Greetings, and welcome to the Global Blood Therapeutics, GBT, investor conference call. At this time, all participants are in listen-only mode. A brief question and answer session will follow prepared remarks. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I'll now turn the call over to Steven Immergut. Please go ahead. Thank you, and welcome to GBT's conference call to discuss new data on its sickle cell programs presented at the European Hematology Association, or EHA, 2022 Hybrid Congress. I'm Steven Immergut, Head of Corporate Communications and Investor Relations, and with me on the call today are Dr. Ted Love, our President and CEO, Dr. Kim Smith-Whitley, Executive Vice President and Head of R&D, Dr. Clark Brown, Lead Investigator on our GBT-601 phase I study and GBT's incoming Vice President of Integrated Science and Clinical Site Excellence, and Dr. Santosh Saraf, Assistant Professor of Medicine in the Division of Hematology Oncology at the University of Illinois Hospital & Health Sciences System. Jeffrey Farrow, our CFO, and Sebastian Stachowiak, Head of Europe and GCC, are also available during our Q&A session. During today's call, Ted will provide a quick company update and our overview of our presence at EHA. Kim will review key data from the Oxbryta and sickle cell disease research that is being presented at EHA, as well as some interesting new data recently presented in partnership with the Department of Defense. Dr. Saraf will share data generated from his center on the potential impact of Oxbryta on kidney disease in patients with sickle cell disease. Dr. Brown will then review GBT-601 data presented at EHA. Kim will then summarize our plans for GBT-601 phase two/three clinical trial, and then Ted will give a few closing remarks before we open up the call for questions. Earlier today, we issued a press release highlighting key data presented at the EHA meeting and the corresponding presentations, which are or will be available soon at gbt.com. In addition, today we will be referring to an accompanying slide presentation which can be viewed on the live webcast of this event. It will then be available again on Sunday in conjunction with our oral presentation on GBT-601 at EHA. Before we begin, I would like to remind you that certain statements that we make on this call that are not historical facts may be forward-looking statements that are subject to risks and uncertainties. Information concerning factors that could cause actual results to differ materially from those expressed or implied by such forward-looking statements are contained in our SEC filings, including but not limited to our most recent quarterly report on Form 10-Q, any EHA press releases. Copies of our SEC filings and press releases can be obtained from the investors page of our company website at gbt.com. The forward-looking statements made on this call are only as of the time they are made, and you should not place undue reliance on such statements. Future events or simply the passage of time may cause our beliefs to change, and we disclaim any obligation to update any forward-looking statements other than as required by law. With that, I'll turn the call over to Ted. Thank you, Steven. I'll be very brief because I really wanna get to the data that will be presented by our scientists, which I think are very exciting. I wanna thank everyone for joining on the call today, and particularly wanna thank our presenters. Dr. Saraf will be presenting data that really supports the concept that Oxbryta will in fact result in saving organs, and we think will be the basis of extending patients' lives. That data is very exciting, so I encourage you to pay careful attention to his presentation. Dr. Brown, who many of you already know, will be presenting an exciting update on the six-oh-one data. Six-oh-one is our second-generation left shifter that we think will provide additional benefit even beyond what we are currently providing patients with Oxbryta. Dr. Kim Smith-Whitley will be presenting data about our real-world evidence, our overall program. I'm particularly excited to point out that she'll be presenting data that shows that Oxbryta can deliver more oxygen to the brain and actually correct some of the cognitive dysfunction that we see in sickle cell models and sickle cell patients. On slide three, I just wanna emphasize that our goal as a company is to make Oxbryta available around the world. We are already launching it in Germany. We are doing great work in France and the United Kingdom with our expanded access program, and actually this past month, we had record enrollment in those programs. We've also initiated reimbursement discussions in the UK, France, and Germany, so that progress is very exciting. Finally, we've also received regulatory approval in Oman. With regard to our clinical pipeline, I'm not gonna read through these points, but I really wanna emphasize that we are making advances on every part of our pipeline with Oxbryta, inclacumab, and six-oh-one, as you will hear about today. Finally, at EHA, again, I won't go through it all, but our programs are, and our abstracts are covering the range of topics, many of which you'll be hearing about in today's presentation. Without further ado, I'll turn things over to Kim to get us started. Thank you, Ted, and hello, everyone. Our retro study, which is a retrospective analysis of 216 patients ages 12 and above from nine sites in the U.S., completed enrollment at the end of 2021. We analyzed medical records before and after initiation of Oxbryta, examining safety, clinical outcome measures, health resource utilization data, and laboratory measures. The results demonstrated overall safety was consistent with HOPE, with a low rate of adverse events, and those events were primarily diarrhea, headache, and rash. We continue to demonstrate that many achieve hemoglobin values above 1.4 grams per deciliter, with approximately one-third achieving changes in hemoglobin of 3 grams per deciliter and higher. Of course, there's also a decrease in markers of hemolysis, including decreases in indirect bilirubin and decreases in reticulocyte percentages over the 12-month period after Oxbryta