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Close to the Edge Episode 5: The March to Cure Sickle Cell Disease with Global Blood Therapeutics’ CEO Ted Love
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Close to the Edge Episode 5: The March to Cure Sickle Cell Disease with Global Blood Therapeutics’ CEO Ted Love
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KEVIN DAVIES: Hello, and welcome to Close to the Edge, the new series from GENEDGE where we invite chief executives and outstanding scientists from groundbreaking biotech and pharma companies to sit down with us to discuss their science, their technology, and their business objectives. I'm Kevin Davies, editor-at-large with GEN and the author of the new book Editing Humanity.
ALEX PHILIPPIDIS: And I'm Alex Philippidis, senior business editor with GEN, Genetic Engineering and Biotechnology News, the publication covering the biotech industry for 40 years. Close to the Edge is an offshoot of GENEDGE, our new premium subscription channel from GEN, providing in-depth, exclusive news, interviews, and analysis of key trends in the biotech industry coupled with a range of multimedia offerings such as this one. More details of our free trial offer are at www.genengnews.com/genedge. That's G-E-N-E-N-G-N-E-W-S, .com/genedge.
ALEX PHILIPPIDIS: On today's episode, we welcome Ted Love, MD, the president and CEO of Global Blood Therapeutics, a developer of treatments for sickle cell disease and other blood-based disorders, based in South San Francisco. Ted, welcome to Close to the Edge, and thanks for joining us.
TED LOVE: Thank you, Alex. It's a pleasure to be here.
ALEX PHILIPPIDIS: Great. First off, Ted, tell us about your background in biopharma. You've previously held positions at several bigger companies, including Onyx Pharmaceuticals; Nuvelo, where you were also CEO; Theravance; and Genentech.
TED LOVE: I'm happy to do so. Well, if you go back to the beginning, I grew up as a kid on a farm in Alabama. And I was very fortunate to be a good student. So I ended up going to college at a small place called Haverford, medical school at Yale. And then I did all of my post-medical-school training in internal medicine and cardiology at the Massachusetts General Hospital, part of Harvard. And then I got recruited to Genentech back in 1992.
TED LOVE: That's when I really decided to redirect my training in medicine and my training in science to try to invent innovative therapies that would really go after very serious diseases. And I'm just thrilled that I've been able to work on things like Herceptin, which has completely changed the world and prospects for women with HER2-positive breast cancer; drugs, most recent like Kyprolis. That is a very effective therapy for myeloma.
TED LOVE: My mother died of myeloma. My mentor at Harvard died of myeloma. So it's really been gratifying to have a career where you make therapies that, really, are fundamentally life-changing for people that are grievously ill. And now we're doing this in sickle cell disease, which I know will be our major focus today.
ALEX PHILIPPIDIS: Great. And tell us, then, about Global Blood Therapeutics and your arrival. And how did you come to connect with Global Blood and join the company?
TED LOVE: It's a great question. And I think it's probably a great idea, Alex-- you just kind of framed the whole issue. So sickle cell disease is a relatively rare but devastating genetic disease. And unfortunately, it occurs in members of our society who are most disadvantaged. They tend to be people who are socioeconomically disadvantaged. And they tend to be people who are disproportionately African American or people of color.
TED LOVE: And I do think because of that, finding real fundamental solutions, therapies has been highly elusive. And this company, Global Blood Therapeutics, was founded about 10 years ago to focus on finding fundamental solutions for sickle cell disease. So I actually came out of retirement because I thought sickle cell disease had waited too long for serious investment in real innovative therapies.
TED LOVE: And we have been very fortunate. The first molecule that we put into the clinic has been highly effective. It received accelerated approval from the Food and Drug Administration. We developed the therapy in a very, very short amount of time. And we've got the data that shows that more than 90% of people who take this therapy have evidence that their disease is being modified by their red cell count going up, showing that their red cells aren't being killed by sickle cell disease.
TED LOVE: And they tell us, I feel better, I've never felt so good in my life, my hemoglobin has never been so normal in my life. And now our goal is to get this therapy to as many patients as we can, obviously starting in the United States, where it's approved, but ultimately getting this available to people with sickle cell disease around the world.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thanks, Alex. Ted, sickle-cell is widely known as the first molecular disease identified by Linus Pauling in the late 1940s, and Vernon Ingram identifying the actual mutation a few years later. We recently interviewed John Evans, the CEO of Beam Therapeutics, on this program, who described the sickle cell mutation as, perhaps, the most famous mutation in the world. Why has it taken so long for the scientific community to really make progress in this disease when we knew so much 70 years ago?
TED LOVE: Underinvestment-- I'll give you an example. Cystic fibrosis is one-third as common in the United States as sickle cell disease. As a consequence, we've got 15 innovative therapies approved over the last 20 years or so for cystic fibrosis compared to, really, nothing for sickle cell disease for a long period-- and, finally, two innovative drugs approved, as you know, at the end of 2019. So it's been underinvestment.
TED LOVE: And we really are out to change that. There are outstanding CF centers of excellence spread all throughout the United States where sickle cell patients get outstanding therapy. None of this has happened in sickle cell disease. Many of us think it's because these patients are more than 90% African American. And they're often poor. They've not had advocates.
TED LOVE: And they've not had supporters. But we are out to change that, Kevin. I mean, that's why our company was started. And we're thrilled to see that is also changing in other companies. But GBT, we feel, is the leader in really driving sickle-cell to be more like what we're seeing in CF, what we're seeing in myeloma, what we're seeing in other serious diseases where there have been innovative therapies that are having dramatic outcomes for patients.
KEVIN DAVIES: Sickle cell patients, I think it is widely known, experience a lifetime-- usually an abbreviated lifetime-- of major pain crises. And I think most of our viewers will have very little comprehension of what that's actually like. I wonder if you could help describe, from your medical-- and, maybe, even personal experience-- what does it feel like to suffer a crisis when you're a sickle cell patient?
TED LOVE: Well, I will talk about crises. But I also want to say that I think one of the unfortunate things is that sickle cell has been described as a disease of pain. And I think that's been terribly stigmatizing-- number one, because it leads people immediately to this conversation about opioids and pain management. And it's also been terrible because it leads people, including physicians, to say to a patient, you're doing pretty well if you're not having pain episodes and being admitted to hospital.
TED LOVE: And that's unfortunate because these patients are also going to die in their late 30s and early 40s. So this pain characterization, while it is part of the disease for many patients, it is not the fundamental basis for patients dying. We know that sickle cell disease is really a disease of chronic severe anemia. It's called sickle cell anemia for a reason. And you die from the accumulated organ damage of chronic anemia.
TED LOVE: These individuals start to become anemic, typically, when they're six months of age. In their first decade of life, many of them will have suffered a stroke or silent ischemic damage, which leads to loss of cognitive function. They lose their capacity to have normal kidney function in the first few decades of life. They lose splenic function. When I was very young, people with sickle cell disease typically died in the first couple of decades of life from infection.
TED LOVE: And I think if we had characterized it as a disease of infection back then, then that would have been a misrepresentation, too. We have solved the problem of infection by-- or largely solved the problem of infection by giving children prophylactic antibiotics and vaccinations. And now what we've uncovered is people don't die of infections, but they die of the accumulated organ damage from the chronic anemia.
TED LOVE: So that's why GBT has said, let's not just focus on pain. Let's focus on what is ultimately causing loss of your brain function, causing loss of your pulmonary function, your cardiac function, your kidney function. Because you can't lose all these organs and expect to live a normal life. And we know the natural history is to die in your late 30s and early 40s.
KEVIN DAVIES: Yeah. You touched on, minutes ago, Ted, about the funding gap between funding for genetic diseases like cystic fibrosis, which primarily affects people of northern European descent, versus sickle cell disease, which, ironically, is one, or two, or three times more common in the United States than CF. Is there any grounds for optimism that that playing field is being leveled? Is that gap narrowing?
KEVIN DAVIES: Do you see any signs of progress, and greater awareness, and imperative to fund research into sickle-cell?
TED LOVE: Well, first of all, let me say that I think our Food and Drug Administration is the best regulatory agency in the world. The Food and Drug Administration, like they do for many diseases, called a meeting now, probably, seven or eight years ago, where they brought in sickle cell patients and sickle cell advocates, not doctors. They brought in patients. And they asked these patients, what do you need to treat your disease?
TED LOVE: What can we be advocating for to help you? And what the patients told the FDA-- it's two things. One, the people at the meeting talked about their pain. But there was a large group of people, an equally large group of people, who were not at the meeting. And what those people said is, I'm not at the meeting because I am so limited by anemia that I don't even have the energy, I don't have the capacity to get on airplanes and travel.
TED LOVE: Now, the patients with pain are anemic, too. And they're suffering, too. But the fundamental thing that they wanted is something that would attack the root nature of their disease. When I was in medical school, we discovered this disease called HIV. And HIV was a death sentence. Everyone that I treated with HIV died.
TED LOVE: We started to make drugs like pentamidine to treat the pneumocystis carinii, treat the downstream consequences of HIV. And that helped patients. But what really helped patients was killing the virus. We need to kill the root cause of sickle cell disease. And just to put things into perspective for individuals, sickle cell disease-- as you pointed out, Kevin-- it's a well-described disease on a molecular level.
TED LOVE: It is a single mutation on a single protein in our body. That protein is wholly contained within our red cells. So for sickle-cell to kill the patient, it has to first kill the red cell. We know that. And that is where the anemia comes from. And the reason sickle-cell kills the red cell is because the mutation on the red cell causes mutation on the hemoglobin, causes the hemoglobin to begin to cluster and organize into rods.
TED LOVE: And those rods physically deform the red cell. That's why they look sickle. It would be like a balloon with a sword inside of it. It's a red cell with a stick inside of it. And those polymers-- that's what we call them. Those polymers rupture the red cell in addition to deforming it. And this is going on constantly. You and I are making about a million red cells a second, just to put it into perspective.
TED LOVE: Sickle cell patients are making 10 million red cells a second. And they're still anemic because this polymerization is rapidly killing their red cells. So that's why GBT said, could we make a therapy, a small molecule, which would bind to sickle hemoglobin and stop it from aggregating into rods? And that's the breakthrough that we came up with. And it's very fundamental. Some people are obviously saying, oh, you're just raising hemoglobin.
TED LOVE: But I would tell you if you have a massive tumor in your brain and I do something to shrink it, I don't know if you're going to live longer or not. But I can tell you what, I think you're going to be happier that I've shrunk your brain tumor. In sickle cell disease, the disease burden is anemia. It's because your red cells are being killed. Our drug is very powerful at reversing it. It's really the same as shrinking your tumor.
TED LOVE: We're growing your red cells toward normal as opposed to letting the disease continue to eat away at your red cells and cause you to be profoundly anemic.
KEVIN DAVIES: We're going to talk more about Oxbryta, your breakthrough drug, and how it works in just a couple of minutes. I just wanted to quickly-- we talked about the funding disparities. I wonder if you would agree with the suggestion that there's also, according to reports in The New York Times and elsewhere, a lack of awareness among many patients with sickle cell disease of some of the currently available screening tools and generic drugs that are available that is exacerbating these disparities that we've already talked about.
KEVIN DAVIES: Do you feel there's still a problem in just the overall awareness of the medical establishment catering to the sickle cell community?
