FDA Awards Orphan Drug Designation to KT-253 in AML

The FDA has granted an orphan drug designation to the novel, highly potent, and selective MDM2 degrader KT-253 for the treatment of patients with acute myeloid leukemia (AML).¹

MDM2 is a critical regulator of p53 and in patients with p53 wild-type disease, the tumor suppressor maintains its ability to modulate cancer cell growth. However, inhibitors designed to upregulate and stabilize p53 expression can increase levels of MDM2, repressing p53 and limiting the effectiveness of these inhibitors. Preclinical studies have shown that KT-253 could overcome the MDM2 feedback loop and induce cancer cell death.

“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, stated in a news 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.”

An ongoing phase 1 trial (NCT05775406) is evaluating the safety and clinical activity of KT-253 monotherapy in patients with high-grade myeloid malignancies, acute lymphocytic leukemia (ALL), lymphoma, or solid tumors.²

All patients are required to have an ECOG performance status of 0 to 2, adequate organ function, and resolution of acute adverse effects (AEs) of any prior therapies to baseline severity or grade 1 or less. In arm A, patients need to have a histologically confirmed solid tumor or lymphoma that is relapsed/refractory to at least 2 prior standard-of-care therapies, or have tumors that do not have available standard therapy.

Arm B is including patients with a primary diagnosis of AML, ALL, relapsed/progressed high-risk myelodysplastic syndrome, or myeloproliferative neoplasms. All tumors must be relapsed/refractory to standard therapies, and prior radiotherapy within 4 weeks of the first dose of KT-253 is not allowed.

Key exclusion criteria for all patients include unstable cardiovascular function, major surgery within 4 weeks of study entry, history of or active concurrent malignancy unless the patient has been disease free for at least 2 years, and prior anticancer therapy within 2 weeks of enrollment. Active uncontrolled or symptomatic central nervous system (CNS) metastases, autologous stem cell transplant within 6 months of first study treatment, and any prior allogeneic stem cell transplant are not allowed in arm A. In arm B, patients cannot have active CNS leukemia, be within 3 months of prior allogeneic stem cell transplant, or be within 30 days of autologous stem cell transplant.

Patients in both arms will receive KT-253 intravenously once every 3 weeks during the dose-escalation portion of the trial.

The co-primary end points are to measure the incidence and severity of AEs, and to establish the maximum tolerated dose and the recommended phase 2 dose of KT-253. Secondary end points include response rates, duration of response, and pharmacokinetics.

References

1. 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. June 22, 2023. Accessed June 28, 2023. https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-receives-fda-orphan-drug-designation-kt-253
2. Safety and clinical activity of KT-253 in adult patients with high grade myeloid malignancies, acute lymphocytic leukemia, lymphoma, solid tumors. ClinicalTrials.gov. Updated June 7, 2023. Accessed June 28, 2023. https://clinicaltrials.gov/study/NCT05775406