Iclusig comes too late to rescue Takeda

Seven years after Takeda acquired Ariad for a seemingly extraordinary $5.2bn Iclusig, one of the target company’s two drugs, has secured a fresh US approval. The green light, on an accelerated basis, came yesterday in front-line Philadelphia chromosome-positive ALL, based on the phase 3 Phallcon study whose data were presented at last year’s ASCO conference.

This marks the second additional nod for Iclusig since the takeover closed, with a 2020 approval adding third-line CML to the BCR-ABL inhibitor’s label. In terms of justifying the acquisition price, however, neither use seems likely to move the needle, given that both represent niche settings in a space where Novartis’s Gleevec is off-patent.

It was Gleevec that defined BCR-ABL inhibition as the standard in CML, becoming established first line and spawning a range of second and third-generation tyrosine kinase inhibitors, including Iclusig. In the nine months ended December Takeda booked Iclusig sales of $273m (+17%), while Incyte, which holds rights in Europe, recorded $112m for all of 2023.

Such numbers reflect just how competitive CML is. Ph-positive ALL might be less crowded, but it’s a relatively small use, where Gleevec is approved in the relapsed/refractory setting, and as part of a chemo combo in first-line paediatric patients.

Phallcon

Now Iclusig has added to its label the fact it beat Gleevec, also as part of a chemo combo, in the phase 3 Phallcon trial.

The benefit, slightly updated versus the data presented at ASCO, is a 30% rate of MRD-negative complete responses, versus 12% for Gleevec (p=0.0004). As this is an accelerated approval it needs to be confirmed later, and it’s likely that Phallcon itself can serve as the confirmatory trial, given that it’s controlled, and will yield event-free and overall survival data in the coming years.

One question will be whether the data will be enough to persuade doctors to prescribe a novel drug rather than cheap generic versions of Gleevec, which came off US patent in 2016. The competition in BCR-ABL inhibition is notable for including Novartis’s own Gleevec follow-on, Scemblix, though this drug is limited to CML, with no advanced trials under way in Ph-positive ALL.

This could clearly be good news for Iclusig and Takeda, though by now it all seems too little, too late. Even at the time Takeda was paying $5.2bn for Ariad in January 2017 it was clear that Iclusig was becoming marginalised, having had its first-line CML trial, Epic, terminated early over vascular adverse event concerns.

Just after the deal closed Takeda discontinued Optic-2L, a study in CML patients who had built up resistance to Gleevec. Iclusig’s label was expanded to third-line or later CML in late 2020, based on the uncontrolled phase 2 Optic trial, but here the drug competes against other BCR-ABL inhibitors, and could be squeezed further by Scemblix’s likely future move into the front line.

The other asset Takeda gained from Ariad was the ALK inhibitor Alunbrig, first approved in ALK-positive NSCLC in April 2017. But this too has struggled – nine-month sales were $139m (+34%) – targeting another highly competitive space where it’s been eclipsed by Roche’s Alecensa and Pfizer’s third-generation drug Lorbrena.

Despite yesterday’s regulatory success the Ariad takeover continues to look like a deal done in exuberant times, when Japanese pharma companies were willing to pay over the odds for biotechs with a US presence.

Selected Iclusig studies

Source: OncologyPipeline & prescribing information.