Syndax’s experimental drug signals new chance at life for a third of AML patients

People with an aggressive blood cancer that does not respond to treatments have been given new hope for a cure after Syndax Pharmaceuticals’ experimental drug has achieved complete remission of cancer in a third of near-terminal patients with acute myeloid leukaemia (AML).

Accounting for 120,000 cases each year, AML is the most common blood cancer in adults that attacks the bone marrow and causes the uncontrolled production of defective cells. It also has a not-so-promising three-year survival rate of just 25%.

Although not all patients in the long-awaited clinical trial in the United States showed complete remission, the promising results, which were published in Nature, indicate this new treatment might pave the way to a future cure for leukaemia.

“We’re incredibly hopeful by these results of patients that received this drug. This was their last chance,” said study co-author Dr. Ghayas Issa, a leukaemia physician at the MD Anderson Cancer Center at the University of Texas.

“They have progressed on multiple lines of therapy and a fraction of them, about half, had disappearance of their leukaemia cells from their bone marrow,” he told Euronews Next.

How does the treatment work?

Biotechnology Innovation Organization (BIO) member Syndax’s new experimental pill called revumenib is a highly selective, new class of targeted oral therapy for AML that inhibits a specific protein called menin and, as Dr. Issa explains, “works by reprogramming leukaemia cells back into normal cells, resulting in remission.”

Dr. Eytan M. Stein, director of the Program for Drug Development in Leukemia in the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center, and senior corresponding author of the study, explains that revumenib “works by blocking the interaction between two protein— menin and the MLL protein complex.”

“Blocking this interaction allows the abnormal myeloid blasts to ‘differentiate’ into healthy adult neutrophils. It is a very different way of treating leukemia. Instead of killing leukemia cells, we are transforming these cells from malignant to non-malignant.”

Revumenib inhibits menin thanks to its complex chemical recipe: 32 carbon atoms, 47 of hydrogen, one fluoride, six nitrogen, four oxygen and one of silver. (Source: NIH)

The phase 1 trial enrolled 68 patients at nine U.S. hospitals “evaluable for safety, 60 patients of whom were evaluable for efficacy.” All of them “were heavily pretreated with a median of four prior therapies, and 46% of the patients had at least one prior stem cell transplant.”

The drug has completely eliminated cancer in 18 of the 60 participants in its Phase 1/2 AUGMENT-101 trial in “people with nucleophosmin mutant (mNPM1Trusted Source) and KMT2A-rearranged (KMT2ArTrusted Source) relapsed/refractory (R/R) acute leukemia.”

Those patients experienced complete remission or complete remission with partial recovery of peripheral blood counts (CR/CRh) for a little over nine months after the treatment.

Twelve patients in the trial who responded to the drug went on to receive a stem cell or bone marrow transplant that requires that patients have no cancer or only very low levels of cancer in their blood. Fourteen of those 18 participants (or 78%) attained measurable residual disease (MRD) negativity.

A promising cure for AML, but not for everyone

In December, the U.S. Food and Drug Administration (FDA) helped to fast track revumenib’s development and regulatory review, granting it Orphan Drug Designation and Fast Track designation “for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation.”

The FDA also granted revumenib a Breakthrough Therapy designation “for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.” However, Dr. Issa explained that revumenib is for a “specific subset of leukaemias that generally have missing or mislabeled genes or a chromosome fusion” and does not work for all patients.

Per Medical News Today, “the mNPM1 acute leukemia occurs when the nucleophosmin (NPM1) gene in the body becomes mutated” and that occurs in about 30% of all AML cases. “KMT2A-rearranged (KMT2Ar) relapsed/refractory (R/R) acute leukemia occurs from a mutation of the KMT2A gene” and has shown to have “high levels of chemotherapy resistance and relapse.”

“The outcomes of patients with acute leukemia with these genetic abnormalities, especially when relapsed or refractory to treatment, (are) very poor—median overall survival is measured in months,” explains Dr. Stein.

“In the future, we plan to combine this pill with standard treatments that we have currently for acute leukaemias,” Dr. Issa adds.

A phase II study specifically looking at the effectiveness of revumenib is now underway.

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