initiation. Very importantly, physician prescribing practices are changing in this cohort, demonstrating a broadening in indications beyond hemolysis and anemia, but addressing a pain to limit acute and chronic pain and reductions in transfusion therapy. On the next slide, at the American College of Sports Medicine annual meeting, the U.S. Naval Medical Research Center reported out on a study of Oxbryta analog 1118. In that study, they were concerned because high-altitude exposure can impair physical and cognitive performance and lead to conditions such as mountain sickness in war fighters. They wanted to look at whether or not there were agents that could be used to limit these physical and cognitive impairments. On this slide, you can see that left shifting the oxygen hemoglobin curve with Oxbryta analog GBT1118 has the potential to improve brain oxygen levels and cognitive performance in animal models exposed to hypoxic conditions. In these rat models, we actually used GBT1118 analog or saline. In the graph to the left of the slide, you can see that with Oxbryta analog, brain oxygen levels decrease less during hypoxic exposure. On the right side of the panel, after exposure to hypoxia, animals then who were previously trained to swim in water and find a platform quickly could not find that platform quickly unless they were receiving the Oxbryta analog. You can see that clearly on the right side of that right panel that the latency time, in other words, that animals who were treated with Oxbryta could find the platform much quicker than those who were not treated with Oxbryta. This data also then supports that oxygen delivery to the brain actually is not only not impaired, but actually is improved with Oxbryta, and that you can use Oxbryta to limit the impact of hypoxic effects on the brain. On the next slide, we have data from the U.K. that looks at two databases, in a retrospective analysis to compare our previously published manuscript data on decreased hemoglobin levels showing an increase in end organ damage. We wanted to, in this study, look at whether or not higher hemoglobin levels were associated with less end organ damage, and that was demonstrated through over 5,000 patients with sickle cell disease ages 12 and over. As you can see, higher hemoglobin values were associated with fewer leg ulcers, fewer pulmonary complications such as pulmonary hypertension and acute chest syndrome, and fewer renal complications including chronic kidney disease and end organ damage or end-stage renal disease. On the next slide, I'm going to turn the presentation over to Dr. Santosh Saraf, who is from University of Illinois Chicago, where he cares for adults living with sickle cell disease, and he has some exciting data to share. Dr. Saraf. Thank you very much for the opportunity to present our research highlighting the role of hemolytic anemia in sickle cell nephropathy. I'd like to thank my colleagues listed below, particularly Dr. Govindan, who performed the majority of the mouse experiments. On the next slide, you'll see my disclosures. Next slide. With better newborn screening and early implementation of penicillin prophylaxis and hydroxyurea, more than 95% of children with sickle cell disease now survive into adulthood in high-income countries. However, survival has only marginally improved in adults, and most contemporary cohorts show that the median survival is still somewhere in the upper 40s. Next. With the changes in survival patterns, there's been a paradigm shift in the cause of mortality, with about half of mortality now being attributed to chronic organ damage involving the heart, lungs, and kidneys. Next figure. Kidney failure has been increasingly recognized as an important contributor to the morbidity and mortality in people with sickle cell disease. Chronic kidney disease is seen in about half of adults with sickle cell disease and contributes to up to 20% of mortality. Furthermore, those who progress to hemodialysis, morbidity and mortality remains high, with about a quarter of patients dying within one year of initiating hemodialysis. It is critical that we develop therapies to protect kidney function in people with sickle cell disease. On the next slide. Many observational studies have tried to understand what is driving the kidney damage in sickle cell disease, and most have pointed to hemolytic anemia being associated with sickle cell nephropathy. There are two parts of the hemolytic anemia term that are contributing to the kidney damage. First, there's hemolysis with release of toxic cell-free hemoglobin and heme, and the kidney is continuously filtering these toxins and is exposed to these inflammatory and oxidative injurious molecules. There's also the anemia, which leads to tissue ischemia and damage. The latter has been observed in animals where progressively lower hematocrits correlate with reduced renal cortical and medullary oxygen delivery, and that leads to more oxidative injury. The most compelling evidence for anemia being a risk factor for sickle cell nephropathy comes from a prospective pediatric cohort from the University of Alabama. In this cohort, they looked at the earliest available baseline hemoglobin concentration, and they observed that this degree of anemia correlated with the risk of developing albuminuria. For every 1 gram lower in hemoglobin concentration, there was a 10% faster rate of developing microalbuminuria, and a hemoglobin less than eight was associated with a 9.1-fold greater risk for developing microalbuminuria. On the figure on the right, our cohort from the University of Illinois, we've observed that hemoglobinuria is strongly correlated with the degree of hemolysis, reflecting the release of cell-free hemoglobin and heme that's freely filtered through the glomerulus. Those patients with sickle cell disease that have hemoglobinuria have a 3.1-fold higher risk of albuminuria progression. On the next slide. Therefore, we conducted a study to investigate whether ameliorating hemolysis with GBT1118, an analog of voxelotor specifically designed to have similar pharmacokinetics in mice, would improve biomarkers of kidney damage and function. We used the Townes model of