 Hey folks, welcome to the podcast. So we're doing a special series of podcasts which I'm recording over Google Hangouts. So we're doing audio and video because for some unknown reason people don't want to come see me face to face right now. But there's always opportunity and the cool thing is I'm able to now podcast with people from all over the world. So we're going to get an amazing eclectic mix of people from different industries, different perspectives to share their story and tell us their thoughts and feelings on what's going on right now and all of that cool stuff. I hope you enjoy it. Please subscribe in all the usual places and enjoy. Awesome, and we're live. Folks, thank you so much for joining me. Today it's great to have Raul Barla, CEO from Imara, with us. Raul, welcome to the podcast. Lewis, pleasure to be here. Thanks for having me. Pleasure, pleasure. Thank you so much. Thank you so much. I had a lot of messages and conversations around sickle cell. The context is it was it's Black History Month over here in the UK. And as some people know, sickle cell adversely affects people from an African and Caribbean descent. And so I was really keen to find someone like you to have a chat with just to kind of give it some context and really find out about it. So thank you so much for coming in. What's maybe to start with? What is sickle cell and what is the history? Yeah, well, first of all, thanks for having me. This is really an important thing in terms of the field because messaging about the complexity of sickle cell and the fact that it has been an interesting disease in the sense of who it affects, why it affects those people. And certainly, to the extent possible, the challenges around treating the disease, these kinds of podcasts and different messaging help a lot. So thanks. Sickle cell is an inherited blood disorder as you noted earlier. It's monogenic in nature. And specifically what that means is there's a mutation in the single part of the gene, specifically the hemoglobin gene, and specifically the beta-globin subunit that creates the disease. And that disease is autosomal recessive, which means that a parent has two copies. Another parent has two copies. You have to get both copies of the sickle gene to actually have sickle cell disease, commonly known as HBSS, which is the most severe form of sickle cell disease. There is also sickle cell trait, which is HBSC. The fundamental basis for the disease, which was discovered in 1910, but really in the 40s and 50s, started to gain greater understanding is that the red blood cell, which carries oxygen from the lungs to the different tissues, has a mutation in it. And that mutation really surfaces when the blood deposits oxygen to the tissue and returns back, returns back to the lungs to actually pick up more oxygen. In that process, a circular red blood cell, which commonly dispenses oxygen, goes back to the lungs to get more oxygen and does that millions of times. In sickle cell disease, that red blood cell changes shape and a polymerization event occurs where the mutated hemoglobin is not able to keep its circular spherical form and turns into what's commonly known as a sickled red blood cell. In doing so, it presents a number of challenges for the patient. The first challenge, of course, is that it does not carry oxygen well because of its sickling effect. Number two, because it's not circular in nature and now is a curved crescent shape, it gets stuck on the way back in capillaries. And that process of being stuck oftenly referred to as a vaso-occlusive crisis or pain crisis, where the blood vessel is actually blocked, causes a number of debilitating effects that compound over time. And those include things such as pain and organ damage, different cardiac problems, something called acute chest syndrome, and most importantly, reduced the lifespan of the sickle cell patient by a number of years, much shorter than a normal healthy adult. Wow. Okay. So it's interesting. So your parents both have to be carriers to ultimately get it. Okay. And then how would you know if you have it? Like what are the actual symptoms? Yeah, that's a great question. So it's an inherited blood disorder, as I said, so you're born with it. And therein lies some of the complexity. It's not something you can get from someone else. It's not contagious. It's not something you contract from being around people who have sickle cell. And importantly, because it's an inherited blood disorder, there's often in developed worlds, including the UK and the US, screening for sickle cell. And so when you're born, your blood is analyzed, and they look for that particular issue. But in developing countries, and this is where I think the sickle cell disease has a bunch of nuances that differentiate itself from other diseases. In the developed world, sickle cells are rare disease in the UK, in the US, and Europe. There's approximately 100,000 people in the US with sickle cell disease, approximately 65 to 75,000 in Europe. But if you look across the Africans of continent, as you noted earlier, there's almost 4 million people with sickle cell disease. To answer your question about how are they diagnosed? Well, oftentimes if there's that newborn screening, they present with things such as fatigue, anemia, things that would indicate to the physician that that child is not growing well, and or is not able to thrive. And those are symptoms that persist throughout their childhood, and of course, manifest in different ways as an adult, including some of the issues that we talked about. Right. So