Gene Therapy in the Treatment of Sickle Cell Disease

Peter Salgo, MD: Let’s talk about gene therapy. We’re talking about expensive, right? We’ve got LentiGlobin BB305 for severe sickle cell disease.

Biree Andemariam, MD: I want to give credit to Sophie over there for teaching all of us, with dollars and cents, how expensive it is to take care of sickle cell disease, for a lifetime. So just putting that frame of reference when we’re talking about cost associated with any novel therapy, whether it [is] disease modifying like we’ve been talking about so far, or curative intent, I just want to put that disclaimer out there.

Peter Salgo, MD: Consider it put.

Biree Andemariam, MD: OK.

Peter Salgo, MD: But it’s a fair disclaimer.

Biree Andemariam, MD: Two billion dollars?

Peter Salgo, MD: How much does it cost to take care of a sickle cell patient versus maybe we frontload this and now we don’t have to do that anymore?

Elliot Vichinsky, MD: Yeah, I understand. In fact, there should be an understanding, of course, of drugs, but frankly, as someone who has dealt with the disease from a public health standpoint, there have been a lot of expensive drugs out there, and there have been no drugs for sickle cell disease. And CAR T [chimeric antigen receptor T-cell therapy], I could go through a whole bunch of single drugs that could cost a million per pop. And I don’t think now that we have a menu to give them, that immediately we should start focusing disproportionately on hemoglobin drugs.

Peter Salgo, MD: If I want to cure this disease, I’ve got to change the genetics. I’m thinking transplant or gene therapy. So where are we with gene therapy? Help me out here.

Sophie Lanzkron, MD, MHS: We’re in an exciting time with this therapy.

Peter Salgo, MD: And I don’t mean that to brush you off. I mean that I’m excited. It’s great stuff. Where are we here?

Biree Andemariam, MD: We’re in relatively early days. There are several strategies of emerging therapy that all have curative intent. The study that’s furthest along is on the order of a couple of years’ worth of follow-up data, and there are newer approaches that have on the order of a few months of data. These approaches include strategies to correct the genetic defect as well as strategies to add genes to also correct the defect.

Peter Salgo, MD: Let’s spell this out. LentiGlobin is a viral envelope, which contains genetic material, which we hope the virus then injects into cells, for lack of a better phrase. And that changes the genome of the host. This viral envelope is an HIV envelope without the HIV genomes, so you’re not giving people AIDS, or even HIV infections. Is that a fair description? Because it’s gotten a lot of negative press.

Jane Hankins, MD, MS: Yes.

Peter Salgo, MD: All right. That makes sense. We have the BB305 drug product. Does it work? How many patients have gone on it?

Sophie Lanzkron, MD, MHS: Well we’re early in this process, and they’re learning how to do it. They’ve had 3 cohorts, and the progress and the amount of hemoglobin-S has decreased. And the A, the vector, has increased over time, and they’re improving on their methodology to improve vector copy number and to get higher hemoglobin-A in the patients who are undergoing the therapy.

Biree Andemariam, MD: Right, because they’re replacing, they’re adding a healthy hemoglobin-A, that’s the whole strategy.

Peter Salgo, MD: Right. That is the strategy. The more end you’ve got in this disease the better. Is that fair enough?

Sophie Lanzkron, MD, MHS: But the key thing to remember is that you need fully myeloablative chemotherapy in order to get these cells to engraft. And I think that’s probably one of the biggest issues, although there are lots of great people thinking about how to change that myeloablative regimen to one that is not myeloablative, so you don’t have issues related to fertility and potentially secondary malignancies.

Biree Andemariam, MD: But all the different strategies include myeloablative therapy right now.

Sophie Lanzkron, MD, MHS: Right, that is correct.

Elliot Vichinsky, MD: If sickle cell is different than thalassemia, which is most of where the gene therapy has been done, though, other diseases are now being done across the field. In thalassemia you can measure how high the hemoglobin goes up and you decrease the problem of ineffective erythropoiesis.

