Regor’s selective approach attracts Roche

Specific inhibition of the CDK4 subtype of cyclin-dependent kinases is largely the domain of Pfizer’s atirmociclib, but as of today there’s a new big pharma in town: Roche has paid $850m up front for a portfolio of CDK4 inhibitors originated by the little-known private US biotech Regor Pharmaceuticals.

Details of the transaction are sketchy, and it’s not even clear how many assets might be involved, but according to OncologyPipeline Regor is developing at least two molecules with CDK4 activity: RGT-419B, in phase 1, and the brain-penetrant RGT-587, still preclinical. RGT-419B claims to have an optimised kinase activity spectrum, but $850m seems rich for such an early-stage asset.

The logic behind hitting CDK4 specifically is the avoidance of toxicity, most notably neutropenia, associated with the established class of CDK4/6 inhibitors Ibrance, Verzenio and Kisqali, which are approved for HER2-negative breast cancer. It’s suggested that hitting CDK6 is responsible for this side effect, which poses an obstacle to achieving complete CDK4 blockade.

Overcoming resistance

Not only that, but RGT-419B is said to be able to overcome resistance to CDK4/6 inhibition. A preclinical poster at the 2020 San Antonio breast Cancer Symposium revealed that this was done through incorporating into the molecule a low level of activity at CDK2, which could combat Cyclin E/CDK2-driven resistance.

It’s notable that Pfizer, whose atirmociclib started phase 3 this year, is being combined with that company’s separate CDK2 inhibitor PF-07104091, also in an effort to combat resistance to CDK4/6 drugs. At ESMO the company claimed a 28% response rate among 18 ER-positive, HER2-negative breast cancer patients who had all received prior CDK4/6 inhibitors.

For its part Regor reported first-in-human data with RGT-419B at last year’s SABCS, from 12 patients, all of whom had also received CDK4/6 inhibitors. Here there were three confirmed responses (one of which relapsed at 32 days), plus one unconfirmed response that was still ongoing at the 26 September 2023 data cutoff.

On the face of it a 25-33% ORR stacks up well against Pfizer’s atirmociclib/PF-07104091 combo in a similar population. An important differentiator between the approaches could be safety, however; Regor reported a 25% rate of neutropenia – all below grade 3 – while Pfizer saw a 27% rate of grade 3 or higher neutropenia, as well as dose-limiting toxicities at the highest doses tested.

Cross-trial comparison in ER+ve HER2-ve breast cancer

Source: ESMO & SABCS.

There are few other CDK4-selective inhibitors in development, but the industry pipeline does include BeiGene’s BGB-43395, which last year entered phase 1.

Also in clinical trials is Jiangsu HengRui’s HRS-6209, while Aucentra’s AU2-94 is in preclinical development, according to OncologyPipeline. Kinnate Biopharma also had a preclinical CDK4 programme, but has now been acquired by Xoma, mostly for its cash balance.

There are also two preclinical assets targeting CDK2/4, namely Iambic Therapeutics’ IAM-C1 and Concarlo Therapeutics’ IpY.20. Interestingly, Pfizer took an anti-CDK2/4/6 molecule, PF-07224826, into phase 1, but then withdrew that trial for “business considerations” – presumably in favour of the atirmociclib/PF-07104091 combo.

Regor will now focus on the rest of its in-house pipeline, which includes GLP-1R agonists for obesity, and oncology projects targeting SOS1 and HPK1. It won’t go unnoticed that none of these was apparently of sufficient interest for Roche to consider paying up to acquire Regor in its entirety.