Roche move endorses Iteos’s Tigit widget

A private Belgian biotech reckons Tigit is the new PD-1, a view Roche’s progress could validate.

Analysis

Roche’s decision to start a large pivotal programme with the Tigit blocker tiragolumab has rekindled enthusiasm about this mechanism, notably sending Arcus’s stock up 70%. This might have overshadowed a third Tigit player, the private biotech Iteos, which nevertheless boasts of a surge of interest behind the scenes.

Iteos’s chief executive, Michel Detheux, has just come back from an investor conference in New York, and tells Vantage: “We are sensing momentum where Tigit could become the first next-generation immunotherapy to be validated by a randomised phase II clinical trial.”

All eyes are on two presentations with Roche’s tiragolumab: a 300-subject single-agent cohort from a dose-escalation study is expected to be unveiled at April’s AACR meeting, followed by results from 135 NSCLC subjects randomised to receive monotherapy or a Tecentriq combo, expected at Asco.

Presumably Roche saw something extremely positive in these data to warrant starting pivotal development (Roche’s next immuno-oncology combo is a big bet on Tigit, January 31, 2020). Some even think the Swiss group is betting on tiragolumab to catch up with Merck & Co and Bristol-Myers Squibb in the immuno-oncology race.

For its part Iteos has just taken its anti-Tigit MAb, EOS-448, into phase I. The trial, says Mr Detheux, will be in 10 mostly solid tumours where Iteos reckons anti-Tigit monotherapy could work, or where PD-(L)1 blockade has failed; registrational studies could include combination with PD-(L)1 or other standards of care.

True, this puts Iteos behind Roche and Arcus, whose AB154 went into phase II last month, but it does not make it immune to recent enthusiasm. The chief exec says before Roche showed its hand in January people would just “listen politely” when he presented Tigit; now they are asking him about EOS-448 before he even starts.

If this translates into partnering talks Mr Detheux and Iteos’s chief operating officer, Matthew Call, are clear: right now it is vital for Iteos to retain a significant interest in the molecule. The company already raised $75m so it has a strong negotiating position, and is planning an “aggressive clinical strategy”.

Underappreciated

What makes the Tigit mechanism exciting is its multi-pronged effect, something Mr Detheux says is underappreciated, and which could differentiate it from the multitude of immuno-oncology strategies that have fallen by the wayside.

The fact that Tigit is an immune checkpoint, whose blockade can release an immune system “brake”, is just one aspect. Another is that it is present on T regulatory cells, so blockade can aid Treg depletion, and that stopping its binding to one ligand, CD155, might enhance a positive co-stimulatory signal through another, CD226.

An anti-Tigit MAb that, like EOS-448, works by antibody-dependent cellular cytotoxicity “could be the key to unblocking immune suppression”, says Mr Detheux. And, “whereas the big players are fighting over combination with PD-(L)1, we are convinced there are multiple other combinations that could be a winning strategy”.

One is A2A receptor inhibition, where Iteos has a phase I asset, EOS100850, designed to work at very high adenosine concentrations in the tumour microenvironment. Data are also due at AACR.

Other A2A players, including Astrazeneca, Corvus and Arcus, are combining this approach with CD73 inhibition, but Mr Detheux reckons this is driven by the need to lower adenosine concentrations to a level where their relatively unsophisticated, competitive antagonists can work.

Neither does he mince his words when it comes to Iteos’s competition in Tigit, saying he is not convinced that Arcus has selected the best antibody, and that Mereo’s etigilimab is “first in class, and poorly potent”.

With only Merck’s MK-7684 having shown a remission to monotherapy Tigit blockade there is all to play for. “Tigit is really hot right now,” says Mr Call. “We think it’s going to be the next PD-1.”

Industry projects targeting Tigit
Project Company Trial Timing
Phase III
Tiragolumab Roche Skyscraper-02, Tecentriq + chemo combo in 1L SCLC 400 subjects; starts 4 Feb 2020
Phase II
MK-7684 Merck & Co Keynote-01A, Keytruda + chemo combo in 1L NSCLC 90 subjects; started 15 Jan 2020
BMS-986207 Bristol-Myers Squibb Monotherapy and Opdivo combo in various tumours 170 subjects; ends Dec 2022
AB154 Arcus Biosciences Combo with PD-1 +/- A2A in 1L NSCLC 150 subjects; started Jan 2020
Phase I
ASP8374 Astellas (ex Potenza) Monotherapy and Keytruda combo in various tumours 363 subjects; ends Jul 2021
BGB-A1217 Beigene Tislelizumab combo in various tumours 39 subjects; ends Apr 2021
SGN-TGT Seattle Genetics Monotherapy and PD-(L)1 combo in various tumours 111 subjetcs; starts 20 Mar 2020
E0S884448 Iteos Therapeutics Monotherapy in solid tumours Phase I just announced
Etigilimab Mereo Biopharma Monotherapy and Opdivo combo in various tumours Marked "terminated" on clinicaltrials.gov
Preclinical
COM902 Compugen IND cleared to start phase 1 in 2020
IBI-939 Innovent IND cleared to start phase 1 in China
AGEN1307 Agenus
Source: EvaluatePharma & company presentations.

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