Should FDA approval of Mylotarg happen later this year – for the second time – the acute myeloid leukaemia space will be in for something of a gold rush. The disease, which typically strikes the elderly, has seen woefully little innovation in decades, but the Pfizer drug is one of four novel agents being reviewed by regulators this year.
The first, Novartis’s Rydapt, won a green light in the US in April, and the strong backing of an advisory committee for Mylotarg this week makes its return look likely. Considering the unmet need in this disease, Celgene and Jazz also have reasons for optimism with their candidates (see table below).
On Tuesday the FDA’s oncology committee voted 6-1 in favour of the risk-benefit profile of Mylotarg, largely based on the Alfa-0701 trial. The phase III study, conducted by a French research group, was submitted along with re-analysed data from several other trials in an attempt to get the drug back on the market.
Concerns about toxicity and lack of benefit caused the drug to be pulled in 2010, after 10 years on the market, but Pfizer continued to support research in the interim. Generically known as gemtuzumab ozogamicin, the antibody-drug conjugate targets CD33, which is expressed on a large proportion of AML tumours.
Changes to the chemotherapy dose and scheduling allowed researchers to discover a less toxic way of administering Mylotarg, although Pfizer never managed to prove that the project can extend survival, normally a must for a drug proposed for first-line use. Still, reviewers were apparently convinced by the use of event-free survival as the primary endpoint in the Alfa-0701 trial, and approval now looks likely.
|Awaiting approval in AML|
|Project||Company||FDA Action date||Target patients||Treatable population||Key clinical result|
|Rydapt||Novartis||Approved 28 Apr||First-line FLT-3 positive||~30%||23% reduction in the risk of death vs chemo|
|Mylotarg||Pfizer||PDUFA ~ 1 Sep||Newly diagnosed CD33+||~80%||44% improvement in event free survival|
|Enasidenib||Celgene/Agios||PDUFA 30 Aug||Relapsed/refractory IDH2+||10-15%||40.3% ORR (71 of 176)|
|Vyxeos||Jazz||PDUFA ~ 1 Dec||High risk (secondary) AML||~40%||31% reduction in the risk of death versus 7+3|
So Mylotarg looks set to follow Rydapt onto the market, although these agents are designed for different patient populations.
Among several other kinases Novartis’s drug hits FLT3, the root of a genetic mutation that causes a particularly aggressive form of the disease.
Similarly, Celgene’s enasidenib hits another cancer-causing mutation, on the IDH2 enzyme; the project was licensed from Agios. The big biotech has filed on the back of a phase I/II trial, although a confirmatory pivotal study is already running. The Idhentify trial is seeking to recruit 280 elderly, refractory patients, and should yield results in mid-2019.
Vyxeos is something of a 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. Surprisingly positive results from a phase III trial of the therapy, which was then owned by Celator, prompted Jazz to swoop and buy out the micro cap drug developer for an eye-watering $1.5bn (Celator rewards investors with stunning Jazz solo, 31 May 2016).
Approval towards the end of the year is therefore a big event for its new owner.
Despite these advances, there have also been setbacks. Seattle Genetic’s vadastuximab talirine was recently abandoned, and perhaps less notably Cyclacel’s sapacitabine failed to show any benefit in the final analysis of the Seamless study. But in the pipeline there several new agents to watch out for – Erytech should report results from a phase II trial designed to support a re-filing of Graspa in October, while phase III data on guadacitabine and idasanutlin from Otsuka and Roche respectively are due next year.
It is frequently said that the five-year survival rate in older AML patients has not improved in 40 years. Developments this year and next should go some way to help improve this statistic.