Bluebird’s tinkering appears to be paying off. Data on the group’s gene therapy Lentiglobin suggest that new manufacturing processes have improved responses as hoped in both beta-thalassaemia and sickle cell disease.
But reality is starting to bite for the much-hyped group, which still looks very keenly valued despite a tumble on the stock market this year; its shares fell 5% today, valuing Bluebird at $6.4bn. A major problem is the lack of a market for Lentiglobin, believes one biotech investor, who is betting against the company on the stock market.
Elegant but not commercial?
Lentiglobin’s efficacy is not in doubt, the investor, who preferred to remain anonymous, told Vantage. “Lentiglobin is an elegant science experiment, and unquestionably works for most, though not all, sickle cell disease and beta-thalassaemia subtypes.”
But the therapy is a “commercial non-starter”, he added, saying Lentiglobin would likely face the same issues as CAR-T and gene therapies that have come before it.
Lentiglobin’s first nod is expected in Europe, where it is under review in the less severe non-β0/β0 beta-thalassaemia subtype.
The filing was based in part on the Northstar-2 trial, updated results of which were reported today at Ash, from a September 14 data cut off in 11 patients with at least three months' follow-up. Of these, 10 had stopped blood transfusions, the primary endpoint of the trial. And, among these responders, haemoglobin levels had returned to a normal or near-normal range of 11.1-13.3g/dl.
The data from Northstar-3, in the more severe β0/β0 disease subtype, were harder to interpret, coming in just three patients, one of whom has not had a blood transfusion since receiving Lentiglobin. This study has a less stringent aim of transfusion reduction rather than independence.
The group’s chief medical officer, David Davidson, conceded in an interview with Vantage that these were early results, but nevertheless dubbed the update “very exciting”. Still, the jury will be out on β0/β0 beta-thalassaemia until more data are available.
In sickle cell disease, the tweaks made to group C of the HGB-206 trial appear to have resulted in a more efficacious therapy. The study’s aim was that 30% of patients’ haemoglobin was the anti-sickling HbAT87Q form encoded by the gene therapy.
|Bluebird's HGB-206 trial in sickle cell disease|
|Group A||Group B||Group C|
|Follow-up||Up to 39 mth||Up to 17 mth||6 mth|
|Anti-sickling HbAT87Q (g/dl)||0.7-2.8||3.4-6.5||4.8-8.8|
|Total Hb (g/dl)||7.6-11.8||11.0-12.3||9.9-13.7|
|As of September 14, 2018. Source: Ash presentations.|
Bluebird appears to be hedging its bets in sickle cell disease – it has also licensed an autologous candidate targeting the BCL11A gene, which aims to increase levels of foetal haemoglobin and which was originally developed by scientists at Dana-Farber/Boston Children’s Cancer. Ash featured promising but early data from one patient treated with the project.
Still, it has not been plain sailing for Bluebird, which reported a case of myelodysplasia in an earlier cohort of the HGB-206 Lentiglobin study on Saturday.
The company blamed this on the busulfan preconditioning regimen used before therapy to damp down patients’ immune systems.
Even if the adverse event was not, strictly speaking, down to Lentiglobin, it highlights an often-overlooked aspect of gene therapy and also stem cell transplantation: the need for busulfan. Another side effect of the chemotherapy can be infertility, and the anonymous investor pointed to the “ominous informed consents” that patients need to sign before beginning Lentiglobin treatment.
Price, as always with advanced therapies, could be an issue, and this could also prove problematic for Lentiglobin. Beta-thalassaemia is most common in Mediterranean and East European populations – hardly countries with booming pharma sectors.
And sickle cell disease predominantly affects people of African descent who, in the US, are more likely to rely on Medicaid.
The final hurdle for Bluebird will be a rapidly evolving competitive landscape, with assets such as Celgene/Acceleron’s luspatercept and Global Blood Therapeutics’ voxelotor coming through.
Bluebird is also facing similar issues in CAR-T, with the BCMA-targeting field becoming increasingly crowded (Ash 2018 – The balancing act behind Bluebird’s Goldilocks CAR, December 3, 2018).
In response to the points raised above, a spokesperson for Bluebird told Vantage that it was too early to speculate on pricing.
On safety, she stressed that busulfan preconditioning was also used before stem cell transplants, adding that in each patient the risk would be weighed against many factors, "including the severity of their disease and the magnitude of benefit expected with Lentiglobin".
She concluded that Bluebird, by targeting the underlying causes of beta-thalassaemia and sickle cell disease, had a different approach to other companies. "The average life expectancy for a patient with sickle cell disease in the US is only 44 years, so if we are able to achieve a transformative treatment effect we expect that many patients and physicians will consider Lentiglobin a compelling option."
The investor in question obviously has a vested interest in the gloomiest scenario for Lentiglobin coming to pass, so his words should be taken with a pinch of salt. But it seems certain that pulling off approval for Lentiglobin, while a great scientific achievement, will not be the end of the road for Bluebird. If launches of other novel therapies can be considered a proxy, then those harbouring expectations of a flawless launch might want to take a step back.