additional objectives included time to engraftment of neutrophils and platelets and durability of engraftment, as well as other efficacy and safety parameters.
CD34+ cells in the GENESIS trial were assessed using both central lab and local lab data, both of which achieved statistical significance (p<0.0001) across all primary and secondary endpoints. The Nature Medicine publication focused on the study’s local lab data, as it was used for all clinical decisions in the study.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects some white blood cells called plasma cells, which are found in the bone marrow. When damaged, these plasma cells rapidly spread and replace normal cells in the bone marrow with tumors. According to the American Cancer Society, in 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and nearly 13,000 people will die from the disease in the U.S. While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.
About Autologous Stem Cell Transplantation
Autologous stem cell transplantation (ASCT) is part of the standard treatment paradigm for a number of blood cancers, including multiple myeloma. In the U.S., nearly 15,000 ASCTs are performed each year with the majority in patients with multiple myeloma. The current standard of care includes the administration of 5-8 daily doses of granulocyte colony stimulating factor (G-CSF), with or without 1-4 doses of plerixafor, and the performance of 1-4 apheresis sessions. For patients unable to mobilize sufficient numbers of cells for harvesting during this primary mobilization phase, rescue therapy is carried out, consisting of 1-4 additional doses of plerixafor on top of G-CSF, and the performance of an additional number of apheresis sessions as necessary.