Global Blood Therapeutics, Inc.

Greetings and welcome to the Global Blood Therapeutics conference call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the prepared remarks. Should anyone require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the call over to Stephen Immergut. Please go ahead.

Thank you, and welcome to GBT's conference call to discuss the company's financial results for the third quarter 2021 and to provide a business update. I'm Stephen Emmergat, Head of Communications and Investor Relations. With me today on the call are Dr. Ted Love, our President and CEO, Jeff Farrow, Chief Financial Officer, David Johnson, or DJ, Chief Commercial Officer, and Dr. Kim Smith-Whitley, Executive Vice President and Head of Arts. During today's call, Ted will provide an update on our progress in the third quarter. Jeff will review our financial results. DJ will give an update on the Oxbrite launch. Kim will discuss our pipeline. And then Ted will give a few closing remarks before opening up the call for questions. Earlier this afternoon, we issued a press release announcing GBT's business progress and financial results for the third quarter ended September 30, 2021. This morning, we issued a press release announcing six data presentations at the upcoming ASH annual meeting in December. We will also hold an R&D event for investors and analysts on November 11th. Before we begin, I would like to remind you that certain statements 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, as well as in today's press release. 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, We disclaim any obligation to update any forward-looking statements other than that as required by law. With that, I'll turn the call over to Ted.

Thank you, Stephen, and good afternoon, everyone. GBT continues to make solid progress on our mission to transform the care of sickle cell disease and improve the lives of patients around the world. We are well-positioned for long-term success, both with Oxprida, which has several upcoming catalyst for potential growth in our robust pipeline, which we believe can help further improve clinical care and SED and expand the market. Turning to the quarter, we delivered approximately 850 new prescriptions in Q3, a decrease compared to the second quarter. This reflects headwinds from the spike in new COVID-19 cases in the U.S. in August and September, which were at their highest levels since early January. In many states, as widely reported in the news, ICU capacity was strained. Many sickle cell healthcare providers were diverted to address this urgent need. Sadly, in early October, COVID deaths in 2021 surpassed the number of deaths in 2020. despite the availability of vaccines this year. While the surges in the pandemic infection rates, especially in areas where many sickle cell patients live, did not subside in Q3, we remain very optimistic for the future, given the tremendous unmet need in this disease. We also continue to refine and expand our commercial efforts to drive Oxprata awareness education, and access. Oxpride's strong fundamental and long-term potential give us confidence heading into 2022. Let's consider the following. The net number of patients taking Oxpride continues to increase each quarter, which contributed to us delivering on our third quarter revenue expectations. The growing body of real-world evidence including new data covering nearly 2,700 patients that will be presented at ASH, validates the role of Oxprida as potential foundational therapy for sickle cell disease. Our market research demonstrates high levels of satisfaction among prescribers and patients who have tried Oxprida. We also have received positive feedback and results from our educational and marketing programs, including our groundbreaking direct-to-consumer advertising campaign. And we have near-term opportunities to significantly expand the number of patients eligible for Oxprida. Importantly, we have an FDA action date of December 25th on our approval application to expand Oxprida label to include patients as young as four years old, along with a new pediatric formulation. In Europe, the market authorization application is on track for potential approval in the first half of 2022. We are in position to further build on these positive fundamentals and near-term catalysts as the pandemic subsides and healthcare visits return to normal. We believe these factors will gradually contribute to new prescription growth in 2022, with potentially more robust growth in the second half of the year. In addition, we believe this timing will coincide with achieving broad payer coverage for children ages 4 to 11, which will help fuel our growth. We are also advancing our pipeline and will have exciting updates at ASHE. For Nclacomab, we will have new phase one data to present that we believe supports the best in class potential. For GBT601, we will present the first data from our phase one study in both healthy volunteers and sickle cell patients. We believe these 601 data will be positioned to provide proof of concept for this program and start to fulfill the tremendous potential we see for GBT-601 to provide a functional cure and appeal for sickle cell disease. All of this activity demonstrates GBT's commitment to this community. And in September, we launched the GBT Foundation, a nonprofit charitable organization that will fund programs that support the sickle cell disease community and beyond through education, empowerment, access, and health equity. Also in September, GBT co-hosted the 10th Annual Sickle Cell Disease Therapeutics Conference, which brings together community leaders to discuss the latest advances and future trends in SED. Importantly, there were several sessions on COVID-19 vaccines, including education on how they work and people sharing their experiences getting the vaccine. This is a critical part of our work, and we will continue to support the sickle cell community. With that, I will turn the call over to Jeff to review our third quarter results.

