ASH 2023 preview – Darzalex gets a first-line boost from Perseus

Despite being approved back in 2015, Genmab and Johnson & Johnson’s multiple myeloma juggernaut Darzalex continues to grow, helped by its penetration into first-line use. Yesterday the groups scored an ASH late-breaker with the phase 3 Perseus trial, evaluating a new first-line combo; but, with Genmab set to lose royalties on the CD38-targeting antibody in 2030, it already has an eye on the future.

Last week at the Jefferies London healthcare conference, the Danish group talked up its next-generation CD38 project, GEN3014, said to be more potent than Darzalex. But J&J, which is also partnered with Genmab on GEN3014, has yet to go all-in on the asset, and appears to be waiting on head-to-head data versus Darzalex.

These results, from a phase 1/2 trial, are due next year, and J&J is also expected to make a decision in 2024 on GEN3014, Genmab’s chief executive officer, Jan van de Winkel, told Jefferies. He added that J&J would lose its income from subcutaneous Darzalex by May 2034, “either because of the Inflation Reduction Act, or the patents running out, or a combination”.

The big pharma therefore has four more years than Genmab to find a replacement for its mega-blockbuster.

Data on GEN3014 will also feature in a poster at ASH, but these will not be head-to-head. The abstract details five remissions, including one complete response, among seven patients with fourth-line or later multiple myeloma receiving GEN3014 monotherapy in a dose-expansion cohort of the same phase 1/2 trial.

By comparison, Darzalex’s late-line monotherapy study, Sirius, recorded an ORR of 29%, albeit across a much greater number of patients. Van de Winkel also conceded that Darzalex’s monotherapy data came more than 10 years ago, in a less heavily pretreated population, and stressed the importance of the upcoming head-to-head data. It seems sensible for J&J to wait.

Perseus

Meanwhile, the spotlight has fallen on the Perseus trial, which tests the quadruplet of subcutaneous Darzalex plus Velcade, Revlimid and dexamethasone, versus a Velcade, Revlimid and dexamethasone triplet, in first-line patients eligible for autologous stem cell transplantation. The primary endpoint is progression-free survival.

The late-breaking abstract notes that at a median follow-up of 47.5 months PFS was significantly improved with the quadruplet versus control, with a hazard ratio of 0.42 (p<0.0001). Median PFS was not reached in either arm, but estimated 48-month PFS rates were 84% for the Darzalex-containing quadruplet versus 68% for control. Overall survival was immature.

These results looks similar to those seen in the phase 2 Griffin study, which tested the same combo, but used intravenous rather than subcutaneous Darzalex.

A second phase 3 trial of the same quadruplet, Cepheus, is ongoing in first-line patients not set to receive stem cell transplant.

Darzalex is already approved in first-line patients eligible for stem cell transplant, as part of a different quadruplet, alongside Velcade, thalidomide and dexamethasone.

The latest data look like they could help entrench Darzalex’s first-line position – but Genmab will have to hope that it can repeat the trick with GEN3014.