Blood Stem Cell Therapy MGTA-456 Showing Signs of Efficacy in Cerebral ALD, Early Trial Data Show

Blood Stem Cell Therapy MGTA-456 Showing Signs of Efficacy in Cerebral ALD, Early Trial Data Show

Magenta Therapeutics’ allogeneic blood stem cell therapy resolved brain inflammation and stopped the loss of white brain matter in two cerebral adrenoleukodystrophy (ALD) patients, early data from a Phase 2 clinical trial shows.

The results were presented at the 2019 Transplant and Cellular Therapy (TCT) Annual Meeting, held Feb. 20–24 in Houston.

ALD, an inherited metabolic disorder, is characterized by the buildup of a type of lipids called very long-chain fatty acids (VLCFA), particularly in the brain, adrenal glands, testis, and skin cells of patients. Cerebral ALD, the most common form of ALD, is marked by an inflammatory process that destroys myelin — the protective layer around nerve cells’ axons. This leads to progressive loss of cognitive and neurological functions including communication and voluntary movement, blindness, and incontinence.

Allogeneic hematopoietic stem cell transplant (HSCT) is seen as the only way of stopping cerebral ALD from progressing. HSCT is based on the transplant of hematopoietic stem cells — cells that can form all types of blood cells in the body — from a genetically similar donor (allogeneic), usually a close relative of the patient.

HSCT’s benefits over the long term are thought to be mediated by replacing microglial cells mainly, which are immune cells of the central nervous system. But for a transplant to be successful, clinicians need to transfer a high number of cells.

“Inherited metabolic disorders are rare diseases that cause progressive damage to multiple organs, including the brain, and are often fatal. Stem cell transplant is the only disease-modifying treatment option but delivering sufficient doses of stem cells has been a persistent challenge,” John Davis, MD, MPH, chief medical officer at Magenta Therapeutics, said in a press release.

“MGTA-456 provides patients with a large number of stem cells to help overcome these challenges,” Davis added.

Magenta’s MGTA-456 is a first-in-class allogeneic stem cell therapy that is produced by expanding cord blood stem cells in a way that leads to a significant increase in the number of  hematopoietic stem cells or HSCs.

The therapy is being tested in a Phase 2 trial (NCT03406962) in patients with inherited metabolic disorders, including cerebral ALD. Its primary outcome, or endpoint, is the success of cell engraftment after the transplant; engraftment refers to the growth of new blood-forming cells that make healthy blood stem cells. Secondary goals are transplant-related safety and tolerability.

The trial, which is currently recruiting at its University of Minnesota site, is looking to enroll 12 patients. More information is available here.

As of January 30, the first five patients treated with MGTA-456 showed successful cell engraftment by day 42 post-transplant. This data stand in marked difference to cord blood cell transplants in similar conditions but without MGTA-456, where engraftment failed in 32% of the cases.

The increase in HSCs with MGTA-456 also reduces the risk of developing neutropenia (low neutrophil counts, a type of immune cell) and platelets. In patients treated with MGTA-456, low neutrophils counts were evident for one day, compared to at least eight days in those given conventional blood transplants.

Two cerebral ALD patients were among the five analyzed, and results showed that gadolinium-enhancing lesions, a mark of brain inflammation, were resolved by 28 days post-transplant, and their resolution was maintained up to 100 and 180 days after transplant in each patient. At the time of the analysis, the Loes score — a way to quantify the severity of white brain matter loss —  remained stable in both patients.

Paul Orchard, MD, with the University of Minnesota detailed these results in the oral presentation, “Robust Engraftment with MGTA-456, a CD34+ Expanded Cell Therapy Product in Patients with Inherited Metabolic Disorders (IMD): Preliminary Phase 2 Trial Results.

“[W]e are pleased that all five evaluable patients treated with MGTA-456 thus far have met the primary endpoints with robust and consistent engraftment,” said Davis, adding that “in patients with cALD [cerebral ALD], we have seen persistent decrease in brain inflammation as measured by imaging. These are early signs that MGTA-456 may provide disease-modifying clinical benefit to these patients.”

Kevin Goncalves, PhD, with Magenta Therapeutics, presented the results of a preclinical study in mice treated with MGTA-456 and analyzed for engraftment of microglia cells in the brain. Microglia are immune cells that act as a support system for the brain. Mice were irradiated or treated with a chemotherapy agent to destroy their bone marrow.

Treatment resulted in a marked increase in hematopoietic cells — an 11-fold and 25-fold increase — and with microglial cells engraftment – by 24- and 60-fold – in the brain of irradiated and chemotherapy-treated mice, respectively.

“Microglial engraftment is more rapid and robust in recipients of MGTA-456 due to the high number of … cells contained in MGTA-456,” the researchers wrote.

These preclinical results were in the poster, “MGTA-456, a First-in-Class Cell Therapy with High Doses of CD34+ CD90+ Cells, Enhances Speed and Level of Human Microglia Engraftment in the Brains of NSG Mice.”