Bluebird preps E.U. filing for revamped thalassemia gene therapy

With new data from a phase 1/2 trial of its LentiGlobin gene therapy in thalassemia in the bag, Bluebird Bio is pushing ahead with a European filing—and it could be that a follow-up in sickle cell disease (SCD) is not too far behind.

The Massachusetts biotech is reporting results from a pair of clinical trials at the European Hematology Association (EHA) in Stockholm this week, including additional data from its NorthStar trials which back up LentiGlobin’s ability to free patients with thalassemia from the relentless need for blood transfusions.

It also has new interim data from the HGB-206 phase 1 study of LentiGlobin in severe SCD which show the therapy can reduce the characteristic sickling of red blood cells in for patients with severe disease by 30% to 60%, above the threshold Bluebird Bio has set for a clinically relevant response.

The imminent filing for LentiGlobin marks a dramatic improvement in the program’s fortunes in the last couple of years. Prospects were looking a little dim in 2015, after initial data from the first NorthStar trial (HGB-204) in thalassemia revealed a highly variable response to treatment which meant conclusions about its efficacy couldn’t be reached.

Tweaks to the manufacturing process and the protocol of trials to prepare patients better for therapy followed and now—combining data from NorthStar with preliminary results of NorthStar-2 (HGB-207) and other studies using the new approach—have put the program firmly back on track, according to David Davidson, M.D., Bluebird’s chief medical officer.

In the case of transfusion-dependent thalassemia, seven of eight NorthStar-2 patients—regardless of their genotype have achieved normal or near-normal total hemoglobin by six months, while eight of 10 patients remain transfusion-free for up to three years in the original NorthStar cohort.

There is clear evidence that patients in North-Star-2 treated with LentiGlobin made using the new manufacturing process are showing improved responses compared to the NorthStar cohort using the unimproved version of the gene therapy, according to Davidson.

”The maturing data from HGB-204 and HGB-207 suggest that one-time treatment with LentiGlobin may address the underlying genetic cause of TDT,” he said.

Bluebird has been saying for some time that Europe will be the place it files its gene therapies first, thanks to a favorable regulatory pathway, in particular its adaptive pathways process—which allows new therapies to be approved in stages based on stepwise collection of data.

““We are on track to submit a marketing authorization application in the E.U. later this year, and we continue to work closely with clinical investigators and regulatory authorities to complete our ongoing clinical trials and bring this important treatment option to patients as soon as possible,” said Davidson.

In the case of SCD, the data suggest that LentiGlobin could convert patients with severe disease to a much less debilitating set of symptoms known as "sickle cell trait," with considerably fewer symptoms and a longer expected life span than the current 44 years on average for patients with full-blown SCD, according to Bluebird’s CMO.

The new SCD data have encouraged Bluebird to seek discussions with regulatory authorities to see what additional clinical trials will be needed to move ahead with filings. It isn’t talking about timeframes for a filing in SCD just yet, but thinks it will have a clearer view of the path forward before the end of the year.

What is clear is that FDA is increasingly extending assistance to companies trying to bring gene therapies through to market. Last November, the agency extended its regenerative medicine advanced therapy (RMAT) designation—which works like a combination of breakthrough status and priority review—to include gene as well as cell therapies. And in a speech delivered last month, Commissioner Scott Gottlieb promised to publish a series of guidance documents to help gene therapy developers bring to market quickly based on data in limited numbers of patients.

The initial clinical efficacy is often established early, and sometimes in small series of patients,” said Gottlieb. “The more challenging questions relate to product manufacturing and quality [and] the durability of response which often can’t be fully answered in any reasonably sized pre-market trial.”

The new data continue a run of good pipeline news from Bluebird, coming just a few weeks after it presented impressive data for its Celgene-partnered CAR-T candidate bb2121 in advanced myeloma at ASCO earlier this month.