Future Directions of Sickle Cell Disease Management

Neil B. Minkoff, MD: I’m finally going to pivot to what you’ve been looking for all day, which is gene therapy. Could you tell us what you know about gene therapy, where we are so far, and what we know about the ongoing studies?

Ahmar U. Zaidi, MD: I’ll start with just a broad approach to how we do it. And gene therapy addresses the issue that we discussed earlier, with bone marrow transplant, of not having a donor. The really interesting part with gene therapy is that the patient serves as their own donor, so this alleviates your issues with finding a donor, this alleviates your issue with posttransplant graft-vs-host disease.

What happens essentially is stem cells, hematopoietic stem cells, are taken out of the patient with sickle cell disease, and then those stem cells are modified. And then after some type of myeloablative regimen or some type of chemotherapy, those stem cells that have been modified—either by gene addition, so the addition of a normal beta-globin gene; or gene editing, which introduces a mutation that ameliorates the polymerization of sickle cells of hemoglobin S—get infused back into the patient.

The data for the bluebird bio, Inc LentiGlobin BB305 clinical trial appears quite promising. They have been updating us along the way with a target, I believe a target of under 20 patients who they wanted enrolled. I think they’re quickly approaching that target of patient number. They have shown the ability to generate a very clear signal from the inserted normal but tagged beta-globin gene. They’ve been able to show as high as almost a 50% reduction in sickle hemoglobin that’s being expressed.

Neil B. Minkoff, MD: Gene therapy is a thing that is taking up all our time. If you go to any of our specialty conferences, managed care conferences, and even the disease-specific conferences, there’s the hope and promise of gene therapy, and the “what are we going to do about the cost, and how are we going to finance this” controversy. Where do you see the roadblocks to therapy, and how do you see us overcoming those? And that’s to both of you.

Maria Lopes, MD, MS: I think the first is the durability. So back to the outcomes. This is surely innovative—it’s new and so promising—but there is some uncertainty around clinical trials. In a year, 2 years, how much data are we going to have at launch? That may lead to some uncertainty around the durability piece. That’s certainly exciting. If the durability is there, all these downstream costs go away, if you will: the hospitalizations, the end-organ damage, the vaso-occlusive crises. My goodness, this is the cure we’re all wanting to see. I think there’s a lot of dialogue around models that hopefully support accountability around the outcomes, so that we’re paying for value. I think the other issue is guidelines, guidelines that help stratify and especially with additional options, who does get what.

Ahmar U. Zaidi, MD: That’s right.

Maria Lopes, MD, MS: There is a need for a more structured approach, so that even from an informed standpoint—patient-shared decision making, caregiver decision making—we can determine who are these patients who can benefit the most from these very innovative and very new treatments.

John C. Stancil, RPh: I think very similarly, we would look at how they’re game changers. They’re going to potentially offer a cure for disease that before now really didn’t have many treatment options. But they’re going to come at a heavy price tag. I think manufacturers are interested in talking about a value-based or outcomes-based contract, so you hold them accountable to the clinical studies that they promised a result.

Neil B. Minkoff, MD: Not to be difficult, but can you do that with the level of churn you have when some of these outcomes might be years down the road?

John C. Stancil, RPh: Well, that will be the challenge, because a lot of times you’re following the patient for 5 years out. We’re exploring that opportunity with a vendor right now that would actually monitor that patient or watch that patient for 5 years out. Some manufacturers are looking at milestone payments. Each year over a course of time you’re making a payment based on an outcome during that year. That’s difficult in a Medicaid program because they may not always be on your Medicaid roll. And so how do you make a payment whenever that patient is not yours any longer?

Neil B. Minkoff, MD: Ahmar, as a clinician looking at this, your focus is obviously the promise of this, right, and what it can do for your patients, what it can do for the disease state, and therefore how you practice medicine. What’s your take on this?

Ahmar U. Zaidi, MD: As far as gene therapy goes, I agree with these guys. This is so new to the game. We really don’t have a good handle on exactly what we’re dealing with, what the long-standing effects are, how long this will maintain. And I’ll tell you, on the patient side there’s a lot of buzz about gene therapy. There are a lot of whispers on social media about gene therapy. And we can’t forget that part of the gene therapy at this point still requires conditioning with chemotherapy, and that gives a lot of patients pause. The same reason that they’ve been uncomfortable with hydroxyurea is that hydroxyurea has been listed as a chemotherapeutic agent. Well, if you’re going to use busulfan as a myeloablative agent, patients are going to have the same hesitation. So although I’m excited, it’s cautious optimism as far as gene therapy goes at this point.

Neil B. Minkoff, MD: There’s a tremendous amount of discussion where to come on this on both sides. But 1 of the things that I think, having been a practicing clinician and then gone over to the payer side as well, is that it’s nice that everybody is converging on the idea of promise but balance, and how we’re going to figure that out. There’s less of the clash that we usually get with new therapies.

John C. Stancil, RPh: It’s the balance between cost and value, but also how do these new emerging therapies fit into the treatment guidelines? Because we’ve got to revamp those.

Ahmar U. Zaidi, MD: Absolutely.

John C. Stancil, RPh: We’re using—I think you said earlier—guidelines that were developed in 2014. Those are going to be thrown away, and all these new emerging therapies have to find their place in those guidelines.

Maria Lopes, MD, MS: Absolutely.

Neil B. Minkoff, MD: Well, I have to say this has been extremely informative. We’re getting to the point at which we’re wrapping up the discussion. And so what I’d like to do is get some final parting thoughts from each of our panelists. I’ll ask you to start, Maria.

Maria Lopes, MD, MS: Sure. I always learn a lot from the thought leader, so I want to thank Ahmar for being here. He certainly taught us a lot. But as we think about what the world is looking like, we need to think about what the payer needs are, best practices in terms of comprehensive care, and what clinicians are lacking, so we’re not duplicating but truly managing holistic care. And the focus on outcomes and data. I always say it starts and ends with data, and certainly with the promise of gene therapy, as well as these very promising treatments, especially as we bring them together, it’s not only the hope but the data that support how we’re managing the disease, how we’re improving indices of success like survival, as well as total resource use, including hospitalizations, ER [emergency room] visits, and pain management.

Neil B. Minkoff, MD: John?

John C. Stancil, RPh: Absolutely. I’m looking forward to collaboration with the thought leaders and the treatment experts to determine what those treatment guidelines are and how these fit into place. I’m excited about this patient population who now are going to have treatment options that never existed before. Equally excited, the providers now have new tools in their tool bag. We’re looking to partner with that. They usually support us, or there’s normally support when we collaborate with them to make sure that we’re maintaining access where appropriate and being able to offer something this patient community has not had.

Neil B. Minkoff, MD: Ahmar, I’ll let you finish up.

Ahmar U. Zaidi, MD: Well, it’s been a long road from 1910. It’s been a long, dark road that has been quite lonesome from the provider side, where we really haven’t had much going on in sickle cell disease. And finally we’re at a point where we’re really going to put a flag on the map in the next decade or 2 on how this disease is managed. We’re fortunate to be supported by individuals like my colleagues on this panel today who help us make sure that we stay reined in and focused on the mission in an economically viable way. But I am just so full of optimism at this point that we are heading toward a future where sickle cell disease patients are no longer invisible.

John C. Stancil, RPh: Right.

Neil B. Minkoff, MD: Thank all of you for your contributions to this discussion. On behalf of our panel, we thank you for joining us, and we hope you found this discussion to be useful and informative.