Kyn Therapeutics in collaboration with Merck has commenced two clinical trials of EP4 receptor antagonist ARY-007.

ARY-007 (grapiprant) is an oral, potent and highly selective antagonist of EP4 receptor, which is a component of the prostaglandin E2 (PGE2) pathway impacting the tumour microenvironment composition.

Preclinical studies have demonstrated that inhibition of EP4 increases the immune response through modulation of multiple immune cell types.

When combined with checkpoint inhibitors it has shown a significant reduction in tumour growth compared to either agent alone.

ARY-007 is now analysed in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in checkpoint-refractory and -resistant solid tumours. This is considered to be an area of high medical need but unmet.

Kyn Therapeutics president and chief executive officer Mark Manfredi said: “The Kyn team believes immunometabolism pathways hold great promise as therapeutics that could deliver breakthrough improvements for patients non-responsive to immunotherapy regimens.

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By GlobalData
“We believe EP4 is the right target and ARY-007 is the right molecule for overcoming the immunosuppressive effects of PGE2.”

“We believe EP4 is the right target and ARY-007 is the right molecule for overcoming the immunosuppressive effects of PGE2 in these cancers where increased pathway expression is associated with poor outcome.”

PGE2 has shown to increase the activity of regulatory immune cells and suppress the activity of effector immune cells.

EP4 inhibition leads to antitumor activity and increases the antitumor activity of checkpoint inhibitors.

Grapiprant was found to be well-tolerated in multiple development studies for a non-oncology indication.

The safety and efficacy of ARY-007 along with pembrolizumab will be analysed in the Phase Ib/I multicenter, open-label, single arm clinical trials.

The trial will include patients suffering with advanced or progressive microsatellite stable (MSS) colorectal cancer (CRC), and with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC) adenocarcinoma.

MSS CRC is considered to be resistant to anti-PD-1 therapies as these agents have only shown activity in the microsatellite instability-high (MSI-H) subset of CRC.

The NSCLC study is enrolling patients whose disease has progressed even while on PD-1 or PD-L1 therapy.

Both studies will have a translational biomarker strategy.