Recoding for Life: An Interview with One of Gene Therapy’s High Fliers

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Bluebird Bio’s investigational gene therapy process
Bluebird Bio’s investigational gene therapy process works by genetically modifying a patient’s own cells. By leveraging homing endonuclease and megaTAL gene editing technologies, this process is advancing therapeutics for severe genetic and rare diseases and cancer.

In 2010, a company founded in 1992 as Genetix Pharmaceuticals changed its plumage, emerging as Bluebird Bio. Since then, Bluebird Bio has been spreading its wings, applying its megaTAL/homing endonuclease gene editing technologies in research and discovery. The company has also been swooping into the clinic, advancing programs for β-thalassemia and sickle-cell disease, cerebral adrenoleukodystrophy, and multiple myeloma.

Nick Leschly
Nick Leschly, CEO of Bluebird Bio

In January 2019, Bluebird Bio’s CEO—or “chief bluebird”—Nick Leschly indicated that Bluebird’s Lentiglobin therapy for β-thalassemia, if approved, could command a price in the region of $2.1 million. Leschly recently expanded on his company’s early successes and current ambitions in an interview that originally appeared in Human Gene Therapy Clinical Development. The interview, which appears here in abbreviated form, was conducted by clinical development editor James M. Wilson, MD, PhD, a pioneer of gene therapy who is currently the head of the Gene Therapy Program at the University of Pennsylvania.

 

Wilson: You were one of the first to lead gene therapy’s renewal by taking charge at Bluebird Bio. How did Bluebird Bio come about, and how did you get involved?

Leschly: It’s nice of you to say that I led the charge, when I think I would rephrase that one a little bit. I came in at a time when a number of folks—including yourself, Philippe Leboulch, Marina [Cavazzana], and I’m sure many others—had already been doing God’s work for the last decade, trying to understand the challenges in gene therapy, to get it to a point where you could really start to realize the dream of transforming the lives of patients with gene therapy.

The goal was for gene therapy to progress not in a kick-the-can way, but in a fundamental, transformative, curative way. I think Bluebird Bio was founded at the time genetics was sort of foundering, at a time when we were asking, “Has the technology advanced far enough? Do we know enough to really go for it?” That was when I was fortunate enough to be part of a venture firm that said, in effect, now is the time, even though the clouds are still a bit dark, to jump in and go for it and really try to invest beyond what is conventionally considered doable.

That was the beginning of it, and then—based on some of the work from Patrick Auborg [INSERM] on adrenoleukodystrophy and some of the work from Philippe Leboulch, Michel Sadelain, and others on β-thalassemia—we said, “Let’s go for it.” We felt that the biological clarity was there, but we had no idea if [an updated approach to gene therapy] was going to work. Quite honestly, we got luckier and went further and faster than we had ever anticipated. Then suddenly, gene therapy became not a bad word or a complex word, but a desirable word. It’s been an incredibly exciting time to be part of gene therapy.

 

Wilson: Along the way, you also leveraged your technology platform in the oncology space. How did that come about, and what is your thinking with respect to that part of your business?

Leschly: As we were leveraging the ex vivo lentiviral platform in the context of monogenic diseases, or going after the hematopoietic stem cell, it became clear that the infrastructure there is exactly what you need to also be able to harness the immune system against cancer.

This thought had certainly been kicking around for many years. Mitch Finer, our CSO, had been very involved, dating back to a number of companies. He said, “Well, we’re going to go through and build all this capability here. Why not try to accelerate on that side?”

Our partner at the time, Celgene, suggested, “Let’s go for that. Let’s try to figure out if we can do chimeric antigen receptors at that next level.” At the same time, a few other players had jumped in—Novartis, obviously—but a dual approach wasn’t popular, and it certainly didn’t inspire strong belief.

It built a nice part of Bluebird Bio that lives on to this day. We are, I think, the only company that has really tackled both sides of this equation: more classic gene and cell therapy versus more oncology cell therapy. That’s been incredible from our point of view—not only to build the company, but also to lever the infrastructure and the knowledge base. That’s an exciting part of our dual platforms.

 

Wilson: You’re the CEO of probably the largest, most successful gene therapy biotech. What did you do in your career to prepare you for the job?

Leschly: When I look at the opportunity ahead of us, the size of our company, and all the good fortune that we’ve had, I ask, “How
did I get to be in such a privileged position?” I am very humbled by it, to be very honest.

What did get me here? I think it comes back to a few things, some fundamentally about my upbringing and lessons about where one should devote effort and energy. I certainly was heavily influenced by my mom and dad. And I’ve learned that after you’ve experienced good fortune, you ask, “How do you give back?”

