FDA Grants Clearance of Investigational New Drug Application for Lanraplenib in Combination With Gilteritinib for R/R FLT3+ AML

A phase 1/2 trial featuring lanraplenib/gilteritinib in patients with FLT3-mutant acute myeloid leukemia will proceed following the FDA’s clearance of an investigational new drug application.

The FDA has cleared an investigational new drug (IND) application for lanraplenib (GS-9876), allowing for a phase 1/2 trial that will examine the safety and efficacy of the agent in combination with gilteritinib (Xospata) in patients with relapsed/refractory, FLT3-positive acute myeloid leukemia (AML) to proceed, according to a press release from drug developer Kronos Bio.

Kronos Bio anticipates that the trial will begin during the fourth quarter of 2021. Lanraplenib was designed to improve pharmacokinetic and pharmacologic properties vs entospletinib (GS-9973), which is notably being evaluated in combination with standard-of-care chemotherapy in patients with newly diagnosed, NPM1-mutant disease as part of a phase 3 study (NCT02343939).

“This [lanraplenib] IND caps off an outstanding year for our [spleen tyrosine kinase (SYK)] portfolio, which we acquired just over a year ago. Since that time, we have nearly completed the integration of the [entospletinib] and [lanraplenib] programs with our systems, built out the requisite clinical, translational, regulatory, and manufacturing infrastructure for [lanraplenib] and [entospletinib] and had successful interactions with the FDA, both for the [entospletinib] phase 3 clinical trial, as well as for [lanraplenib] in relapsed/refractory FLT3-mututated [patients with] AML. The stage is now set to demonstrate the value of SYK inhibition for patients with this life-threatening disease,” Jorge DiMartino, MD, PhD, chief medical officer and executive vice president, clinical development of Kronos Bio, said in a press release.

The IND marks the first oncology indication for lanraplenib, which previously demonstrated tolerability in a clinical trial that included 250 patients with autoimmune diseases, as well as healthy volunteers. Moreover, pre-clinical findings indicated anti-leukemic activity with the agent in NPM1-positive and FLT3-mutant AML blood and bone marrow samples; lanraplenib proved to be comparable with entospletinib.

Lanraplenib’s pharmacokinetic profile allows for a once daily dosing regimen in a fed or fasted state and appears to be compatible with proton pump inhibitors. This suggests that the investigation therapy may be better suited to the chronic treatment paradigm than entospletinib.

The phase 1/2 trial examining lanraplenib will utilize a dose-escalation and -expansion cohort design, the first phase of which will evaluate the safety, pharmacokinetics, and anti-leukemic activity of the agent in an escalating once daily dose plus a standard dose of gilteritinib. FLT3 measurable residual disease negativity will also be examined in those who achieve a complete response in addition to assessing the predictive value of certain biomarkers that may be associated with clinical outcomes.

Investigators expect to have initial data from the first phase of the trial during the second half of 2022. After a recommended dose is selected by investigators, an expansion cohort of approximately 30 patients will be enrolled to better evaluate the safety of the investigational drug in addition to better understanding its anti-leukemic properties; these data are likely to emerge during the second half of 2023.

“Based on the existing clinical data and differentiated pharmacologic properties of [entospletinib] and [lanraplenib], we have designed a complementary development strategy that seeks to maximize the impact of both investigational medicines. [Entospletinib] is entering a registrational phase 3 clinical trial that may support its accelerated approval to treat newly diagnosed NPM1-mutated AML patients in combination with chemotherapy for a defined duration of treatment. [Lanraplenib’s] differentiated pharmacologic properties support its evaluation as a component of more extended combination dosing regimens with gilteritinib or venetoclax [Venclexta]/azacitidine, which are dosed to progression. We believe this precision oncology approach will allow us to systematically address patients with genetic mutations present in more than two-thirds of the AML patient population,” DiMartino concluded.

A second phase 1/2 trial is planned that will examine lanraplenib in combination with venetoclax (Venclexta) plus azacitidine in those with newly diagnosed, NPM2-positive and/or FLT3-mutant AML who are over the age of 75 and are not candidates for intensive induction chemotherapy. This trial is expected to yield data during the first half of 2023, with proof-of-concept data emerging in late 2023 or early 2024.

Reference

Kronos Bio announces FDA clearance of investigational new drug application for lanraplenib (LANRA) for treatment of patients with acute myeloid leukemia (AML). News release. Kronos Bio. July 27, 2021. Accessed July 27, 2021. https://bit.ly/2V9NzrI