Takeda draws a cautious line under Iclusig

Takeda has made a cautious bet to challenge Novartis’s chronic myelogenous leukaemia (CML) drug Scemblix, taking an option on a future licensing deal covering Ascentage Pharma’s similarly acting olverembatinib.The move marks the Japanese group’s second attempt at becoming a significant player in CML, after it bought Ariad for an extraordinary $5.2bn in 2017; with Ariad came the CML drug Iclusig. But, despite Iclusig’s billing as a third-generation kinase inhibitor, that drug is now limited to a late-line CML setting, and with first and second-line CML studies terminated Takeda has evidently gone to Ascentage in the search for something better.The olverembatinib deal seems rich too – an up-front fee of $100m only gives Takeda the rights to a future opt-in, whose formal exercise would presumably involve the Japanese group handing across an even larger chunk of cash. But then it does include key ex-China markets, including the US, Europe and Japan, for a product that already has regulatory approval.That green light is in China, where olverembatinib is licensed to Innovent, and western approvals depend on the phase 3 Polaris-2 study, which only began last month. In the meantime, the CML space has been shaken up by Novartis, whose third-generation TKI Scemblix put up stellar data at ASCO, on the back of which it looks likely to have its label broadened from its currently approved third-line use to the front line.Third-line CMLOlverembatinib’s Chinese approval is broadly similar to Scemblix’s current US label: CML patients in whom first and second-generation TKIs (for instance Novartis’s Gleevec and Tasigna respectively) have failed, and in chronic-phase CML carrying the T315I mutation.This is backed by a registrational phase 2 study, whose data were presented at last year’s ASH conference. Here olverembatinib beat best available therapy on event-free survival, its primary endpoint, cutting risk of progression or death by 60%, and investigators highlighted the trial’s setting as representing the largest population of CML patients resistant to first as well as second-generation TKIs. That’s all very well, but the real battle here will be against the third-generation Scemblix, in the front-line setting – assuming that olverembatinib manages eventually to break into this.For Iclusig, the drug Takeda acquired along with Ariad, first-line CML was already out of reach when that takeover closed in 2017, Ariad having terminated the Epic study four years earlier. Takeda then canned Iclusig’s second-line Optic-2L trial, leaving everything hanging on the third-line CML approval that finally came in the US four years ago.By then Iclusig had become marginalised. Olverembatinib offers Takeda a second shot here, though between 2017 and now the treatment of CML has changed considerably, and it’s about to change further. Selected BCR-ABL tyrosine kinase inhibitors for CMLDrugCompanyGenerationUS statusSupporting trialsGleevecNovartis1stApproved 1st lineNCT00006343SprycelBristol Myers Squibb2ndApproved 1st lineDasisionTasignaNovartis2ndApproved 1st lineEnestndBosulifPfizer2ndApproved 1st line (but usually used later)BforeIclusigTakeda (ex Ariad)3rdApproved 3rd line; 1st-line Epic & 2nd-line Optic-2L trials terminatedOpticScemblixNovartis3rdApproved 3rd line; awaiting 1st-line approvalASC4firstOlverembatinibAscentage/ Innovent/ Takeda3rdPhase 3 2nd-line trial started May 2024 (approved 3rd line in China)Polaris-2Source: OncologyPipeline.