Merck & Co., Daiichi's ADC directed against B7-H3 sprints into late-stage testing

15 Jan 2024
firstwordpharma.com
ADCPhase 2Phase 3License out/inClinical Trial Termination
One of a trio of antibody-drug conjugates (ADCs) that formed the basis of a multi-billion-dollar alliance between Merck & Co. and Daiichi Sankyo last fall is making a quick advance into Phase III testing. According to a recent update on ClinicalTrials.gov, the study of ifinatamab deruxtecan (I-DXd) is expected to get underway in March to evaluate the B7-H3–targeting ADC in patients with relapsed small-cell lung cancer (SCLC).
The partnership, signed last October, is a lucrative one for Daiichi Sankyo. In addition to receiving $4 billion upfront, the company is also eligible for another $18 billion in other potential payments and milestones. In exchange, Merck received ex-Japan rights to I-DXd, as well as two other ADC candidates – HER3-directed patritumab deruxtecan and raludotatug deruxtecan, which targets CDH6.
While the companies predict the drugs could generate "multi-billion dollar worldwide commercial revenue" by the mid-2030’s, the deal – and a greater focus on ADCs in general – may also help Merck weather looming patent expirations for Keytruda coming in the latter half of the decade.
Recruitment in the upcoming Phase III trial has not yet started, but it is expected to enroll 468 participants and will compare the efficacy and safety of I-DXd monotherapy with treatment of physician's choice. Objective response rate (ORR) and overall survival (OS) are the primary endpoints.
Hints of promise
Daiichi Sankyo said in September that I-DXd had shown an "encouraging" ORR of 52.4% in heavily pretreated patients with extensive-stage SCLC enrolled in a Phase II trial. This included one complete response and 10 partial responses. Meanwhile, median progression-free survival was 5.6 months and median OS was 12.2 months as of data cutoff of January 31, 2023.
Despite the confidence with which Merck embarked on the Daiichi partnership, there is some question as to whether it may have been overly generous betting on targets that have been the focus of significantly fewer prior deals in comparison to HER2 and TROP2.
For example B7-H3 – so far, more popular for cell therapies than ADCs – has a limited deal history, with no public ADC deals addressing the target since 2021. However, companies such as MacroGenics, Mabwell Therapeutics and Minghui Pharmaceutical are working on some in-house candidates. Others that have shown an interest include GSK, which recently struck a deal to co-develop Hansoh Pharmaceutical's B7-H3-targeting compound HS-20093.
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