And sickle cell disease is a little more complicated in that, while you can raise a healthy hemoglobin, unless you totally correct the level, you really don’t yet know what the biologic affects are going to be. There are markers going on that are encouraging. But, actually, whether the biology of sickle cell has been stopped, we do have suggestions at levels at which phenotypes will be improved. And they have done computer modeling about how much is in each cell. We haven’t actually measured the amount within each cell yet.

But I think it’s quite encouraging. And there are newer ones, there are new therapies coming out, new modifications. So, we’re all very excited about it, and I think it offers for patients who don’t have an HLA match a really golden opportunity to be treated without the risk of graft-versus-host disease. Because really what you do with gene therapy is you do an autologous transplant, and that’s really what you’re talking about.

Peter Salgo, MD: It’s your own DNA.

Elliot Vichinsky, MD: Right. And the newer technologies are coming out. Eventually the editing and nucleuses and other things, if they can improve some of the vector numbers and things, down the line we will see progression where this is going to pan out.

Jane Hankins, MD, MS: Yeah, I agree. I think the new iterations of the gene therapy, now gene editing, I think they’re really becoming more sophisticated with CRISPR. Other people are using it.

Peter Salgo, MD: I think CRISPR would come up with anything.

Jane Hankins, MD, MS: No, no, it’s pretty important. I think it’s a breakthrough and so they are now disrupting the genes that inhibit the fetal hemoglobin production and all of a sudden you produce a lot of fetal hemoglobin.

Biree Andemariam, MD: They had a press release last month that showed the first patient with sickle cell disease that got the CRISPR-based gene therapy, by month 4, had 46% fetal hemoglobin, I believe. Was that the number on month 4?

Jane Hankins, MD, MS: Yeah, so it’s encouraging.

Biree Andemariam, MD: And I think there’s at least some people who believe that the more targeted you can be and more precise you can be about your gene therapy strategies, the less likelihood of off-target effects.

Peter Salgo, MD: Am I the only one who’s amused by the fact that we’re quoting press releases as opposed to clinical trials?

Biree Andemariam, MD: Well I will say, to that point, you’re right, because we’re all academics and it probably sounded funny. But I think from spending a lot of time in the patient community, I will say that it is very important that the community of patients with sickle cell, and their caregivers, has access to this information.

Jane Hankins, MD, MS: That’s right.

Biree Andemariam, MD: And they’re not getting it from medical journals. So, I actually commend the sponsors of these trials who try to get information for the masses. So, thank you for clarifying that, but I think it’s important.

Jane Hankins, MD, MS: I completely agree.

Peter Salgo, MD: I was a journalist on television, on the other end of all these press releases. Some great, some not so great, some investigators needed funding, so there came a press release. You’ve got to know who to trust.

Elliot Vichinsky, MD: I have some concerns. I do think patients should be educated, and I think there is a public awareness. But when the releases come out, still I just came from a meeting, when you talk about gene therapy, many of the patients don’t grasp that they’re getting myeloablative therapy. They hear the words gene therapy and they think they’re getting this thing. But I do think it needs to be on the table. And frankly the therapy for non-beta 0, beta 0 has been approved in Europe. And so, there are a lot of things that are going to change, and I think patients should be informed. I just want it to be including the good and the risks.

Peter Salgo, MD: Well that is a risk. In other words, if you’re going to do this, and that 40% sounds really exciting, did that press release mention the downside? What’s the risk? How many were not happy with this? How many failed? What’s the data?

Biree Andemariam, MD: So, from my interpretation, this was on NPR [National Public Radio], it was the perspective of the patient, and so whatever the patient says.

Jane Hankins, MD, MS: That’s right.

Biree Andemariam, MD: So, there wasn’t really the opportunity for that kind of balance. And you’re right. So, there was 1 patient, so how much can you say?

Transcript edited for clarity.