transgenic sickle mice, and this model in our lab and several other labs have shown that the kidney pathology that you see in this Townes model mirrors what we see in people with sickle cell disease. We provided these mice with either GBT1118 or a control chow starting at 12 weeks of age until 24 weeks of age. We chose these ages because these ages correlate respectively with when the earliest signs of kidney damage are observed and when chronic kidney disease is observed. Consistent with the clinical results with voxelotor, the transgenic sickle mice treated with GBT1118 had an improvement in hemoglobin concentration and a reduction in hemolysis reflected by a reduced reticulocyte percentage. Also consistent with our human data, less hemolysis was associated with reduced hemoglobinuria. On the next slide, you'll see that the improvement in hemolysis and hemoglobinuria resulted in improvements in kidney injury biomarkers to the main components of the kidney nephron, the glomerulus, and the proximal tubules. This included a reduction in nephrin, seen on the left, a biomarker of glomerular damage, and an improvement in kidney injury Molecule 1 or KIM-1, a biomarker of proximal tubular injury. On the next slide, you'll see that in addition to the improved hemolysis and hemoglobinuria improving biomarkers of kidney injury, we also observed stabilized albuminuria, an improvement in proteinuria, and stabilized cystatin C, a much more accurate measure of glomerular filtration in sickle cell disease. These measures of kidney function remained similar to the sickle mice at 12 weeks and to control non-sickle mice or AA mice at 24 weeks of age. In contrast, the sickle mice that were not treated with GBT1118 had progressive worsening of albuminuria, proteinuria, and a significantly higher serum cystatin C concentration at 24 weeks of age. On the next slide, we also investigated what the effects of improved hemolytic anemia would be at a molecular level. We isolated glomeruli and the kidney cortex of the treated and untreated mice and looked at hypoxia hallmark genes. We wanted to look at how these genes are affected by GBT1118. What we observed was that most of the hypoxia genes were downregulated or were improved in the glomerulus and kidney cortex. This included a reduction in the gene expression of SLC2A1 and STC1. These are two really key genes that carry out the hypoxia cascade from hypoxia-inducible factor, so consistent with hypoxia being improved in these regions. On the next slide, we wanted to also look at how the preclinical data matches our patient data. We first investigated whether voxelotor would lead to improved markers of kidney function in patients with sickle cell disease. Leveraging observational clinical data from five patients with sickle cell anemia and CKD Stage 1 through 3. We focused on albuminuria, an important biomarker of early kidney damage that predicts rapid decline in EGFR. The age range of this cohort was 23-59 years, four were female, and two were on hydroxyurea, and three on an ACE inhibitor or ARB therapy. Patients were treated with voxelotor, prescribed according to their primary provider for a range of 4-16 months. Consistent with the HOPE trial, patients with CKD Stage 1 through 3 demonstrated an improvement in hemolysis reflected by a rise in hemoglobin concentration and a reduction in reticulocyte counts. These patients also had an improvement in albuminuria observed in all five patients treated with voxelotor, which you'll see on the figure on the left there, where all of those patients showed a decline in their urine albumin concentration on treatment. The mean reduction in albuminuria at the last available assessment was by 25%. This is really interesting because this is a cutoff that's been shown in the non-sickle cell literature to lead to a reduced risk of kidney disease progression and improved mortality. We also compared these results to a cohort of age and sex-matched patients with sickle cell anemia and a similar degree of albuminuria. In this group that did not receive voxelotor, but had a similar burden of kidney disease, followed for a similar period of time, we saw that the degree of albuminuria progressively worsened, which you could see on the curve on the right. On the next slide. These encouraging results have been the basis for a pilot study that we are currently enrolling and following patients in. We are selecting those patients with sickle cell anemia and a combination of hemoglobinuria and albuminuria, and this represents a very high-risk group of patients for kidney disease progression. Patients will be randomized to either voxelotor 1500 milligrams daily or standard of care, and we are monitoring them for 48 weeks on therapy. The primary outcome is albuminuria, but we are also measuring other biomarkers of kidney function and injury. In our preliminary results, two patients have been randomized to voxelotor. Both of these patients have demonstrated resolution of hemoglobinuria and an improvement in albuminuria at 48 and 36 weeks of therapy. In contrast, the patient that's been randomized to standard of care has continued to have persistent hemoglobinuria and worsening of his albuminuria at 24 weeks of follow-up. Next slide. In conclusion, improved hemolytic anemia with GBT1118 reduces hemolysis, and this is an Oxbryta analog. It reduces hemolysis, leads to less cell-free hemoglobin and heme exposure to the kidney. This in turn leads to improved biomarkers of kidney damage and function, prevents histopathology and ultra-structural damage to the nephron, and reduces expression of most hypoxia hallmark genes differentially expressed. For example, SLC2A1 and STC1. Strategies to mitigate hemolytic anemia may provide a targeted approach to preserve and improve kidney function in sickle cell disease where there is an urgent need. On the next slide, you'll see my acknowledgments, including collaborators at UIC, Global Blood Therapeutics, the Hektoen Institute, University of Pittsburgh, University of Ibadan, Loyola University, and support that we have received from NIH, GBT, and UIC. Thank you very much. Thank you, Dr. Saraf. We're encouraged to see your data demonstrating