Skip to main content

Arcus makes its HIF2α pitch

After living in the shadow of Arcus’s TIGIT project, casdatifan might soon come into its own.

Arcus Biosciences this week made a push to turn investor attention to its HIF2α inhibitor casdatifan. Until now this had sailed under the radar, but Arcus claims it's already looking better than Merck & Co’s Welireg, the first marketed drug with this mechanism.

After a speedy review the FDA last year approved Welireg for second/third-line kidney cancer, even though the supporting Litespark-005 study had disappointed by not showing an overall survival benefit. Meanwhile, Arcus has been hit by a worsening dataset with its lead anti-TIGIT MAb domvanalimab, partnered with Gilead, and casdatifan offers a new asset to which value can be attached.

Indeed, last year Evercore ISI analysts were already highlighting casdatifan, which was then coded AB521 and had yet to generate any clinical data, as accounting for much of Arcus’s $1.5bn valuation even if domvanalimab turned out to be a zero. On Wednesday Arcus presented the first clinical case reports, and on this basis the omens for casdatifan look good.

Such considerations are important for the chances of a deal. Gilead can opt into casdatifan’s development on proof of concept, and Arcus promises to deliver full data from 30 patients in the 100mg dose-expansion cohort of casdatifan’s Arc-20 trial at a medical conference in the second half of 2024; ESMO seems a possibility.

Not only that, but Arcus’s chief executive, Terry Rosen, told investors this week: “We’ve had plenty of inbound interest from other companies that might see a strategic fit with the rest of their portfolio.” Arcus shares closed yesterday up nearly 20%.

First data

So what’s behind the enthusiasm? Arc-20’s dose-escalation cohort enrolled 12 solid tumour patients, and among the four that had kidney cancer casdatifan caused nearly 30% tumour reduction in two, and “almost no tumour growth for more than 14 months” in a third, Arcus revealed.

All the patients had progressed on VEGF & PD-(L)1 blockade, and three of the four were fourth line or later. Dose-expansion, meanwhile, focuses on second-line or later kidney cancer, and among the 30 patients enrolled at 100mg Arcus has boasted of already seeing an ORR that, if unconfirmed as well as confirmed responses are considered, is similar to that in Welireg’s Litespark-005.

This is promising because Welireg appears to be limited by pharmacokinetics and a significant amount of primary progression, while the hope is that casdatifan can stabilise tumour growth faster with less progressive disease, and accordingly give longer PFS. Rosen said Welireg’s 22% ORR and 5.6-month median PFS left room for improvement.

The basis for this is pharmacokinetic data showing that just 20mg of casdatifan gives exposure similar to 120mg of Welireg (the approved dose). Thus Arcus argues that it’s able to hit HIF2α “harder than Welireg”, while showing rates of anaemia and hypoxia similar to those with the Merck drug.

“We’re pushing this programme as hard as possible,” Rosen said, adding that a phase 3 casdatifan trial would begin in early 2025.

Given that Welireg’s US approval validated HIF2α inhibition, it’s surprising how few others are following suit. OncologyPipeline reveals only three clinical-stage HIF2α inhibitors in the industry pipeline beyond Welireg and casdatifan, and just this year Novartis confirmed that it had discontinued its contender, DFF332.


HIF2α inhibitor pipeline

Welireg (belzutifan)HIF2α inhibitorMerck & Co (ex Peloton)Approved for Von Hippel Lindau disease & post PD-(L)1+VEGF inhibitor (given sequentially or in combination) renal cell carcinoma; various other settings being studied
NKT2152HIF2α inhibitorNiKang TherapeuticsPh1/2 in 2nd-line renal cell carcinoma
Casdatifan (AB521)HIF2α inhibitorArcus BiosciencesArc-20 ph1 trial, dose expansion in 2nd-line+ renal cell carcinoma
BPI-452080HIF2α inhibitorBetta PharmaceuticalsPh1 in solid tumours
HS-10516HIF2α inhibitorHansoh PharmaPh1 in 2nd-line renal cell carcinoma
AND021HIF2α inhibitorKind PharmaceuticalsPreclinical
SMP-215Anti-HIF2α ADCXilingyuan PharmaceuticalPreclinical
DFF332HIF2α inhibitorNovartisDiscontinued in ph1
ARO-HIF2Anti-HIF2α RNAiArrowheadDiscontinued in ph1
SDGR4HIF2α inhibitorSchrödingerDiscontinued after Bristol Myers Squibb returned rights

Note: updated to clarify Welireg's approved setting. Source: OncologyPipeline.


Molecular Drug Targets