Novel MDM2 Degrader KT-253 Receives FDA Orphan Drug Designation In AML

Escalating doses of intravenous KT-253 will be administered to patients in 2 arms once every 3 weeks in 21-day cycles in a phase 1 study (NCT05775406).

The FDA has granted orphan drug designation to the novel MDM2-targeting degrader KT-253 for the treatment of patients with acute myeloid leukemia (AML), according to a press release from Kymera Therapeutics.

MDM2 is a regulator of the most common tumor suppressor, p53, which remains intact in approximately 50% of cancers. Other small molecule inhibitors, designed to stabilize and upregulate p53 expression, can induce a feedback loop that increases MDM2 levels, represses p53, and thereby impedes efficacy. KT-253 has demonstrated an ability to overcome this feedback loop and induce cancer cell death. MDM2 overexpression and amplification is implicated in AML, hence the designation.

The agent will be evaluated in a phase 1 study (NCT05775406) for patients with relapsed/refractory high-grade myeloid malignancies, including AML, acute lymphocytic leukemia (ALL), lymphoma, and solid tumors. The study will begin with a dose escalation phase to identify the recommended phase 2 dose (RP2D).

“This orphan drug designation reinforces the potential of KT-253 to advance the treatment of AML by targeting MDM2, a protein that has been challenging to effectively drug with conventional medicines,” Nello Mainolfi, founder, president, and chief executive officer of Kymera Therapeutics, said in the press release. “We have a significant opportunity to deliver an important new medicine that acts on this common cancer mechanism, and we look forward to rapidly advancing KT-253 in AML and exploring its potential in other hematological and solid tumors.”

The aforementioned open-label phase 1 study will include 2 arms. Patients with lymphomas or advanced solid tumors will be assigned to one, and those with relapsed/refractory high grade myeloid malignancies or ALL will be assigned to the other. Escalating doses of intravenous KT-253 will be administered to patients in both arms once every 3 weeks in 21-day cycles.

The primary end points are the RP2D as well as the frequency and severity of adverse effects (AEs) graded according to CTCAE v5.0 criteria. Secondary end points include the pharmacokinetics and clinical activity, defined as the percentage of patients who experience a morphologic leukemia free state, complete remission (CR), or a CR with partial hematologic recovery according to International Working Group criteria. Duration of response is another secondary end point.

Patients must have relapsed/refractory disease following 2 or more prior standard-of-care treatments or tumors for which standard therapies are unavailable to be eligible for inclusion. They must also have an ECOG performance status between 0 and 2, and any acute effects from prior therapy must be resolved to baseline severity. Adequate organ and bone marrow function and the passage of at least 4 weeks since radiotherapy prior to the first dose of study drug are among the other inclusion criteria.

Patients with ongoing unstable cardiovascular function, or those who underwent any major surgery within 4 weeks of study entry, are excluded from the study. Other exclusion criteria include any history of, or active, concurrent malignancy, unless the patient has been disease-free for 2 or more years. Patients with any exposure to anticancer therapy within 2 weeks or 5 half-lives of study entry are also excluded, as are those with known, active, uncontrolled, or symptomatic central nervous system metastases. Prior allogeneic hematopoietic stem cell transplant is also an exclusion criterion.

References

Kymera Therapeutics receives FDA orphan drug designation for KT-253, a novel, highly potent and selective MDM2 degrader for the treatment of acute myeloid leukemia. News Release. Kymera Therapeutics, Inc. June 22, 2023. Accessed June 30, 2023. https://bit.ly/3XvM8jo