TED LOVE: I do. I think that we have issues in sickle cell at every level. We have some outstanding sickle cell physicians in this country that I know, and really admire, and have great respect for. But on the whole, the standard of care for sickle cell patients in this country is terrible. It's terrible in the lack of number of physicians who are trained well to treat sickle cell disease.
TED LOVE: It's terrible in terms of being proactive about treating this disease. My point earlier about pain, we tell people they're doing OK if they're not in pain, but they're not. We know that we now have tools. We really have two tools that are disease-modifying. Hydroxyurea-- unfortunately, hydroxyurea is a cancer drug. And it has a black-box warning around having a secondary cancer risk.
TED LOVE: That's not optimal. But that has been the only tool we really had in sickle cell disease. Now we have another disease-modifying therapy that the FDA has approved. If my child had sickle cell disease, my child would be offered both of those therapies. I would demand both of those therapies. Because I think disease modification is the pathway toward extending survival.
TED LOVE: That's true in every disease. If you fundamentally go after the HIV virus, the patient has a chance to live longer.
KEVIN DAVIES: Before I hand it over to Alex, just take us back to 2012 or the run up to the founding of GBT. Who, in particular, deserves credit for taking this lofty notion of building a company to focus on this unmet-- really unmet-- medical need. And what were the challenges in getting GBT off the ground?
TED LOVE: Well, there are two people that I would cite. One is Charles [INAUDIBLE],, and the other one is David Phillips. Those are two individuals that I've known for a long time. And they've both been very successful at founding companies. I don't know whether it was Charles's idea or David's idea. But the truth be known, there was an earlier attempt-- I think in the '80s or '90s-- to make a small molecule that would stop the sickle hemoglobin from polymerizing or sticking together.
TED LOVE: Unfortunately, that therapy had significant side effects and was never fully developed. David and Charles had the wisdom to say, maybe we shouldn't give up on that approach. Maybe you simply need to make a different molecule. Because as we know, there have been nonsteroidal inflammatory drugs that have been removed from the market because of toxicity. And yet we have Advil in every Safeway.
TED LOVE: It's very safe. So just because one drug is unsafe, it doesn't mean you can't make a molecule in that same class that does the same thing that's safe. And that's really what they did. They basically said, let's go after this again and see if we can make something that's even more effective and safe. And that's what we pulled off.
KEVIN DAVIES: Was there any challenge in raising money in those early years?
TED LOVE: Well, we were very fortunate.
KEVIN DAVIES: [INAUDIBLE] that's a rare disease. It's a socially, economically disadvantaged population. I could see there might be some resistance.
TED LOVE: You could. And I think that had been one of the historical challenges. You're absolutely right, Kevin. GBT was very fortunate in that Charles was a partner at Third Rock Ventures, which, as you know, it's a very successful venture firm. So when they founded the company, they put in the first $50 million. And then they called me and said, we need you to raise more money.
TED LOVE: And that's something I've done over my career pretty well, is tell the story about science, tell the story about them, and medical need, and get investors. And I estimate I've raised over $1.5 billion since the company was founded. So we have been very fortunate in that we have an amazing story. There are a lot of patients. And we've made therapies or a therapy which is highly effective.
TED LOVE: So I think our investors have been well rewarded. And I think we have challenged the thinking that you can't make a successful company around sickle cell disease. We've made a very successful company. And we're just getting started.
KEVIN DAVIES: Great. Alex, over to you.
ALEX PHILIPPIDIS: Thanks, Kevin. On Oxbryta, it was approved late in 2019 by the FDA. If you could tell us about that small molecule drug, how it came to be developed, and fairly quickly in the prepandemic era-- if I recall, about almost six years from the time the molecule was formed to the time you got regulatory approval?
TED LOVE: Yeah, it was a very, very short timeline, Alex. So the company was incorporated in 2011. We didn't have, really, many employees or even facilities. So we really kind of rented some chemists from an adjacent company. The first molecule or the molecule that we put in the clinic was called GBT-440 back in the old days, which meant it was the 440th molecule that our chemists made.
TED LOVE: We put that molecule through all of the requisite animal studies to support studies in man. We began our first studies in man in January of 2015, the first study in man. We completed our pivotal study in June of 2018. And we submitted and got approval from the FDA in November of 2019.
TED LOVE: So this was a record pace. And I think that's appropriate. What I say to people all the time-- and I've said this throughout my career whether I'm working on breast cancer, or whether I'm working on colon cancer, or whether I'm working on myeloma. My position is people are dying. People are dying, and you need to do something about it.
TED LOVE: And you can't be cavalier about it. It doesn't mean you cut corners. But it does mean you do the quality work and you do it with a sense of urgency. So our company has operated with the belief that sickle cell patients are dying. And they need help. And we took that attitude into how we designed our studies. We took that attitude into how we conversed with the Food and Drug Administration.
TED LOVE: And that's how we were able to do this, Alex, in, quite frankly, record time.
ALEX PHILIPPIDIS: Mm-hmm. You've explained, a little earlier, the challenge of the biology. What were some of the key challenges the Global Blood overcame for Oxbryta to advance from discovery all the way to patients?
TED LOVE: Well, one of the challenges was to get off of the emphasis on pain. The truth is only a minority of sickle cell patients have very, very frequent pain episodes. Many have, even, no pain episodes. One of the young women that I talked about a lot in our corporate presentation lives in Atlanta. I think she's about 15 years old now. And the slide that I had in our presentation, I think, was her at 12 years old.
TED LOVE: And the slide said, I've had one stroke, I've had eight major surgical procedures, and I've never had a pain episode in my life. Her name is [? Deej. ?] [? Deej ?] is clearly dying of sickle cell disease. She's not having pain now. She's dying of the consequences of chronic anemia. Sometimes acute episodes of lack of blood delivery, being the stroke that she had and being some of the other procedures that-- people with sickle cell disease lose their bones.
TED LOVE: So they end up with hip replacement, shoulder replacement. They end up with pulmonary hypertension. And they end up dying of heart failure because of that. As I said, they end up with strokes. They end up with silent strokes that reduce their cognitive function. So this disease is not sparing any organ in the body. And it makes sense because blood is how we nourish our organs.
TED LOVE: And if you don't have proper blood, you cannot nourish your organ. So the pathophysiology of this disease makes perfect sense, right? If you're profoundly anemic starting at age 6 and you manage to not die of infections because of the loss of splenic function, what do you think you're going to die of? You're going to die of undernourished organs.
TED LOVE: And the main nourishment that we're supplying what our blood is oxygen.
ALEX PHILIPPIDIS: How did Oxbryta overcome the challenge that your earlier 440 molecule didn't?
TED LOVE: Oh, so 440 actually is Oxbryta.
ALEX PHILIPPIDIS: Oh, I'm sorry.
TED LOVE: That was the old name. But you may be referring to, how did it overcome the challenges of this earlier drug that I mentioned that was discontinued?
ALEX PHILIPPIDIS: Yes.
TED LOVE: So that drug, actually, was remarkable. It showed evidence of reversing the anemia in sickle cell disease literally within days. And I was very fascinated by that. Unfortunately, about half of the individuals-- sickle cell patients or normal volunteers-- exposed to this, within about 10 days, would develop swollen, painful lymph nodes. And that was a very scary consequence.
TED LOVE: And it was common, as I said. It occurred in about half the patients. And that drug was discontinued. And there were no followup attempts to make a follow on drug. So we basically made a drug that has features which are very similar, Alex, to that drug but has no issue around allergic response like this other drug did.
TED LOVE: So it was really just, try it again. Like I said with the nonsteroidals, some nonsteroidals were killed because they had immune response, actually. And yet we have Advil in every Safeway. So you don't give up on a single drug class because of one molecule. In fact, it's very common that we make multiple molecules to compare them to each other and see if we can make improvements.
TED LOVE: In fact, in our pipeline now, we have a third-generation Oxbryta molecule that is much more potent. In fact, it is so potent that we think it will be equal to gene therapy. We think it will be curative in a daily pill. And it won't have issues associated with it of bone marrow ablation or risk of a major, expensive upfront procedure.
TED LOVE: It'll simply be, take one small pill a day and you may be cured. So we are working very hard on the next generation. So iteration, in our business, is critical.
ALEX PHILIPPIDIS: Great. And I'll get to some of that pipeline a little later. But I was curious by something you mentioned earlier, the challenge of bringing this drug to patients-- most of whom, as you pointed out, are patients of color. How does GBT market Oxbryta and how does it bring it?
TED LOVE: Yeah. So we really needed to kind of flip how people were thinking from not just pain but, what is really going on in sickle cell disease? And we've been now trying to get people to understand that a disease that occurs on one protein that's trapped inside your red cell is really killing the red cells first. It's killing the red cell first. If you have a tumor in your brain, the organ that's going to be the basis of you dying is your brain.
TED LOVE: And the same is true in sickle cell. If you've got a mutation on a protein that exclusively resides in your red cell, the red cell is going to be the basis through which this disease is going to kill you. It's completely simple and straightforward. Yet, as I said, Alex, there'd been this enormous focus on pain. And so we were developing drugs that were only indicated for people who had pain.
TED LOVE: And I thought that would be an enormous disservice. So I was very strident early on. We are not going to develop a drug focused on pain. We are going to focus on the fundamental basis of this disease, which is the hemoglobin polymerization that's killing the red cell. And what we ultimately agreed to with the Food and Drug Administration is that the primary endpoint for our drug's approval would be stopping the polymerization from killing the red cell.
TED LOVE: And you measure that by measuring the hemoglobin going up. The hemoglobin is only down because the polymerization is killing the red cells. And if you reverse that, the hemoglobin can go up. And in fact, we have many patients now that are out there in the real world, in the United States, taking Oxbryta, and their hemoglobin is perfectly normal-- perfectly normal.
TED LOVE: I bet-- and we need to prove this. I bet those people are going to live longer and better than their peers who are not given access to therapy. So that's what I was trying to point out at the beginning, Alex. It's my job to innovate, and make a good therapy, and get it approved by demonstrating it's safe and effective.
TED LOVE: And then the next part of my job is to do anything I need to do to change the world to say, let's treat sickle cell patients proactively. Let's not wait on pain episodes. Let's not wait on strokes. I'm a cardiologist by training, as you know. This would be like me having somebody with hypertension and saying, you haven't had a stroke yet, so you're doing pretty good.
TED LOVE: I'm not going to do that. I know the natural history of hypertension. I'm going to lower your blood pressure. And if you don't take your medicines, I'm going to talk to you more. I'm going to beg you. I'm going to cajole you. Because I know the consequence of chronic hypertension. We know the consequence of chronic anemia and hemolysis of sickle cell disease.
TED LOVE: We don't need to continue to study that.
ALEX PHILIPPIDIS: I also wanted, Ted, to talk about another challenge for Oxbryta, which is the need to broaden patient focus and sickle cell disease beyond your initial patient population served by Oxbryta. I know GBT has said it will seek approval for Oxbryta in pediatric patients by some point later this year, in ages 4 to 11. So how has that gone about in, especially, children given the vulnerability there?
TED LOVE: I think it's going very well. And you are so right, Alex, that this is critical. As I mentioned, sickle cell patients begin to suffer irreversible damage likely as early as six months old. So we want to get the drug approved, actually, to begin at that age. Our initial label was based on a study where we only studied individuals 12 and older. The initial drug development was really around a pill formulation.