Oxbryta's clinical benefit on the kidneys. Now let's transition to another way we are exploring Oxbryta's potential to reduce organ damage through the HOPE-Kids 2 study, which is our post-approval confirmatory study using transcranial Doppler flow velocity to assess the ability of Oxbryta to decrease TCD values and stroke risk in children ages two to 15 years. We're now approximately 50% enrolled and on track to deliver on our post-approval commitment to FDA. We're also active in many countries outside of the U.S., including Nigeria, Egypt, Oman, Kenya, Ghana, and Saudi Arabia. When we go into these areas, we not only start the study, but we train individuals on the TCD machine, and we're committed to providing Oxbryta to the study participants post-study indefinitely. On the next slide, you can see that our SHAPE survey, our multinational study composed of a quantitative online survey of patients, caregivers, and HCPs, is being presented here at EHA. This will be also presented next week at the fourth Global Congress on Sickle Cell Disease in Paris. We will be hosting a media launch event of the full study results. This study is important for several reasons. It allows us to quantitatively understand the challenges in sickle cell disease and how we can help patients not just with innovative medicines but with their overall health and well-being. There's a significant number of respondents at a global scale, and this really provides a current view of the burden of sickle cell disease. The survey included 919 individuals living with sickle cell disease, their caregivers, and HCPs. Patients were primarily concerned about their long-term health, including the risk of organ damage, and caregivers also expressed negative experiences receiving care in emergency departments. The healthcare providers face a complex environment when treating individuals with sickle cell disease, largely addressing differences in socioeconomic status and ethnic background and emphasizing the need for education and more resources. Stay tuned for more information on this very important study on Monday, June thirteenth. I'm pleased to introduce Dr. Clark Brown, who's going to present an update on GBT- 601. He is the head of sickle cell disease clinical research at CHOA and will be joining GBT this summer as head of integrated science and clinical site excellence. Dr. Brown. Thank you. It is a pleasure to present highlights of the experience from the ongoing first inpatient trial of GBT-601. On Sunday's presentation at EHA, I will include additional data from healthy volunteers portion of the study. Those slides should be available soon on the GBT website. Here are my disclosures. Next slide. This diagram is a refresher of the study design. The design included treatment of the same six patients who started with a single dose of 100 milligrams, followed by a washout period of 8 weeks. Based on the single dose PK and on the healthy volunteer MAD data, the chosen dose for the first patient MAD cohort was 50 milligrams daily after loading doses. The dose chosen for the MAD-two cohort was 100 milligrams daily. Endpoints of safety, tolerability, and changes in anemia and hemolysis matched to the GBT-601 concentrations were assessed during the entire study period, including a four-month washout at the end of MAD-2. Next slide. The favorable PK parameters of GBT-601 did lead to a significant improvement in hematological response and a mean hemoglobin occupancy of greater than 30%. On the right is the change in hemoglobin from the start of the MAD-1 cohort through the last dose of the MAD-2 cohort. The observed mean hemoglobin increase for all patients was 2.3 gram per deciliter. For context, the red line illustrates the average hemoglobin increase of 1.1 gram per deciliter achieved with the FDA-approved 1,500 milligram dose of Oxbryta. All six patients receiving GBT-601 achieved this benchmark, and four out of the six patients had a hemoglobin change of 2.7 grams per deciliter or higher. These hematologic improvements were achieved with the favorable safety profile. All doses were well-tolerated in patients with sickle cell disease. The clinically substantial increase in hemoglobin was also associated with improved red blood cell function and markers of hemolysis. The left graph shows typical rightward shift of the P50 associated with sickle hemoglobin or sickle red blood cells that is improved with the drug as expected. In the middle, on average, a 54% reduction in the percent reticulocytes occurred, and a similar trend was found using the absolute reticulocyte count. Again, the red line shows contrast to the average change achieved with the FDA-approved dose of Oxbryta. Of note, the change in erythropoietin levels were also measured. However, no trend was found in the small cohort that would be considered clinically significant. It is encouraging to see the two patients with significant elevations of serum EPO levels improve when on drug. Next slide. Consistent with reduction of reticulocytes, improvements in the indirect bilirubin on the left and LDH on the right were observed. Again, the improvement was significantly better when compared to daily Oxbryta. Next slide. Here we assess red blood cell function. Deformability of the sickle red blood cell can be assessed ex vivo using ektacytometry. The LoRRca system can trace changes in red blood cell deformability during a controlled gradient of deoxygenation and reoxygenation. The results with GBT-601 treatment are dramatic. In all six patients, all three Oxygenscan parameters showed a significant improvement, approaching values seen in people with sickle cell trait. Next slide. The graph shows the strong correlation between hemoglobin improvement to decline in the sickle red blood cell. On the left, after MAD-1 and MAD-2 treatment over an eight-week period, there was a mean decrease of 76% in the sickle red blood cell. After patients stopped therapy, the number of sickle red blood cells returned near baseline. On right, you can see hemoglobin response was similar. The mean hemoglobin of 2.3 grams per deciliter increase we already reviewed. The return to near baseline levels after the washout period was as