Reality Bites again for Amgen

The quiet termination of Amgen’s AMG 794 isn’t the first setback this company has had in developing so-called Bite molecules. Signs that this technology wasn’t delivering emerged around three years ago, since when numerous further discontinuations have ensued, of which AMG 794’s is just the latest.

It’s true that the Bite technology, which Amgen acquired through its 2012 purchase of Micromet for €1.2bn, has resulted in two marketed drugs, Blincyto and Imdelltra. But the former has taken a long time to gain a commercial foothold, while it’s too early to tell how the latter will perform in the market; remarkably, Amgen’s clinical pipeline now includes just one other Bite.

This project is AMG 305, a dual-acting Bite against CDH3 and mesothelin that entered a phase 1 solid tumour study a year ago. There also appear to be three preclinical Bites that are still active, and all show signs of Amgen tinkering with design to improve on the characteristics of this type of T-cell engager.

The Bite format involves a T-cell engaging construct that retains only some features of an antibody, such as the binding domains, but is only a fraction of the size of a full MAb. This has some advantages, but on the debit side it can result in the need for continuous IV infusion – something that has held back Blincyto – in addition to causing cytokine release syndrome.

While at the time of Micromet’s acquisition only the molecule that became Blincyto, plus the since discontinued anti-EpCAM Bite solitomab, were publicly disclosed, in Amgen’s hands the development of numerous others followed. Until recently these each targeted just one antigen, and AMG 305 is the most advanced example of a Bite that hits two.

Two other preclinical assets, profiled preclinically at AACR in 2022, are also dual-acting (BCMA x CS1 in one case and CD123 x Flt3 in the other), as well as incorporating half-life extension – presumably a response to the fact that Blincyto’s continuous dosing requirement is caused by that molecule’s short half life.

Setbacks

Amgen thus still sees some potential in the Bite approach, but it’s impossible to ignore just how many setbacks it’s had along the way.

In early 2021 it emerged that Amgen was stopping development of three such projects: pavurutamab because of apparent toxicity, AMG 673 because of target overlap with the similarly acting AMG 330, and AMG 596 owing to “portfolio prioritisation”. But at the time the group’s disclosed R&D pipeline still listed eight Bites in development, including tarlatamab, which would later become Imdelltra.

Now that portfolio has almost entirely been wiped out. Toxicity continued to plague Bites, with pavurutamab’s phase 1 multiple myeloma study having been paused pending FDA discussions to optimise safety monitoring. A separate anti-BCMA Bite, AMG 420, was canned because of toxicity and the need for continuous IV infusion.

Before this week’s termination of AMG 794 on clinicaltrials.gov, the study registry in April noted the scrapping of a phase 1 trial of the anti-Claudin18.2 Bite AMG 910. Moreover, Amgen’s T-cell engager strategy outside Bites hasn’t gone smoothly either: last October AMG 340, a full-format bispecific MAb acquired along with Teneobio for $993m, was discontinued.

The development of bispecifics was never going to be easy, but it’s notable that others have now caught up with Amgen; approved projects now include three anti-CD20 and two anti-BCMA T-cell engagers.

The ups and downs of Amgen’s Bite development

Note: *all Bites additionally hit CD3, as a means of T-cell engagement; HLE=half-life extension. Source: OncologyPipeline.