Just like buses, three come at once in leukaemia regulatory queue

After decades of disappointment in the treatment of acute myeloid leukaemia, regulators could find themselves considering three new therapies for approval by the end of the year.

News yesterday that Celgene will seek accelerated approval for the Agios-partnered AG-221 adds the most surprising candidate to this group. Since AG-221 has only generated data from a phase I/II trial so far this move was far from expected – hence the 26% surge in Agios’s share price yesterday.

Celgene plans to submit the IDH2 inhibitor to the FDA by the end of the year on the back of data still emerging from the large mid-stage trial. A total of 250 patients with advanced haematological cancers driven by the IDH2 mutation have been recruited and split between five cohorts. Most have various forms of relapsed or refractory AML, the setting in which the filing will be made.

At ASH last year the company presented data from 159 of these patients, with an overall response rate of 37%. Complete responses were seen in 18%. Perhaps the data have improved, prompting Celgene’s decision to charge forward.

The project, which now has the generic name enasidenib, blocks the metabolic enzyme IDH2 which, when mutated, causes cells to proliferate quickly. Celgene exercised an option over it in 2014, putting Agios in line for $120m in milestones and low-to mid-teen royalties.

The big biotech turned down rights to a similar IDH1 inhibitor, AG-120, which Agios has pushed on with. This will hopefully also be filed next year on an accelerated basis, Agios said, setting up the regulatory AML pipeline for another boost.

Three years

Speaking at an investor presentation yesterday Michael Pehl, head of Celgene’s oncology business, added little else to the data reported so far. He described the asset as a “great drug” that took only three years from the first dosing of patients to the regulatory path.

Given the abject lack of options in this type of leukaemia, Celgene looks to have a good chance of winning early approval – a confirmatory phase III trial is under way, and orphan drug and fast-track designations are already secured.

There is some sort of precedent here with Mylotarg, the only targeted agent to reach the market in AML, although the antibody-drug conjugate proved so toxic that it was withdrawn in 2010. It was granted accelerated approval on the basis of an ORR of 26%.

For many reasons, however, this does not represent a yardstick; one is that Mylotarg targeted CD33, which is expressed on most AML cells, while IDH represents a small genetic subtype. IDH2 is mutated in 10% to 15% of adult AML, and IDH1 in 5% to 10%.

The other two agents heading to regulators are also not directly comparable, although Novartis’s midostaurin is also targeting a genetic subtype.

The agent won breakthrough therapy designation in February for the treatment of newly diagnosed FLT3-mutated AML, and Novartis confirmed to EP Vantage that the filing process worldwide had commenced.

The project is backed by data from a phase III trial that found a 23% improvement in overall survival in patients eligible to receive standard induction and consolidation chemotherapy.

Different beast

The third contender, Vyxeos, is a very different beast; it uses a liposomal preparation to deliver the same two components as the 7+3 regimen of cytarabine and daunorubicin that has been used for many years as standard induction therapy.

In its pivotal study it boosted the successful induction rate from 33% to 48%; new owner Jazz Pharmaceuticals plans to start a rolling submission in the third quarter, which should be completed by the end of the year or early 2017.

Alongside this progress, however, there have also been setbacks. Boehringer Ingelheim in June said a phase III trial of volasertib failed – the addition of the PLK1 inhibitor to chemotherapy generated no significant difference in objective response rates. Work with the compound in AML is continuing, however, the company said.

Meanwhile, long-awaited data from Cycalel’s Seamless trial of sapacitabine should be released any day now, although hopes for a positive readout are very low (Event – Cyclacel’s date with decitabine, 22 August 2016).

Still, with three on their way to regulators and a full pipeline of readouts in the next couple of years, the outlook for AML is improving (Therapy focus – Hopes rise for a breakthrough in leukaemia logjam, February 25, 2016). 

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @AmyEPVantage on Twitter

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