Adding Aphexda helps to collect more stem cells for ASCT in trial

FDA decision on Aphexda expected by Sept. 9

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by Steve Bryson, PhD |

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Aphexda (formerly motixafortide), BioLineRx’s experimental add-on therapy, greatly increased the number of blood stem cells collected for autologous stem cell transplants (ASCT), a life-extending treatment for multiple myeloma.

While Aphexda generated more stem cells with fewer pre-treatments, it may also help patients who do not generate enough cells to be eligible for a transplant.

These are the main findings of the Phase 3 GENESIS clinical trial (NCT03246529), whose positive data convinced the U.S. Food and Drug Administration to review the company’s application seeking Aphexda’s approval. A reply from the agency is expected by Sept. 9.

“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,” John DiPersio, MD, PhD, the trial’s principal investigator, said in a company press release.

“These data highlight the potential of [Aphexda] plus G-CSF, if approved, to enhance the treatment options for clinicians and patients with multiple myeloma undergoing ASCT,” added DiPersio, who is a professor of medicine and the director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine in Missouri.

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Complete results of the trial were published in the journal Nature Medicine, in the study “Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.”

In myeloma, white blood cells that normally produce antibodies, called plasma cells, become cancerous and grow out of control in the bone marrow. This interferes with the production of hematopoietic stem cells (HSCs), which give rise to all types of blood cells, including white blood cells, red blood cells, and platelets.

Autologous hematopoietic stem cell transplant (ASCT) is a standard treatment for eligible myeloma patients that has been shown to improve survival.

HSCs are collected from a patient using a procedure called apheresis, whereby a machine draws blood and separates cells into different types. Then, healthy HSCs are returned to the patient in the form of a transplant to generate new, healthy blood cells.

In advance of apheresis, transplant candidates receive injections of granulocyte colony-stimulating factor (G-CSF). This stimulates the HSCs to move, or mobilize, from the bone marrow into the bloodstream, allowing more cells to be collected.

However, this mobilization process is slow, usually requiring four to eight daily infusions and up to four apheresis sessions. Furthermore, some patients are unable to produce enough HSCs with this standard approach.

Aphexda is designed to enhance stem cell mobilization into the bloodstream by blocking CXCR4, a receptor protein that plays a role in retaining stem cells within the bone marrow.

There has not been significant innovation in stem cell mobilization treatments in over a decade…. These data highlight the potential of [Aphexda] plus G-CSF, if approved, to enhance the treatment options for clinicians and patients with multiple myeloma undergoing ASCT.

Trial included 122 adults with multiple myeloma

GENESIS enrolled 122 adult patients from 18 sites in the U.S., Germany, Italy, Hungary, and Spain. They were randomly assigned to receive either G-CSF plus Aphexda (90 patients) or G-CSF plus a placebo (42 patients).

Trial participants were representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with about 70% in both groups receiving Revlimid (lenalidomide) as part of induction regimens.

Older age and exposure to Revlimid-based regimens, including four-drug combinations, can impair HSC mobilization, BioLineRx stated in the release.

“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,” DiPersio said.

Meeting GENESIS’s primary goal, one dose of G-CSF plus Aphexda allowed significantly more patients to mobilize at least six million HSCs per kg in no more than two apheresis sessions compared with G-CSF plus a placebo (92.5% vs. 26.2%). The likelihood of reaching this goal was 53 times higher with add-on Aphexda.

Similar results were seen after one apheresis session (88.8% vs. 9.5%), attaining a key secondary goal. Here, the likelihood of success was 118 times better with Aphexda.

More of those given Aphexda collected the minimum number of HSCs required for ASCT after one apheresis session than with G-CSF alone (96.3% vs. 64.3%). Also, to collect enough HSCs, fewer G-CSF injections were needed per patient with Aphexda versus a placebo (5.26 vs. 8.12), as well as fewer apheresis procedures (1.23 vs. 3.24).

The median time to new blood cell growth (engraftment), graft durability 100 days after ASCT, and progression-free survival and overall survival were similar between the two groups and “consistent with contemporary outcomes,” the researchers wrote.

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Aphexda group generated 10.5 times more primitive hematopoietic stem cells

A deeper analysis of participant samples revealed that, compared with those given G-CSF plus a placebo, those in the Aphexda group generated 10.5 times more primitive HSCs, which are early stem and progenitor cells capable of giving rise to multiple blood cell types.

Significantly more of these cells were also generated with the Aphexda combo than with other G-CSF approaches, according to reports from previous studies.

In addition, gene activity analyses within these primitive HSCs showed that Aphexda preferably mobilized subsets of cells with increased activity in pathways associated with enhanced self-renewal and regeneration.

These analyses “were not designed to understand potential clinical outcomes; nevertheless, we believe the findings are of interest and a compelling area for further research,” DiPersio said.

G-CSF plus Aphexda had a favorable safety profile and was generally well-tolerated. The most commonly reported adverse events were temporary injection site reactions.

“The upfront use of a single injection of [Aphexda] added to G-CSF resulted in rapid, robust and reliable mobilization of optimal numbers of [HSCs] in [multiple myeloma] patients undergoing ASCT,” the researchers wrote.

“This first peer-reviewed publication of results from the Phase 3 GENESIS trial are an important validation of the potential of [Aphexda] 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 [Aphexda] with the aim of advancing care for patients with multiple myeloma,” Rachmilewitz added.