Recombinant Human Kynurenine-Degrading Enzyme Program
Ikena’s IK-412 is an engineered human kynurenine-degrading enzyme that may be able to reduce tumor resistance to checkpoint inhibitors and may address shortcomings of other kynurenine-reducing approaches.
Kynurenine-Degrading Enzyme Program
IK-412 is an engineered human kynurenine-degrading enzyme.
Kynurenine is a metabolite of the tryptophan degradation pathway and has long been recognized as an important contributor to immunosuppression. Recent clinical data from BMS suggests that increased kynurenine is an adaptive resistance mechanism to anti-PD1 therapy in multiple cancers. Kynurenine is produced by the enzymes indoleamine-pyrrole 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2). Increased kynurenine production has been linked to tumor growth and therapeutic resistance.
Ikena designed IK-412, an engineered human kynurenine degrading enzyme to be optimized to degrade kynurenine regardless of the source from the kynurenine-producing enzymes IDO1 or TDO2 and to have high stability in plasma. Direct catalytic degradation of kynurenine itself, rather than merely inhibiting IDO or TDO, may be a superior way of modulating the immunosuppressive tumor microenvironment and may achieve antitumor response. This approach, therefore, has the potential to result in improved outcomes for patients with tumors that express IDO1 or TDO2 or both.
In preclinical studies, after a single dose of IK-412 in non-human primates, we observed durable depletion of over 95% of serum levels of kynurenine. In other preclinical studies, in a murine syngeneic model of colorectal cancer, we also observed antitumor activity when dosed both as a monotherapy and in combination with checkpoint inhibitors and increased overall survival when dosed in combination with checkpoint inhibitors.
Ikena plans to submit an IND for IK-412 in the second half of 2021. To inform our indication selection, we developed several translational assays, including an immunohistochemistry assay using IDO1 or TDO2 antibodies to guide selection of certain solid tumors. The first-in-human clinical trial will be focused on patients with cancers that express high kynurenine levels, reflecting our biomarker-based, rational drug development approach. Our IK-412 program is partnered with BMS, which has the right to exclusively license the program through the completion of the Phase 1b portion of the clinical trial.
For more information, please see the press release announcing the Ikena-Bristol Myers Squibb partnership.
IK-412 has met Ikena’s target development candidate profile:
- Active and stable
- Non-immunogenic in preclinical species
- Can be dosed weekly or biweekly
Preclinically, IK-412 has shown
- Durable and significant depletion of kynurenine after a single dose
- Superiority to IDO1 selective inhibition in both kynurenine depletion and immune stimulation
- Antitumor activity as a single agent and in combination with other therapies in preclinical models of cancer