Bluebird set for EU beta-thalassaemia filing, but no cure yet


Yesterday’s New England Journal of Medicine publication of pooled data from two studies of Bluebird’s Lentiglobin position the group to file this gene therapy for conditional EU approval in beta-thalassaemia.

Given gene therapy’s recent history the small number of treated subjects – 22 – should probably not be too troubling. Rather, given the likely pricetag of this once-and-done therapy, two other issues might be more relevant: the fact that Lentiglobin can still not be called a cure, and that the initial EU filing will rely largely on an older manufacturing process than that planned for the US.

That Lentiglobin is not a cure – at least yet – is evident from the NEJM data, which relate to the two trials Bluebird aims to use for an EU conditional filing: the multinational Northstar and the single-centre HGP-205.

The data were first presented at Ash in December, and showed transfusion independence achieved in 12 of 13 patients with mild disease but only two of nine severe subjects. Even in transfusion-independent subjects it would be premature to use the word “cure” until follow-up of several years is seen.

New manufacturing

Still, both of these trials use an old manufacturing process, and Bluebird will hope that doubts about Lentiglobin’s curative value can be allayed with a new method. The group says the EU filing will be supplemented by data from the two US trials that use new manufacturing, which it says is the intended commercial process.

In the US new manufacturing was implemented precisely because of waning responses in some patients with the most severe form of the disease, genotype β0/β0. When two such subjects were reported to have gone back on blood transfusions in 2015 Bluebird’s share price crashed.

At Ash nerves were calmed when Bluebird presented initial findings from a new trial, Northstar-2, which used its new manufacturing method.

Northstar-2 enrols only subjects with less severe, non-β0/β0 disease, the population that will be Bluebird’s initial focus. The filing strategy has Northstar-2 backing an FDA submission, while a separate US registrational study, Northstar-3, is focusing on β0/β0 disease, but has only just started enrolling.

EU filing plans make it relevant to consider pooled Northstar and HGB-205 data; however, while these do include eight β0/β0 subjects (plus one with another serious genotype, ISV1-110), EU filing will also only concern non-β0/β0.

Bluebird's beta-thalassaemia trials with Lentiglobin
Trial Purpose Manufacturing Genotype Ash 2017 data Trial ID
Northstar (HGB-204) EU conditional approval filing Old Non-β0/β0 (mild) 9 of 10 pts transfusion-free NCT01745120
β0/β0 (severe) 2 of 8 pts transfusion-free
HGB-205 EU conditional approval filing Old Non-β0/β0 (mild) 3 of 3 pts transfusion-free NCT02151526
ISV1-110 (severe) 1 of 1 pt transfusion-free
Northstar-2 (HGB-207) US filing (supplement EU filing) New Non-β0/β0 (mild) 3 of 3 pts transfusion-free NCT02906202
Northstar-3 (HGB-212) US filing (supplement EU filing) New β0/β0 (severe) 1st pt treated Nov 2017 NCT03207009
Source: Ash, NEJM.

Perhaps this is why Bluebird feels sufficiently comfortable with relying on data with the old manufacturing method for the time being, though eventually it aims to switch to the new system, which presumably is the only way it can address severe genotypes, which will be pursued later.

Dave Davidson, its chief medical officer, previously told EP Vantage: “The [Northstar-2 and 3] trials with the improved manufacturing will serve as the basis for the filing with the FDA and also allow us to flip the conditional EU approval to a full approval.”

The signs are good – so far. Five of the first six non-β0/β0 subjects treated in Northstar-2 are at month three producing 6g/dl or more of the engineered HbAT87Q globin that Lentiglobin replaces. 6g/dl is considered the level below which patients need to go on transfusions, and in Northstar the median at month three was only 2g/dl.

For now Bluebird investors have to hope that old manufacturing in non-β0/β0 disease is enough for EU regulators. Hopes of a cure for all beta-thalassaemia patients, including severe disease, must remain on hold for now.

This story has been corrected to reflect Bluebird's EU filing plan.

To contact the writer of this story email Jacob Plieth in London at or follow @JacobPlieth on Twitter

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