Thank you, Ted. Total net revenue from sales of Oxbrider was $52.1 million for the third quarter of 2021, consistent with the guidance range we provided. Third quarter revenue increased by 15.2 million, or 41% year over year. On a sequential basis, third quarter revenue increased by 9.5% from the second quarter. This sequential growth was driven by the continued increase in the net number of patients on Ospirida, including demand from existing and new patients, and reflected lower new prescriptions in the quarter, a trend that we believe could continue into the fourth quarter. Days of inventory on hand in the third quarter was relatively flat, although absolute levels of inventory increased, reflecting the growing Oxypride of patient base. Growth to net was approximately 14%, a slight decrease from the second quarter, reflecting less Medicaid and copay deductions, partially offset by higher 340B sales. Like most in our industry, we saw lower than anticipated new prescriptions in the third quarter, primarily driven by the surge in COVID cases from the Delta variant. We believe this headwind will continue in the fourth quarter, and we remain cautious on the overall COVID environment, given we are heading into the winter months and there continues to be lower rates of vaccination among Black Americans as compared to the overall population. Sales are also typically impacted in the fourth quarter by major holidays. including significantly lower visits to HCPs as offices shut down in the second half of December. Given these factors, for the fourth quarter, we expect revenue of approximately $54 to $56 million. This range assumes an incremental increase in gross to net and flat inventory dynamics compared to the third quarter. While in the prior year we saw an increase in inventory levels in the fourth quarter, we don't have enough history to predict the trend with certainty. Looking forward, we continue to anticipate as the pandemic gradually improves and as we gain more traction with our commercial efforts, we will see a corresponding improvement in new prescriptions and revenue growth. Now, turning to expenses. Cost of sales for the third quarter was $830,000 as compared with $513,000 for the third quarter of 2020 and consistent on a gross margin basis year-over-year. Cost of sales was low in both years, as the majority of the manufacturing costs related to Oxbrita sales were incurred prior to FDA approval and thus were recorded as an R&D expense. R&D expense for the third quarter of 2021 was $51 million, compared with $40 million for the same period in 2020. The increase in R&D expense in the third quarter was primarily due to costs related to the advancement of our preclinical programs, as well as our GBT-601 Phase 1 study and two n-clacomab Phase 3 studies. We continue to anticipate an incremental increase in R&D expense in the fourth quarter, driven by the n-clacomab studies, which includes the $5 million milestone payment by GBT and the advancement of GBT-601 and other pipeline activities. SG&A for the third quarter of 2021. was $68 million, compared with $55 million for the same period in 2020. The increase in SG&A expense was primarily due to increased employee-related costs, including non-cash stock compensation, and supporting the commercialization of Oxbrita, including the rollout of new materials and our direct-to-consumer advertising. Other factors driving this increase were our measured expansion into Europe and the initiation of multiple Oxbrita investigator-sponsored studies. We anticipate another stepwise increase in SG&A expense in the fourth quarter driven by these same factors as well as launch readiness activities in preparation for potential pediatric approval. Net loss for the third quarter was $71 million compared to $60 million for the same period in 2020. Basic and diluted net loss per share for the third quarter was $1.13 per share compared with $0.97 per share for the same period in 2020. We continue to be well-positioned with a strong balance sheet with cash, cash equivalents, and marketable securities of $417 million at quarter end, compared with $561 million at December 31, 2020. This includes the opportunistic addition of approximately $44 million during the quarter from net equity proceeds from our at-the-market or ATM financing agreement. And with that, I will now turn the call over to DJ.

