Daiichi could be rewarded for persisting with Vanflyta

A front-line trial yields a positive result two years after the drug got a US complete response letter.

Persistence sometimes pays off in drug development, as Daiichi Sankyo might soon find out. Two years after the FDA kicked out a filing for Vanflyta in relapsed/refractory AML, the drug’s front-line AML study, Quantum-First, has read out positively for overall survival.

This does not necessarily make Vanflyta a shoo-in for US approval; much will depend on the safety profile it has shown in Quantum-First, given that cardiac toxicity had in 2019 played a part in Vanflyta’s negative adcom vote and CRL. Novartis and Astellas will keep a close eye on this AML niche, and on the safety of their competing drugs.

These two competitors are Rydapt and Xospata, and like Vanflyta they target Flt3, a kinase that drives some types of AML. Both have US approval for Flt3-positive AML, Rydapt for front-line patients and Xospata in the relapsed/refractory setting.

Vanflyta secured approval in Japan, and its Quantum-R trial showed an OS benefit of 26.9 weeks in relapsed/refractory patients, versus 20.4 weeks for salvage chemo (p=0.019). However, the data were slated at a US adcom, which questioned patient censoring, imbalances in chemo intensity and the confounding effect of follow-on treatments.

Perhaps worst of all was cardiac toxicity, an adverse effect that was substantially higher with Vanflyta than with chemo. The panellists voted eight to three against approval, and the FDA followed with a CRL in June 2019.

Front line

Now the spotlight will fall on Quantum-First, which compared Vanflyta plus chemo against chemo alone in 539 front-line Flt3-positive AML patients. OS was its sole primary endpoint, and while Daiichi says this has read out positively the full data, including safety, are being kept back for a scientific meeting.

Interestingly, Astellas’s Xospata failed a front-line AML trial called Lacewing a year ago, though that had looked at monotherapy as well as a chemo combo. Its US label carries a boxed warning of differentiation syndrome, a potentially fatal side effect involving the proliferation of myeloid cells seen in 3% of treated subjects.

Xospata's relapsed-refractory US approval came courtesy of the Admiral trial, first on an accelerated basis based on remission rates, and then formalised when Admiral reached its survival endpoint, showing median OS of 9.3 months, versus 5.6 months for chemo alone (one-sided p=0.0004).

Meanwhile, Novartis’s Rydapt secured a front-line label based on survival in the academic-sponsored Ratify/CALGB 10603 study, which showed it to reduce risk of death by 23% (p=0.016). Hyperglycaemia and QT prolongation, seen at grade 3 or above in 2% of Rydapt recipients, are notable adverse events, but the label carries no boxed warning.

Crenolanib?

Another player had previously also tried to break into Flt3-mutant AML: Arog Pharmaceuticals, which had acquired the kinase inhibitor crenolanib from Pfizer for $12.5m 11 years ago.

Crenolanib remains in clinical trials in front-line as well as relapsed-refractory AML, though these are still one to three years away from reading out, and moreover Arog’s status is unclear.

The group had tried to raise $75m in a 2018 flotation, but its prospectus revealed that crenolanib’s US patents expired in 2020-24. The IPO failed to come off, and a year later the SEC was ordering Arog to pull the listing document, having received no response from the company to a formal request.

With two drugs marketed already Flt3-mutated AML is probably too small a niche to sustain a player without IP protection. Whether Daiichi tries again to make it three is the next question.

Selected work in Flt3-positive AML
Project Company 2026e sales First line Relapsed/refractory
Rydapt Novartis $240m Ratify None
US approved (showed mOS benefit) NA
Xospata Astellas $794m Lacewing Admiral
Terminated for futility US approved (showed mOS benefit)
Vanflyta Daiichi Sankyo $40m Quantim-First Quantum-R
Toplined positive for mOS CRL (showed mOS benefit)
Crenolanib Arog (inactive?) NA* ARO-021 ARO-013
Ends Nov 2022 (EFS primary) Ends Oct 2024 (3yr delay; EFS primary)
Note: *private company, so no sellside forecasts. Source: company statements, product labels, Evaluate Pharma & clinicaltrials.gov.

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