Merck KGaA’s xevinapant gets SMACked down

Merck KGaA had been the leading proponent of hitting the intrinsic apoptotic pathway, with the Debiopharm-licensed xevinapant, but yesterday it disclosed the discontinuation of its key Trilynx study for futility.

The news is a blow both to Merck’s cancer ambitions and to other groups testing this approach – a cohort that has dwindled in recent years, and now features BeiGene and China’s Ascentage Pharma and Chia Tai.

Merck's stock fell 8% this morning.

IAP and SMAC

Hitting the inhibitor of apoptosis (IAP) family of proteins is thought to restore apoptosis in cancer cells; a related approach is mimicking SMAC, the IAPs’ natural inhibitor.

However, various projects have been shelved following lacklustre efficacy, including Novartis’s LCL161 and IGM Biosciences’ birinapant, both SMAC mimetics.

Xevinapant, which Merck licensed from Debiopharm in March 2021 for €188m up front, blocks three members of the IAP family, XIAP, cIAP1 and cIAP2. Merck had been testing the project in locally advanced squamous cell carcinoma of the head and neck.

The first-line pivotal Trilynx study enrolled 730 patients with unresected disease, and compared xevinapant plus cisplatin and radiotherapy versus cisplatin and radiotherapy alone, with a primary endpoint of event-free survival.

Merck yesterday said a pre-planned interim analysis found that the trial was unlikely to meet this endpoint. The company also scrapped another phase 3 head and neck study, known as X-Ray Vision, testing adjuvant xevinapant in patients undergoing resection.

An investigator-sponsored phase 3, XXL_2022-01, in first-line head and neck cancer is still ongoing, but hopes for this cannot be high now.

If the IAP pipeline now looks sparse, then so does Merck’s oncology portfolio. After xevinapant its next most advanced cancer project is pimicotinib, a CSF-1R inhibitor licensed from Abbisko for $70m last year. That asset is in a phase 3 trial for tenosynovial giant cell tumour, but even if it succeeds there are questions about the size of this market.

Other targets Merck is pursuing include SLC6A8, via the Inspirna-originated ompenaclid, and PARP1 via M9466, licensed from Jiangsu Hengrui.

The IAP inhibitor/SMAC mimetic pipeline

Source: OncologyPipeline.