Thank you, Jeff, and good afternoon, everyone. I will provide an update on three key metrics that will give you further insight into our progress. These metrics are new prescriptions for Oxbrita, which informs underlying patient demand, the number of healthcare providers prescribing Oxbrita, which captures the progress we are making in adoption, and payer coverage, which speaks to the access environment for Oxbrita. First, new prescriptions. There were approximately 850 new prescriptions for Oxbrita during the quarter. reflecting progress with our recently launched initiatives offset primarily by the headwinds from the spike in COVID-19 cases in August and September, driven by the spread of the Delta variant. Unfortunately, many of the regions that had the highest growth in the Delta wave also have the highest numbers of sickle cell disease patients, including many southern states such as Texas and Georgia. This resulted in fewer interactions between healthcare providers and SCD patients and fewer engagements between healthcare providers and our field teams. In addition, we saw that some SCD clinicians, particularly in the southern states, were pulled away from routine patient care in order to treat COVID-19 patients. All of this contributed to fewer new prescriptions in the quarter. As we monitor the COVID environment and think about recovery, we believe the key leading indicators that are predictive of a return to growth are the improvement in industry-wide new-to-brand prescriptions and SCD patient visits beginning to return to historical levels. In order to improve our ability to drive new prescriptions, we have a variety of strategies to drive Oxbrita awareness, adoption, and adherence. We regularly evaluate the size and structure of our commercial operations to optimize our engagements. And in fact, in October, we reorganized some of our commercial functions into two business years. We believe this change will enhance communication, alignment, and synergies, and ultimately accelerate growth in the number of patients on Oxbrita. I remain confident in our team's strategies and tactics and believe they will be positive growth drivers going forward. Our targeted patient campaign launched at the end of July and features actual Oxbrita patients and their families. It clearly highlights Oxbrita messages and serves as an empowering call to action for patients to engage with their healthcare providers. The commercial, which broke ground as the first of its kind in sickle cell disease, well exceeded its targeted audience reach in the initial month of the campaign. While it is still early to measure pull-through prescriptions, we are seeing encouraging signs that more patients are seeking information about Oxprida. The campaign is running on multiple channels, including connected TV, social media, in print, and can be viewed on Oxprida.com. To complement our DTC campaign, we continue to focus on education. We believe having a fundamental understanding of the root cause of SCD is critical in understanding the value of Oxbrita and initiating patients on therapy. In the fourth quarter, we are activating a specialized sickle cell clinical team through an established partner to do virtual education on SCD pathophysiology with our targeted HCPs. They will also set up branded engagements for our sickle cell therapeutic specialists. This team is actively being trained and will be deployed starting December 1st and throughout 2022. We are also educating HCPs on the importance of improving oxygen delivery, reducing hemolysis, and educating patients on the potential impact of low hemoglobin. In Q3, we also successfully conducted branded Oxbrita speaker education events with patients. We believe having trained HCP experts providing education directly to patients is another important way to inform patients about their disease and Oxbrita. It is our goal that as branded and unbranded awareness increases, the large portion of SCD patients that remain untreated with any therapy engage with their HCPs and initiate oxbritotherapy. In the third quarter, we continued to make progress improving new prescription conversions. New offerings like CoverMyMeds, which make the prior authorization process easier and more efficient for healthcare providers, are helping us improve the rate and speed of taking new prescriptions from enrollment to a patient starting on therapy. During the quarter, Oxbrita adherence, which includes compliance and persistence, was stable and within the range of our analogs. In addition, a significant number of patients that discontinued therapy are restarting on Oxbrita. To further support adherence, in the fourth quarter, we plan to launch two new features for GBT Source Solutions, our patient hub. First, we are improving our email communications with newsletters timed to a patient's journey with GBT Source that provide information on how to access and use the hub and ongoing support provided by our nurse adherence program. Second, we are optimizing our communications with patients by deploying mobile messaging with a focus on increasing engagements and reducing discontinuation. Our market research also continues to support the strong fundamentals of Oxbrita. Nearly all patients report that they experience some form of symptom improvement and are likely to recommend it to others. and nearly all healthcare providers who are aware of Oxbrita have already prescribed it or plan to in the future. That said, the research also shows that COVID-19 continues to negatively impact patients' ability to maintain their appointments and complete lab work to monitor their disease. Looking at Oxbrita use, we continue to see broad range of characteristics, such as a baseline hemoglobin and VOC burden, suggesting that prescribers are increasingly recognizing the importance of addressing polymerization and long-term health, which leads me to my second metric, healthcare provider penetration. During the quarter, total interactions with healthcare providers remained below pre-pandemic levels. Hospitals and institutions in states like Texas, Louisiana, and Florida were restrictive or cautious about in-person visits. Against this backdrop, we still added about 130 new prescribers in the quarter, bringing our total prescribers to more than 1,800 since launch. When we look at the breakdown of riders, we continue to see prescriptions being written by both specialists and non-specialists, which we believe is a positive trend for the long-term trajectory of the launch. Turning to payer coverage, in 2020, we achieved broad coverage with more than 90% of covered lives having access in the United States. This strong coverage has contributed to improved efficiency in converting new prescriptions to patient starting therapy. We are now focused on making it easier for physicians to prescribe and patients Evox Brita. This includes streamlining the process for physicians with Cover My Meds, working with plans to simplify patient-level process for coverage, and providing access to our co-pay program. Our team is also laying the groundwork for the potential pediatric label expansion by meeting with payers to educate and prepare them for the expansion of the approved patient population down to four years old. This work gives us confidence that we can achieve broad coverage for the four to 11-year-old age group faster than than we did in the adolescent and adult population. On a similar note, I also want to highlight that our teams are well underway with launch preparations. This includes ongoing engagement with HCP targets that serve a large number of pediatric patients to discuss Oxprida's current approved indication, gaining experience through the pediatric early access program, advancing medical and scientific education initiatives, including sharing initial data from the EAP such as the pediatric quality of life data presented at FSCDR through our medical science liaisons, and finalizing our market research and related launch strategies. I'm confident that we will be well prepared for potential pediatric expansion, and the entire team is extremely excited at the opportunity to bring Oxbrita to younger pediatric patients who we believe can benefit from Oxbrita. And with that, Kim will now talk about the developments in our pipelines.

