UPDATE: Bristol’s search for Yervoy mark II

Bristol-Myers Squibb’s 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 that the group was beginning a massive phase I study with a new anti-CTLA4 project. This, and a separate asset licensed from Cytomx, look like two 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 would initially not reveal the identity of BMS-986218 – the entry just calls it a “monoclonal antibody” – but later confirmed that it was an internal anti-CTLA4 project, said Umer Raffat, an analyst with Evercore ISI.

Mr Raffat had earlier suggested that BMS-986218 might have been the Cytomx asset, based on the timing of the disclosure of the Cytomx deal extension and the fact that the Clinicaltrial.gov entry appeared shortly afterwards, but this turned out not to be the case. The study, in solid tumours, is due to start within the next week.

The trial has an interesting design: Yervoy monotherapy and BMS-986218 monotherapy are being compared against BMS-986218 combined with Opdivo. True, this will not directly show whether BMS-986218 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 follow-on anti-CTLA4 work that gave rise to BMS-986218 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.

Meanwhile, 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 tumour microenvironment – so the goal is to avoid off-tumour effects.

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  Bristol-Myers Squibb Phase I Afucosylated Mab
CTLA-4 probody Cytomx Preclinical Licensed to Bristol-Myers Squibb
AGEN2041 Agenus Preclinical Macrophage-mediated
XmAb20717 Xencor Preclinical Anti-CTLA4 & anti-PD-1 bispecific
ADC-1015 Alligator Bioscience Preclinical Anti-CTLA4 & anti-Ox40 bispecific
PD-L1/CTLA-4 Research Project Sorrento Therapeutics Preclinical Anti-CTLA4 & anti-PD-L1 bispecific
PRS-010 Pieris Pharmaceuticals Preclinical Lipocalin scaffold 
Onc-392 Oncoimmune Preclinical Option to Pfizer
Anti-CTLA4 CAB project Bioatla Research project Conditionally active biologic; option to Pfizer
Immuno-Oncology II Olipass Research project Oligonucleotide technology

The main mechanistic competitor to Yervoy is Astrazeneca’s 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, to license it to the UK company. The only other clinical asset seems to be in development by Agenus, 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.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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