BeOne looks to a degrader combo

BeOne Medicines, vying to get the first BTK degrader approved, is now prepping for phase 3 trials of its contender BGB-16673 in combination with the group’s investigational next-gen BCL2 inhibitor sonrotoclax.

The company recently revealed pivotal plans in relapsed/refractory chronic lymphocytic leukaemia, but has other studies in the works, Amit Agarwal, BeOne’s haematology chief medical officer, said in an interview with ApexOnco. Details are scant for now, with Agarwal not disclosing specific diseases, only saying: “We’re looking at a couple of areas.”

One of these could be Waldenström's macroglobulinaemia, a slow-growing type of non-Hodgkin’s lymphoma, BeOne’s fourth-quarter presentation suggests.

Evolving

In relapsed CLL, where BeOne plans to test a fixed-duration therapy, Agarwal was reluctant to say what the control arm might be, adding: “It’s an evolving landscape.”

This will be relevant since Lilly’s non-covalent BTK inhibitor Jaypirca recently bagged full FDA approval in the post-BTK setting. BeOne hasn’t been shy about starting head-to-head trials in the past, and is already pitting BGB-16673 monotherapy against Jaypirca in the pivotal Cadance-304 trial, in post-BTK inhibitor CLL.

Ultimately, BeOne hopes to get BGB-16673 approved both as a monotherapy and as part of a combo in the relapsed setting.

The group’s most advanced BTK degrader rival is Nurix, whose bexobrutideg is in the phase 2 Daybreak CLL-201 trial, designed to support accelerated approval in relapsed CLL, and which is set to start the confirmatory Daybreak CLL-306 study this half.

Both are testing monotherapy, but Nurix is also looking at combos in phase 1/2, including a pairing with the established BCL2 inhibitor Venclexta.

Sonrotoclax is designed to be more potent than Venclexta. BeOne’s project is awaiting an FDA approval decision in relapsed/refractory mantle cell lymphoma this half, but the most important use will be CLL, where the next big readout will be from the front-line Celestial-TNCLL (301) trial, due this year.

Solid plans

While BeOne is best known as a haematology player, it also has ambitions in solid tumours beyond its approved anti-PD-1 MAbTevimbra. The group’s chief medical officer in solid tumours, Mark Lanasa, called out five projects that he believes have promise here.

The most advanced of these is the CDK4 inhibitor BGB-43395, which is set to go into phase 3 soon in front-line, ER-positive, HER2-negative breast cancer, where a letrozole combo will be pitted against letrozole plus a CDK4/6 inhibitor like Novartis’s Kisqali and Pfizer’s Ibrance.

Here, the group is trying to catch Pfizer, whose rival CDK4 asset atirmociclib started an identically designed phase 3 trial, Fourlight-3, in January 2025.

BeOne’s solid tumour pipeline highlights

Source: OncologyPipeline & company presentation.

Lanasa reckons that BGB-43395 could have a better safety profile than atirmociclib, but this will need to be borne out in phase 3. BeOne last year dropped development of BGB-43395 in second-line breast cancer, citing an evolving competitive landscape.

Another intriguing asset is BGB-B2033, which hits both GPC3 and 4-1BB. While the former has become a popular target, largely in Car-T, attempts to activate co-stimulatory domains such as 4-1BB haven’t gone well.

However, Lanasa claims that BeOne has seen “a number of clinically meaningful” responses among PD-(L)1 inhibitor-pretreated liver cancer patients receiving BGB-B2033; data are due to be presented in the second quarter.

ADCs

As for its ADCs, BeOne looks like it could need a biomarker strategy for its B7-H4-targeting BG-C9074. That project should start phase 3 within the next 12 months, putting it behind GSK/Hansoh’s mocertatug rezetecan and AstraZeneca’s puxitatug samrotecan.

Meanwhile, BeOne is one of several players keeping faith with CEACAM5 despite setbacks. The company previously discontinued an anti-CEA x 4-1BB bispecific, BGB-B167.

BeOne’s current ADCs use topoisomerase 1 inhibitors, but further down the line the group is developing multispecific ADCs and projects with non-cytotoxic payloads, such as RAS inhibitors, Lanasa said. However, it isn’t currently working on dual-payload projects – an area of increasing interest.