FDA green lights first-in-human study of infusion leukemia treatment
Trial testing therapy for hard-to-treat cancer expected to start by year's end
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The U.S. Food and Drug Administration (FDA) has given Orum Therapeutics the go-ahead to launch its first clinical trial testing ORM-1153, an experimental treatment for certain types of blood cancer, including acute myeloid leukemia (AML).
The first-in-human study, which will test the safety and potential effectiveness of the infusion therapy, is expected to start before the end of the year, according to a company press release announcing the FDA clearance. The Phase 1 trial (NCT07809906) is expected to enroll approximately 42 people with relapsed or treatment-resistant AML and other forms of blood cancer at two sites in the U.S., with the possibility of expanding to other regions.
The developer stated that the trial will focus on assessing the tolerability, pharmacological properties, and “preliminary antitumor activity” of ORM-1153.
AML is an aggressive form of blood cancer that starts in immature cells, called myeloid progenitor cells, which normally develop into certain types of blood cells. Symptoms often develop suddenly over days or weeks, and may include fatigue, easy bleeding, and infections.
ORM-1153 is a so-called degrader-antibody conjugate or DAC. It combines an antibody that binds CD123 — a protein found at high levels on almost all AML cells, but at low levels in healthy cells — with a protein-degrading molecule targeting GSPT1, a protein needed for cancer cells to survive.
After binding to CD123 on an AML cell, ORM-1153 is taken into the cell, where its degrading molecule recruits the cell’s protein-degradation machinery to destroy GSPT1. This is intended to selectively damage AML cells while limiting effects on healthy cells, according to the company.
“FDA clearance of … ORM-1153 is an important milestone for Orum, bringing another first-in-class DAC into the clinic and extending our approach into CD123-expressing hematologic malignancies,” said Olaf Christensen, MD, Orum’s chief medical officer.
“By combining cell-selective delivery with targeted protein degradation in a single molecule, we believe ORM-1153 has the potential to improve treatment efficacy and tolerability for patients with severe [blood cancers],” Christensen said.
In the lab, AML treatment was more potent than approved therapies
In preclinical studies, ORM-1153 showed activity against AML cells expressing CD123, but little against cells lacking the target. The company reported that the treatment was about 1,000 times more potent than Venclexta (venetoclax) in one AML cell line and showed activity comparable to Mylotarg (gemtuzumab ozogamicin), another antibody-based therapy. Both drugs are widely approved globally, including in the U.S. and Europe, for treating AML.
ORM-1153 also showed activity in AML samples derived from patients with different genetic profiles, including those with high-risk mutations in the TP53 and FLT3 genes, the developer noted.
In an AML mouse model, ORM-1153 reduced leukemia burden by 93% after 14 days of treatment and was associated with improved survival compared with standard treatment with the chemotherapy drug azacitidine plus Venclexta.
In repeat-dose studies in monkeys, ORM-1153 showed a preliminary broad therapeutic window between the dose that showed anti-leukemic activity in mice (0.1 mg/kg) and the highest dose in monkeys that did not cause severe toxicity (6 mg/kg). Reported off-target effects included mild, reversible reductions in platelets, cell fragments that help with blood clotting, and increases in liver enzymes.
In the Phase 1 trial, participants will receive the drug via intravenous, or into-the-vein, infusions at escalating doses in successive groups.
The study will primarily assess ORM-1153’s safety and tolerability after about 24 months, or two years, and help determine the optimal dose. Researchers will also examine how the treatment behaves in the body, its effects on biological markers, the development of immune responses against it, and early signs of anti-leukemic activity, for up to three years.
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