Thank you, DJ, and good afternoon, everyone. On today's call, I will provide a preview of the data we will present at the ASH annual meeting in December, along with an update on our efforts to potentially expand the label and geographic reach of Oxbrita. We will present three posters at ASH that further support the safety and efficacy of Oxbrita. The first is an expansion of the previously reported symphony claims analysis, which now includes nearly 2,700 sickle cell patients ages 12 and older. The second covers durability of response and safety data for the long-term use of Voxprida and the open label extension of the Phase 3 HOPE study. And the third is an updated readout from our retrospective retro registry in 10 U.S. sites. As a reminder, we recently launched the retro and prospect post-marketing registries to enable a deeper understanding of Oxbrita's long-term efficacy and safety and provide additional real-world evidence that we believe will support its use in sickle cell disease patients. We plan to update our educational materials reflecting this data so that our MSLs can proactively share the latest real-world evidence immediately after the ASH meetings. turning to the pipeline. For Enclacimab, our P-selectin inhibitor for reduction of VOCs, we have initiated two phase three studies collectively named Thrive. One is evaluating the reduction of VOCs over a 48-week treatment period, and the other is evaluating the 90-day VOC readmission rates following an initial VOC hospitalization, which tragically occurs in around 50% of patients. At the ASH meeting, we will present data from our phase one study of enclaquimab in healthy volunteers, the results of which we believe support its best-in-class potential as a medicine for quarterly dosing. We believe this would be a meaningful improvement for patients compared to monthly dosing and aligns well with a typical sickle cell disease practice schedule of quarterly check-ins. For GBT601, our next generation hemoglobin polymerization inhibitor, we are excited to present the first data from our phase one study at the ASH meeting. This includes data from healthy volunteers and in patients with sickle cell disease. In both the preclinical data and the healthy volunteer data that was released today in our abstract, we observed a linear PK and dose-dependent increase in hemoglobin occupancy with 601. The single-dose healthy volunteer data exceeds the corresponding right of hemoglobin occupancy achieved over a similar single-dose range. If the sickle cell patient data at ASH continues this trend and shows hemoglobin modification in the 30% plus range, we believe GBT601 could be a potential best-in-class therapy. And what's really exciting for patients is that we believe this level of efficacy has potential to eliminate all symptoms and long-term organ damage in many patients, providing a functional cure and a once daily pill. As the FDA continues to review our approval applications for potential pediatric expansion, We also continue to see strong interest in our early access protocol, which we expanded from 50 up to 150 patients age 4 to 11. We believe that beginning treatment earlier has the potential to modify the course of the disease and alleviate future serious and life-threatening complications by mitigating red blood cell sickling and destruction. Turning to Europe. We remain on schedule with their review of our marketing authorization application. We continue to believe our MAA could be approved in the first half of 2022. In advance of potential approval, we are building momentum with early access programs with a particular focus on France, the United Kingdom, and Germany, which are of the highest strategic importance. We are also working to make Oxbrita available in the Middle East and potentially also in Latin America. In the Gulf Cooperation Council region, we are ahead of schedule on our regulatory filings. And in October, we received approval for Oxbrita in the United Arab Emirates, our first approval outside of the US. Altogether, our label and global expansion plans are intended to give us the opportunity to reach more than 350,000 sickle cell patients around the world over the next several years. And as we make progress against this goal, we will continue to explore strategies to bring our therapies to patients in limited resource geographies, such as Africa and India. Finally, we'll be pleased to share more on our pipeline and activities to expand access to our innovative therapies at our R&D Day next week. In addition to the research I just went over, the event will include a panel of sickle cell disease experts who will discuss their experience with Oxbrita and its place in the sickle cell disease therapeutic landscape. And I will host a fireside chat with a sickle cell disease advocate and the mother of three children with sickle cell to provide insight into the pediatric patient journey and experience. And with that, I'll turn it back over to Ted.

