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Bristol-Myers Squibb’s (NYSE:BMY) 2011 launch of Yervoy heralded the world’s first immune checkpoint inhibitor anticancer drug. However, in subsequent years its mechanism of action – CTLA4 inhibition – became notorious for remarkable levels of toxicity, and the drug has been sidelined by the advent of the anti-PD-1 class.

Still, Bristol could hardly be expected to throw in the towel, and evidence recently emerged suggesting that the group was beginning a massive phase I study with a new anti-CTLA4 project licensed from Cytomx. This looks like one of just a handful of industry assets attempting to hit CTLA4 (see table below).

On the other hand, caution about CTLA4 targeting was likely triggered by the severe immunological side effects seen with Yervoy. Moreover, as far as immune checkpoints go, PD-1/PD-L1 provided a much safer and still efficacious mechanism, prompting an explosion in industry projects with this activity.

CTLA4 avenues

However, Bristol continues to pursue CTLA4 inhibition via at least two avenues beyond Yervoy: patents reveal that internally it has studied additional modification of anti-CTLA4 antibodies, while its deal with Cytomx was recently extended, for $200m, with an anti-CTLA4 probody progressing to IND-enabling studies.

Analysts’ interest was piqued by the appearance on the Clinicaltrials.gov registry of a study of BMS-986218 in 531 patients – an extraordinarily high number for a first-in-human trial. Bristol will not confirm the identity of BMS-986218 – the entry just calls it a “monoclonal antibody”, but Umer Raffat, an analyst with Evercore ISI, thinks that it is the Cytomx asset.

He bases this view on the timing of the disclosure of the Cytomx deal extension, and the fact that the Clinicaltrial.gov entry appeared shortly afterwards; the study, in solid tumors, is due to start within the next week.

Another indication that the trial concerns an anti-CTLA4 asset is its design: Yervoy monotherapy and BMS-986218 monotherapy are being compared against BMS-986218 combined with Opdivo. True, assuming that BMS-986218 is an anti-CTLA4 this will not directly show whether it is better than Yervoy, but then Bristol probably does not want to risk asking this question.

That said, the group clearly wants a less toxic anti-CTLA4 asset. The Cytomx project comprises a standard MAb with a peptide added at its binding site, with the aim of masking the molecule’s activity until the peptide is cleaved by proteases in the tumor microenvironment – so the goal is to avoid off-tumor effects.

Meanwhile, Bristol’s own follow-on anti-CTLA4 work is based on mouse data suggesting that engineering to remove fucose sugar units from the antibody’s Fc region (afucosylation) enhances activity, and could thus yield a CTLA4 blocker with an improved therapeutic index.

Industry anti-CTLA4 projects
Project Company Status Note
Yervoy Bristol-Myers Squibb Marketed Launched in 2011
Tremelimumab AstraZeneca Phase III Licensed from Pfizer
AGEN1884 Agenus Phase I NK cell-mediated
BMS-986218 Cytomx* Phase I Licensed to Bristol-Myers Squibb
AGEN2041 Agenus Preclinical Macrophage-mediated
Follow-on anti-CTLA4 Bristol-Myers Squibb Preclinical Afucosylated MAb
CTLA4 Research Project Sorrento Therapeutics Research project Anti-CTLA4/PD-L1 bispecific
Immuno-Oncology II Olipass Research project Oligonucleotide technology
Anti-CTLA4 CAB project Bioatla Research project Conditionally active biologic; option to Pfizer
Note: *Cytomx/Bristol deal assumed to relate to BMS-986218.

The main mechanistic competitor to Yervoy is Astrazeneca’s (NYSE:AZN) tremelimumab, a key test of which will come in the hotly awaited readout of the Mystic trial, which combines it with durvalumab in first-line lung cancer.

Tremelimumab monotherapy disappointed repeatedly in trials, which is likely what prompted its originator, Pfizer (NYSE:PFE), to license it to the UK company. The only other clinical asset seems to be in development by Agenus (NASDAQ:AGEN), a US biotech that came late to the immuno-oncology party, and whose aim for 2017 is to figure out a feasible dose of AGEN1884 to combine with its anti-PD-1 agent AGEN2034.

Blocking PD-1 has clinical benefit, but adding CTLA4 makes it work better, Agenus’s corporate presentation insists. Toxicity notwithstanding, Bristol also continues to cling to this view.

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