expected. Upon cessation, the elimination of drug was slow with reversal of the improved hematological parameters. Next slide. The best evidence of 601's ability to improve health of the sickle red blood cell is visualized by the patient's blood smears. The top shows two individual blood smears pretreatment. The number of sickle forms that were significantly reduced after the MAD-2, and the majority of the cells retain a morphology more typical of a normal red blood cell. Next slide. All the hematologic benefits occurred at doses that were well-tolerated. No dose reduction or drug discontinuation occurred. There were few SAEs. The three Grade 3 vaso-occlusive events occurred in two patients. All were deemed unrelated to GBT-601. No VOCs were observed during the washout period. Most telling, all patients are interested in restarting therapy, which we have done. I'm excited for the potential of this therapy, and that it will have a significant advancement for our patients. Thank you, and I will turn the presentations back over to Dr. Smith-Whitley. Thank you, Clark. On the next slide, we're going to begin to outline our plans for our phase II-III. I just want to reiterate that this builds on the study design that we had for the MAD-1 and MAD-2. I agree with Dr. Brown that this is very impressive that all six participants expressed a desire to restart therapy. In fact, that's the first time that I've seen that. Patients will receive a 300 milligram BID loading dose at restart, followed by a 150 milligram daily maintenance dose for six weeks. We'll be studying the same endpoints that we reviewed for the earlier MAD portion in the phase I, and we anticipate that we'll have data to provide on this cohort by end of year. Next slide. In discussing our phase II study design plans, we're planning on 60 participants with similar inclusion criteria to phase I study, although not excluding recent VOCs. We'll be exploring 100, 150, and 200 milligram dose levels, although the 200 milligram cohort will be delayed behind the 100 and 150 milligram cohorts. This will be followed with loading doses of 200, 300, and 400 milligrams twice daily for four days prior to the maintenance dose of 100, 150, and 200. We believe that these higher doses will really result in higher average hemoglobin occupancy and hemoglobin increases, and show improvements in red blood cell health. We anticipate initiation by the end of the summer and hope to have some early results from the phase II before end of year. On the next slide, we can see our plans for our 2/3, as we expect this 2/3 design will allow us to advance more quickly into the pivotal phase III portion of the 2/3 study. Based on this plan, we're anticipating submission for full approval rather than accelerated approval. We plan to have data from our phase I, as well as early results from the phase II portion before going to the FDA to finalize our phase III plan. This will help us confirm the dose and trial design with FDA to finalize the protocol and initiate the study. The phase III portion of the study is planning for hemoglobin increase as a main endpoint, but we're also considering a variety of secondary endpoints that can demonstrate clinical benefit. Patients in our GBT-601 trials will have the opportunity to enroll in an open label extension study. At some point in the future, we also plan to open an expanded access study for compassionate use with patients that are not responding to existing therapies. On the next slide. We're encouraged with our data to date. We believe that GBT-601 has best-in-class potential. It's based on Oxbryta's established mechanism of action with a new intellectual property. It has the potential for a single pill to be dosed once daily and hopefully with better tolerability considering the lower dose. We also have the potential to demonstrate clinically superior efficacy in a variety of clinical outcomes related to our ability to achieve target hemoglobin occupancy of 30% or higher consistently. With that, I'll turn the call back to Ted. Thank you, Kim. Thank you, Clark. Thank you, Dr. Saraf. I hope you've all found these presentations as compelling and exciting as I have, and I know you all want to get on to the Q&A. Before we do that, I want to emphasize a couple of points. One is that I hope you see that we are executing on our mission to make sickle cell a well-managed chronic disease. We're doing that today by making that available to patients in the United States and increasingly around the world. We're not standing still. We're moving our pipeline with six-oh-one to make a further advance beyond the important advance that we've already delivered with Oxbryta. Finally, with inclacumab, we think we can further provide a superior therapy for decreasing VOCs as well as decreasing hospital admissions. Some of the key takeaways today are that we're generating real evidence to drive and encourage Oxbryta use with the vision that we can improve kidney function. In fact, we can improve cognitive function, and we can extend patients' lives by protecting their organs. Our SCD research is focused on proving that raising hemoglobin is in fact the most powerful way to protect organs and extend survival. Finally, with GBT-601, we think we can do this better than anyone in the world by providing a left shifter that will allow patients to reliably and easily get to high levels of oxygenation with a simple daily pill that could be administered anywhere in the world. With that, we'll go on to questions. Thank you. We'll now be conducting a question-and-answer session. To start, please limit yourself to one question. If we have time remaining, we will take follow-up questions. To ask a question today, please press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we poll for questions. Thank you. Thank you. Our first question is from the line of Joon Lee with Truist Securities. Please proceed with your question. Hi. Thanks for taking our questions and for the presentations. Could you please go over the partial pressure of oxygen data for 601? It may have been slides 28 or 29. Sorry I missed that, but just wanted to understand what that was and if there's any read-through to tissue