TED LOVE: Individuals 12 and older can typically take pills. And because of body size, we were able to use a single dose. So our initial effort was really focused on 12 and older. But we've been doing studies for some time now in the 4-to-11 age group. And we now have sufficient data to go to the FDA and request approval for that age group. And we are currently studying individuals down to that six-month-old age.
TED LOVE: And we will have that data, we hope, sooner than later, and go in and ask for the extension of the label down to that age group. Because the goal here is to take a young individual who's showing the development of the anemia of sickle cell disease, see if you can go in and correct that anemia before any body organ damage occurs, and fight that anemia off. It's very similar to what we do in HIV.
TED LOVE: If you or I were to have a child born with HIV, we would treat them. We wouldn't wait for them to become neutropenic. We wouldn't wait for them to develop opportunistic infections. We would go right in, and we would put them on a powerful regimen, an HIV regimen. And they would need to take it. But guess what?
TED LOVE: That child would live a normal life. We can do this in sickle cell disease.
ALEX PHILIPPIDIS: And in fact, earlier this month, the company announced some new data from the Phase 2A HOPE Kids 1 study. If you could talk about that, since it was of int--
TED LOVE: Yeah, so that's-- you just pointed out the study. So that is a study that we did in this 4-to-11 age group. And what it essentially shows is what we expected, which is the drug works just as well in that age group. And importantly, it looks just as safe. And that would be the basis of the FDA extending the label to the lower age group. And then we think, again, we're going to be able to do the same thing in that 6-to-4 age group, to ask for an approval down to six months.
TED LOVE: Now, the other thing I have to point out is that we needed a new formulation. Four-year-olds don't like pills. And six-month-olds-- there's no way, right? We all remember our kids. What do you do? So we needed a pediatric formulation. And we've developed that as well. So the pediatric formulation was developed more slowly.
TED LOVE: It took more time to develop it. But now we've got a pediatric formulation that's also part of this FDA submission.
ALEX PHILIPPIDIS: Will that be a liquid form? Or how would you get kids to take it?
TED LOVE: It becomes a liquid form. It's what we call a dispersable tablet. So it's a tablet that you simply add a little water to, and it just turns into liquid. We do that because we don't have to use stabilizers. If you put it in liquid form, you'll need to put stabilizers in. And stabilizers have risks associated with them. So we wanted to come up with a solid formulation that's convertible to liquid on demand to allow the lack of stabilizers.
ALEX PHILIPPIDIS: You're watching Close to the Edge, the new show from GENEDGE, the premium subscription channel with genetic engineering and biotechnology news. I'm Alex Philippidis, joined by Kevin Davies. And we're talking to Ted Love, the CEO of Global Blood Therapeutics. Now, a few months, Ted, after Oxbryta's approval, the world began to shut down from COVID-19. How did COVID-19 affect the rollout and the uptake of Oxbryta as well as GBT's overall operations?
TED LOVE: It's had a big impact. I think that the COVID pandemic had an impact, basically, on everybody in the world, right? But it was even worse in the sickle-cell community. I think everyone knows that the mortality rate for COVID was about three times higher in the Black community than the non-Black community in the United States. That's where sickle cell is. We know that the financial impact in terms of jobs, et cetera, was greater in the African-American community than it was in other communities.
TED LOVE: That's sickle-cell. We also know that when the CDC put out guidelines for who's most at risk to die or have very serious consequences if they get COVID, sickle-cell was high on the list. So our patients were being affected in ways that were amplified. So we did have an impact. Our patients weren't going in to see their doctor, many times because they were being told, don't get on a bus, don't get on a train, don't run the risk of getting exposed.
TED LOVE: But that also meant they weren't in a position to be evaluated and to be started on novel therapies. Now, what we tried to do, Alex, is we tried to really encourage physicians, healthcare providers-- use telemedicine. And we've been significantly successful. But there are physicians and there are patients that are less likely to do that.
TED LOVE: So we need to get beyond the pandemic so that we can reinvigorate the effort to get patients back in to see their physicians face to face, as well as telemedicine, but then begin to have these conversations about, how are we going to fight your sickle cell disease at a fundamental level? How are we going to fundamentally modify this disease to try to give you a chance to live to be 50, 60, 70, or 80?
TED LOVE: The way we're going to do that is disease modification.
ALEX PHILIPPIDIS: Yeah, that's one key challenge. Another challenge has revolved around price. At a list price reported last year at $125,000 a year, Oxbryta's generated criticism that it's been priced too high. How do you justify that list price? And how has the company worked to contain expenses for patients and sort of cushion the price impact on them?
TED LOVE: Yeah, I'm glad you brought up price. Because I think price and access are different things. And I think sometimes people conflate the two. So let me just say, first, about our price, we put a lot of time into thinking about an appropriate price. And we spent time talking to payers about our price before we set our price. We talked to our board a lot about our price. And we came up with several points I want to emphasize. One is we said, we're an orphan disease.
TED LOVE: Let's price ourselves in the lower half of orphan diseases. There are drugs out there, for CF for example, that cost two or three times what Oxbryta costs. And I think sickle-cell patients deserve therapies even if the cost is one-third of the costs or one-half of the costs of CF drugs. Because I think the CF patients deserve therapies. The other thing I will have said, this is a rare disease.
TED LOVE: It is a rare disease. So if you price it as if it's cardiovascular disease, you're going to go out of business. You are going to go out of business because there aren't enough patients. So the patient cost does have to correlate with the patient number. And we've seen that over, and over, and over again in orphan disease.
TED LOVE: The third thing I will say is that we have committed to no price increases for three years. So we want people to know this is the price, and the price is not going to change for three years. We took very bold steps to make sure we were thoughtful about our price. Now, we'll get to access. Because of charging a reasonable price, we can afford to do some things that are important in sickle cell disease.
TED LOVE: One, if you have sickle cell disease and you have no insurance, we give you the drug free. We can afford to do that because we have a reasonable price that allows us to pay for that. Because we've got to pay for that. We also have created a patient hub. It's very common in rare diseases that companies have patient hubs which support the patient with concierge services and support physicians with services to help them deal with the bureaucracy of a health care system, understand their insurance, get financial help when they need help, get help getting to the doctor when you need to get to the doctor.
TED LOVE: We pay for all of that. That's part of our price. And that's never been done in sickle cell disease. A generic, repurposed cancer drug is not going to pay for that. That's been one of the problems, Alex, in sickle cell disease. There's been no money here. And people like me-- were doing it, because we're saying you can't make any money in sickle cell disease.
TED LOVE: But if you can't make any money in sickle cell disease, why would investors invest in a company that's going to go nowhere? So this, obviously, we want it to be thoughtful. But you can look at a lot of drugs and prices. And you'll see that our price is definitely not in the upper half of orphan drugs. We're in the lower half. And we're comfortable with that.
TED LOVE: But we're also comfortable that we have charged enough to allow us to do what we need to do for sickle cell patients that are on our therapy, support physicians that are trying to do things to help our patients, and also continue to invest in our pipeline to bring more therapies for sickle cell patients. That's how the ecosystem works. And by the way, let me ask one other thing.
TED LOVE: Our drug is going to be free eventually. Our drug is going to go off patent. And it's going to be dirt cheap. So we've got a limited window in which the patent protection can pay for our company to survive. But when it goes off patent, if we haven't made more innovative therapies, we're going out of business because that drug is going to be, essentially, free.
TED LOVE: And I think that is one of the wonderful things. During the COVID crisis, one of the more effective drugs we discovered for treating, unfortunately, was dexamethasone. How much do you pay for dexamethasone now? Nothing, it's basically free. Highly effective, a great gift to the world, but it's been paid for and gone. And that's one of the things I do love about our industry, is that we make great innovations.
TED LOVE: We have a window where we can charge. And we should charge a fair price. And we should be thoughtful about our pricing. We should be thoughtful about our price increases. But the world needs to also recognize that there is a limited window. After that window, you probably aren't going to pay anything significant for these small-molecule drugs.
ALEX PHILIPPIDIS: You mentioned pipeline just now. And by the time Oxbryta goes off patent, possibly one, if not both, of these candidates in your pipeline and, now, in clinical trials might be well on the way to patients in GlycoMAb and O21601. How far into development are both? And what kind of milestones can we expect for those candidates this year?
TED LOVE: So I'll start with GlycoMAb, and GlycoMAb is at the last stages of clinical testing. It's in phase three. And we were able to get there quickly for two reasons. One is that we acquired in GlycoMAb from Genentech Roche, that had been pursuing the antibody, a [INAUDIBLE] inhibitor, to treat cardiovascular disease. They decided to get out of cardiovascular disease entirely.
TED LOVE: And so they iced the program. We called them up. And we said, we think [INAUDIBLE] inhibitor could work to treat the pain of sickle cell disease. This was developed for pain. It blocks the stickiness of the cells in the blood that adhere to the vascular wall and cause blockages that lead to the pain episode. So this drug is not targeting the fundamental nature of sickle cell disease.
TED LOVE: But it is targeting the pain episodes. We have a lot of confidence this will work because there is already, as of about a year ago-- actually, about the same time that Oxbryta was approved, [INAUDIBLE] from Novartis was approved. And it's a very effective agent for treating pain episodes, as demonstrated by a study where they took individuals who were having frequent pain episodes. They randomized them to receive [INAUDIBLE] or to receive placebo.
TED LOVE: And they saw between a 40% and 50% reduction in pain episodes. The challenge with the molecule is that it's intravenous. And it has to be infused every month. And GlycoMAb has been designed to be infused four times a year-- still intravenous, but only four times a year. And that actually fits very nicely with the frequency of when patients should be going in to see their doctor anyway.
TED LOVE: So we think it's going to be, potentially, a better molecule in terms of decreasing the pain episodes, but quite frankly, just much more practical and easy for a patient to take in for a hospital or for a physician to administer 4 times a year versus 12 times a year.
ALEX PHILIPPIDIS: Great. And GBT also expanded its pipeline in sickle cell disease in March by licensing, from Sanofi's Bioverativ subsidiary, two early-stage research programs, one that pursues a novel anti-sickling mechanism. The other leverages a new approach to reduce inflammation and oxidative stress. How has development progressed on those since then? And when can any o r both of these be expected to reach the clinic?
TED LOVE: So those are early-stage. And we do want to emphasize that we're excited about those targets, but they are very early-stage. And Alex, as you know, our business is very risky. Only about 1 out of 10 things that we actually put into humans even will make it to approval. And we're not even that far along yet. So those are early-stage-- very promising, but early-stage. The second molecule, which I didn't talk about, was 21601, which stands for 21,601.
TED LOVE: So it was the 21,601st molecule we synthesized. It took us a long time, and a lot of chemistry, and a lot of biology to make something significantly better than Oxbryta. If we look at Oxbryta, the question is, what could we improve, Alex? It's pretty safe. It's highly effective. But it doesn't appear to be curative in the majority of patients.
TED LOVE: And we're also giving three relatively larger-sized pills per day. So what if we could reduce that to one very small pill a day and achieve enough hemoglobin modification? That's what we're doing. We're modifying the hemoglobin to make it not stick together anymore. And once we get to about a third of the hemoglobin doesn't aggregate, sickle cell basically looks like sickle trait.
