Ringside sends Immunome towards filing

Keenly awaited results of the phase 3 Ringside study of Immunome’s lead project, the small-molecule gamma secretase inhibitor varegacestat, have been deemed sufficiently strong for the company to file them for US approval in the second quarter of next year.

With Immunome’s stock up 20% on Monday morning the markets likely see this company as a takeover target, given that SpringWorks, the developer of the first approved gamma secretase inhibitor, Ogsiveo, was bought by Merck KGaA for almost $4bn. On all key efficacy metrics Ringside has shown varegacestat to be better than Ogsiveo, on a cross-trial basis.

One possible source of disappointment might be that varegacestat’s response rate in Ringside, a pivotal study in 156 patients with desmoid tumours, came in at 56%, which is lower than the 64% it scored in its phase 2 trial. However, few would realistically have expected a mid-stage result to be repeated in phase 3, and Ogsiveo scored just 41% in its registrational Defi trial.

An especially strong part of Ogsiveo’s label is the progression-free survival advantage that the drug showed over placebo, amounting to a 71% reduction in risk of progression or death across the Defi trial. In fact, Ringside has managed to beat even this, with varegacestat yielding an astonishing 0.16 hazard ratio for PFS.

Cross-trial comparison of Ogsiveo vs varegacestat in desmoid tumours

Note: *rate of alopecia in phase 2 was 50%. Source: US prescribing information & Immunome.

Though Immunome kept other key data back for presentation at a scientific conference, one key safety metric appeared to favour varegacestat. This was ovarian toxicity, an adverse event known to be a class effect of gamma secretase inhibitors, and one that limits their potential in women of childbearing age.

Any-grade ovarian toxicity was seen in 56% of Ringside patients treated with varegacestat, a number that seems meaningfully lower than the 75% cited on Ogsiveo’s US label, which also includes a warning about it. Immunome put its potential advantage down to varegacestat having different pharmacokinetics than Ogsiveo, and using a different dose.

The different profile is already seen as possibly resulting in varegacestat being more efficacious, with Immunome saying its molecule has a 78% longer half life than Ogsiveo. One toxicity yet to be disclosed is alopecia, which was seen in 50% of phase 2 patients, but whose rate in Ringside hasn’t been disclosed.

What now?

At least based on the data Immunome has toplined varegacestat looks like an approvable drug, so it’s worth considering its possible path towards launch.

The company insists that it wants to launch the drug itself in major markets, saying that targeting an indication like desmoid tumours, which are relatively rare and slow growing, is well within its capability. For now all it’s saying about deal-making is that it would consider local distributors in minor markets, and perhaps partnering in Asia.

However, solo launches by biotechs have an underwhelming track record, and the desmoid tumour market, once touted as holding blockbuster potential, is already showing signs of saturation: Ogsiveo sold $172m in 2024, but revenues this year are tracking at around $260m, though if varegacestat offers a meaningfully better profile it might be able to target more patients.

Immunome as a whole is being positioned as an ADC company – it’s run by Clay Siegall, the former head of Seagen – its next most-advanced pipeline asset is an anti-ROR1 conjugate, and IND filings for three more ADCs are due next year. Varegacestat is a small-molecule outlier, so Immunome should maximise its value as soon as it can.