oxygenation after 601. Thank you. That's a good question, and the data actually does show there's improvement as we expect in the P50 curve and even the P20 to the point that we see with the normal red blood cell when patients are on the 601. That data supports the fact that we are still getting oxygen delivery to the tissue. Joon, I'll just emphasize. The problem with left shifting or the problem with right shifting is that the affinity for oxygen by the sickle hemoglobin is so low that by the time the red blood cells get to the deep tissues, they've already released all the oxygen. By left shifting, you're actually allowing the hemoglobin to hold onto the oxygen more tightly so that it's available for the deep tissues to remove it. The data that Kim has shown shows that the tissues are readily able to receive that oxygen, as evidenced by more oxygen in the deep tissues, specifically the brain and the kidney tissues in there. Thank you so much. Thank you. Our next question is from the line of Paul Choi with Goldman Sachs. Please proceed with your question. Hi. Thank you. Good morning, everyone, and thanks for taking our question. I also have a question on 601, which is for Dr. Brown, regarding the first six patients. Can you maybe just help us with the relationship between the hemoglobin occupancy and the observed hemoglobin changes? You know, I guess there's not as clear linear relationship and some variability. I was wondering if you could maybe articulate were there any, you know, patient-specific factors that accounted for the difference in magnitude, and then how you think about that relationship as predicting as you expand to the phase II higher doses. Thank you very much. Thanks for the question. There was variability between the occupancy that we measured and the hemoglobin response. You know, right now, I don't really feel comfortable what is the cause of that variability, but I do think it's probably related to the hyperhemolysis of some patients compared to others. Because I think that is kind of influencing basically the blood versus plasma ratio and affecting the clearance. Paul, I'll just add that I don't think there's ever been an intervention in sickle cell disease where there's been a direct correlation of the effect of the drug and the hemoglobin response. I think that's true with Oxbryta. It's been true with gene therapy. I think it's even been true with bone marrow transplantation. Patients do in fact have underlying conditions, such as their renal status and other factors, which will dictate the appropriate response to the same intervention, even at the same level of intervention. Okay, thanks for the call. I'll jump back in queue. Our next question is from the line of Gregory Renza with RBC Capital Markets. Please proceed with your question. Hey, Ted, and team. Thank you very much for holding the call, and congrats on the update. Maybe a question just to follow up on GBT-601, just in the event I missed this. Dr. Brown, speaking about the mean decrease of 76% as it rebound following that washout period. I'm just curious if you could comment a bit on how variable that was with respect to the level of decrease of sickling for those six patients, and perhaps what that clinical significance is and the influence with GBT-601. Thank you very much. With the washout period, we did see a return back to baseline in the hemoglobin and the percent sickle cells. We haven't analyzed all the data yet as far as the multiple endpoints. We did follow those patients either every 2-4 weeks. It will be interesting to see what the trend was. Hi, it's Kim. The other thing that I would add is that with Sprida measured at the same period of time in treatment, that we had a 45% reduction. I think that the other thing that we learned with Oxbryta is that the longer you're on therapy, the greater reduction occurs over time. This is just the tip of the iceberg that just reflects the minimum of weeks of therapy on 601. Got it. Thank you very much. Our next question is from the line of Mark Breidenbach with Oppenheimer. Please proceed with your question. Hey, guys. Thanks for this presentation and thanks for taking my question. I'll ask something that's different from 601. You know, I just wanted to say thanks for the update on the enrollment of HOPE-Kids 2. I'm wondering if you're getting to the point where you can extrapolate when enrollment might be completed by, when we might see data from that study. You know, I guess I'm curious if there are plans to run a study in sickle nephropathy in parallel with HOPE-Kids 2 that could potentially serve as an alternative confirmatory trial for Oxbryta. Thanks for taking the questions. Thank you, Mark. Those are great questions. With regard to the timeline, what I would say is that we feel very confident about reaffirming our commitment to the FDA that we would get these trials done by 2026. We likely are able to exceed those timelines, but we're not giving an update beyond reaffirming our commitment to delivering what we promised the FDA. With regard to other studies, you are absolutely right. We are doing a variety of studies looking at organ protection. We talked about the brain today. Dr. Santosh Saraf presented some of his early data. We have full intention to fully explore all of the organ saving and ultimately the life-saving benefits of these therapies. Okay, great. Thank you. Thank you. Our next question is from the line of Jason Gerberry with Bank of America. Please proceed with your question. Hey, guys, thanks for taking my question. Maybe a question for Dr. Brown. Just thoughts on ultimate development pathway and endpoint selection and where you stand on this idea of higher hemoglobin, less hemolysis, maybe equates to disease modification or the desire to see an outcome measure. Just a question for the GBT team in terms of thinking about the pivotal study. You mentioned secondary endpoints. Are there any of focus for you that will be pre-specified as you start to think about that, or will that be an update to come later? Thanks. Thank you for that question. I mean, the correlation between hemoglobin level and clinical status is building. I think with getting to hemoglobin