TED LOVE: People with sickle trait have 50-50, right? They've got 50% normal hemoglobin, 50% sickle hemoglobin. But they have a normal life expectancy. We actually know, through a lot of science, that you don't even need to get to 50% non-polymerizing hemoglobin. If you can get to about 30%, 35%, the disease starts to look like trait.
TED LOVE: So 601 is the molecule where we think we will reliably get everyone above this 30%, 35% modification, which we think will be curative. And we'll do so with one small pill per day. If we can pull that off, that is another big step beyond Oxbryta.
ALEX PHILIPPIDIS: Mm-hmm. And 601 is how far along, you said?
TED LOVE: 601 is currently in what we call phase 1-2. So we are looking at 601 in normal volunteers, a pretty large number, be about 60, where we give the normal volunteers either single doses or multiple doses of 601. We also give the therapy with and without food. We do a variety of things just to make sure that there's nothing unusual about how the drug is absorbed in combination with food, for example, as we go into development.
TED LOVE: We'll move from the normal volunteers, quickly, into sickle cell patients, where we'll then be able to look at, are you modifying the disease? And we've now developed really, really cool technologies that allow us to look at the red cell and see if we make the red cell look like the red cell of a patient with sickle trait as opposed to the red cell of a patient with sickle cell disease. If you can do that, you're pretty sure that you've converted the phenotype to being that of trait.
TED LOVE: It's all in the red cell. So we really are very focused on demonstrating disease modification by increasing survival of red cells. But we also can look very intimately, now, at the function of the red cell. And we can do so under oxidative stress, which is what causes sickle cell disease to really advance. That's what causes the polymerization to accelerate and the destruction of the red cell to accelerate.
TED LOVE: So we can look at the physiology of the red cells under profound hypoxic stress to see if the cells are behaving, again, more normally, like patients with sickle trait as opposed to sickle disease.
ALEX PHILIPPIDIS: Great. And we're going to learn a little bit more on the landscape of sickle cell therapies. Over to you, Kevin.
KEVIN DAVIES: Thanks, Alex. Ted, the other exciting new arm in sickle cell therapy is, I would say, in the gene therapy and gene-editing space. We've seen specials on 60 Minutes showing some remarkable patient success stories, receiving various gene therapy treatments from companies like bluebird, Sangamo, Graphite Bio, Beam Therapeutics, and of course, the amazing results with Victoria Gray and the CRISPR Therapeutics Vertex trial published about six months ago.
KEVIN DAVIES: I know you welcome all of this progress. But could one see these efforts as potentially encroaching on your own market? Do you still have the inside track? How do you view the landscape?
TED LOVE: I don't think about it that way. I mean, as you know, Kevin, I came out of retirement to help sickle cell patients. So the more options for these patients, the more excited I am, quite frankly.
KEVIN DAVIES: Yep.
TED LOVE: I would say, however, that one of the challenges with the genetic procedures is that they require ablation of the bone marrow. We have to literally ablate the existing cells in the bone marrow. And we use chemotherapy to do that. And we know that there is a secondary risk that you could develop cancer, that you could be infertile after that. So those procedures have significant risk associated with them.
TED LOVE: We're hopeful that we can do the same thing. We're all trying to create enough non-polymerizing hemoglobin to make people look like trait. So you can do that by inserting a gene into the hematopoietic stem cells, like bluebird is doing. If you get enough expression of that gene with an alternative hemoglobin that doesn't polymerize, that phenotype begins to look like trait. That's absolutely beautiful.
TED LOVE: The same is true with CRISPR. We can go in and we can turn on the gene that produces fetal hemoglobin. And if you can produce enough fetal hemoglobin, you begin to look like trait. But we can also take a sickle hemoglobin molecule, attach an Oxbryta to it or a 601 to it, and it doesn't polymerize either. So what we're trying to do is create options.
TED LOVE: And we hope that our options won't have any serious complications associated with it. But you will have to take it every day. So I think there's room for all sorts of therapies. I do think a therapy which is a simple pill-- if it's approximately equally effective, that will be the preferred approach by most people. But I invite investment in sickle cell disease. And I invite options for patients.
KEVIN DAVIES: You said Oxbryta-- you were very candid in saying it's not a cure. What has been the range of patient responses? Do some patients fare better taking the drugs than others? And do you have the beginnings of an understanding of what may explain that variability?
TED LOVE: What we've found is that the more of the hemoglobin you modify, the more normal the patient becomes. Now, there is a limitation to what your bone marrow might do if it's been damaged by two or three decades of sickle cell disease. But in general, what we've found is that if we can modify about a third of the hemoglobin, the patient largely begins to look like they've got trait and not sickle cell disease. Unfortunately, with Oxbryta, it's very hard to get to that level.
TED LOVE: And in fact, we published this, that with the dose of Oxbryta which is approved, we're not getting there. About 25% of the hemoglobin is modified. It's very helpful. And it's very helpful scientifically because the rate at which the hemoglobin polymerizes is concentration-dependent. It's actually concentration-dependent to the 15th power.
TED LOVE: So very small changes in the available hemoglobin which can polymerize is very powerful. So 25% is nothing to sneeze at. But it's not that magical 30%, 35%. And that's why we're developing 601, to try to get to that level.
KEVIN DAVIES: Is 601 chemically derived from Oxbryta? Or is it a completely different shell of a compound?
TED LOVE: It is a completely different compound. It does share some similarities. It will be in the same class, but it is a very different molecule. For example, the halflife of Oxbryta is very long. It's about three days. The halflife of 601 is about a month. And the reason why is that when 601 binds your hemoglobin, it really sticks to it.
TED LOVE: It does come off. It isn't the halflife of the red cell. But it is very long. And that is what allows us to likely give a much, much smaller dose and yet bind a higher fraction of the hemoglobin. We don't think we need to get beyond about 30%, 35% to be effectively curative in all patients. We're going to be able to see this kind of data, I think, next year.
TED LOVE: We're already committed to develop some proof-of-concept data and make that available at the American Society of Hematology meeting later this year. But we'll be doing larger studies with a larger number of patients. What we really want to do, quite frankly, is to get into children at six months. Because we think we can, almost always, we think, make those children look normal.
KEVIN DAVIES: Sickle cell disease, of course, originated in Africa. Studies suggest about 7,000 years ago is when the mutation first arose. Are you in a position to do anything to help distribute Oxbryta or other drugs to the African population? I'm sure that's not your initial focus. You've got to build the engine first. But what are you able to do, if anything, at the moment in Africa?
TED LOVE: There are two things that we can do right now. And right-- by the way, we are working on making our drug available around the world-- Africa, India. And we've got to figure out how to do this much the way Gilead has been very successful at making their HIV drugs available around the world, and they have to figure out how to make that work for countries that are very poor countries, very low-resource countries. So we're working on all of that.
TED LOVE: What we're doing today is, number one, we are doing trials globally. And we made a commitment in the very beginning that if you volunteer for a clinical study with a GBT product and that product is benefiting you, as evidence from the study, we will provide that drug for you free until it's available through other means. Until your government is buying it, we're going to give it to you free.
TED LOVE: So we have patients already, all around the world, that are receiving Oxbryta free. We've also been starting expanded-access programs. Now, they're limited in terms of what we can do. But in countries that are low-resource, the drug will be completely free. We can't afford to do that for everyone, but we are doing that for as many as we can. Ultimately, we want to partner with big philanthropic organizations-- perhaps like the Gates Foundation, perhaps the Clinton Foundation, perhaps the World Health Organization-- much like Gilead has done, and use their support.
TED LOVE: And we'll make the drug. Or we'll get partners to make the drug and make it available. If we pull that off, Kevin, we think we'll be able to save millions of lives. And that's just going to be exciting, to pull this off. And I think we're going to get there.
KEVIN DAVIES: That's excellent. Just time for a couple of final questions-- Alex, over to you.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. Ted, looking ahead, a little bit big-picture, how well positioned is the biotech industry to finally develop treatments for patients whose conditions have not had good solutions-- not only SCD, but some other conditions that have been tough to treat?
TED LOVE: I think the rate of science and us being able to apply science is accelerating. I mean, every day, as you know, we see new companies being created using novel technology. We saw during COVID, right? I mean, who would have estimated that we would go from identifying the pathogen and having an approved and highly effective vaccine in less than a year?
TED LOVE: We did it using mRNA. Now, mRNA technology has been around for years. But the application of that technology positioned Moderna and Pfizer to really do something that I think people would have thought unfathomable a few years ago. So I think the rate of acceleration of us being able to use novel technology, novel science, it's accelerating.
TED LOVE: And I think that's going to continue, which is why I'm so excited and, quite frankly, proud of our industry.
ALEX PHILIPPIDIS: And what do you see, Ted, as the industry's greatest challenges it faces in working to develop these treatments and deliver them to patients?
TED LOVE: I think one of our biggest challenges is something you already brought up, which is pricing. And we've got to really work through a process to do two things. One is for people to understand the benefit of investment in science and the benefit of therapies. I cannot imagine the toll, the economic and social toll, that would have been impacted on the United States had we not been able to make the vaccines that we made.
TED LOVE: So having this industry continue to be around is critical for future patients, future pandemics, for our future medical problems. And we've really got to come to grips with that. I think there's improvements that need to be made in our industry side. But I think a lot of improvements need to be made in our society and not reflexively think that if your therapy is $125,000 a year, there's something wrong.
TED LOVE: There's not necessarily anything wrong with that. It may be that's because there are only 100,000 patients. And it does cost a billion dollars or a couple of billion dollars to make these therapies. And we're trying to make multiple. We're trying to make multiple of them. But we need to be restrained about how we set pricing. We need to be clear about price increases, and why are you increasing your price by 15% just because you want to grow-- We need to be responsible.
TED LOVE: So I think the existential threat, I think, for our industry is price controls. I think the minute we start to have the United States negotiate directly over the price of our therapies, I think the game is over. Because that's kind of what we're already up against in most other parts of the world. And we don't get a price that supports innovation. We often, quite frankly, just get a price that barely supports the infrastructure to sell one drug.
TED LOVE: That's why, many times, small companies like ours are struggling to launch your first drug in Europe. Because you're making so little money you can't even pay for the infrastructure. Now, if you get a second drug, you can start to pay for the infrastructure with two drugs. But for small companies, the price is so thin, you often are losing money to help patients in those countries.
TED LOVE: That's not sustainable.
KEVIN DAVIES: Yep. Well, Ted, you've made great progress, as you've described over the past hour with us. And we wish you every success. If you can develop a true cure in a small, orally administered pill for sickle cell disease, which has been a scourge for so long, that would be just an amazing story. So congratulations on the progress you've made so far. And thanks to our special guest, Ted Love and the CEO of Global Blood Therapeutics, for joining us on Close to the Edge.
KEVIN DAVIES: And we wish him and all the folks that GBT the best of luck going forward. Coming up on Close to the Edge, we'll be sitting down with more inspiring biotech CEOs. So we hope you'll tune in for those conversations.
ALEX PHILIPPIDIS: Remember, GENEDGE is your source for the latest in-depth information on biotech entrepreneurship from the GEN team. We hope you'll take a closer look and consider a free trial subscription. Close to the Edge, this one is produced by [INAUDIBLE].. For Kevin Davies, I'm Alex Philippidis. Thanks for taking the time and watching. And goodbye for now.
