Magenta Therapeutics’ stem cell therapy MGTA-456 leads to clinically meaningful and lasting benefits in neurological and cognitive functions — as well as a resolution in brain inflammation — in children with cerebral adrenoleukodystrophy (CALD), according to one-year follow-up data from a Phase 2 clinical trial.
The results of the study, “MGTA-456 Cell Therapy in Inherited Metabolic Disease (IMD) Yields Rapid and Durable Long-Term Improvement of Disease-Specific Outcomes in a Phase 2 Trial,” were presented at the 2020 Transplantation and Cellular Therapy (TCT) Annual Meeting, held recently in Orlando, Fla.
Adrenoleukodystrophy (ALD), a rare inherited metabolic disorder, is characterized by the toxic buildup of very-long-chain fatty acids (VLCFAs) in several tissues and organs. It mainly affects the brain and the adrenal glands, which are small hormone-producing glands located above the kidneys.
CALD, one of the most common forms of ALD, is marked by an inflammatory process that destroys myelin — the protective layer around nerve cells that allows fast communication between them — leading to the progressive loss of cognitive and neurological functions.
Allogeneic hematopoietic stem cell transplant (HSCT) is seen as the only way of halting disease progression in CALD patients. It is based on the transplant of healthy hematopoietic stem cells — cells that can form all types of blood cells in the body — from a genetically identical donor (allogeneic) to replace the patient’s diseased cells.
The procedure is done after depleting the patient’s own blood cells through chemotherapy or radiation.
HSCT’s benefits are thought to result from the ability of the donor’s hematopoietic stem cells to give rise to healthy microglia cells — specialized immune cells of the central nervous system, comprised of the brain and spinal cord.
However, HSCT’s therapeutic potential has been limited by a major challenge so far — the need for a large number of stem cells.
Magenta’s MGTA-456, a HSCT, was designed to overcome this problem by expanding the donor’s blood stem cells in the laboratory to numbers higher than those achieved with other standard methods, according to Magenta. MGTA-456 is currently being developed as a potential treatment for inherited metabolic diseases, including CALD, and blood cancers.
An open-label Phase 2 clinical trial (NCT03406962) is evaluating MGTA-456’s safety and effectiveness in up to 12 children, ages 6 months to 16 years, with inherited metabolic disorders, including CALD, Hurler syndrome, metachromatic leukodystrophy, and globoid cell leukodystrophy.
Its primary goal is to assess cell engraftment success — or the growth of the transplanted stem cells — measured by the numbers of neutrophils, a type of white blood cells. Secondary goals include safety and tolerability measures. The participants are followed for one year after transplant, and those eligible may enter a five-year follow-up study (NCT04008849).
Previous six-month data on the first five patients — two children with CALD and three with Hurler syndrome — showed that all of them achieved a successful stem cell engraftment. Low neutrophils counts were evident for a median of one day, compared with at least eight days after conventional HSCT. That means that MGTA-456 led to the faster recovery of blood and immune cells.
In addition, the two CALD patients showed sustained resolution of brain inflammation on magnetic resonance imaging (MRI) scans as early as 28 days after treatment. Neurological function and the Loes score — which quantifies disease severity based on brain abnormalities and atrophy seen on MRI scans — also were stable at six months.
Now, the newly announced data at one-year of follow-up for these first five patients showed that the benefits seen at six months were sustained over one year, consistent with an efficient and durable, or lasting halt in disease progression.
Notably, cognitive function also remained stable throughout the follow-up period, with no deterioration in Wechsler IQ Scale and Vineland Adaptive Behavior Scales.
“Treatment with MGTA-456 in patients with IMDs [inherited metabolic diseases] shows early, robust engraftment and immune reconstitution, features that are highly associated with improved clinical outcomes,” the researchers said, adding that the treatment “shows compelling potential to rapidly and durably improve outcomes in [inherited metabolic disease] patients.”
Regarding safety, two episodes of skin-only acute graft-versus-host disease — GvHD, a serious complication in which the transplanted cells start attacking the host’s body — were observed and resolved with steroid treatment. No chronic GvHD was reported.
“The clinical demonstration of rapid and durable resolution of disease in patients with inherited metabolic disorders is very compelling; it’s particularly encouraging as these results are not seen with currently available treatments, nor with gene therapies under investigation,” John Davis, MD, Magenta Therapeutics’ chief medical officer, said in a press release.
Davis also noted that MGTA-456 data on blood cancers using frozen samples “validate the introduction of cryopreserved 456 product into the Phase 2 trial of inherited metabolic diseases, crucial for the establishment of multi-center trials, as well as eventual global patient access.”
MGTA-456 recently received regenerative medicine advanced therapy (RMAT) designation from the U.S. Food and Drug Administration (FDA) for the treatment of inherited metabolic disorders, including CALD. This designation is meant to speed up the development and approval of promising therapies for serious or fatal diseases, and potentially address unmet medical needs.
Magenta expects to complete the trial’s enrollment during this year. It also plans to continue working with the FDA under the RMAT designation to design a registration-enabling study, and to have discussions with the European Medicines Agency regarding MGTA-456’s development in Europe.