levels that are significantly higher than what the patient has been experienced, we'll see a reduction in the clinical complications. Obviously, we would like to see a strong signal with things such as vaso-occlusive crisis, acute chest syndrome, and other complications. I think we'll start to see that in the phase two, and then obviously those will be measured in the phase three. Yeah. I would just add to what Clark just said, is that we are very, very interested in following the experience from what Oxbryta has shown us. We know that Oxbryta, the higher the hemoglobin modification, the lower the pain frequency. That would obviously be something that we would want to continue to explore alongside other measurements of acute and chronic complications. Got it. Thank you. The next question is from the line of Yatin Suneja with Guggenheim Partners. Please proceed with your questions. Thank you for taking my question. Two questions, both for the docs. Could you just comment on or maybe like what is a good level of hemoglobin increase that might be desirable? Maybe if you can also comment what are the risks or consideration of increasing hemoglobin too much or above a certain threshold? This is sort of a one question I have. The other one, if you can also comment, is you know how high do you think is the correlation between hemoglobin increase and VOC? Thanks. I'll start, and feel free, Clark and Kim, to add. I would just turn the question around a little bit about how high the hemoglobin should go. The question is, how normal do you want your patient to be? How much of disease burden do you want to take away? Because that's what these drugs are doing. They're correcting the molecular basis of the destructive nature of sickle cell disease, which is polymerization. As we've talked about, as you decrease that, depending on the underlying condition of the patient, the hemoglobin is going to go up. It's going to go up in some patients in normal range. I think one of the slides that Kim showed actually showed the patients had hemoglobin rises of the magnitude of 8 grams per deciliter in some cases. Those patients are doing great. As we've shown, they have fewer pain events as their hemoglobin goes up. The data about what's likely to happen with their organ preservation, and I think survival, is very striking. I would just ask, how normal do you want to be with sickle cell disease? We think being perfectly normal would be a wonderful outcome, and we've never seen any adversity related. The other thing I'll point out is that Clark did mention that even when we stopped 601, these patients did not have any evidence of any kind of rebound effect. I think getting these hemoglobins to normal is what we'd love to do. It's not going to happen in every patient because of the underlying disease. Our goal, quite frankly, is to ultimately treat children very early and make those children completely normal. Try to keep them normal throughout their life. We think if we can do that, you could actually produce a normal survival. A lot of the thinking about raising hemoglobin too high, in fact, all of the thinking is, it's really been driven by transfusing patients on top of their unmodified, untreated sickle cell, sickle red blood cells. That's not what's going on in these patients. These patients are getting all of their red cells treated and modified. They're not sickling. You see that on the morphology slides that we presented. We feel tremendously good about this, and we feel tremendously good, quite frankly, when a patient shows normalization of their hemoglobin, their retics, their bilirubin, their LDH. We'd love for these patients to look like you and I, and we think that's gonna be the best outcome for them. Just to add anecdotally, with the patients that I've followed on Oxbryta, they see basically improvement in their quality of life. Obviously, we talk about the organ damage and the vaso-occlusive crisis, but just the fact of seeing these middle school kids have a reduction in their jaundice and improvement in their fatigue to the point that they can do more normal activities is significant, and I think will drive compliance with the medicine. I think it just supports published data from Vivien Sheehan at your institution, Clark, that demonstrates that individuals on Oxbryta have diminished viscosity. That just is consistent with the in vitro data. Thank you. Our next question is from the line of Andreas Argyrides with Wedbush Securities. Please just use your question. Yeah, good morning. Thanks for taking our question, and thanks for the presentation. Just to add on to the other questions here. You mentioned that you're using the same inclusion/exclusion criteria for the phase II, but not excluding patients with VOCs. Maybe just the reasoning behind that or any thoughts around that? Thanks. The reason that we're expanding our inclusion criteria is that we really don't want to limit our ability to enroll on the study. Of course, that we want to make sure that we are getting the full spectrum of individuals, with multiple clinical complications with sickle cell disease. All right. Thanks for that. The next question is from the line of Benjamin Burnett with Stifel. Please share your question. Hey, thank you very much. I thought the data on the effects of the Oxbryta analog on oxygen exposure in the brain of rodents was really interesting. I guess, how did their rate of exposures compare in terms of hemoglobin modification to what you achieve in patients, either you know, with those rat studies, either Oxbryta or with 601? I actually don't think the benefit in, for example, the cognitive function in the mice is focused on hemoglobin going up. It's simply focused on allowing the body to take up more oxygen in a hypoxic environment and then understanding if that modified hemoglobin releases the oxygen, so you can measure it in the brain. Lastly, does the animal have an improvement in cognitive functions, in this case, measured by their capacity to remember where the platform in the water was? I think it's demonstrating is that you don't need to be anemic. The actual left-shifting itself provides therapeutic benefit. That's actually one of