CEimpact Podcast

Sickle Cell's Cure: CRISPR

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Sickle cell disease (SCD) is a devastating medical condition causing pain, fatigue, and early mortality. Join host, Geoff Wall, as he evaluates a new gene therapy via CRISPR that may cure SCD.
 
The GameChanger
CRISPR is a new method to develop targeted gene editing treatments. Lovo-cel is the first FDA-approved therapy and may treat sickle cell disease (SCD) - for only $2 million.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
FDA Approval. https://www.fda.gov/vaccines-blood-biologics/lyfgenia.

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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Discuss what CRISPR is and how it can be used to treat diseases
2. Describe the use of lovotibeglogene autotemcel (lovo-cel) for sickle cell disease and its safety and efficacy data

0.05 CEU/0.5 Hr
UAN: 0107-0000-24-031-H01-P
Initial release date: 1/8/2024
Expiration date: 1/8/2025
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome to Game Changers clinical conversations. I am your host, jeff Wall. I'm a professor of pharmacy practice at Drake University and internal medicine clinical pharmacist at Methodist Hospital. So today we are going to talk about something a little bit different from the normal primary care stuff we talk about, and that's because this is an issue that has really been all over the lay media and, I think, in the general medical media well, and that's the new two treatments that have been approved by the FDA for sickle cell disease.

Speaker 2:

Now, again, I'm well aware of the fact that, other than maybe treating things like being an occlusive crises or pain or something like that, the average primary care physician is probably not going to run into patients with sickle cell disease. But this could be and I think many experts think will be the tip of what will become a common way to approach a lot of genetically born diseases, with the intent, I think cure might be a bit of an overstep by just a bit at this point, but pretty close to it. And the ability to use CRISPR to alter the sequencing of genes that allows you to fix problems that are genetic problems obviously has implications in a wide variety of diseases, many of them life threatening or, at the very least, diseases that have a high morbidity associated with them and high cost associated with them. As well, as patients utilize the healthcare system in indirect costs when these patients can't work because of their overwhelming diseases, and sickle cell disease certainly fits that criteria. It's a full set of sickle cell disease. It's a life threatening blood disorder. It affects about 100,000 people in the United States.

Speaker 2:

If you've never worked with sickle cell patients, it's hard to describe those who've not seen these patients, the pain that they deal with on a daily basis, the fact that they're completely fatigued and wiped out all the time, the fact that they're at higher risk for certain infections because many of them have essentially infarcted their spleen, so they're at high risk of a lot of encapsulated organisms. Again, it's just. It not only shortens life, but it definitely makes that short life much more painful, much more difficult and, as you might imagine, sickle cell patients are heavy utilizers of the healthcare system quite appropriately, and there's been numerous studies that have noted that, because almost everybody who has sickle cell disease is black that there's depth of bias and, in some cases, racism, when it comes to these patients going to the emergency room and not getting the appropriate treatment they should. We actually did a pod a couple of years ago where experts in this field decided to open up their own sickle cell emergency room, for example, and they had tremendous success and quite a bit of decrease in costs to the healthcare system. This therapy has the potential to eliminate that completely, and I suspect that the clinicians in those clinics would be very happy about it.

Speaker 2:

So what are these therapies? We actually have two therapies that have been FDA approved. I'm only going to try to pronounce the official chemical names once, because they're pretty long exogamma globgene auto micell, which everybody's calling exocell that's what I would do and that's a combined agent from Burtex pharmaceuticals and CRISPR therapeutics. And then the other is lipobelotogene auto micell, or liba cell, and this comes from a company called Bluebird Bio, and they don't use CRISPR. They actually use a different type of gene editing tool called the lentiviral vector.

