Gene Therapy for Sickle Cell Disease

Ify Osunkwo, MD, MPH: The last section is emerging therapies. Right now there’s a lot of excitement about gene therapy, and currently there’s a LentiGlobin BB305 product that is used to treat severe sickle cell disease using the gene therapy mechanism. Dr Kanter, can you talk about the Mark Walters, MD, abstract and what we should look forward to with the gene therapy for sickle cell disease?

Julie Kanter, MD: Yes, absolutely. It’s important to know that there’s 2 different types, really more than 2, but 2 kind of buckets of gene therapy. One is what we would consider gene addition therapy. We’re adding in a gene but not changing the genome of the person that we’re adding that gene to. In sickle cell disease, we do this by adding in a gene that makes healthy, normal hemoglobin, hemoglobin A in this trial. In gene editing, you’re actually doing a different thing, where you go in and actually edit the genome and you can do this at several different places. And there are different abstracts that do this in different ways to either increase fetal hemoglobin, that baby hemoglobin that’s healthier, or that even have the potential to edit the sickle hemoglobin itself and increase hemoglobin A. That’s still in the mice and not yet in the people.

What we’re seeing in LentiGlobin so far, we have 2 abstracts that are looking at both the first groups, groups A and B, and then the group C, the most current group. What we’re seeing is super exciting. Our A and B groups show sustained T87Q [beta-globin] production. In those first groups, we didn’t get as high as we wanted, that healthy hemoglobin. It worked, they made some, but not enough to be what we would consider curative. It was disease-modifying for sure. Definitely those individuals have decreased symptoms of disease, but they’re still making quite a lot of sickle hemoglobin. As we move into our group C though, we’re seeing their phenotype, their blood looks just like someone with sickle cell trait. It seems to be moving along those curative lines.

All the way through from A to C, we know that it’s persistent, so some of our patients who were in that first group are now 3, 3-and-a-half years out and they have that same amount of gene, of that new gene being expressed. We don’t see that gene going away. We’re seeing it’s very safe and that we’re not seeing any of the concerns for what we call the reappearance of the virus. We turn the virus off when we put it in, and we’re not seeing it turn back on. We’re not seeing that the new gene puts itself in the genome anywhere that it could be dangerous. One of the big concerns with gene addition therapy is that that gene could insert and turn on a cancer gene, and we’re not seeing that, which is really encouraging.

Ify Osunkwo, MD, MPH: That’s really exciting because I think that’s the biggest challenge we’ve had with gene therapy for other conditions, right?

Julie Kanter, MD: Absolutely.

Ify Osunkwo, MD, MPH: You try to fix 1 problem, you cause another problem. It looks like this seems to be moving in the right direction.

Julie Kanter, MD: So far, so good. Certainly we’re seeing great gene insertion right where it’s supposed to be without any, what we would call clonal response, and great hemoglobin production that we hope will be curative someday. Right now, what we can tell you is that the hemoglobin are looking fantastic, and the hemolysis we’ve been talking about is just about gone.

Matthew Heeney, MD: The other big excitement about gene therapy is that it doesn’t have the problems that we spoke about earlier in terms of stem cell transplant, and that all patients don’t need a donor, they’re their own donor. It also removes one of the major post-transplant complications of graft vs. host disease. It immediately opens up a therapy to all patients and removes one of the more concerning morbidities post-transplant.

Julie Kanter, MD: I know one of the therapies is happening at your hospital. Can you tell us a little bit more about that therapy there?

Matthew Heeney, MD: We also have a gene addition approach using a lentiviral vector, but instead of inserting the modified LentiGlobin beta-globin type, we’re actually trying to use a different non-sickling globin. In this case we would be trying to reactivate the gamma globulin by knocking down a transcription factor called BCL11A, which is known to make that fetal-to-adult switch in the perinatal period. By harnessing this natural machinery, we try to flip back or switch back to making fetal hemoglobin. Again, it’s another gene addition approach. It’s quite interesting in that it’s a single hairpin RNA knockdown approach, so it’s really the first time that’s been used in gene therapy, which is quite exciting. We’ll also be presenting here the 5 patients who’ve been treated so far and have had quite a good effect with the fetal hemoglobin induction, both from a hematologic indices point of view, as well as from a clinical point of view.