KEVIN DAVIES: Goodbye. [MUSIC PLAYING]
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KEVIN DAVIES: Hello, and welcome to Close to the Edge, the new series from GENEDGE where we invite chief executives and outstanding scientists from groundbreaking biotech and pharma companies to sit down with us to discuss their science, their technology, and their business objectives. I'm Kevin Davies, editor-at-large with GEN and the author of the new book Editing Humanity.
ALEX PHILIPPIDIS: And I'm Alex Philippidis, senior business editor with GEN, Genetic Engineering and Biotechnology News, the publication covering the biotech industry for 40 years. Close to the Edge is an offshoot of GENEDGE, our new premium subscription channel from GEN, providing in-depth, exclusive news, interviews, and analysis of key trends in the biotech industry coupled with a range of multimedia offerings such as this one. More details of our free trial offer are at www.genengnews.com/genedge. That's G-E-N-E-N-G-N-E-W-S, .com/genedge.
ALEX PHILIPPIDIS: On today's episode, we welcome Ted Love, MD, the president and CEO of Global Blood Therapeutics, a developer of treatments for sickle cell disease and other blood-based disorders, based in South San Francisco. Ted, welcome to Close to the Edge, and thanks for joining us.
TED LOVE: Thank you, Alex. It's a pleasure to be here.
ALEX PHILIPPIDIS: Great. First off, Ted, tell us about your background in biopharma. You've previously held positions at several bigger companies, including Onyx Pharmaceuticals; Nuvelo, where you were also CEO; Theravance; and Genentech.
TED LOVE: I'm happy to do so. Well, if you go back to the beginning, I grew up as a kid on a farm in Alabama. And I was very fortunate to be a good student. So I ended up going to college at a small place called Haverford, medical school at Yale. And then I did all of my post-medical-school training in internal medicine and cardiology at the Massachusetts General Hospital, part of Harvard. And then I got recruited to Genentech back in 1992.
TED LOVE: That's when I really decided to redirect my training in medicine and my training in science to try to invent innovative therapies that would really go after very serious diseases. And I'm just thrilled that I've been able to work on things like Herceptin, which has completely changed the world and prospects for women with HER2-positive breast cancer; drugs, most recent like Kyprolis. That is a very effective therapy for myeloma.
TED LOVE: My mother died of myeloma. My mentor at Harvard died of myeloma. So it's really been gratifying to have a career where you make therapies that, really, are fundamentally life-changing for people that are grievously ill. And now we're doing this in sickle cell disease, which I know will be our major focus today.
ALEX PHILIPPIDIS: Great. And tell us, then, about Global Blood Therapeutics and your arrival. And how did you come to connect with Global Blood and join the company?
TED LOVE: It's a great question. And I think it's probably a great idea, Alex-- you just kind of framed the whole issue. So sickle cell disease is a relatively rare but devastating genetic disease. And unfortunately, it occurs in members of our society who are most disadvantaged. They tend to be people who are socioeconomically disadvantaged. And they tend to be people who are disproportionately African American or people of color.
TED LOVE: And I do think because of that, finding real fundamental solutions, therapies has been highly elusive. And this company, Global Blood Therapeutics, was founded about 10 years ago to focus on finding fundamental solutions for sickle cell disease. So I actually came out of retirement because I thought sickle cell disease had waited too long for serious investment in real innovative therapies.
TED LOVE: And we have been very fortunate. The first molecule that we put into the clinic has been highly effective. It received accelerated approval from the Food and Drug Administration. We developed the therapy in a very, very short amount of time. And we've got the data that shows that more than 90% of people who take this therapy have evidence that their disease is being modified by their red cell count going up, showing that their red cells aren't being killed by sickle cell disease.
TED LOVE: And they tell us, I feel better, I've never felt so good in my life, my hemoglobin has never been so normal in my life. And now our goal is to get this therapy to as many patients as we can, obviously starting in the United States, where it's approved, but ultimately getting this available to people with sickle cell disease around the world.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thanks, Alex. Ted, sickle-cell is widely known as the first molecular disease identified by Linus Pauling in the late 1940s, and Vernon Ingram identifying the actual mutation a few years later. We recently interviewed John Evans, the CEO of Beam Therapeutics, on this program, who described the sickle cell mutation as, perhaps, the most famous mutation in the world. Why has it taken so long for the scientific community to really make progress in this disease when we knew so much 70 years ago?
TED LOVE: Underinvestment-- I'll give you an example. Cystic fibrosis is one-third as common in the United States as sickle cell disease. As a consequence, we've got 15 innovative therapies approved over the last 20 years or so for cystic fibrosis compared to, really, nothing for sickle cell disease for a long period-- and, finally, two innovative drugs approved, as you know, at the end of 2019. So it's been underinvestment.
TED LOVE: And we really are out to change that. There are outstanding CF centers of excellence spread all throughout the United States where sickle cell patients get outstanding therapy. None of this has happened in sickle cell disease. Many of us think it's because these patients are more than 90% African American. And they're often poor. They've not had advocates.
TED LOVE: And they've not had supporters. But we are out to change that, Kevin. I mean, that's why our company was started. And we're thrilled to see that is also changing in other companies. But GBT, we feel, is the leader in really driving sickle-cell to be more like what we're seeing in CF, what we're seeing in myeloma, what we're seeing in other serious diseases where there have been innovative therapies that are having dramatic outcomes for patients.
KEVIN DAVIES: Sickle cell patients, I think it is widely known, experience a lifetime-- usually an abbreviated lifetime-- of major pain crises. And I think most of our viewers will have very little comprehension of what that's actually like. I wonder if you could help describe, from your medical-- and, maybe, even personal experience-- what does it feel like to suffer a crisis when you're a sickle cell patient?
TED LOVE: Well, I will talk about crises. But I also want to say that I think one of the unfortunate things is that sickle cell has been described as a disease of pain. And I think that's been terribly stigmatizing-- number one, because it leads people immediately to this conversation about opioids and pain management. And it's also been terrible because it leads people, including physicians, to say to a patient, you're doing pretty well if you're not having pain episodes and being admitted to hospital.
TED LOVE: And that's unfortunate because these patients are also going to die in their late 30s and early 40s. So this pain characterization, while it is part of the disease for many patients, it is not the fundamental basis for patients dying. We know that sickle cell disease is really a disease of chronic severe anemia. It's called sickle cell anemia for a reason. And you die from the accumulated organ damage of chronic anemia.
TED LOVE: These individuals start to become anemic, typically, when they're six months of age. In their first decade of life, many of them will have suffered a stroke or silent ischemic damage, which leads to loss of cognitive function. They lose their capacity to have normal kidney function in the first few decades of life. They lose splenic function. When I was very young, people with sickle cell disease typically died in the first couple of decades of life from infection.
TED LOVE: And I think if we had characterized it as a disease of infection back then, then that would have been a misrepresentation, too. We have solved the problem of infection by-- or largely solved the problem of infection by giving children prophylactic antibiotics and vaccinations. And now what we've uncovered is people don't die of infections, but they die of the accumulated organ damage from the chronic anemia.
TED LOVE: So that's why GBT has said, let's not just focus on pain. Let's focus on what is ultimately causing loss of your brain function, causing loss of your pulmonary function, your cardiac function, your kidney function. Because you can't lose all these organs and expect to live a normal life. And we know the natural history is to die in your late 30s and early 40s.
KEVIN DAVIES: Yeah. You touched on, minutes ago, Ted, about the funding gap between funding for genetic diseases like cystic fibrosis, which primarily affects people of northern European descent, versus sickle cell disease, which, ironically, is one, or two, or three times more common in the United States than CF. Is there any grounds for optimism that that playing field is being leveled? Is that gap narrowing?
KEVIN DAVIES: Do you see any signs of progress, and greater awareness, and imperative to fund research into sickle-cell?
TED LOVE: Well, first of all, let me say that I think our Food and Drug Administration is the best regulatory agency in the world. The Food and Drug Administration, like they do for many diseases, called a meeting now, probably, seven or eight years ago, where they brought in sickle cell patients and sickle cell advocates, not doctors. They brought in patients. And they asked these patients, what do you need to treat your disease?
TED LOVE: What can we be advocating for to help you? And what the patients told the FDA-- it's two things. One, the people at the meeting talked about their pain. But there was a large group of people, an equally large group of people, who were not at the meeting. And what those people said is, I'm not at the meeting because I am so limited by anemia that I don't even have the energy, I don't have the capacity to get on airplanes and travel.
TED LOVE: Now, the patients with pain are anemic, too. And they're suffering, too. But the fundamental thing that they wanted is something that would attack the root nature of their disease. When I was in medical school, we discovered this disease called HIV. And HIV was a death sentence. Everyone that I treated with HIV died.
TED LOVE: We started to make drugs like pentamidine to treat the pneumocystis carinii, treat the downstream consequences of HIV. And that helped patients. But what really helped patients was killing the virus. We need to kill the root cause of sickle cell disease. And just to put things into perspective for individuals, sickle cell disease-- as you pointed out, Kevin-- it's a well-described disease on a molecular level.
TED LOVE: It is a single mutation on a single protein in our body. That protein is wholly contained within our red cells. So for sickle-cell to kill the patient, it has to first kill the red cell. We know that. And that is where the anemia comes from. And the reason sickle-cell kills the red cell is because the mutation on the red cell causes mutation on the hemoglobin, causes the hemoglobin to begin to cluster and organize into rods.
TED LOVE: And those rods physically deform the red cell. That's why they look sickle. It would be like a balloon with a sword inside of it. It's a red cell with a stick inside of it. And those polymers-- that's what we call them. Those polymers rupture the red cell in addition to deforming it. And this is going on constantly. You and I are making about a million red cells a second, just to put it into perspective.
TED LOVE: Sickle cell patients are making 10 million red cells a second. And they're still anemic because this polymerization is rapidly killing their red cells. So that's why GBT said, could we make a therapy, a small molecule, which would bind to sickle hemoglobin and stop it from aggregating into rods? And that's the breakthrough that we came up with. And it's very fundamental. Some people are obviously saying, oh, you're just raising hemoglobin.
TED LOVE: But I would tell you if you have a massive tumor in your brain and I do something to shrink it, I don't know if you're going to live longer or not. But I can tell you what, I think you're going to be happier that I've shrunk your brain tumor. In sickle cell disease, the disease burden is anemia. It's because your red cells are being killed. Our drug is very powerful at reversing it. It's really the same as shrinking your tumor.
TED LOVE: We're growing your red cells toward normal as opposed to letting the disease continue to eat away at your red cells and cause you to be profoundly anemic.
KEVIN DAVIES: We're going to talk more about Oxbryta, your breakthrough drug, and how it works in just a couple of minutes. I just wanted to quickly-- we talked about the funding disparities. I wonder if you would agree with the suggestion that there's also, according to reports in The New York Times and elsewhere, a lack of awareness among many patients with sickle cell disease of some of the currently available screening tools and generic drugs that are available that is exacerbating these disparities that we've already talked about.
KEVIN DAVIES: Do you feel there's still a problem in just the overall awareness of the medical establishment catering to the sickle cell community?