Speaker 2:

But in any event, the thought behind how these work is just absolutely fascinating and I think would be considered science fiction even as recently as 50 or 60 years ago, where we have a fairly simple process of editing the genomic sequencing of cells, and so in this case, as we know, sickle cell disease basically involves a single point mutation in hemoglobin. So patients with sickle cell disease do not produce hemoglobin A that most people do produce, and in fact have a sickle form of hemoglobin. When this sickle form of hemoglobin does not carry oxygen well, and so that's the other patients have a lot of problems with with poor oxygen and hypoxic states. Also, because of the sickle shape, it gets caught and blocked in in certain areas of the body. So it actually acts as kind of a tag that more and more sickle cells arrive at and then you lead that leads to occlusions of the veins and sometimes even the arteries, and so these patients can get these, these micro occlusions that can lead to unbelievable pain, can lead to organ damage and in some cases stroke as well because of the blockage, and which can reach the brain. So you know it's a serious disease.

Speaker 2:

We could spend an entire pod talking about the evolution of sickle cell disease, and one of the theories of the evolution of sickle cell disease that I've always thought was fascinating was that it's an actual positive evolutionary pressure to to to fend off patients with malaria. Remember that malaria is is is very common and it still kills millions of people every year, and that that an evolutionary response to malaria was the development of sickle cells, because sickle cells do not usually get infected with the malaria by or the malaria parasite. Kind of interesting, if true. That would be kind of an interesting way that that that evolution sought to to to take care of one problem and basically have another one. So, but that's a whole, that's a whole pod in and of itself. So let's go ahead and talk about these agents.

Speaker 2:

The exocell agent, again, is the one that uses CRISPR technology, and remember that CRISPR technology and there's a number of great books out there that I encourage you to read that describe what exactly CRISPR is and the and the incredible effort it took and money it took to get CRISPR technology up and running basically allows, with with a fairly simple I mean not so simple, I could do it, but a fairly simple process, for scientists trained in this to basically easily alter a genetic sequencing, and they can do it at one point, they can do it at several points, etc, etc. So you know, in theory and again this is kind of in theory you can use CRISPR to basically alter the genetic sequencing of any cell and you can block that cell from being produced again. So if you had a cell for that, for example, was causing a negative effect in the body, you theoretically should be able to go in and block that particular cell from being made ever again and had that cell line die out. Or you can alter the gene to produce a cell that is replacing a mutated cell in the body that's leading to a certain disease. And that's that's exactly what's going on here, that that we're using CRISPR to actually alter stem cells to produce, instead of hemoglobin f to put to preload, which is the, the sickle cell, or hemoglobin s, excuse me, which is the sickle cell of hemoglobin d?

Speaker 2:

Hemoglobin a, which is is, is the actual, you know, normal hemoglobin that adults do produce. So what happens in the technology is is they and this is true for both leba cell and for exa cell is they? They take some bone marrow from the patient with sickle cell disease. They then condition it, make it undergo this CRISPR process or this other lentiviral vector process that allows them to alter those stem cells so that they can start producing hemoglobin a. And it's not exactly hemoglobin a, it's. It's hemoglobin a that that has some small changes in it, but they are noted in in the in these studies. Yeah, but it does basically everything hemoglobin a does they then do what they would do under normal circumstances, which is perform an autologous stem cell transplant? So, basically, the the patient is conditioned receiving, you know, close to lethal doses of of chemotherapy or, in some cases, radiation that essentially destroys existing bone marrow, and then the patient is engrafted with that, with the, the transferable bone marrow it grows in, it starts doing the job of of the previous bone marrow. But now you have this CRISPR edited or gendered or cells that now produce hemoglobin a instead of sickle hemoglobin. So I mean, that's that that's a very layperson description of of what happens, but I think that that generally, is the gist of how this works.

Speaker 2:

Now, the advantage of this, over which was what was considered the previous cure for severe sickle cell disease, which was, um, uh, allogenic stem cell transplant, is that allogenic stem cell transplant, the patient is is getting an infusion of someone else's cells, and that means that, uh, they're essentially trading one set of problems for another. While they may be cured of their, of their sickle cell disease, they're gonna have all the problems associated with with grappers as host disease and increased levels of infections and all that other stuff. And if you're using your own cells, most of those problems go away and really the only risk occurs in that first hundred days while you're in grafting your own cells back. So, um, you know, yes, up front it's, it's, it's a little scary, but but these patients do far, far better than allogenic stem cell transplant patients. So that's kind of the, the process by which that happens. Um, the, the, the FDA, improved the uh exagel based on a study called the Clim SCD 121 cell.