I’m not a scientist. I’m not a clinician. I work with scientists, and I’m married to a clinician. If you’re in that in-between position, how do you play? I love that nexus because it is where you can really make a big difference.

That was part of that early genesis I had, and then I stumbled into a number of companies that led to the other side. At Millennium Pharmaceuticals, I ended up getting a number of mentors—including the CEO Mark Levin and the head of R&D Robert Tepper—who were willing to help me dream a little bigger. They were willing to give me a chance that honestly, I didn’t deserve at the time. I left Millennium with them to start Third Rock Ventures, which then led to the opportunity here at Bluebird Bio, even though my resume certainly did not warrant me being CEO of any company! And they said, “You know what? We believe in the company, and we’ll do an assist model.”

The point of that story is that you must have some fundamental interest and be willing to prioritize who you surround yourself with. If they’re willing to give you a shot, run at it. So far, obviously, I feel really privileged and honored by that, and hopefully I’ve done the best with what they honestly gave me the opportunity to do.

 

Wilson: As the leader of a pioneering gene therapy company, what are your thoughts relating to regulatory and commercial challenges?

Leschly: These challenges are energizing but also daunting. I personally love the fact that we don’t know what the path ahead looks like. I love the fact that the science we have here is very, very disruptive, but also that there are many more unknowns than there are knowns.

What keeps me going is the fact that I know that if we can start to disentangle how this works, the benefit—the rainbow on the other side—will be incredible. It will change lives and families. It will do all kinds of important things. So, I think that’s what accounts for the Bluebird Bio culture of asking how we can stay attuned to our ultimate purpose in everything we do.

It starts with the science and leads to the medicine, but to your point, there’s so many firsts along that way where we’ve taken a position and said, “We’ve also got to be willing to be a catalyst for change in a system that doesn’t know how to deal with disruption.”

That starts with the regulatory process. How do you make sure that the risk benefit, the size of studies, and the magnitude of studies are reflective of the kind of benefit you’re hoping to achieve? These are not small, incremental improvements we’re looking for.

With a transformative product, you probably don’t need as many patients to build resolve—it’s life or death. The regulatory agencies have been tremendous in both the United States and Europe. In the last five years, they’ve come a long way in their discussions of transformative products.

Although there has been pushing and pulling, we’re feeling encouraged. I think the data has allowed us all to be a bit more, let’s say, disruptive. Being disruptive is translating into a willingness to ask how one should price a one-time, potentially curative treatment. At Bluebird, we certainly feel that it’s important to weigh the question in a way that’s commensurate with the value equation and considers the interests of all stakeholders.

Such questions should be addressed in a forward-looking way. I think the industry has had moments when it didn’t do a great job on some of that, sharing some of that value and risk. We’ve taken an aggressive stance on that front, and payors, governments, and others, I think, are leaning in as well.

 

Wilson: What is your ethos? How do you apply your principles throughout your organization?

Leschly: That is a huge and daunting question. As long as we care about our culture and who we are and how we bring our best selves, as long as we care about doing the right thing, as long as we authentically stand by our purpose and work to justify the privilege that we’ve been given, then we’re okay. The minute we get lazy or complacent or entitled, then I think it’s just a regression toward some inevitable meme.

We’ve done a good job. Part of it is the types of people we hire, but also the types of diseases we work on—diseases that profoundly affect families. They have bad days. They have serious challenges. Our mundane individual challenges—paychecks, stock prices, workplace difficulties—just don’t stack up.

We are committed to a higher purpose. We call it “recoding for life.” The therapeutic modality that we’re privileged to work with has such significant impact that you can start talking about recoding for life. The best way to achieve this purpose is to make it personal and care an awful lot about it.

 

Wilson: It has been great discussing Bluebird Bio’s journey. It sounds as though you’ve got some exciting milestones ahead of you.

Leschly: The line we use is, “We’re dangerously close to the starting line.” It has been a long time coming. But hopefully with our β-thalassemia product and the other four products we’re cranking on, at least the later-stage ones, the starting line really is close.

Science is complicated, and there are many factors in the ecosystem that must be aligned. That’s the cool part. Not everything is going to go perfectly, and there are going to be many bumps and unknowns along the way. But there’s a very durable effort underway that’s inspiring to everyone involved. We should remember to pay homage to the titans who built the foundation that made our work possible. We should honor everybody who has been involved for so many years, the great names and the unsung heroes alike.

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