SAN FRANCISCO – As he began his J.P. Morgan Healthcare Conference presentation, Bluebird Bio Inc. CEO Nick Leschly added to the usual disclosures by priming attendees for "a tremendous amount" of forward-looking statements, something that has probably become standard operating procedure in the gene therapy space in recent years, a lesson Bluebird knows well.

This week alone, the company's stock (NASDAQ:BLUE) has experienced marked activity beyond the macroeconomic influences, starting Monday, when investors learned that further data from the firm's Lentiglobin BB305 program would not be forthcoming until this year's American Society of Hematology (ASH) meeting.

The stock regained some ground Tuesday; it closed Wednesday at $46.17, down $3.64. And that's a far cry from the company's amazing 52-week high of $197.35.

"This past year has been, let's just say, interesting on a lot of dimensions," said Leschly, whose late Tuesday afternoon presentation in the Colonial Room at the Westin St. Francis largely eschewed the slide-pack in favor of a 20-minute recap of gene therapy that came across as part broad-strokes description of the space and part pep talk.

As to whether gene therapy as a field is sustainable, Leschly said the evidence appears "pretty doggone favorable" when looking at data across "a whole host of companies, not just Bluebird," he said. Only a few years ago, gene therapy was limited to academic and research centers; now, it thrives in an ecosystem of its own, with players in venture capital, public and private biotechs and big pharma. On top of that, the technology has been expanding. "It's not just about monogenic diseases," Leschly said, ticking off growing interest in spaces such as T-cell receptor and chimeric antigen receptors and the rise of gene-editing platforms.

That rapid advancement means Bluebird is constantly tweaking its platform, though Leschly stressed that the goal is "optimization, not a reset on any program."

"We believe we're having a significant amount of results with the existing platform, but we want to do better," he noted.

Bluebird's viral approach inserts functional genes into the patient's own hematopoietic stem cells ex vivo, and then transplants the modified cells into the patient by infusion. Its lead products are Lenti-D for adrenoleukodystrophy (ALD) and Lentiglobin BB305 candidate for beta-thalassemia major and sickle cell disease.

RIDING THE ROLLER COASTER

The company proved an investor fave during the ASH 2014 meeting, with data from the phase I/II HGB-2015 study showing that seven of seven (100 percent) beta-thalassemia patients no longer required transfusions following a one-time treatment with Lentiglobin BB305. Bluebird soared on the news – later news that a sickle cell disease patient also was transfusion-independent following treatment with Lentiglobin BB305 bolstered the stock even more.

But what goes up often comes down, especially in biopharma. Investors punished Bluebird's shares in the latter part of 2015 when data from additional patients in the phase I/II Northstar study, including some with the more severe beta-zero (β0/β0) genotype, failed to show the same robust response. (See BioWorld Today, Nov. 6, 2015.)

That "interesting roller coaster," Leschly said, is "what happens when data perfection meets a really bullish market, and it's what happens when data imperfection meets a really jittery market."

But the company points to the "totality of the evidence" in beta-thalassemia – and so far in sickle cell – and anecdotal evidence from individual patients. One sickle cell patient, a 13-year-old boy who had required transfusions since the age of 5, "is now free of sickle cell-related events [and] free of transfusions" following Lentiglobin BB305 treatment, Leschly said. "We have more work to do, absolutely," he added, though he called developing the therapy for sickle cell disease "more of an engineering challenge than a fundamental belief challenge."

The plan now is to advance Lentiglobin BB305 in non-β0/β0 beta-thalassemia patients, with upcoming studies HGB-207 and HGB-208 anticipated to enroll only those with non-β0/β0 genotypes. Data from those pivotal studies will be needed for FDA approval.

Bluebird, however, could have a faster pathway in Europe. Leschly said the firm already has spoken with EU regulators and will pursue conditional approval based on data from the earlier Northstar and HGB-205 studies.

Still, much work remains. Leschly said Bluebird "is not satisfied" with the responses seen in β0/β0 patients and is still figuring out the right pathway for sickle disease. The company also awaits interim data from the Starbeam study in ALD later this year and continues to advance its gene therapy efforts in oncology. In the latter field, Bluebird already has secured interest from a major player, signing Celgene Corp. to a multiproduct deal in 2013. (See BioWorld Today, March 22, 2013.)

And, with $901.7 million in cash as of Sept. 30, Bluebird is solidly capitalized – the firm estimates sufficient runway through 2018 – to see those programs advance.

SHIFTING THE DIALOGUE

But in gene therapy – and most drug development these days – getting to market isn't the end of the road: There's still the issue of pricing, made even more complex by the prospect of a curative product that might require only a single administration.

The first gene therapy to win approval in Europe – none have yet gained an FDA nod – wasn't actually administered as a commercial product for more than two years while payers wrangled over reimbursement. Glybera (alipogene tiparvovec, Uniqure NV), approved for enzyme lipoprotein lipase deficiency, was priced at $1.1 million in Germany. (See BioWorld Today, March 5, 2015.)

Pricing and reimbursement are "always going to be complicated," Leschly said, and there's a "tremendous amount of noise." But, at the end of the day, showing up with a "highly innovative, potentially curative treatment . . . is going to blow through this."

But the key, he added, is "establishing the right kind of conversation with payers."

Part of it is about adjusting behaviors, from a short-term mindset to a longer-term mindset, and not just for payers; Wall Street and policymakers, too, will have to start thinking longer term.

With luck, however, a wave of first gene therapy approvals is not that far away. "I hope the next five years are the five years that gene therapy has been looking for for the last 35 years," Leschly said. "I hope that multiple products get to the marketplace."