First Patient Dosed in Phase 1 Trial Testing Small Molecule Treatment CA-4948 for AML

First Patient Dosed in Phase 1 Trial Testing Small Molecule Treatment CA-4948 for AML

The first patient has been dosed in a Phase 1 trial investigating the small molecule CA-4948 as a treatment for people with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS).

The primary goal of the multicenter, open-label dose escalation study (NCT04278768) is to determine the maximum tolerated and recommended dosage for future Phase 2 investigations. Curis, which is developing CA-4948, intends to share initial trial data by the end of 2020.

The trial expects to enroll 18 AML or high-risk MDS patients to investigate CA-4948’s safety, clinical activity, pharmacokinetics — how a treatment moves throughout the body — and pharmacodynamics, or the interactions between the body and a compound.

The initial patient dosed was given 200 mg of CA-4948, to be taken twice daily as an oral treatment. The 200 mg dosage was chosen from preclinical studies, as well as from a separate, ongoing Phase 1 trial (NCT03328078).

For every three patients enrolled, the researchers will increase the dosage, unless two or three of the first six participants experience an adverse reaction to the treatment. If that occurs, subsequently enrolled patients will receive a lower dose.

The maximum tolerated dosage, along with other findings from the trial, will be considered by a safety committee and the researchers to determine a recommended dose for a planned Phase 2 trial of CA-4948.

The Phase 1 trial is currently recruiting eligible AML and MDS patients at Nebraska Cancer Specialists, in Omaha, and the University of Texas MD Anderson Cancer Center, in Houston. More information can be found here.

AML is a type of leukemia that starts in the bone marrow — the soft inner part of certain bones, where new blood cells are made — but usually moves quickly into the blood. MDS, meanwhile, is a group of disorders caused by poorly formed blood cells or ones that don’t work properly.

The development of CA-4948 stems from recent research that provided evidence of an underlying genetic mutation that could be driving AML or MDS progression in some patients.

That research, led by primary investigators Daniel Starczynowski, PhD, of the Cincinnati Children’s Hospital, and Amit Verma, MD, of the Albert Einstein College of Medicine, was presented at the American Society of Hematology (ASH) Annual Meeting & Exposition in December 2019. It directly inspired the development of CA-4948.

Genetic mutations in AML and MDS patients were investigated in that study, which focused on their effect on a complex in the body called the spliceosome. Its function is to provide quality control during the process of decoding DNA to make proteins.

It had previously been observed that people with AML and MDS have mutations that may affect spliceosome function. The study found a specific protein that was not being processed correctly by the spliceosome in these patients.

In particular, a longer form of the protein interleukin-1 receptor-associated kinase 4 (IRAK4), called IRAK4-L, was being produced by spliceosomes with specific mutations found in people with AML and MDS.

The findings showed that IRAK4-L, whose normal form is involved with signaling pathways of the immune system, potentially impacted more than half of the AML and MDS population.

When the two doctors “demonstrated the important pathogenic role of IRAK4 in MDS/AML in their seminal publication in Nature Cell Biology and presentation at ASH last December, everyone in the AML/MDS community paid attention, including our team at Curis,” James Dentzer, the company’s president and CEO, said in a press release.

Curis began investigating CA-4948 — designed to block the activity of IRAK4 — as a treatment for AML and MDS patients.

“We quickly worked with our clinical investigators and the U.S. Food and Drug Administration (FDA) to design a study of CA-4948, our first-in-class IRAK4 inhibitor, in this population,” Dentzer said. “We are pleased to announce today, just six months later, that we have initiated this new study and successfully dosed our first patient.”

The research into IRAK4 is unique, the scientists said, as no candidate had previously been isolated as an individual target for AML and MDS treatment.

“Historically, no single oncogenic driver of AML and MDS has been known to impact the majority of patients,” said Guillermo Garcia-Manero, MD, chief of the myelodysplastic syndromes section at the MD Anderson Cancer Center.

“Recent studies have changed this understanding,” he said. “With CA-4948, we may now have a single drug that can directly target a key driver of disease in these patients.”

Garcia-Manero said MD Anderson is “delighted” to be a lead clinical site in the study of this new treatment candidate.