As abstracts from next month's meeting of the American Society of Hematology (ASH) in Orlando poured out Thursday morning, analysts keyed in on interim data reported by Bluebird Bio Inc., which included the first bifurcated results from the treatment of beta-thalassemia patients with Lentiglobin BB305.

The Cambridge, Mass.-based company reported that transfusion independence was achieved in patients with beta-thalassemia major with non-beta-zero (non-β0/β0) genotypes followed for at least six months in the Northstar and HGB-205 studies. However, varying degrees of transfusion reduction – and no transfusion independence – occurred in patients with the more challenging beta-zero (β0/β0) genotype.

The disclosure, which suggested that Bluebird's gene therapy treatment might not offer a cure across the entire patient population, sent investors into a panic. Shares (NASDAQ:BLUE) fell $19.79, or 22 percent, to close at $70.36. More than 8.2 million shares were traded, or nearly seven times the company's three-month rolling average.

Analysts, however, were much more restrained, concurring in lockstep that the Lentiglobin BB305 data – still early – presented no cause for alarm.

Bluebird said that, across all beta-thalassemia major genotypes, a median HbAT87Q level of 5.2 g/dL was achieved in the seven Northstar patients followed for six months or more. David Davidson, Bluebird's chief medical officer, said longer follow-up was needed to assess the extent of HbAT87Q production and the impact on transfusion requirements in patients with the β0/β0 genotype, since they produce no functional beta-globin at baseline.

"Patients are starting to sort by genotype, reflecting the amount of T87Q that is likely required to impact their disease," added Bluebird CEO Nick Leschly on a conference call with analysts. T87Q is an engineered beta-globin derived from Bluebird's gene therapy.

Non-β0/β0 genotypes likely represent about two-thirds of the addressable beta-thalassemia major population in the U.S. and Europe, according to Leschly, who posed – and answered – a series of questions about the data.

Reflecting on whether the company was surprised by the genotype split in thalassemia, Leschly replied, "Not really. It has been very clear that the β0/β0 genotype produces no endogenous beta-globin, making it the highest clinical hurdle for T87Q production."

He added, "We freely acknowledge that it would have been great to have every patient, regardless of genotype, become transfusion-independent out of the gate, but that is not the case. There's more work to be done to best serve all patients."

Across the board, Bluebird is treating thalassemia major patients, Leschly noted, pointing to the severe disease burden and transfusion dependence of all patients at baseline.

"We're really pleased to see clear consistency in results among non-β0/β0 patients, not only for medical reasons but also for development reasons," he said. Without commenting on the specifics of regulatory discussions, "our overall strategy for pursuing regulatory approval remains unchanged," Leschly added.

Piper Jaffray analyst Joshua Schimmer acknowledged the message was "maybe not what the Street wanted, but we're fine with it." He gently chided Bluebird execs for the "apologetic" tone of the ASH call, which came one day after the company presented its third quarter financial results.

β0/β0 patients "are heavily, heavily transfusion dependent," Schimmer wrote. "It's hard for us to imagine their transfusion requirements were not reduced meaningfully with Lentiglobin, which should help prevent iron overload-related complications."

More complete data at ASH, promised by Bluebird, "should help us better appreciate the role of Lentiglobin in these patients and whether release specs can yield even better results," he added. "Even if we have to give up on this population entirely, we wouldn't change our model assumptions."

Meanwhile, the sickle cell patient population that Bluebird is treating with Lentiglobin "remains in good shape," Schimmer wrote. Although he reduced the company's price target to $204 from $213 to reflect higher expenditures and lower partner revenue, "our impression of the Lentiglobin opportunity is unchanged."


For sickle cell disease, Bluebird reported that the first treated patient is producing increased levels of HbAT87Q since the last report in June, with HbAT87Q representing 48 percent of total hemoglobin at nine months post-infusion. The patient remains transfusion independent without sickle cell-related adverse events as of the ASH data cutoff.

Oppenheimer & Co. Inc. analyst Wendy Lam called Thursday's stock sell-off an overreaction and emphasized the early nature of the data.

"Longer-term follow-up is necessary to see how β0/β0 patients will ultimately respond," she wrote. "That said, we expect irrational movement in the stock due to investors not fully comprehending the scientific reasons for variability in patient response. We maintain our positive long view on BLUE, as we believe results reported to date still support regulatory approval and uptake."

Meanwhile, Bluebird said it will present three posters from the immuno-oncology side of the house describing preclinical data on the development of bb2121 in multiple myeloma, including details on the company's manufacturing platform and scientific insights into engineering more potent chimeric antigen receptors (CAR) that may apply broadly across its oncology portfolio.

Oncology was the theme of other ASH abstract releases, and analysts took up that call, as well. Jefferies analyst Biren Amin noted that Paris-based Cellectis SA surpassed "a huge milestone" with the report that a single patient received its allogeneic UCART19 therapy under a compassionate use protocol. The 11-month-old child was diagnosed with high-risk CD19+ ALL and had failed on stem cell transplant as well as Blincyto (blinatumomab, Amgen Inc.). The patient received chemotherapy immediately prior to lympho-reduction, then proceeded with administration of UCART-19 cells and was judged disease free, as measured by lack of blast leukemic cells, approximately 28 days post-transplant.

"In our view, this provides the first clinical evidence of clinical activity of UCART19 and provides confidence in the allogeneic gene editing approach developed by CLLS," Amin wrote.

He also applauded Kite Pharma Inc., of Santa Monica, Calif., calling investigator-reported data on KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma "impressive" at one month follow-up. Findings, he said, showed that KTE-C19 "can be centrally manufactured and give robust responses, and persist for at least one month." Although one patient died from an intracranial hemorrhage that was deemed unrelated to the drug and some safety events were noted, "we believe the data bodes very well for the phase II pivotal portion of the ZUMA-1 trial that recently initiated," Amin wrote, suggesting that interim data from the first 50 patients would drive a biologics license application filing by the end of 2016.

And Piper Jaffray's Schimmer pointed to Houston-based Bellicum Pharmaceuticals Inc., which is advancing BPX-501 from its Chemical Induction of Dimerization (CID) platform. A CaspaCIDe-enabled T-cell addback, BPX-501 "at the appropriate cell dose seems to confer protection against infection in patients undergoing haplo-identical transplant for non-malignant disorders," Schimmer wrote. But, "the product also has potential utility in the larger setting of haplo-identical transplants for malignant disorders and also has the potential to extend into the broader allogeneic transplant setting," including safe allogeneic transplantation with significant donor mismatch, he noted.

The ASH meeting is scheduled to begin Dec. 5.