why is it so common in people from African and Caribbean backgrounds? Yeah, so it's an interesting, very interesting question. There is some literature that suggests, or at least implies, that part of the reason from an evolutionary perspective that sickle cell disease is more endemic in those countries, is that it was and is continues to be at least a mechanism to lower the risk of death due to malaria. And so some of those, at least, evolutionary trends suggest, because I think things are changing, that patients with sickle cell disease tend to be protected from diseases like malaria for a number of different reasons. Now, I think the reality is, if you look at some of the more recent data, specifically the REACH trial, which was a trial conducted with hydroxyurea in Africa with patients, specifically kids with sickle cell disease, they did not see patients with sickle cell disease contract malaria any less than patients who didn't have. So I think some of those evolutionary trends, which again, evolution is such a long span, may have at least implied that there is a rationale for why sickle cell is more endemic in those countries versus in developed countries. But there again lies a complexity around the literature that's not exactly well understood, and certainly evolution is not that well delineated as you know. Fine. So we're still working on really understanding why? I think so. Do we see it in other ethnic groups and backgrounds? Not as much. No, I think you kind of nailed it in the beginning to suggest that it's mostly African-American, Caribbean people from Trinidad. There is really a more specific set of patients that suffer this unfortunate disease. I would say that in the beta thalassemia, closely related disease to sickle cell, you do see a difference with a number of patients really being driven by Asian subcontinents as opposed to African subcontinents. And so beta thalassemia certainly overlaps with sickle cell to some extent, but you can see population and geographic differences between those two diseases versus within the sickle cell paradigm. Right, right. What about treatment? Obviously, you're developing treatments at the moment, which should be great to hear about, but if you do have sickle cell, is that for life or can it get treated effectively now? Yeah. So there are a number of different treatment options available for patients. I'll say that the first one for patients with more moderate to potentially severe disease is hydroxyurea. Hydroxyurea is a chemotherapeutic actually that's been refashioned for use in sickle cell because it increases something called fetal hemoglobin. And fetal hemoglobin is beneficial to a sickle cell patient because it thwarts the ability for that polymerization event to happen and more specifically increases the affinity of hemoglobin and oxygen, which enables it to carry oxygen better than that mutated beta unit, beta globin subunit that we talked about earlier. And hydroxyurea works. It's actually a generic drug, has been deployed in a number of different areas, including Africa. The challenge is, of course, it has a blackbox warning and so there are a number of different safety concerns associated with hydroxyurea. In terms of more recent approvals, there have been two. And is that, so just on that, is that widely available? It is. It's not widely used for reasons that are both real in terms of its potential toxicity and also because of some perceived toxicity that it may or may not have. And so it is really, I would say, useful but not well-adopted therapy. Right. But at the end of 2019, so approximately a year ago, there were two new approvals in the space, one from Global Blood in Oxbreda that increased his hemoglobin, so not a different mechanism than hydroxyurea and one from Novartis called chrysalisumab, which is a infusion therapy that addresses a different aspect of sickle cell disease, which goes into kind of the basis for the disease, one being the one we talked about around the red blood cell and the polymerization, and two being around bad actors that surround the red blood cell, white blood cells, platelets, the endothelial cell wall, who also contribute to those occlusive crises that we talked about. And chrysalisumab, which was recently approved, is a P-selectin antibody that inhibits P-selectin. And P-selectin, higher levels of P-selectin make the white blood cell more sticky and adhere to the side of the endothelial cell wall, contributing to those phase occlusive crises. So in an interesting way, to answer your question, from the oral therapy side and infusion therapy side, there hasn't been a lot since hydroxyurea. But most recently, 2019, there's been some really interesting and new drugs being approved. And I think those are really important. And maybe the last point I'll just make is bone marrow transplants and a number of different more invasive therapies are available and are potentially curative, but are quite risky related to some of the potential side effects. And those fall in line earlier therapies that are being developed in the gene therapy, gene editing category, which again have a lot of promise and are innovative, but have potential risk associated with being given that therapy. Okay. And what are you guys doing? Yeah, so well, thanks for the opportunity. So we are kind of taking what we think is the best best in class approach by both having a drug that induces fetal hemoglobin, which is what hydroxyurea does, without the toxicity and potentially has the impact on reducing the adhesion aspects of the white