Speaker 2:

Um, again, these are going to be small studies because, um, it's a pretty expensive process and they would do want to target patients who have severe manifestations, at least up front sickle cell disease. And so this study basically did this process we just talked about and, it's worth noting, they get a single infusion, that's it. You know, after the autologous stem cell transplant, really no other therapy is given for the patient. And so what happens then is they monitor the patient over the course of 12 months, 24 months, et cetera, et cetera, and they wanna look at things like, you know, occlusive crises. So, again, how many times do they have this big, you know, wave of pain that is completely overwhelming, or they're at risk of developing plots in their body or strokes and things along those lines. That's the thing they wanna take a look at.

Speaker 2:

They of course measured hemoglobin A and fetal hemoglobin, which again are the hemoglobins that you should have without sickle cell disease. They also measured just general hemoglobin levels and well, and what they found in this first study with the exa-cell was they found that over a 12 month period that they originally did this therapy in 31 patients, 28 of these patients remained completely free of being occlusive cases for almost two years. So almost everybody who got this therapy essentially had no pain, essentially had no being occlusive cases, had an increase in quality of life, weren't hospitalized, et cetera, et cetera, et cetera. So I mean pretty traumatic responses that seem to be pretty durable over two years. They did note that one patient died about nine months after receiving an exa-cell infusion and remember that at least for that first several months after the stem cell transplant, even an autologous stem cell transplant patients are gonna be at risk for infection, some other problems along those lines. They found that in general patients hemoglobins rose from below sixes up to 11, which is almost normal, that they remained at that level afterwards or wasn't any sort of failure or levels going back to normal. Basically this was a durable response that lasted for a long time. So essentially a one-time functional cure is what the head of the study basically suggested. So again, pretty dramatic results and as you might imagine why you've heard so much about it in the lay media, because yes, sickle cell disease is a terrible disease, but there's a wide ranging number of diseases out there that have a one or two point mutation that if we can figure out how to fix it, that the patient could essentially be cured, and that goes from muscle diseases to a CNS diseases, et cetera, et cetera. So I mean this could be as big a breakthrough in the treatment of medicine as the dental and penicillin was in the 1950s.

Speaker 2:

So the other big therapy being looked at is levosel and again it's fairly similar to exosel. It just uses a different gene editing technology which basically it's called a lentoviral vector. So it's a viral vector that is easily controlled and easily manipulated to let make it do what you want it to, and then it's delivered into the genome to make its modifications. In that, but other than that the entire therapy is exactly the same. It's a one-time, single dose infusion that the patient gets. After they have a autologous conditioning, they take the autologous themselves, they undergo this treatment and then are injected back and re-graphed into the patients.

Speaker 2:

There's two studies that are being looked at and have what has been recently published in the England Journal. The other was just announced last week at the American Society of Hematology meeting, and this is an important meeting study because it's the first five-year study. So this is data where they're actually gone out to five years of these patients, which is pretty impressive. But the first study that was published in the England Journal of Medicine last year looked at patients between ages 12 and 50 who had received a diagnosis of sickle cell disease and the appropriate genotype. They had to be fairly active, so their performance scores had to be pretty decent, and if they were under age 18, there's other performance scores they had to look at as well. They had to have failed a trial of hydroxyurea, which is considered the standard care of sickle cell because it pushes the development of hemoglobin S to hemoglobin F, which, while it isn't as good as hemoglobin A, is the fetal hemoglobin that doesn't sickle as much.

Speaker 2:

These people had to fail that 24 month history of active treatment for sickle cell disease and they were actually not eligible to receive a autologous stem cell transplant. So these were patients who would basically run out of other options is really the only way to kind of take a look at it. They looked at again. These weren't a ton of patients, as you might imagine, because it's a fairly small or smaller disease state, but they did look at patients who had sickle cell disease and had recurrent basal occlusive events and I think the average was four in a year.