the reasons that I've been particularly excited about the mechanism of left-shifting in sickle cell disease, because you start out with individuals that actually have what I think is a very serious problem of being pathologically right-shifted. Okay. That's helpful. If I could add just a clarification. Is the amount of drug effect in mice, like, how does that compare to what you'd expect with Oxbryta or 601? They were actually dosed to achieve a level, I believe at least that would be consistent with 30% modification and higher. Remember these animals were also not at steady state. This was really reassuring to us that we were seeing this much impact without even being at steady state. Right. Maybe, Dr. Saraf, I don't know if you can answer the question. Sure. He was in fact looking at sickle mice and sickle patients, and he was using targeting kind of the dose that we're using of Oxbryta commercially, trying to tie that to Oxbryta. Maybe Dr. Saraf could speak to his benefit, but I think he made the case was due to correction of hemolysis, primarily, I think. Yeah. With the GBT1118, our hemoglobin occupancy really mirrored what was seen in the HOPE study. Very, very similar occupancy at six weeks and 12 weeks of therapy. Then the hemoglobin response of 1-2 grams also is very similar to what was seen in the HOPE study. In our lab and in our model, the effects of the GBT1118 seem to really match the clinical experience with voxelotor. Awesome. Super helpful. If I could just one quick clarification question on the design of the 601 phase 2 study. I guess, is there a scenario where you focus on the higher dose cohorts in that phase II if the phase I MAD 3 cohort implies a higher dose is better? Like, could that inform kind of where you go with the phase 2? We're really curious about what happens when we treat at 100 milligrams with a larger number of individuals living with sickle cell disease for a longer period of time. We really wanna capture that. And- Okay. You know, that's one of the reasons we're looking at 100, 150, and 200. As Kim Smith-Whitley mentioned, we're bringing the patients back from the phase 1 study and bringing them in at 150. But we really do, as Kim Smith-Whitley said, we need to understand what are the long-term implications of 100? It may be that 100 is enough, but we're not gonna make that assumption. We're also studying 150 and 200. I think we've got a very strong strategy here to make sure we don't leave efficacy on the table. Thank you. The next question is from the line of Raju Prasad with William Blair. Please proceed with your question. Thanks for taking the question. Just curious to know in the retro trial, if you kind of looked at the subset of patients that are, you know, super responders on hemoglobin levels or durability of response. I'm just, you know, thinking about the endpoints of reduced transfusions or VOCs in that patient population and, you know, whether or not with 601 being kind of a more potent version if, you know, we could end up seeing some clinical benefits there. Thanks. Yeah, I think that's exactly right. We're really going to have to look at the retrospective data and analyze that. We didn't have the opportunity to do all of our clinical endpoints. It is very hopeful that if we're seeing that much increase in hemoglobin, that we're also seeing hemoglobin modification that would result in a decrease in acute pain episodes. I think you're exactly right. The opportunity to improve consistently higher modification, so to speak, with 601, should have clinical benefits there as well. Great. Ted, you had mentioned that since 601's a smaller molecule, sometimes you can get two, you know, two molecules to bind. Are you seeing that or is there a way to test that in clinical development? Just curious to see if there might be a difference between in vivo versus clinical or in human mechanisms of action there. Thanks. Yeah, great question. We could only test that by getting to 100% modification, and which we probably would never do. The reason we've done that in animal studies is that you really wanna expose animals to a massive overdose to see if it's safe. Of course, what we've seen is that even with these massive overdoses where you bind 100% of their hemoglobin, you continue to dose enough that you now are getting 40% of the molecules which are accepting two 601 molecules. It's a massive dose. We would never do this in humans, but it is very reassuring stuff that it's tolerated in animals very well. Thank you. Our next question is from the line of Yanan Zhu with Wells Fargo. Please proceed with your question. Hi. Your line is open for question. Thanks for taking my question. The preclinical and clinical data presented by Dr. Saraf are very intriguing. This is a question for the company. I was wondering, in the HOPE study, have you by chance captured hematuria and albuminuria data, and could you go back and see if you can recapture what Dr. Saraf has seen in his pilot study? Also very quick question with regard to the target hemoglobin occupancy in the GBT-601 study. What are the occupancy at 150 mg and at 200 mg? Thank you. I can say, and maybe defer to Kim on the second part, but in the HOPE study, we really didn't focus on those kind of parameters. Not only did we not recruit the right patients like Dr. Saraf has recruited, we did not even collect the data in a manner that it really should be collected. As you know, clinical studies typically are well-designed to measure one thing, and the HOPE study clearly was not focused on renal function. Although, we do feel, looking at Dr. Saraf's data, that if you look at the right patient population and collect the right findings, that it's very encouraging that you're likely to see benefit. To the second part of your question, we're expecting that those doses should give us hemoglobin modification in the ranges between 40 and 60. Great. Thank you. Thank you. I just wanna thank everyone for your questions, and thank you for your attendance today, and we look forward to updating you further in the future. Thank you. This will conclude today's conference. Thank you for your participation. You may now disconnect your lines at this time.