blood cell in the P selected. So I'm our 687 is a multimodal drug. And we fundamentally felt as you asked earlier that designing a drug that could be given on a global basis mandates that it's oral, that it can withstand high temperature, that it can withstand high humidity, even if the bottle is left open, can be transported without a cold chain or refrigerated transport needed. And so this drug really I think is really built for a global opportunity that addresses both the rare patients in the developed world, as well as the developing world patients, which are numerous. How close is it to being available? So, you know, we're in development, we're in phase two B. And so while we've had some new approvals, I think what our goal is to get to this to market as soon as possible. But in order to do that, as you know, you have to run the appropriate clinical trials that both demonstrate a benefit of the drug and hopefully minimal risk to taking the drug. So we're in the process of doing that recruiting insights that include Europe and the UK as well as the US. Great. Great. Good luck with all of that. I look forward to a look forward to hearing a further update. One thing we spoke about or fair last time, which I had no idea about and which was fascinating, which was the discriminatory practices in certainly the US. I'd love to hear a bit more about that. Yeah. So, you know, great question. And obviously not an easy topic to talk about for a lot of people, but let me try to kind of convey my perspective on this across a number of different issues. Number one, I think African Americans, at least in the US, have been mistreated vis-a-vis medical therapies. There is a legacy of testing on African Americans that goes back to the 20s and 30s, some of the issues with the Tuskegee experiment. And so there's a legacy of mistreatment and medical, I would say, not malfeasance, but at least medical malpractice on behalf of African Americans in the US. So you mean there was like kind of illegal testing on Africa? Yeah. I wouldn't use the term illegal, but I just use the term as maybe unfair or not well-controlled and or questionable design. Okay. And so that legacy of issues, which are numerous, has translated into medical skepticism by the African American community in the US and probably to some extent in Europe as well. And so those two forces at play create a nervous and I would say patient population that's very skeptical of new therapies for all the reasons we just mentioned. So that therein lies one problem, historical precedence driving current activity. Number two, the challenge with sickle cell disease, unlike cancer or other therapies, is that patients are in very severe pain as a result of those pain crises that we talked about earlier. And that pain often needs to be addressed by strong medication, including opioids at times. And a lot of patients in the US, and when I mean a lot, I mean the substantial number are on Medicaid. And so a lot of the places that they have to go to seek treatment are unfortunately not always a primary care physician, but the emergency room. And so why is it why the emergency room? Surely if they have this disease, which in the US is known from birth, presumably in all cases, why do they have to go to the emergency room to get the drugs that they need? Yeah, I think, and again, it's not all patients, but a sizable number need to go to the emergency room for a number of different reasons. One of them, of course, they're in pain and they need immediate treatment. The emergency rooms place to go if you're in pain at five in the morning or two a.m. you have to go to the ER. Number two, I think going back to that medical skepticism point and kind of institutional bias, a lot of these patients as they get older and leave the pediatric hospitals, do take their care into their own hands and certainly may not seek regular treatment and regular checkups as we all do, not just specific to that community. The challenge, of course, is for those patients to continue to see either their primary care physician, potentially hematologist, a specialist. And unfortunately, again, for reasons that are not specific and necessarily clear, those patients are not getting the type of regular care that they otherwise may if they were not African-American. That could be part of the medical establishment. It could be institutional bias. It could be racist. It also just could be somewhat relying on the patient to follow up and those patients don't seem to want to follow up. And of course, they have a chronic disease that's continuingly to produce comorbidities and pathology. And it's just, it's not easy for them on a day-to-day basis. Yeah. Being in the U.S. and obviously, in the U.K. and we have the National Health Service, which is free, is there also a kind of a cost issue involved as well? Well, I'm not an expert in that, but I can say that certainly seeking treatment in the ER or emergency room has its own set of challenges from a cost basis. And certainly to kind of follow that analogy, I do think that physicians are very thoughtful, but in a very busy emergency room department where they're dealing with trauma and lots of different things, I think the challenge is, of course, a patient coming in that's seeking opioids because they're in substantial and debilitating pain and that happening on a regular basis may create undue or unfair skepticism related to sickle cell disease. And so, taking a step back, as you think about therapies for sickle cell disease, I think you have to address a number of different