Speaker 2:

In these patients or patients who had a history of overt stroke were also included. So people might have had a stroke from their sickle cell disease were included as well. They then again underwent chemo myeloblation again kind of a destruction of their own bone marrow, and then received levocell infusion. Then, just like the previous study, they wanted to take a look at outcomes, including the number of, you know, occlusive episodes, the amount of hemoglobin A being produced, their overall hemoglobin and quality of life and what they basically found. They took a look at this patients and they had again 36 patients in the study, again not huge.

Speaker 2:

And they received a single infusion of levocell. And this first study in the England Journal of follow up was 35 months, so actually close to three years, in these patients and they found that basically the development of this hemoglobin A and again it's not pure hemoglobin A, it's hemoglobin A T87Q levels rose from 4.5 and 6 months post infusion to 8.7. So basically hemoglobin A levels were essentially at 8.7 in these patients and then it went up, even further to 11.8, which, again, in most patients, is low normal.

Speaker 2:

So again, just incredible increased numbers of hemoglobin A production and basically normalizing these patients hemoglobin as well. When they took a look at you know occlusive events, they actually found that 90 to 97% of patients had complete resolution of you know occlusive events during the time period of the study.

Speaker 2:

And they found that levels of pain dramatically dropped. There were no strokes in any of these patients, etc. Etc. So, again, just unbelievable results from this therapy. Now, of course, you know there's no free lunches, we're all well aware. So, you know, one of the things that I think we really need to take a hard look at is safety, especially in a study that only has, you know, 30 to 40 patients in it. What did they find? That's, you know. Again, something I think we need to be a little bit cautious about before running around saying this is, you know, the cure for a cell disease in all patients.

Speaker 2:

It's worth noting that almost all of the side effects in the study were because of the autologous stem cell transplant. So after that had been completed, and after the first, you know, you know, three to nine months of the reengrafting, most side effects basically were nothing and didn't really have any side effects whatsoever. But it is worth noting that this will not be an easy therapy for patients that first, you know, three to nine months after, they're going to be at risk for infection, they're going to be at risk for the side effects of the, you know, suppressive regimens. We have them on, and so it's something worth noting. In the study itself, they noticed that you know some of the common side effects you would see in stem cell transplants.

Speaker 2:

Stomatitis is extremely common in stem cell transplants. About 70% of patients had that. A large number of them had abnormalities in their complete blood count, neutropenia, amemia, leukocytopenia. Small percentage of patients developed a probably not true venal occlusive disease but did find an increase in their LFTs and their bilirubens, which, again, is that not uncommon effect that you're going to see with stem cell transplants, even autologous stem cell transplants? Despite all that they did do health related quality of life data and again the numbers were just incredible and really dramatically improved pretty much across all the domains that they looked at. So you know, do we have any data showing that this is even more durable? Now we're going to talk about that after we hear from our sponsor, CE Impact.

Speaker 1:

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Speaker 2:

So we're back talking about what could be, you know, always dangerous to use this word a miracle treatment. This really could alter how we treat not only sickle cell disease patients but again, a wide variety of other types of diseases. Even within this same, you know, classification of diseases. A far higher number of patients have beta thalassemia, which is kind of a cousin of sickle cell disease, and not all those patients have serious problems that need to have something as dramatic as this done. But there is a percentage of patients who have similar symptoms with beta thalassemia compared to sickle cell disease, and there's no reason this therapy couldn't work for them. I'm just obviously using the CRISPR or the other technology to make a slight change in another point mutation, basically. So the process of the seven was that the part of the study that looked at health related quality of life, this same group of patients that we just talked about in the wing internal medicine, actually went forward another few, a few months Actually, looking at 48 months, that was essentially 5 years out and they wanted to take a look again more durability and side effects than anything else and what they basically found was, yes, the, this single infusion of CRISPR, altered stem cells or other types of altered stem cells did find an incredibly durable response. For example on a scale of 1 to 10, pain intensity. The baseline pain score in these, in these patients in the study, was 4.8. And by month 48, it was down to 2.5, basically cut in half, and that number is it was pretty much the same number just a little bit smaller than it was at month 6. So you know again, very, very durable response. The same with pain interference in patients lives on a scale of 1 to 100. The mean was 58 in these patients and that dropped anywhere from 10 to 12 and stayed that way through month 48. So at least out to 5 years that seemed to really help. Fatigue wasn't quite as durable. The 1 wonders if fatigue. You know there are other factors that may contribute to that. So I think that that's kind of worth noting. But overall when they took a look at health reported quality of life, most of the numbers showed really big improvements and that read, those real big improvements were were maintained over over 5 years.