TED LOVE: I do. I think that we have issues in sickle cell at every level. We have some outstanding sickle cell physicians in this country that I know, and really admire, and have great respect for. But on the whole, the standard of care for sickle cell patients in this country is terrible. It's terrible in the lack of number of physicians who are trained well to treat sickle cell disease.
TED LOVE: It's terrible in terms of being proactive about treating this disease. My point earlier about pain, we tell people they're doing OK if they're not in pain, but they're not. We know that we now have tools. We really have two tools that are disease-modifying. Hydroxyurea-- unfortunately, hydroxyurea is a cancer drug. And it has a black-box warning around having a secondary cancer risk.
TED LOVE: That's not optimal. But that has been the only tool we really had in sickle cell disease. Now we have another disease-modifying therapy that the FDA has approved. If my child had sickle cell disease, my child would be offered both of those therapies. I would demand both of those therapies. Because I think disease modification is the pathway toward extending survival.
TED LOVE: That's true in every disease. If you fundamentally go after the HIV virus, the patient has a chance to live longer.
KEVIN DAVIES: Before I hand it over to Alex, just take us back to 2012 or the run up to the founding of GBT. Who, in particular, deserves credit for taking this lofty notion of building a company to focus on this unmet-- really unmet-- medical need. And what were the challenges in getting GBT off the ground?
TED LOVE: Well, there are two people that I would cite. One is Charles [INAUDIBLE],, and the other one is David Phillips. Those are two individuals that I've known for a long time. And they've both been very successful at founding companies. I don't know whether it was Charles's idea or David's idea. But the truth be known, there was an earlier attempt-- I think in the '80s or '90s-- to make a small molecule that would stop the sickle hemoglobin from polymerizing or sticking together.
TED LOVE: Unfortunately, that therapy had significant side effects and was never fully developed. David and Charles had the wisdom to say, maybe we shouldn't give up on that approach. Maybe you simply need to make a different molecule. Because as we know, there have been nonsteroidal inflammatory drugs that have been removed from the market because of toxicity. And yet we have Advil in every Safeway.
TED LOVE: It's very safe. So just because one drug is unsafe, it doesn't mean you can't make a molecule in that same class that does the same thing that's safe. And that's really what they did. They basically said, let's go after this again and see if we can make something that's even more effective and safe. And that's what we pulled off.
KEVIN DAVIES: Was there any challenge in raising money in those early years?
TED LOVE: Well, we were very fortunate.
KEVIN DAVIES: [INAUDIBLE] that's a rare disease. It's a socially, economically disadvantaged population. I could see there might be some resistance.
TED LOVE: You could. And I think that had been one of the historical challenges. You're absolutely right, Kevin. GBT was very fortunate in that Charles was a partner at Third Rock Ventures, which, as you know, it's a very successful venture firm. So when they founded the company, they put in the first $50 million. And then they called me and said, we need you to raise more money.
TED LOVE: And that's something I've done over my career pretty well, is tell the story about science, tell the story about them, and medical need, and get investors. And I estimate I've raised over $1.5 billion since the company was founded. So we have been very fortunate in that we have an amazing story. There are a lot of patients. And we've made therapies or a therapy which is highly effective.
TED LOVE: So I think our investors have been well rewarded. And I think we have challenged the thinking that you can't make a successful company around sickle cell disease. We've made a very successful company. And we're just getting started.
KEVIN DAVIES: Great. Alex, over to you.
ALEX PHILIPPIDIS: Thanks, Kevin. On Oxbryta, it was approved late in 2019 by the FDA. If you could tell us about that small molecule drug, how it came to be developed, and fairly quickly in the prepandemic era-- if I recall, about almost six years from the time the molecule was formed to the time you got regulatory approval?
TED LOVE: Yeah, it was a very, very short timeline, Alex. So the company was incorporated in 2011. We didn't have, really, many employees or even facilities. So we really kind of rented some chemists from an adjacent company. The first molecule or the molecule that we put in the clinic was called GBT-440 back in the old days, which meant it was the 440th molecule that our chemists made.
TED LOVE: We put that molecule through all of the requisite animal studies to support studies in man. We began our first studies in man in January of 2015, the first study in man. We completed our pivotal study in June of 2018. And we submitted and got approval from the FDA in November of 2019.
TED LOVE: So this was a record pace. And I think that's appropriate. What I say to people all the time-- and I've said this throughout my career whether I'm working on breast cancer, or whether I'm working on colon cancer, or whether I'm working on myeloma. My position is people are dying. People are dying, and you need to do something about it.
TED LOVE: And you can't be cavalier about it. It doesn't mean you cut corners. But it does mean you do the quality work and you do it with a sense of urgency. So our company has operated with the belief that sickle cell patients are dying. And they need help. And we took that attitude into how we designed our studies. We took that attitude into how we conversed with the Food and Drug Administration.
TED LOVE: And that's how we were able to do this, Alex, in, quite frankly, record time.
ALEX PHILIPPIDIS: Mm-hmm. You've explained, a little earlier, the challenge of the biology. What were some of the key challenges the Global Blood overcame for Oxbryta to advance from discovery all the way to patients?
TED LOVE: Well, one of the challenges was to get off of the emphasis on pain. The truth is only a minority of sickle cell patients have very, very frequent pain episodes. Many have, even, no pain episodes. One of the young women that I talked about a lot in our corporate presentation lives in Atlanta. I think she's about 15 years old now. And the slide that I had in our presentation, I think, was her at 12 years old.
TED LOVE: And the slide said, I've had one stroke, I've had eight major surgical procedures, and I've never had a pain episode in my life. Her name is [? Deej. ?] [? Deej ?] is clearly dying of sickle cell disease. She's not having pain now. She's dying of the consequences of chronic anemia. Sometimes acute episodes of lack of blood delivery, being the stroke that she had and being some of the other procedures that-- people with sickle cell disease lose their bones.
TED LOVE: So they end up with hip replacement, shoulder replacement. They end up with pulmonary hypertension. And they end up dying of heart failure because of that. As I said, they end up with strokes. They end up with silent strokes that reduce their cognitive function. So this disease is not sparing any organ in the body. And it makes sense because blood is how we nourish our organs.
TED LOVE: And if you don't have proper blood, you cannot nourish your organ. So the pathophysiology of this disease makes perfect sense, right? If you're profoundly anemic starting at age 6 and you manage to not die of infections because of the loss of splenic function, what do you think you're going to die of? You're going to die of undernourished organs.
TED LOVE: And the main nourishment that we're supplying what our blood is oxygen.
ALEX PHILIPPIDIS: How did Oxbryta overcome the challenge that your earlier 440 molecule didn't?
TED LOVE: Oh, so 440 actually is Oxbryta.
ALEX PHILIPPIDIS: Oh, I'm sorry.
TED LOVE: That was the old name. But you may be referring to, how did it overcome the challenges of this earlier drug that I mentioned that was discontinued?
ALEX PHILIPPIDIS: Yes.
TED LOVE: So that drug, actually, was remarkable. It showed evidence of reversing the anemia in sickle cell disease literally within days. And I was very fascinated by that. Unfortunately, about half of the individuals-- sickle cell patients or normal volunteers-- exposed to this, within about 10 days, would develop swollen, painful lymph nodes. And that was a very scary consequence.
TED LOVE: And it was common, as I said. It occurred in about half the patients. And that drug was discontinued. And there were no followup attempts to make a follow on drug. So we basically made a drug that has features which are very similar, Alex, to that drug but has no issue around allergic response like this other drug did.
TED LOVE: So it was really just, try it again. Like I said with the nonsteroidals, some nonsteroidals were killed because they had immune response, actually. And yet we have Advil in every Safeway. So you don't give up on a single drug class because of one molecule. In fact, it's very common that we make multiple molecules to compare them to each other and see if we can make improvements.
TED LOVE: In fact, in our pipeline now, we have a third-generation Oxbryta molecule that is much more potent. In fact, it is so potent that we think it will be equal to gene therapy. We think it will be curative in a daily pill. And it won't have issues associated with it of bone marrow ablation or risk of a major, expensive upfront procedure.
TED LOVE: It'll simply be, take one small pill a day and you may be cured. So we are working very hard on the next generation. So iteration, in our business, is critical.
ALEX PHILIPPIDIS: Great. And I'll get to some of that pipeline a little later. But I was curious by something you mentioned earlier, the challenge of bringing this drug to patients-- most of whom, as you pointed out, are patients of color. How does GBT market Oxbryta and how does it bring it?
TED LOVE: Yeah. So we really needed to kind of flip how people were thinking from not just pain but, what is really going on in sickle cell disease? And we've been now trying to get people to understand that a disease that occurs on one protein that's trapped inside your red cell is really killing the red cells first. It's killing the red cell first. If you have a tumor in your brain, the organ that's going to be the basis of you dying is your brain.
TED LOVE: And the same is true in sickle cell. If you've got a mutation on a protein that exclusively resides in your red cell, the red cell is going to be the basis through which this disease is going to kill you. It's completely simple and straightforward. Yet, as I said, Alex, there'd been this enormous focus on pain. And so we were developing drugs that were only indicated for people who had pain.
TED LOVE: And I thought that would be an enormous disservice. So I was very strident early on. We are not going to develop a drug focused on pain. We are going to focus on the fundamental basis of this disease, which is the hemoglobin polymerization that's killing the red cell. And what we ultimately agreed to with the Food and Drug Administration is that the primary endpoint for our drug's approval would be stopping the polymerization from killing the red cell.
TED LOVE: And you measure that by measuring the hemoglobin going up. The hemoglobin is only down because the polymerization is killing the red cells. And if you reverse that, the hemoglobin can go up. And in fact, we have many patients now that are out there in the real world, in the United States, taking Oxbryta, and their hemoglobin is perfectly normal-- perfectly normal.
TED LOVE: I bet-- and we need to prove this. I bet those people are going to live longer and better than their peers who are not given access to therapy. So that's what I was trying to point out at the beginning, Alex. It's my job to innovate, and make a good therapy, and get it approved by demonstrating it's safe and effective.
TED LOVE: And then the next part of my job is to do anything I need to do to change the world to say, let's treat sickle cell patients proactively. Let's not wait on pain episodes. Let's not wait on strokes. I'm a cardiologist by training, as you know. This would be like me having somebody with hypertension and saying, you haven't had a stroke yet, so you're doing pretty good.
TED LOVE: I'm not going to do that. I know the natural history of hypertension. I'm going to lower your blood pressure. And if you don't take your medicines, I'm going to talk to you more. I'm going to beg you. I'm going to cajole you. Because I know the consequence of chronic hypertension. We know the consequence of chronic anemia and hemolysis of sickle cell disease.
TED LOVE: We don't need to continue to study that.
ALEX PHILIPPIDIS: I also wanted, Ted, to talk about another challenge for Oxbryta, which is the need to broaden patient focus and sickle cell disease beyond your initial patient population served by Oxbryta. I know GBT has said it will seek approval for Oxbryta in pediatric patients by some point later this year, in ages 4 to 11. So how has that gone about in, especially, children given the vulnerability there?
TED LOVE: I think it's going very well. And you are so right, Alex, that this is critical. As I mentioned, sickle cell patients begin to suffer irreversible damage likely as early as six months old. So we want to get the drug approved, actually, to begin at that age. Our initial label was based on a study where we only studied individuals 12 and older. The initial drug development was really around a pill formulation.