Thank you, Kim. In closing, GBT continues its leadership in sickle cell disease and is well positioned for long-term success. We are fine-tuning our commercial activities as we continue to drive awareness and adoption of Oxforda and prepare for multiple growth opportunities ahead. While COVID-19 continues to have an impact, our country is making progress. This pandemic will come to an end. And we are seeing progress in the sickle cell disease community as more people impacted by the disease receive COVID-19 vaccination. As we move forward, GBT's commitment to supporting the sickle cell community is stronger than ever as we strive to improve the lives of our patients. As we approach the end of the year, I want to take a moment to highlight that we recently celebrated our 10-year anniversary. I want to thank everyone that's been involved with our success over the past decade. We have truly made incredible progress and are grateful to be positively impacting the lives of patients. We received a significant recognition for this impact last week with Dr. Sprider receiving the very prestigious Pre-Gallien USA Award for Best Biotechnology Product. Some of our original discovery team for Oxprata were on hand to receive the award in New York City. It is a tremendous honor to receive this award and the result of hard work by so many. Yet it was bittersweet, as shortly thereafter, we learned of the passing of Hertz Nazir, a well-known sickle cell warrior and talented artist who used his personal battle and his powerful artwork to advocate for patients and raise awareness of the disease. We knew Hertz well. He was in our office a few days before his passing and presented GBT with an installation, a beautiful and complex depiction of sickle cell disease and the hope to transform it. Sadly, Hertz lost his battle far too young, like most sickle cell patients. I know Hertz would have wanted all of us, patients, advocates, healthcare providers, companies, and investors to come together as a community to collectively move forward to a future in which sickle cell disease is a well-managed condition. On his behalf and on the behalf of patients everywhere, we at GBT will not stop until we achieve this goal. Now, before we open the call for questions, we wanted to briefly comment on the GBT-601 abstract that was published by ASH this morning. I've invited Brian Cathers, our Chief Scientific Officer, to join us. Brian?