Ify Osunkwo, MD, MPH: And toxicity?

Matthew Heeney, MD: The toxicity seems to be mostly related to the myeloablative conditioning that is still used in all of these gene therapy trials. Ultimately once we have a proof of principle that these integrative or gene addition approaches are helpful, then maybe we’ll be able to move to reduce the toxicity related to the conditioning.

Ify Osunkwo, MD, MPH: The million dollar question is how much does this cost?

Julie Kanter, MD: Well, we actually have a $1.5 million to $2 million answer for you. The therapy has actually been approved in thalassemia in Europe, and it does carry a price tag that’s pretty hefty. It’s a price tag that is only paid if successful. The way that they have done this in Europe is that I think it’s $2 million, $1.5 million?

Nirmish Shah, MD: It’s $1.8 million over 5 years.

Julie Kanter, MD: $1.8 million over 5 years. But it’s only done if the gene therapy is successful. It’s given in segments to make sure that it’s not just successful but pretty much curative.

Nirmish Shah, MD: Correct. It gives you optimism. I think that the price tag is something that we’re going to have to have continued discussions about. But at least from a sickle cell standpoint, it gives you optimism that we have another disease, a chronic blood disease, that has a cleaner outcome technically. They’re on transfusions, and now they’re not on transfusions, where sickle cell disease is much more nuanced for sure. But I think that is definitely something that makes us optimistic about where we’re going.

Ify Osunkwo, MD, MPH: That sounds like a very hefty price tag, but I think, Biree, you mentioned earlier that 1 sickle cell individual could cost that much in a year with severe chronic organ damage.

Biree Andemariam, MD: Conceivably. I think $1.8 million might be high, but conceivably there are some patients who spend more days of the year in the hospital than out. They’re in the minority, but that does exist.

Ify Osunkwo, MD, MPH: And over their lifespan.

Biree Andemariam, MD: The novel therapies that we’re talking about right now, the ones that were FDA approved, are not cheap. The estimates based on what the companies have put out in press releases are about $100,000 per annum for a disease-modifying therapy. It wouldn’t take you that many years of being on 1, maybe 2, maybe 3 of these disease-modifying therapies before you’ve already paid for your gene therapy. The question is, in a single-payer system, that’s pretty clean. In a system like we have in the United States, who’s on the hook for the amortized…?

Julie Kanter, MD: For the lifetime cost.

Biree Andemariam, MD: If more than half of patients living with sickle cell disease in this country right now have Medicaid, and they have Medicaid at the time that they get their gene therapy, but then they get healthy and they’re able to work, and they get private insurance, who’s on the hook for years 3, 4, and 5? Is it still Medicaid? Is it the private payer? Is it going to make it hard for people who are in that 5-year window to get insured elsewhere? I don’t know that those details have been worked out.

Julie Kanter, MD: We have such a problem with that in that so many of our patients are on disability so that they can have health insurance. They want to work, and we all know that working is productive for everyone. I think it’s important that people, when they see an individual with sickle cell disease who is on disability, really understand that sometimes, unfortunately, it’s forced. There is no other option for that individual.

Ify Osunkwo, MD, MPH: If they work too much they lose their insurance benefits. It’s not the SSI [supplemental security income] benefits they’re worried about, it’s the medical insurance. They can’t get the medication, they can’t pay for preventive care, then they live their life in the hospital and spend more money on the acute care side and do poorer. It is a complicated, very nuanced conversation that we’ll continue to have over the next several years.

Transcript edited for clarity.