ASH – Bluebird and GBT hammered on sickle cell disappointments

Nobody said gene therapy was easy. But the new data on two patients with sickle cell disease treated with Bluebird Bio’s LentiGlobin are lacklustre in the extreme, and the therapy’s failure to live up to the highly promising results seen in the first patient treated has seriously disheartened investors.

Bluebird’s stock is down 35% in early trading today as its shareholders digest news that the haemoglobin gene was not successfully transfected into the new patients in large enough numbers to have a meaningful effect on the disease. Efficacy might pick up over time, but given that the promise of gene therapy is of a one-off treatment and near-instant cure even an eventual improvement will represent a fairly dismal showing. And another sickle cell therapy, Global Blood Therapeutics’ GBT440, has also performed poorly.

Over the rainbow

The data presented yesterday at the annual meeting of the American Society of Hematology come from Bluebird’s HGB-206 trial and concern two patients who, three and five months after receiving LentiGlobin, are producing healthy red blood cells in levels far below those necessary to make a difference to their health.

At three months, one patient had 3% marked haemoglobin – that produced from the introduced gene – contributing to overall anti-sickling haemoglobin levels of 13%. In the patient followed for five months the figures were 12% and 15% respectively. An overall anti-sickling haemoglobin level of 30% is thought to be disease-modifying.

The results stand in contrast to those reported in the summer at the European Hematology Association meeting – from a different trial, HGB-205 – which showed LentiGlobin to be working very nicely in the first sickle cell patient treated (Bluebird feathers nest while going is good, June 25, 2015).

This patient is still doing very well according to Bluebird, with an anti-sickling haemoglobin level of 49%, almost all of which was produced from the transduced gene. The patient has not required a blood transfusion or a hospital visit for over nine months.

Perhaps Bluebird would not have fallen so far had LentiGlobin’s showing in its other indication, beta-thalassemia, not also been poor. The updated results had not changed meaningfully from their initial release last month (ASH preview – Cellectis steals the limelight, November 6, 2015).

Despite the poor Bluebird data sickle cell experts at the ASH meeting refused to dismiss the gene therapy concept, though they warned that it could only be performed at some sites.

“Probably in future gene therapy could change things but it would not be useful in developing countries or countries with limited resources,” said Dr Barbara Capelli, from the International Observatory on Sickle Cell Disease in France, during a panel session.

“We’re very excited about the limited number of patients with sickle cell disease undergoing gene therapy,” said the panel’s moderator, Dr Alexis Thompson, a paediatric haematologist from Ann & Robert H Lurie Children's Hospital of Chicago. She described the gene therapy results as “certainly very encouraging”.

Thicker than water

And while Bluebird’s gene therapy is not a raging success, another – much simpler – therapeutic approach under investigation is also far from satisfactory.

Data from a trial of Global Blood Therapeutics’ small molecule GBT440, which binds oxygen to haemoglobin more tightly and thus prevents clumping of sickle haemoglobin, indicated that the therapy is not without merit – but again the results underwhelmed compared with what had been previously released.

Data from all 30 patients in the company’s phase I/II trial showed that median sickle cell counts fell by 56% in patients given 500mg of GBT440 and by 46% in those given a 700mg dose. In placebo patients median sickle cell counts increased by 14%.

Nice reductions. But there are two problems here. The first and most obvious is the lack of a dose response. And there is also the better earlier data: the first six patients treated with GBT440 had seen their sickle cell counts drop by closer to 80% when Global Blood went public back in September. Global Blood has fallen 25% on the Nasdaq so far today.

Dr Claire Hemmaway of Queens Hospital, UK, who presented the data yesterday, said: “GBT440 offers a well-tolerated, once-a-day and possibly disease-modifying therapy.” Asked whether any patient had had improvement in symptoms, she said that one patient indicated an improvement in fatigue, but as the study was still blinded there was no way to know whether they were on GBT440 or placebo.

Full data will be released next year. If GBT440 can be shown to work it has meaningful advantages over LentiGlobin, being much cheaper, easier to administer – it is a once-daily pill – and less mechanistically complex.

For now, though, both assets have their problems, and both companies have suffered accordingly. Expectations were high considering sickle cell is a bitterly hard disorder to treat. If one or both manage to solve their issues the rewards could be significant.

To contact the writer of this story email Elizabeth Cairns in London or Jacob Plieth in Orlando at [email protected]or follow @LizEPVantage or @JacobPliethon Twitter

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