Merck goes pivotal with acquired assets

Just over a year after Merck & Co gained rights to Orion’s prostate cancer hope ODM-208, on the back of first-in-human data, the US group is kicking off pivotal trials, with two phase 3 studies in slightly different settings due to start next month.

This features among a flurry of phase 3 initiations, newly listed on the clinicaltrials.gov registry over the past few days, that will also see sacituzumab tirumotecan enter its fifth pivotal trial and nemtabrutinib its third. Those last two assets came via Merck's deals with Kelun and Arqule respectively, so the activity sees the US group making a significant push with externally sourced assets.

It’s notable that ODM-208 seems to be making faster progress than nemtabrutinib, a non-covalent BTK inhibitor earlier coded ARQ 531, which Merck got through a $2.7bn takeover of Arqule back in 2019. After the deal things went quiet for a while while Merck confirmed much of Arqule’s work, before finally taking nemtabrutinib into phase 3 eight months ago.

Orion

It was in July 2022 Merck paid $290m for co-development rights to Orion’s CYP11A1 inhibitor ODM-208/MK-5684. This came as Orion focused on its Bayer-partnered Nubeqa, marketed for hormone-sensitive and non-metastatic castration-resistant prostate cancer.

The setting for ODM-208 is metastatic castration-resistant prostate cancer after a novel androgen agent (NHA). This is a fast-changing space, and Merck’s interest was triggered by ASCO-GU 2022 data in post-Zytiga and/or Xtandi patients, 32% of whom achieved ≥50% PSA decline, a number that rose to 68% in a subgroup with a mutation in the androgen receptor ligand-binding domain.

The compound’s first phase 3 studies are also in a post-NHA setting, and will compare ODM-208 versus an alternative NHA – implying a relatively low bar to success. The trials differ in terms of whether patients have also received chemotherapy, and whether they were castration-resistant or still hormone-sensitive when they received their first NHA.

Non-covalent BTK

Meanwhile, BTK inhibitors like nemtabrutinib are seen as an improvement over first-generation, covalent drugs, largely by virtue of their ability to target a downstream mutation called C481. The most advanced non-covalent BTK inhibitor is Lilly’s Loxo/Redx-derived Jaypirca, though this will not feature in Merck’s study.

Instead, that first-line CLL trial, called Bellwave-011, will pit nemtabrutinib against either Johnson & Johnson/AbbVie’s Imbruvica or AstraZeneca’s Calquence. And nor will it test BeiGene’s Brukinsa, quickly emerging as the best covalent BTK inhibitor. BeiGene is separately touting a BTK degrader, BGB-16673, which it reckons could work in patients progressing on covalent as well as non-covalent BTK inhibition.

Recently revealed phase 3 trials of Merck & Co projects

Notes: NHA=novel hormonal agent, meaning Zytiga, Xtandi or similar; HSPC=hormone-sensitive prostate cancer. Source: new clinicaltrials.gov listings 15-17 Nov 2023.

In May 2022 Merck paid Kelun $47m for undisclosed ADC projects later revealed to include the TROP2-directed sacituzumab tirumotecan, and the final phase 3 trial in Merck’s recent flurry of pivotal initiations concerns this asset.

While doubling down on ADCs through October’s $5.5bn deal with Daiichi Sankyo, Merck initiated a phase 3 trial of sacituzumab govitecan in second-line lung cancer. The project is also in three Kelun-sponsored phase 3 trials, and its fifth pivotal study will now test it in second-line endometrial cancer, a setting in which Keytruda and GSK’s Jemperli are used.

Patients have to have received platinum chemo as well as immunotherapy, which effectively means Jemperli; the GSK drug was recently approved as a front-line combo, though interestingly only in MSI-high or mismatch repair-deficient disease.