Speaker 2:

They wanted to look at total hemoglobin A in these patients. Again we said that you know it's about 3 years. They were maintaining global levels and kind of the 11 range, you know again, which would be kind of low, normal I think. And again, it's worth noting that almost all patients maintained a hemoglobin in 11 or 12 ranges by the end of the study. So you know, even after 5 years of receiving the single infusion, these patients essentially maintain the right development of hemoglobin A and a normal or low normal hemoglobin in these patients. So you know, an extremely durable response, as we mentioned. Also, side effects at 5 years Seemed fairly compatible with placebo. There were still a couple of patients who had elevated LFTs, but other than that there was essentially no significant side effects that far out from the stem cell transplant. So you know, just absolutely incredible.

Speaker 2:

But of course this is going to come at the price and that's unfortunately like so many of these, of these blockbuster therapies. What's really going to make it problematic is that it's estimated that a single infusion and again this does count you know, getting the stem cell transplant, which isn't cheap either, I mean just getting the same planning of itself, you know, approaches a million dollars, but the treatment all told, with everything in, is about 2 million dollars. And yes, you heard me right. So I mean again, if you were to treat every patient that stems or a sickle cell disease. It would bankrupt the healthcare system.

Speaker 2:

And so, you know, like so many things, I mean they were really going to have to target patients who have failed and have significant symptoms despite treatments like hydroxyurea. Patients maybe have had strokes previously because there are risks of having further strokes. You know, again, I, you know that's going to kind of, you know, end up in the realm of the pharmacogenomics people and unfortunately, the people at PBMs are trying to work that calculus. But I think it's worth noting that if we're talking about a disease where a single infusion essentially gives patients a functional cure, I think you know insurance companies should. They probably won't, but they should take a look at lifetime costs, right? Patients sickle cell disease are unfortunately frequent users of the healthcare system.

Speaker 2:

They're in the emergency room often, they're seeing their doctors frequently, they're hospitalized frequently, and I don't know how many ER visits and hospitalizations adds up to 2 million dollars. You may think a lot, but as someone who works in a hospital I can tell you a four or five days stay in the hospital ain't cheap and if someone gets admitted to the hospital a couple of times a year for this you could reach cost neutrality actually pretty quick. Now again, I'm sure there's many other factors involved, but I'm hopeful probably stupidly so, but hopeful that insurance companies do take a look at this and really take a look at, you know, the societal costs, the costs to, you know, insurance companies, particularly the cost to companies such as Medicaid. Unfortunately, many patients with sickle cell disease are a low, so then a low, lower socioeconomic strata. Many of them are on their state Medicaid programs. You know it does this, does taking a look at the highest disease burden patients and stay. Look, you know we're going to pay for this because not only is the right thing to do for the patient but overall it's going to save us money. It'll be very interesting what happens with that.

Speaker 2:

So again, you know the lay media has gotten kind of nuts about this and this is one of those times I kind of agree with them. I mean, I I'm hoping we look back on on these couple of studies and 10 years from now we'll have, you know, great treatments for muscular dystrophy, great treatments for type 1 diabetes, great treatments for, you know, rheumatoid arthritis, great treatments for a lot of these diseases that at least start out genetically. And then and then there may be a case where, where environment pushes the disease to its active form. But I think there, even if you just don't count you know this and count kind of the rare diseases that we know, single point, mutations make a rolling. That it's you know again, if we would be a very cool thing if 10 years from now we could say those diseases are rare or not really seen at all. So that's it for this week of game changers. I hope you like what you heard. We'll see you next week. But remember, time flies. I don't know where it's going, but the most important day is today.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on game changers clinical conversations.