Trial Will Test New Combination Regimen for Stem Cell Collection

A clinical trial will assess a combination of MGTA-145 plus plerixafor as a new regimen for aiding in the collection of blood stem cells from adults and adolescents with sickle cell disease (SCD).

The proof-of-concept trial, a collaboration between Magenta Therapeutics and Bluebird Bio, may establish this new combination as a better mobilization regimen for these patients.

Such a much-needed regimen would provide an important alternative for people with SCD who cannot use more common mobilization agents due to the risk of vaso-occlusive crises and death, researchers said.

Many SCD treatments in development — including Bluebird Bio’s LentiGlobin — require the collection of a patient’s blood stem cells for genetic modification. A more effective stem cell collection regimen could optimize the patient experience with such treatments, according to the investigators.

Under the collaboration, the stem cells collected during this trial will be fully characterized, and Magenta will conduct preclinical studies to assess if they are amenable to gene editing and whether they successfully enter the bone marrow in mouse models.

“Achieving reliable and rapid stem cell mobilization and a simplified collection process can ensure the entire patient experience is optimal with respect to therapeutic outcome,” John Davis Jr., MD, head of research and development and chief medical officer, Magenta Therapeutics, said in a press release.

“We look forward to collaborating with bluebird bio to evaluate MGTA-145 as the preferred mobilization option for people with sickle cell disease,” Davis said.

Gene therapy approaches currently in development for SCD mostly work to correct the defective HBB gene, which is mutated in SCD, or to increase the production of fetal hemoglobin in red blood cells. Fetal hemoglobin is a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart.

In the majority of cases, this is done in hematopoietic stem cells, which are the cells in the bone marrow that originate all immune cells. These stem cells are collected from the patient, engineered to produce the gene sequence of interest, and introduced back into the patient in the form of a stem cell transplant.

However, the collection of stem cells from people with SCD is not without challenges. Notably, common mobilization agents — such as granulocyte-colony stimulating factor (G-CSF) — can trigger the painful vaso-occlusive crises that characterize the disease, or even death.

In its studies, Bluebird has been using a different mobilizing agent, called plerixafor, that inhibits the CXCR4 receptor — a receptor that retains these cells in the bone marrow — in stem cells. By blocking CXCR4, stem cells are able to leave the bone marrow and enter circulation, allowing doctors to collect these cells from the blood.

While it has proven effective, patients still require multiple collection cycles to generate enough stem cells for gene therapy, which places a significant burden on them.

Magenta’s MGTA-145 is CXCR2 activator that mobilizes stem cells through a distinct mechanism, and could be used in combination with plerixafor, potentially enabling the collection of sufficient stem cell numbers in a single collection step.

It also may enable stem cell collection on the exact same day of dosing, contrasting with the administration of G-CSF five to seven days before collection.

In a recently completed Phase 1 trial in healthy volunteers, the combination of MGTA-145 and plerixafor was well-tolerated and induced a rapid mobilization of functional stem cell numbers. That allowed for the collection of sufficient cells in a single day.

Data from preclinical studies also showed that stem cells collected with the new regimen were amenable to gene editing and were successfully engrafted, meaning the transplanted cells survived and expanded in the bone marrow.

“The incorporation of bluebird bio’s experience in this area of treatment will be immensely valuable in further developing MGTA-145 plus plerixafor to address the remaining unmet needs in gene therapy approaches for diseases like sickle cell disease,” Davis said.

Under the recent collaboration, the companies will fund the upcoming clinical trial in SCD patients, but Magenta will retain the rights to MGTA-145.

“In this initial study, we hope to establish whether the combination of plerixafor with MGTA-145 can generate appropriate … stem cells with a single round of mobilization,” said Dave Davidson, MD, chief medical officer at Bluebird Bio.

“If successful, we hope to evaluate this novel mobilization regimen with LentiGlobin to make another step forward in the treatment of patients with SCD,” Davidson said.

No details about the clinical trial have been released as yet.