AstraZeneca and Incyte say IDO

The risk of the barrage of R&D announcements that AstraZeneca has unleashed in its quest to demonstrate the opportunism of Pfizer’s takeover bid is that potentially important developments get lost in the noise.

Still, avid followers of immuno-oncology will recognise the relevance of today’s news that the UK firm is to collaborate with Incyte on a mid-stage clinical trial. This sizzling field of research is fast moving towards just such combinations, as evidenced just hours later by Bristol-Myers Squibb and Celldex Therapeutics’ move to combine their respective immunotherapies.

Astra’s effort basically mimics that of Merck & Co, which in February announced three collaborations involving immuno-oncology combinations, including a phase I/II study of MK-3475 with Incyte’s IDO inhibitor INCB24360 in non-small cell lung cancer.

Today’s non-exclusive deal will see INCB24360 combined with Astra’s MEDI4736 in a phase I/II trial in tumours including melanoma, NSCLC, and head and neck and pancreatic cancers. MEDI4736 targets the tumour-expressed ligand PD-L1 while MK-3475 is an anti-PD-1 antibody, but the theory behind the IDO combo is the same.

PD-1 is expressed on the surface of T-cells, and its interaction with PD-L1 is thought to allow tumour cells to evade a normal T-cell killing mechanism, hence the logic of blocking either PD-1 or PD-L1. IDO (indoleamine 2,3-dioxygenase) is an enzyme that breaks down tryptophan, prompting T-cells to become inactive – a mechanism that tumour cells can also hijack to dampen the immune response.

Thus combining the two approaches could potentiate the antitumour response or allow similar activity at lower, and safer, doses of each component.

Of course, there are many other possible combinations of immuno-oncology mechanisms; Bristol’s deal will see a phase I/II study later this year with the company’s anti-PD-1, nivolumab, combined with varlilumab, Celldex’s CD27-targeting MAb. Varlilumab is thought to act like the natural ligand CD70 to stimulate CD27, a critical molecule in T-cell activation.

The trial will be run by Celldex, which has received $5m up front from Bristol. The Astra/Incyte deal did not specify any payments, but in this case the clinical study will be funded jointly.

Well advanced

Like Merck and Bristol, Astra is well advanced with other combination immunotherapy approaches: two phase I studies are under way combining MEDI4736 with Astra’s own anti-CTLA4 antibody tremelimumab, mimicking the combination of nivolumab with Bristol’s marketed anti-CTLA4, Yervoy.

Astra is even set to start a phase I study of MEDI4736 with MEDI0680 – this appears to be the only instance of the anti-PD-L1 and anti-PD-1 mechanisms being combined.

Interestingly, only one other company seems to have clinical-stage IDO inhibitors: NewLink Genetics has indoximod in phase II and NLG-919 in phase I, though neither is in combination trials, and indeed Merck and Astra’s choice of Incyte as a partner could be taken as a snub to NewLink.

EvaluatePharma lists no other CD27-targeting MAbs beyond varlilumab, though CD70 agents are being developed by several companies.

Selected trials of MEDI4736 and INCB24360
Status Design Primary completion Trial ID
MEDI4736 (AstraZeneca)
Phase III 880 NSCLC pts (Pacific) May 2017 NCT02125461
Phase II 210 NSCLC pts (Atlantic) Apr 2015 NCT02087423
Phase I/II 69 melanoma pts, combo with Tafinlar and/or Mekinist Jan 2017 NCT02027961
Phase I 102 solid tumour pts, tremelimumab combo Dec 2016 NCT01975831
Phase I 208 NSCLC pts, tremelimumasb combo Jan 2017 NCT02000947
Phase I 47 NSCLC pts, Iressa combo Oct 2017 NCT02088112
Phase I 150 advanced malignancies pts, MEDI0680 combo Jan 2017 NCT02118337
INCB24360 (Incyte)
Phase II 110 ovarian cancer pts, vs tamoxifen Sep 2014 NCT01685255  
Phase II 40 MDS pts Sep 2015 NCT01822691
Phase I/II 136 melanoma pts, Yervoy combo Aug 2014 NCT01604889
Phase I/II NSCLC, MK-3475 combo
Phase I/II Various solid tumours, MEDI4736 combo

In addition to the Incyte collaboration Astra’s recent PR offensive has seen the group announce positive phase III data with the psoriasis project brodalumab and the saxagliptin/dapagliflozin diabetes combo, as well as phase II results for mavrilimumab (rheumatoid arthritis) and sifalimumab (lupus) (Astra’s brodalumab hit is perfectly timed, May 12, 2014).

With heavy irony Bryan Garnier analysts asked today, “What could make this company so active in disclosing clinical data at such speed?” The truth is that at a time when immunotherapy combinations are the rage, and given tonight’s unveiling of the abstracts for the world’s most important oncology meeting, Asco, Astra has timed things excellently.

Still, Pfizer’s reluctance to raise its bid quickly has sparked concerns that the company is already close to the limit of its valuation for Astra, and a further sweetening might come at just £53 per share rather than the knockout £55-plus, Panmure Gordon analysts speculate.

Astra’s protestations about the disruptive effect of Pfizer on its science and on patients’ health aside, what the UK group basically wants is a much higher bid. Equally importantly, however, Astra must persuade its own investors that it is worth it holding out for more.

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

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