issues. Making sure the community understands that the goal for this disease, the goal for this therapy is ultimately to help. And that's not just done in a quick fashion. It's to really build relationships. And that's what Tamara's been doing for a number of years, not even related to the clinical trial but just related to establishing that we care about the community. The community also really drives the ability for patients to seek treatment. Number two, to really think about the patient in terms of how frequently they have to come in, the type of medication they may want to be on, the types of challenges that they're dealing with specifically related to COVID-19. So thinking about the patient is the other thing that we've really focused on. So community, patient. And then we have really started thinking about education and removing some of these institutional biases that we talked about, which can only be done as a therapeutics community and obviously give credit to Tamara for doing the real impact grants, give credit to GVT for doing their own grant system and the number of other companies building out not just the therapeutics vantage point, but the opportunity to really help the community as part of treating the disease. Great. So in the U.S. then, and you seem to hear about your thoughts on Africa, as you touched on earlier. So if you have sickle cell disease, you need the treatment, are there clinics then that adults can go to if they've taken ownership of their own treatment that they have presumably be able to go to a clinic and someone manages their care? Yeah. And it's a great question. And I think there's a number of innovative physicians and physician groups and hospitals working with this specific issue. And just to highlight one out of UConn, there's actually a sickle cell center where patients would be triaged in the ER and actually ultimately go receive treatment in that specific sickle cell center and the PI free and Miriam has done a fabulous job of helping bridge those issues that we talked about vis-a-vis coming into the ED, having a pain crisis, needing opioids, needing care, and then getting that specialized care in kind of a separate part of the hospital. And so those clinics are actually popping up in part due to federal funding, in part due to some of the community funding. And frankly, in the never too late recognition that this is really a debilitating disease and needs a specialized approach for treatment. Yeah. In the US, and you touched on earlier, the cynicism towards, say, the establishment, are you finding that people don't want treatment? They'd rather opt not for no treatment than to trust? Yeah, I think it's a little bit, my view on that is they are, I think maybe skeptical of new treatments, but open to be educated. You will find that the patient population here really cares a lot about future generations and helping future generations. And they know that clinical trials are component in that. I think what companies need to keep working on, as I said, is you're not just treating the patient, you're treating that skepticism that you noted, you're treating the community that's dealt with some of these issues that have been unfair. And I think it takes time. Yeah. Yeah, that's true. What about in Africa? And you mentioned one of the goals of your treatment is to be available globally. What are the roots for people to be able to get it ultimately? Excuse me, what are the... So in Africa, in the US, it's well established that there's sickle cell sensors, there's a good healthcare system, although people need to pay. In Africa, how can people get the medicine that they need? So for example, for your root, once you've developed and all of your stuff's been approved, what's the root for distribution for your medicine? It's a great question. I think you'd have, at least we believe and we haven't quite worked this out yet, and I'm sure other companies are thinking this too, that the route would probably be a combination of working with philanthropic organizations such as Bill and Melinda Gates, working with the WHO, finding a set group that can help us dispense this medicine in an affordable, low-cost, broad way that allows us not only to fulfill the obligation that we've set out for ourselves in terms of treating the world, but to do it in a way that is somewhat controlled and somewhat managed as opposed to a small company like us trying to do it for safe discussion. Interesting. How far are we from an actual cure? There are, bone marrow transplants are risky, but there is technically a cure for sickle cell disease, but the risks are pretty high. I would say that we are on the way with gene editing and gene therapy. I think those have the promise for cures. I think oral therapies have the promise for disease modification, but not necessarily a cure. I'd say what's great about this field is it was pretty quiet from 1945 to 2005. Now I think you're starting to see the fruits of investment by companies, biotechs, and larger and new innovative approaches like CRISPR and gene therapy. I can't say there'll be a cure for everyone in the next five to 10 years, but there will be hopefully cures for several, and hopefully oral drugs, which we believe remain the mainstay of therapy, will help patients along the way. Awesome. Raoul, thank you so much. Really informative. Really appreciate you taking the time to come on the podcast, and good luck. Good luck with all of your activities. Thanks for this. Appreciate your time, and good luck as well. Stay healthy. Thank you, Ani. Bye-bye.