On December 6, 2021 Kronos Bio, Inc. (Nasdaq: KRON), a company dedicated to transforming the lives of those affected by cancer, reported that the first patient has been dosed in the registrational Phase 3 AGILITY clinical trial of entospletinib, a selective inhibitor targeting spleen tyrosine kinase (SYK), in combination with standard of care anthracycline and cytarabine (7+3) chemotherapy (Press release, Kronos Bio, DEC 6, 2021, View Source [SID1234596475]). This trial is the first in acute myeloid leukemia (AML) to use measurable residual disease (MRD) as the primary endpoint and has the potential to support accelerated approval of entospletinib by the U.S. Food and Drug Administration (FDA) as a treatment for patients newly diagnosed with NPM1-mutated AML who are fit for intensive induction.
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"With the initiation of this trial, we are taking an important step forward for patients with AML, a form of blood cancer that has been difficult to treat historically," said Norbert Bischofberger, Ph.D., president and chief executive officer of Kronos Bio. "Even with current therapies, about half of people newly diagnosed with NPM1-mutated AML will die from the disease within five years. The use of the novel endpoint of MRD provides a pathway to potentially bring entospletinib to patients more quickly."
Entospletinib is Kronos Bio’s lead product candidate, and the company expects to share data from the trial in the second half of 2023. The randomized, double-blind, placebo-controlled trial is designed to assess the efficacy and safety of entospletinib in combination with intensive induction and consolidation chemotherapy in approximately 180 adults who have been newly diagnosed with NPM1-mutated AML. This trial will test the hypothesis, based on robust preclinical and Phase 2 clinical data, that NPM1 mutation leads to dependency on SYK signaling. The NPM1 mutation is present in about 30% of all adult patients with AML.
"We are pleased to be participating in this trial, with the goal of improving outcomes for patients with AML," said Karamjeet S. Sandhu, M.D., assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, a world-renowned research and treatment organization near Los Angeles that was the first to dose a patient in the trial. "Patients with NPM1-mutated AML are in need of better treatment options, and we are excited that we are the first center to begin treating a patient in this trial."
The primary endpoint of the trial is MRD negative complete response (CR), as measured by molecular detection of mutant NPM1 alleles in bone marrow, which affords a high degree of sensitivity to detect MRD. Numerous clinical studies have shown that patients with NPM1 mutations who achieve MRD negative CR after induction chemotherapy survive longer than patients who achieve CR but have detectable MRD. If successful, this would be the first time MRD is used as the basis for seeking accelerated approval in AML.
The decision to proceed with this trial design was made after an End-of-Phase 2 discussion with the FDA. In the trial, patients will be randomized 1:1 to receive either entospletinib or placebo in combination with standard induction and consolidation chemotherapy. Remission and MRD status will be assessed after the first two cycles of chemotherapy and patients may receive up to a total of five cycles. Event-free survival (EFS) is a key secondary endpoint, and mature EFS data will potentially be used to support full approval.
Kronos Bio acquired entospletinib and another SYK inhibitor, lanraplenib, from Gilead Sciences in July 2020. As previously announced, under the agreement with Gilead, the initiation of the Phase 3 trial triggers a $29 million milestone payment from Kronos Bio to Gilead. The payment will be recorded in the fourth quarter.
Lanraplenib is being developed for the treatment of patients with relapsed/refractory FLT3-mutated AML and patients newly diagnosed with NPM1-mutated and/or FLT3-mutated AML who are older than 75 years old or are not eligible for intensive induction chemotherapy.
About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) primarily affects adults and is one of the most difficult-to-treat blood cancers. AML starts in the bone marrow, impairing its ability to produce mature red blood cells, white blood cells and platelets. Without treatment, patients die within weeks to months from progressive bone marrow failure leading to infections, bleeding and heart failure. Approximately 20,000 people are diagnosed with AML in the United States each year, with the NPM1 genetic mutation found in approximately 30% of cases. Relapse in AML is common, and despite available treatments, nearly 11,000 people die from the disease each year in the United States.
About Measurable Residual Disease
Measurable residual disease (MRD) is a term that describes small numbers of leukemic cells that are still detectable during or after treatment, even when a patient has achieved complete response by standard criteria. Remaining leukemic cells in the body can become active and start to multiply, resulting in a relapse of the disease, which is fatal for most patients. Achieving MRD negativity, which is associated with longer remissions and improved survival, means that a treatment has reduced the number of leukemic cells to below the limit of detection by the most sensitive analytical methods. MRD can be detected using fluorescently labeled antibodies that recognize specific proteins on the surface of the leukemic cells (multi-parameter flow cytometry (MFC)) or by molecular methods such as DNA sequencing or polymerase chain reaction (PCR). Molecular methods are viewed as more sensitive and reliable than MFC, but require a unique mutation or DNA sequence that is only found in the leukemic cells. NPM1 mutations provide that unique sequence in patients with NPM1-mutated AML.
About Entospletinib
Kronos Bio is developing entospletinib for the frontline treatment of NPM1-mutated acute myeloid leukemia (AML). Entospletinib is a selective inhibitor targeting spleen tyrosine kinase (SYK), a critical node in a dysregulated transcription regulatory network within AML defined by persistent high expression of the transcription factors HOXA9 and MEIS1 (HOX/MEIS). Multiple AML driver mutations, including NPM1 and MLL gene rearrangements, have been associated with elevation of HOX/MEIS. Entospletinib has been investigated in more than 700 patients with a variety of hematologic malignancies, including AML, with clinical results observed in patients with AML who have NPM1 mutations and MLL rearrangements that support further development of the therapy.