Chief Scientific Officer (CSO) Philip Gregory told BioWorld Today that, while Bluebird Bio Inc. didn't "want to speculate as to how the molecules do their thing, from an output perspective, we understand it very well," and the company was pleased (along with investors) that the planned phase III trial with Lentiglobin BB305 can go ahead with enhancements without filing a new IND.

The Cambridge, Mass.-based firm opened HGB-207, its global, multicenter study in 15 patients with transfusion-dependent beta-thalassemia with non-β0/β0 genotypes. Transduction enhancers of the hematopoietic stem cell (HSC) manufacturing process will become part of the work under an existing IND, though some on Wall Street had fretted otherwise. Transfusion independence at 12 months is the primary endpoint of the trial, intended as pivotal in the U.S. and confirmatory in the EU for the disorder, which reduces the production of hemoglobin.

Lentiglobin works by inserting a functional human beta-globin gene into a patient's own HSCs ex vivo and then transplanting those modified cells into the patient by infusion. Enhancers are intended to improve vector copy numbers, percentage of vector-containing cells and T87Q hemoglobin expression levels. They'll be part of ongoing studies in severe sickle cell disease (SCD), too, the company said.

In the procedure, Bluebird adds two small molecules into the manufacturing process that are said to have a dramatic impact on the transduction of CD34+ cells – an increase of two to three times in vector copy numbers (VCN). They also increase the percentage of cells that have at least one copy to T87Q-globin, thereby upping the level of transduction. J.P. Morgan analyst Cory Kasimov noted that the small-molecule additives are "washed away in the process and thus are not entering the patient. Importantly, the end drug product is no different – still just the patient's modified HSCs – so the data generated to date remain relevant; no reset button needs to be hit with the new manufacturing process," he wrote in a research report.

CSO Gregory said that "we have not resolved [the mechanism with regard to the T87Q-globin] at the angstrom level, but it's well known in the field that a critical and difficult point for virus entry to the cell is that initial point of viral contact" and the ensuing process of engagement. One molecule that's introduced operates at entry level while the exact functioning of the other "is ill-defined, at this point" but known to work beyond the entry to increase transduction, he said.

"The decision to use an amendment process vs. a new IND is largely a function of the analytics you can do that say the cell product at the end is equivalent in all the ways the FDA cares about with respect to the safety of that potential product," Gregory said. "For example, if you were to add a new piece of DNA to the cell that provided it with an additional functionality, it would be very hard to assert that the product is equivalent" to the original.

'SUPPORTIVE' DATA COMING AT ASH

With the enhancers, Gregory said, "the virus doesn't change, the payload doesn't change and, because we have good analytics around how to look at and examine the phenotype of these cells at the end of the process, we were able to convince both ourselves initially and also the FDA that this product was obviously something different – otherwise we wouldn't be excited about putting it into the clinic – but it's not different in such a way that changes the risk."

Although some analysts expected no new IND, it wasn't a sure thing, Gregory said. "Was there some risk the FDA would disagree with us on this? Sure, there are very few things that are black and white. We felt fairly confident going into this that we had good analytics to make a strong argument that scientifically these products could be considered and tested under the same IND."

The manufacturing improvements are not the only ones going into trials, analyst Kasimov pointed out. Bluebird also implemented changes to the busulfan preconditioning – the myeloablation regimen – and optimized cell numbers, while proceeding with a better understanding of the demographics of patients who respond better, as well as how they might be managed in order to improve response. "Some of these changes had been implemented by mid-2016, so the clinical update at [the American Society of Hematology (ASH) meeting in early December] will provide some initial insight, with more substantial clinical data with the process improvements coming in 2017," he wrote.

Gregory said that "on a research level, we continue to explore improvements to all of our products," whether T cell-based or HSC. "The search for molecules that would do this has been longstanding – it certainly predates my arrival at Bluebird. There are alternatives out there." Encouraging data on VCN improvements rolled out at the American Society of Gene & Cell Therapy meeting in May. ASH is "always a big meeting for us," he added. "We'll be able to, we hope, share some additional data around the enhancements that we've put in place," findings that are "supportive of the decision the FDA has made" regarding the IND. But "more definitive clinical data will be [coming] next year," he said.

Working with lentiviral-based gene therapies, T-cell immunotherapy and gene editing, Bluebird focuses on severe genetic diseases and cancer. Its Lenti-D candidate is in a phase II/III study called Starbeam in cerebral adrenoleukodystrophy, and the Lentiglobin BB305 bid is undergoing a total of three studies in transfusion-dependent beta-thalassemia and severe SCD. The lead oncology program, bb2121, is an anti-BCMA CAR T effort partnered with Summit, N.J.-based Celgene Corp. Bb2121 is being studied in a phase I trial for the treatment of relapsed/refractory multiple myeloma.

Shares of Bluebird (NASDAQ:BLUE) closed Thursday at $57.51, up $4.70.