TED LOVE: Individuals 12 and older can typically take pills. And because of body size, we were able to use a single dose. So our initial effort was really focused on 12 and older. But we've been doing studies for some time now in the 4-to-11 age group. And we now have sufficient data to go to the FDA and request approval for that age group. And we are currently studying individuals down to that six-month-old age.
TED LOVE: And we will have that data, we hope, sooner than later, and go in and ask for the extension of the label down to that age group. Because the goal here is to take a young individual who's showing the development of the anemia of sickle cell disease, see if you can go in and correct that anemia before any body organ damage occurs, and fight that anemia off. It's very similar to what we do in HIV.
TED LOVE: If you or I were to have a child born with HIV, we would treat them. We wouldn't wait for them to become neutropenic. We wouldn't wait for them to develop opportunistic infections. We would go right in, and we would put them on a powerful regimen, an HIV regimen. And they would need to take it. But guess what?
TED LOVE: That child would live a normal life. We can do this in sickle cell disease.
ALEX PHILIPPIDIS: And in fact, earlier this month, the company announced some new data from the Phase 2A HOPE Kids 1 study. If you could talk about that, since it was of int--
TED LOVE: Yeah, so that's-- you just pointed out the study. So that is a study that we did in this 4-to-11 age group. And what it essentially shows is what we expected, which is the drug works just as well in that age group. And importantly, it looks just as safe. And that would be the basis of the FDA extending the label to the lower age group. And then we think, again, we're going to be able to do the same thing in that 6-to-4 age group, to ask for an approval down to six months.
TED LOVE: Now, the other thing I have to point out is that we needed a new formulation. Four-year-olds don't like pills. And six-month-olds-- there's no way, right? We all remember our kids. What do you do? So we needed a pediatric formulation. And we've developed that as well. So the pediatric formulation was developed more slowly.
TED LOVE: It took more time to develop it. But now we've got a pediatric formulation that's also part of this FDA submission.
ALEX PHILIPPIDIS: Will that be a liquid form? Or how would you get kids to take it?
TED LOVE: It becomes a liquid form. It's what we call a dispersable tablet. So it's a tablet that you simply add a little water to, and it just turns into liquid. We do that because we don't have to use stabilizers. If you put it in liquid form, you'll need to put stabilizers in. And stabilizers have risks associated with them. So we wanted to come up with a solid formulation that's convertible to liquid on demand to allow the lack of stabilizers.
ALEX PHILIPPIDIS: You're watching Close to the Edge, the new show from GENEDGE, the premium subscription channel with genetic engineering and biotechnology news. I'm Alex Philippidis, joined by Kevin Davies. And we're talking to Ted Love, the CEO of Global Blood Therapeutics. Now, a few months, Ted, after Oxbryta's approval, the world began to shut down from COVID-19. How did COVID-19 affect the rollout and the uptake of Oxbryta as well as GBT's overall operations?
TED LOVE: It's had a big impact. I think that the COVID pandemic had an impact, basically, on everybody in the world, right? But it was even worse in the sickle-cell community. I think everyone knows that the mortality rate for COVID was about three times higher in the Black community than the non-Black community in the United States. That's where sickle cell is. We know that the financial impact in terms of jobs, et cetera, was greater in the African-American community than it was in other communities.
TED LOVE: That's sickle-cell. We also know that when the CDC put out guidelines for who's most at risk to die or have very serious consequences if they get COVID, sickle-cell was high on the list. So our patients were being affected in ways that were amplified. So we did have an impact. Our patients weren't going in to see their doctor, many times because they were being told, don't get on a bus, don't get on a train, don't run the risk of getting exposed.
TED LOVE: But that also meant they weren't in a position to be evaluated and to be started on novel therapies. Now, what we tried to do, Alex, is we tried to really encourage physicians, healthcare providers-- use telemedicine. And we've been significantly successful. But there are physicians and there are patients that are less likely to do that.
TED LOVE: So we need to get beyond the pandemic so that we can reinvigorate the effort to get patients back in to see their physicians face to face, as well as telemedicine, but then begin to have these conversations about, how are we going to fight your sickle cell disease at a fundamental level? How are we going to fundamentally modify this disease to try to give you a chance to live to be 50, 60, 70, or 80?
TED LOVE: The way we're going to do that is disease modification.
ALEX PHILIPPIDIS: Yeah, that's one key challenge. Another challenge has revolved around price. At a list price reported last year at $125,000 a year, Oxbryta's generated criticism that it's been priced too high. How do you justify that list price? And how has the company worked to contain expenses for patients and sort of cushion the price impact on them?
TED LOVE: Yeah, I'm glad you brought up price. Because I think price and access are different things. And I think sometimes people conflate the two. So let me just say, first, about our price, we put a lot of time into thinking about an appropriate price. And we spent time talking to payers about our price before we set our price. We talked to our board a lot about our price. And we came up with several points I want to emphasize. One is we said, we're an orphan disease.
TED LOVE: Let's price ourselves in the lower half of orphan diseases. There are drugs out there, for CF for example, that cost two or three times what Oxbryta costs. And I think sickle-cell patients deserve therapies even if the cost is one-third of the costs or one-half of the costs of CF drugs. Because I think the CF patients deserve therapies. The other thing I will have said, this is a rare disease.
TED LOVE: It is a rare disease. So if you price it as if it's cardiovascular disease, you're going to go out of business. You are going to go out of business because there aren't enough patients. So the patient cost does have to correlate with the patient number. And we've seen that over, and over, and over again in orphan disease.
TED LOVE: The third thing I will say is that we have committed to no price increases for three years. So we want people to know this is the price, and the price is not going to change for three years. We took very bold steps to make sure we were thoughtful about our price. Now, we'll get to access. Because of charging a reasonable price, we can afford to do some things that are important in sickle cell disease.
TED LOVE: One, if you have sickle cell disease and you have no insurance, we give you the drug free. We can afford to do that because we have a reasonable price that allows us to pay for that. Because we've got to pay for that. We also have created a patient hub. It's very common in rare diseases that companies have patient hubs which support the patient with concierge services and support physicians with services to help them deal with the bureaucracy of a health care system, understand their insurance, get financial help when they need help, get help getting to the doctor when you need to get to the doctor.
TED LOVE: We pay for all of that. That's part of our price. And that's never been done in sickle cell disease. A generic, repurposed cancer drug is not going to pay for that. That's been one of the problems, Alex, in sickle cell disease. There's been no money here. And people like me-- were doing it, because we're saying you can't make any money in sickle cell disease.
TED LOVE: But if you can't make any money in sickle cell disease, why would investors invest in a company that's going to go nowhere? So this, obviously, we want it to be thoughtful. But you can look at a lot of drugs and prices. And you'll see that our price is definitely not in the upper half of orphan drugs. We're in the lower half. And we're comfortable with that.
TED LOVE: But we're also comfortable that we have charged enough to allow us to do what we need to do for sickle cell patients that are on our therapy, support physicians that are trying to do things to help our patients, and also continue to invest in our pipeline to bring more therapies for sickle cell patients. That's how the ecosystem works. And by the way, let me ask one other thing.
TED LOVE: Our drug is going to be free eventually. Our drug is going to go off patent. And it's going to be dirt cheap. So we've got a limited window in which the patent protection can pay for our company to survive. But when it goes off patent, if we haven't made more innovative therapies, we're going out of business because that drug is going to be, essentially, free.
TED LOVE: And I think that is one of the wonderful things. During the COVID crisis, one of the more effective drugs we discovered for treating, unfortunately, was dexamethasone. How much do you pay for dexamethasone now? Nothing, it's basically free. Highly effective, a great gift to the world, but it's been paid for and gone. And that's one of the things I do love about our industry, is that we make great innovations.
TED LOVE: We have a window where we can charge. And we should charge a fair price. And we should be thoughtful about our pricing. We should be thoughtful about our price increases. But the world needs to also recognize that there is a limited window. After that window, you probably aren't going to pay anything significant for these small-molecule drugs.
ALEX PHILIPPIDIS: You mentioned pipeline just now. And by the time Oxbryta goes off patent, possibly one, if not both, of these candidates in your pipeline and, now, in clinical trials might be well on the way to patients in GlycoMAb and O21601. How far into development are both? And what kind of milestones can we expect for those candidates this year?
TED LOVE: So I'll start with GlycoMAb, and GlycoMAb is at the last stages of clinical testing. It's in phase three. And we were able to get there quickly for two reasons. One is that we acquired in GlycoMAb from Genentech Roche, that had been pursuing the antibody, a [INAUDIBLE] inhibitor, to treat cardiovascular disease. They decided to get out of cardiovascular disease entirely.
TED LOVE: And so they iced the program. We called them up. And we said, we think [INAUDIBLE] inhibitor could work to treat the pain of sickle cell disease. This was developed for pain. It blocks the stickiness of the cells in the blood that adhere to the vascular wall and cause blockages that lead to the pain episode. So this drug is not targeting the fundamental nature of sickle cell disease.
TED LOVE: But it is targeting the pain episodes. We have a lot of confidence this will work because there is already, as of about a year ago-- actually, about the same time that Oxbryta was approved, [INAUDIBLE] from Novartis was approved. And it's a very effective agent for treating pain episodes, as demonstrated by a study where they took individuals who were having frequent pain episodes. They randomized them to receive [INAUDIBLE] or to receive placebo.
TED LOVE: And they saw between a 40% and 50% reduction in pain episodes. The challenge with the molecule is that it's intravenous. And it has to be infused every month. And GlycoMAb has been designed to be infused four times a year-- still intravenous, but only four times a year. And that actually fits very nicely with the frequency of when patients should be going in to see their doctor anyway.
TED LOVE: So we think it's going to be, potentially, a better molecule in terms of decreasing the pain episodes, but quite frankly, just much more practical and easy for a patient to take in for a hospital or for a physician to administer 4 times a year versus 12 times a year.
ALEX PHILIPPIDIS: Great. And GBT also expanded its pipeline in sickle cell disease in March by licensing, from Sanofi's Bioverativ subsidiary, two early-stage research programs, one that pursues a novel anti-sickling mechanism. The other leverages a new approach to reduce inflammation and oxidative stress. How has development progressed on those since then? And when can any o r both of these be expected to reach the clinic?
TED LOVE: So those are early-stage. And we do want to emphasize that we're excited about those targets, but they are very early-stage. And Alex, as you know, our business is very risky. Only about 1 out of 10 things that we actually put into humans even will make it to approval. And we're not even that far along yet. So those are early-stage-- very promising, but early-stage. The second molecule, which I didn't talk about, was 21601, which stands for 21,601.
TED LOVE: So it was the 21,601st molecule we synthesized. It took us a long time, and a lot of chemistry, and a lot of biology to make something significantly better than Oxbryta. If we look at Oxbryta, the question is, what could we improve, Alex? It's pretty safe. It's highly effective. But it doesn't appear to be curative in the majority of patients.
TED LOVE: And we're also giving three relatively larger-sized pills per day. So what if we could reduce that to one very small pill a day and achieve enough hemoglobin modification? That's what we're doing. We're modifying the hemoglobin to make it not stick together anymore. And once we get to about a third of the hemoglobin doesn't aggregate, sickle cell basically looks like sickle trait.
