December 09, 2019

Ash 2019 – for Car-T the bispecific antibody threat is real

As numerous Car-T therapies battle it out in the burgeoning BCMA field, Ash shows that the real threat could come from elsewhere.

By the time the dust settles this year’s Ash might be best remembered as the conference at which the bispecific antibody threat to Car-T became real. A case in point is multiple myeloma, where targeting BCMA has long been a hotbed of Car-T activity.

While duelling anti-BCMA Car-T therapies continued to do battle at Ash, yesterday Regeneron became the latest group to suggest that a bispecific MAb could be at least as good. That came a day after Bristol-Myers Squibb’s own T-cell engager, CC-93269 – until now a virtually unknown asset – first knocked a hole in the Car-T approach.

The CC-93269 data look even more impressive than the Ash abstract had suggested. In particular, the highest CC-93269 dose, 10mg, appears more active than many anti-BCMA Car-Ts, with 89% overall response rate and a 44% rate of complete remissions.

CC-93269 efficacy, via Bristol-Myers Squibb's Ash presentation.

True, there are numerous caveats, most importantly that the 10mg dataset comprises just nine subjects; there will also clearly be differences in baseline patient characteristics when comparing across multiple studies.

But it cannot be denied that Car-T now has a competitor to be reckoned with: the most advanced Car-T therapy in this space, Bluebird/Bristol’s ide-cel, has just yielded a 73% ORR and 31% CR rate respectively (82%/35% for the highest dose) in its pivotal Karmma study.

As for patient characteristics, the CC-93269 population had failed a median of five prior therapies, with 67% having triple-refractory disease. Karmma subjects had all failed at least three therapy lines, and 84% were triple-refractory.

Perhaps the most impressive aspect of the CC-93269 result is that none of the subjects given the highest dose had progressed at seven months or more after responding. This is a vital consideration at a time when patient relapses are becoming a big problem with BCMA-targeted Car-T.

If Car-T suddenly looks vulnerable then Regeneron could be another beneficiary. The company yesterday reported the first clinical data for REGN5458, its own take on the anti-BCMA T-cell engager approach.

REGN5458 differs structurally from CC-93269, the latter having two BCMA binding domains for instance, but the principle behind both is the same. An Ash poster yesterday revealed four responses (one complete) in the first seven REGN5458-treated subjects, with dose escalation still ongoing and dose-limiting toxicity not yet reached.

Remarkably, this population has failed a median seven lines of systemic therapy. On the debit side, one of the partial remitters relapsed after seven weeks, though the other three responses are ongoing, one 30 weeks out and counting.

For comparison, Glaxosmithkline has a BCMA-targeting antibody-drug conjugate, belantamab mafodotin, whose Dreamm-1 study yielded a 60% ORR. Belantamab’s pivotal Dreamm-2 trial, known to have read out positively, was apparently submitted as an Ash late-breaker, but ultimately did not make it into this year’s conference.

Like Car-T but different

A T-cell engager like CC-93269 binds the target antigen at one end and interacts with a T cell at the other, thus bringing the latter into close proximity with the target tumour cell. The effect is similar to that of a Car-T approach, but is achieved with an antibody, with all its possible convenience advantages.

As with any immune system-stimulating strategy, safety is an important consideration, and in the CC-93269 trial one patient died of cytokine release syndrome. There were similar single deaths in Karmma and in Cartitude-1, a study of a separate anti-BCMA Car, Johnson & Johnson’s JNJ-4528.

Investors will now want to know how the weekend’s shift of the BCMA tectonic plates might play out. By virtue of its Celgene acquisition Bristol looks to be in pole position, boasting CC-93269 in addition to several Car-T assets; but if it prioritises CC-93269 over ide-cel then obviously the latter’s originator, Bluebird, could lose out.

Also under threat is JNJ-4528 and other cell therapies, including Poseida’s. And Roche – which has consistently refused to buy into Car-T on the grounds that this is impractical and expensive – could see major vindication.

On Saturday Roche fired its own shot across the bows in the shape of mosunetuzumab, a bispecific MAb that showed activity in patients who had relapsed on Car-T. This is by no means the end for cell therapy, but expectations will have to be reset.