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)|
|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|
|Newly into clinical trials…|
|RG6129 / RO7444973||HLA-A*02 Mage-A4 T-cell engager||NCT05129280||Mage-A4+ve solid tumours|
|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)|
|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.|