A year of Tigit (and Alzheimer’s) for Roche

With four pivotal tiragolumab readouts, Roche’s 2022 will not only be the year of Alzheimer’s.

Two years after kicking off Tigit mania with the start of nine pivotal studies of its contender, tiragolumab, Roche will find out whether its bet has been worth it. 2022 will be the year that four of these studies yield data, the Swiss company told investors today.

This will be an important theme to watch as many investors focus instead on Alzheimer’s disease, and the impending phase 3 readouts of gantenerumab’s Graduate-1 and 2 trials. But it is clear that Roche is not taking its foot off the Tigit pedal, despite phase 2 studies indicating tiragolumab’s potential lying mainly in PD-L1-high lung cancer.

As such the big question will be whether tiragolumab’s huge pivotal programme suggests significant activity in any of the other tumour types Roche highlighted at today’s fourth-quarter presentation. In terms of 2022 catalysts these comprise second-line cervical, and front-line SCLC and oesophageal cancers, in addition to PD-L1-high first-line NSCLC.

Tiragolumab's 2022 pivotal readouts
Study Setting Design Primary endpoints Enrolment completed (n)
Phase 3
Skyscraper-02 1L SCLC Tecentriq + chemo combo, vs Tecentriq + chemo PFS & OS Q1 2021 (470)
Skyscraper-01 1L PD-L1 "high" NSCLC Tecentriq combo, vs Tecentriq PFS & OS Q3 2021 (500-600)
Skyscraper-08 1L oesophageal cancer Tecentriq + chemo combo, vs chemo PFS & OS Q4 2021 (500)
Pivotal phase 2
Skyscraper-04 2L PD-L1+ve cervical cancer Tecentriq combo, vs Tecentriq ORR* Still enrolling (172)
Note: *OS is a secondary endpoint. Source: Roche & clinicaltrials.gov.

Based on recent events, cervical cancer at least looks like a long shot. The quick front-line approval and formal second-line label for Merck & Co’s Keytruda, based on controlled studies showing a survival benefit, have already claimed the scalp of Agenus’s balstilimab.

Balstilimab’s filing was based on remission rates in an uncontrolled study, and it is clear that only survival data will now do. Tiragolumab’s Skyscraper-04 trial, a Tecentriq combo in second-line, PD-L1-positive disease, primarily tests ORR, with OS a secondary endpoint.

Apart from the primary focus on ORR, it is not clear whether Tecentriq, a drug not approved for cervical cancer, will now be deemed an appropriate comparator in this setting. A further indication of how competitive this cancer is is Sanofi/Regeneron’s recent withdrawal of a second-line Libtayo filing – backed by an OS benefit versus chemo, not Keytruda.

Still, the main tiragolumab catalyst remains Skyscraper-01, in PD-L1-high first-line NSCLC, as a Tecentriq combo. The phase 2 Cityscape trial had shown a 77% reduction in risk of death versus Tecentriq in PD-L1 ≥50% expressers, a benefit Roche today reminded investors was “eye-popping”. Skyscraper-01 is much bigger than Cityscape, so only the most aggressive bulls expect such a result to be repeated.

Of the other two pivotal readouts, in SCLC tiragolumab plus Tecentriq and chemo will aim to outdo the Tecentriq chemo combo in its approved use, though no clinical data for tiragolumab have ever been reported in this cancer. A hit in oesophageal cancer would represent a new setting for tiragolumab and Tecentriq alike.

In and out

Roche’s fourth-quarter update also included news of an unusually large number of new molecular entities entering the clinic for the first time, as well as numerous phase 1 and 2 discontinuations.

The existence of many of those in the former category has barely been disclosed before, so their mechanisms remain unknown, though two new Chugai projects, SPYK04 and LUNA18, appear to target the Ras/Map kinase pathway.

An intriguing Alzheimer’s asset, RG6289, is also new to phase 1. Its mechanism is undisclosed, and it is distinct from RG6035, the brain-shuttle version of gantenerumab that has been in phase 2 since early 2021.

These and other assets will remain closely watched, but as far as 2022 catalysts go gantenerumab’s readout is the “biggest one of all”, Bill Anderson, head of Roche’s pharma business, told investors.

Roche assets moving into the clinic, and moving out of development
Project Mechanism Trial Indication
Newly into clinical trials…
RG6129 / RO7444973 HLA-A*02 Mage-A4 T-cell engager NCT05129280 Mage-A4+ve solid tumours
RG6289 ? ? Alzheimer's disease
RG6341 / GDC-6599 ? ? Asthma
RG6392 / RO7497987 ? ISRCTN92655801  Cancer
RG6501 / OpRegen* RPE cell therapy ? Geographic atrophy
LUNA18 Ras inhibitor NCT05012618  Ras+ve solid tumours
SPYK04 Undisclosed small molecule NCT04511845 Tumours with Map kinase pathway alterations (eg, Braf/Ras+ve)
…and discontinued
RG6232 / RO7293583 Anti-Tyrp1 T-cell engager NCT04551352 (ph1) Tyrp1+ve melanomas
PCO371  PTH1 receptor antagonist NCT04209179 (ph1 stopped for poor risk/benefit) Hypoparathyroidism
RG7835 / RO7049665 IgG Fc-IL-2 mutein fusion protein NCT04790916 (ph2 stopped for lack of efficacy) Autoimmune hepatitis
RG7992 / RO7040551 / BFKB8488A Anti-FGFR 1 & Klotho beta MAb NCT04171765 (ph2) Nash
RG6367 / SPK 7001 REP 1 gene therapy NCT02341807 (ph2) Choroideraemia
Note: *licensed from Lineage Cell Therapeutics. Source: Roche, Chugai, clinicaltrials.gov & Evaluate Pharma.

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