TED LOVE: People with sickle trait have 50-50, right? They've got 50% normal hemoglobin, 50% sickle hemoglobin. But they have a normal life expectancy. We actually know, through a lot of science, that you don't even need to get to 50% non-polymerizing hemoglobin. If you can get to about 30%, 35%, the disease starts to look like trait.
TED LOVE: So 601 is the molecule where we think we will reliably get everyone above this 30%, 35% modification, which we think will be curative. And we'll do so with one small pill per day. If we can pull that off, that is another big step beyond Oxbryta.
ALEX PHILIPPIDIS: Mm-hmm. And 601 is how far along, you said?
TED LOVE: 601 is currently in what we call phase 1-2. So we are looking at 601 in normal volunteers, a pretty large number, be about 60, where we give the normal volunteers either single doses or multiple doses of 601. We also give the therapy with and without food. We do a variety of things just to make sure that there's nothing unusual about how the drug is absorbed in combination with food, for example, as we go into development.
TED LOVE: We'll move from the normal volunteers, quickly, into sickle cell patients, where we'll then be able to look at, are you modifying the disease? And we've now developed really, really cool technologies that allow us to look at the red cell and see if we make the red cell look like the red cell of a patient with sickle trait as opposed to the red cell of a patient with sickle cell disease. If you can do that, you're pretty sure that you've converted the phenotype to being that of trait.
TED LOVE: It's all in the red cell. So we really are very focused on demonstrating disease modification by increasing survival of red cells. But we also can look very intimately, now, at the function of the red cell. And we can do so under oxidative stress, which is what causes sickle cell disease to really advance. That's what causes the polymerization to accelerate and the destruction of the red cell to accelerate.
TED LOVE: So we can look at the physiology of the red cells under profound hypoxic stress to see if the cells are behaving, again, more normally, like patients with sickle trait as opposed to sickle disease.
ALEX PHILIPPIDIS: Great. And we're going to learn a little bit more on the landscape of sickle cell therapies. Over to you, Kevin.
KEVIN DAVIES: Thanks, Alex. Ted, the other exciting new arm in sickle cell therapy is, I would say, in the gene therapy and gene-editing space. We've seen specials on 60 Minutes showing some remarkable patient success stories, receiving various gene therapy treatments from companies like bluebird, Sangamo, Graphite Bio, Beam Therapeutics, and of course, the amazing results with Victoria Gray and the CRISPR Therapeutics Vertex trial published about six months ago.
KEVIN DAVIES: I know you welcome all of this progress. But could one see these efforts as potentially encroaching on your own market? Do you still have the inside track? How do you view the landscape?
TED LOVE: I don't think about it that way. I mean, as you know, Kevin, I came out of retirement to help sickle cell patients. So the more options for these patients, the more excited I am, quite frankly.
KEVIN DAVIES: Yep.
TED LOVE: I would say, however, that one of the challenges with the genetic procedures is that they require ablation of the bone marrow. We have to literally ablate the existing cells in the bone marrow. And we use chemotherapy to do that. And we know that there is a secondary risk that you could develop cancer, that you could be infertile after that. So those procedures have significant risk associated with them.
TED LOVE: We're hopeful that we can do the same thing. We're all trying to create enough non-polymerizing hemoglobin to make people look like trait. So you can do that by inserting a gene into the hematopoietic stem cells, like bluebird is doing. If you get enough expression of that gene with an alternative hemoglobin that doesn't polymerize, that phenotype begins to look like trait. That's absolutely beautiful.
TED LOVE: The same is true with CRISPR. We can go in and we can turn on the gene that produces fetal hemoglobin. And if you can produce enough fetal hemoglobin, you begin to look like trait. But we can also take a sickle hemoglobin molecule, attach an Oxbryta to it or a 601 to it, and it doesn't polymerize either. So what we're trying to do is create options.
TED LOVE: And we hope that our options won't have any serious complications associated with it. But you will have to take it every day. So I think there's room for all sorts of therapies. I do think a therapy which is a simple pill-- if it's approximately equally effective, that will be the preferred approach by most people. But I invite investment in sickle cell disease. And I invite options for patients.
KEVIN DAVIES: You said Oxbryta-- you were very candid in saying it's not a cure. What has been the range of patient responses? Do some patients fare better taking the drugs than others? And do you have the beginnings of an understanding of what may explain that variability?
TED LOVE: What we've found is that the more of the hemoglobin you modify, the more normal the patient becomes. Now, there is a limitation to what your bone marrow might do if it's been damaged by two or three decades of sickle cell disease. But in general, what we've found is that if we can modify about a third of the hemoglobin, the patient largely begins to look like they've got trait and not sickle cell disease. Unfortunately, with Oxbryta, it's very hard to get to that level.
TED LOVE: And in fact, we published this, that with the dose of Oxbryta which is approved, we're not getting there. About 25% of the hemoglobin is modified. It's very helpful. And it's very helpful scientifically because the rate at which the hemoglobin polymerizes is concentration-dependent. It's actually concentration-dependent to the 15th power.
TED LOVE: So very small changes in the available hemoglobin which can polymerize is very powerful. So 25% is nothing to sneeze at. But it's not that magical 30%, 35%. And that's why we're developing 601, to try to get to that level.
KEVIN DAVIES: Is 601 chemically derived from Oxbryta? Or is it a completely different shell of a compound?
TED LOVE: It is a completely different compound. It does share some similarities. It will be in the same class, but it is a very different molecule. For example, the halflife of Oxbryta is very long. It's about three days. The halflife of 601 is about a month. And the reason why is that when 601 binds your hemoglobin, it really sticks to it.
TED LOVE: It does come off. It isn't the halflife of the red cell. But it is very long. And that is what allows us to likely give a much, much smaller dose and yet bind a higher fraction of the hemoglobin. We don't think we need to get beyond about 30%, 35% to be effectively curative in all patients. We're going to be able to see this kind of data, I think, next year.
TED LOVE: We're already committed to develop some proof-of-concept data and make that available at the American Society of Hematology meeting later this year. But we'll be doing larger studies with a larger number of patients. What we really want to do, quite frankly, is to get into children at six months. Because we think we can, almost always, we think, make those children look normal.
KEVIN DAVIES: Sickle cell disease, of course, originated in Africa. Studies suggest about 7,000 years ago is when the mutation first arose. Are you in a position to do anything to help distribute Oxbryta or other drugs to the African population? I'm sure that's not your initial focus. You've got to build the engine first. But what are you able to do, if anything, at the moment in Africa?
TED LOVE: There are two things that we can do right now. And right-- by the way, we are working on making our drug available around the world-- Africa, India. And we've got to figure out how to do this much the way Gilead has been very successful at making their HIV drugs available around the world, and they have to figure out how to make that work for countries that are very poor countries, very low-resource countries. So we're working on all of that.
TED LOVE: What we're doing today is, number one, we are doing trials globally. And we made a commitment in the very beginning that if you volunteer for a clinical study with a GBT product and that product is benefiting you, as evidence from the study, we will provide that drug for you free until it's available through other means. Until your government is buying it, we're going to give it to you free.
TED LOVE: So we have patients already, all around the world, that are receiving Oxbryta free. We've also been starting expanded-access programs. Now, they're limited in terms of what we can do. But in countries that are low-resource, the drug will be completely free. We can't afford to do that for everyone, but we are doing that for as many as we can. Ultimately, we want to partner with big philanthropic organizations-- perhaps like the Gates Foundation, perhaps the Clinton Foundation, perhaps the World Health Organization-- much like Gilead has done, and use their support.
TED LOVE: And we'll make the drug. Or we'll get partners to make the drug and make it available. If we pull that off, Kevin, we think we'll be able to save millions of lives. And that's just going to be exciting, to pull this off. And I think we're going to get there.
KEVIN DAVIES: That's excellent. Just time for a couple of final questions-- Alex, over to you.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. Ted, looking ahead, a little bit big-picture, how well positioned is the biotech industry to finally develop treatments for patients whose conditions have not had good solutions-- not only SCD, but some other conditions that have been tough to treat?
TED LOVE: I think the rate of science and us being able to apply science is accelerating. I mean, every day, as you know, we see new companies being created using novel technology. We saw during COVID, right? I mean, who would have estimated that we would go from identifying the pathogen and having an approved and highly effective vaccine in less than a year?
TED LOVE: We did it using mRNA. Now, mRNA technology has been around for years. But the application of that technology positioned Moderna and Pfizer to really do something that I think people would have thought unfathomable a few years ago. So I think the rate of acceleration of us being able to use novel technology, novel science, it's accelerating.
TED LOVE: And I think that's going to continue, which is why I'm so excited and, quite frankly, proud of our industry.
ALEX PHILIPPIDIS: And what do you see, Ted, as the industry's greatest challenges it faces in working to develop these treatments and deliver them to patients?
TED LOVE: I think one of our biggest challenges is something you already brought up, which is pricing. And we've got to really work through a process to do two things. One is for people to understand the benefit of investment in science and the benefit of therapies. I cannot imagine the toll, the economic and social toll, that would have been impacted on the United States had we not been able to make the vaccines that we made.
TED LOVE: So having this industry continue to be around is critical for future patients, future pandemics, for our future medical problems. And we've really got to come to grips with that. I think there's improvements that need to be made in our industry side. But I think a lot of improvements need to be made in our society and not reflexively think that if your therapy is $125,000 a year, there's something wrong.
TED LOVE: There's not necessarily anything wrong with that. It may be that's because there are only 100,000 patients. And it does cost a billion dollars or a couple of billion dollars to make these therapies. And we're trying to make multiple. We're trying to make multiple of them. But we need to be restrained about how we set pricing. We need to be clear about price increases, and why are you increasing your price by 15% just because you want to grow-- We need to be responsible.
TED LOVE: So I think the existential threat, I think, for our industry is price controls. I think the minute we start to have the United States negotiate directly over the price of our therapies, I think the game is over. Because that's kind of what we're already up against in most other parts of the world. And we don't get a price that supports innovation. We often, quite frankly, just get a price that barely supports the infrastructure to sell one drug.
TED LOVE: That's why, many times, small companies like ours are struggling to launch your first drug in Europe. Because you're making so little money you can't even pay for the infrastructure. Now, if you get a second drug, you can start to pay for the infrastructure with two drugs. But for small companies, the price is so thin, you often are losing money to help patients in those countries.
TED LOVE: That's not sustainable.
KEVIN DAVIES: Yep. Well, Ted, you've made great progress, as you've described over the past hour with us. And we wish you every success. If you can develop a true cure in a small, orally administered pill for sickle cell disease, which has been a scourge for so long, that would be just an amazing story. So congratulations on the progress you've made so far. And thanks to our special guest, Ted Love and the CEO of Global Blood Therapeutics, for joining us on Close to the Edge.
KEVIN DAVIES: And we wish him and all the folks that GBT the best of luck going forward. Coming up on Close to the Edge, we'll be sitting down with more inspiring biotech CEOs. So we hope you'll tune in for those conversations.
ALEX PHILIPPIDIS: Remember, GENEDGE is your source for the latest in-depth information on biotech entrepreneurship from the GEN team. We hope you'll take a closer look and consider a free trial subscription. Close to the Edge, this one is produced by [INAUDIBLE].. For Kevin Davies, I'm Alex Philippidis. Thanks for taking the time and watching. And goodbye for now.
KEVIN DAVIES: Goodbye. [MUSIC PLAYING]
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