Thank you, Ted. Good afternoon, everyone. As Ted and Kim said, we are excited for the potential of GBT601. Our 601 abstract actually includes two studies. One is a healthy volunteer study looking at single doses and multiple ascending doses of 601. The second is looking at single and multiple ascending doses in SCD patients. I'm going to discuss the data in the single dose healthy volunteer study and how we interpret this data. With each single dose, we measured hemoglobin occupancy levels. From a single dose of 601 at 50 milligrams, the mean preliminary occupancy was just under 1%. At the 1,400 milligram dose, the mean preliminary percent hemoglobin occupancy was 25%. This exceeded the hemoglobin occupancies reported for healthy volunteers receiving single doses of voxelotor over a similar dose range. When plotting this data and the voxelotor data together on a graph, the trend line for 601 is definitely steeper than that which we saw with voxelotor. What does this mean for the multiple dose study? In general, with a long half-life drug, additional separation would be expected to occur with multiple dose data versus the single dose data in healthy volunteers as well as patients. Before I wrap up, I also wanted to clarify that the reference to the GBT601 abstract used to support the comparison to voxelotor published in error. The correct publication has the title, Pharmacokinetics and Pharmacodynamics of Voxelotor in Healthy Adults and Patients with Sickle Cell Disease, which was published in the British Journal of Clinical Pharmacology in February of 2019. I also wanted to mention that GBT601 was well tolerated with the healthy volunteer study and the single-dose study of SCD patients. While there was one serious AE in the healthy volunteer study, this AE was not related to the study drug. Overall, we are encouraged by the data we have seen in healthy volunteers and are excited to continue our phase one study, which is ongoing. If the sickle cell patient data continues this trend that we are seeing in healthy volunteers, and shows hemoglobin modification in the 30% plus range, as we have said before, we believe GBT-601 could be a potential best-in-class therapy. With that, we'll now open the call for questions. Operator?

Thank you. We will be now 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. If you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants 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. The first question is from Jason Gerberry of Bank of America. Please go ahead.

Hey, guys. Good evening. Thanks for taking my question. My question has to do with the previous animal data for 601, the towns model data. I think you guys may have addressed this in a past forum, but I forget what the response was, so I'm going to ask it again. I assume you looked at VoxSolitor in a similar animal model. I'm just wondering how consistent these improvements are in receptor occupancy. in using voxelotor versus 601, and ultimately the increases in hemoglobin that you saw with voxelotor versus 601, if you could just clarify that, because I know in the publication there isn't a voxelotor arm.

So with voxelotor, it's a little bit complicated, but only in sickle cell mice. In sickle cell mice, unlike every other species we've tested, voxelotor has unpredictable exposure. So we can't get the occupancies, the target occupancies that we'd like. So in the published studies with voxelotor, Several animals did achieve the target occupancies, and we see robust responses in the town's mouse model. But what we do see with 601 in comparison is significantly lower doses were able to achieve the target occupancies. In addition, at similar occupancy with 601, we see significantly greater efficacy as compared to voxelotor.

Got it. Okay. Thank you.

The next question is from Akash Tiwari from Jefferies. Please go ahead.

Thanks so much. So if we look at the data today, NHLV601 looks about three to five times more potent than Oxbrita. And I guess the simple math we're all doing is saying if it's getting dose about 10x lower than Oxbrita with 100 and 200 milligram MAD dose, are we really going to get a fair shot on goal in terms of hitting that 30% modification threshold and kind of the downstream effect you get in hemoglobin? Now, you've talked about the loading dose and you've mentioned that it'll be applied twice and will basically accelerate the process to getting a steady state hemoglobin modification. So, A, what is the loading dose and how will it be applied for 601? And do you feel that the data at ASH will be a fair read on 601's ability to increase hemoglobin and modify HBS? And then maybe if I can sneak this in, can you also comment on if you would be willing to pursue an accelerated approval pathway with 601? and if we may get details on that at the R&D day. Thank you.

Yeah, Cash, that was a couple of questions, but I'll start out with saying that the way the study is designed is the patients get a single dose, and then those same patients will get a loading dose followed by a maintenance dose, and we will look at that data, and then we'll recalculate giving them another loading dose followed by another maintenance dose. So we really have two shots on goal, if you will, to get to this 30% modification. And the goal here, and that's really the concept that we're trying to prove. We already know with Oxbrita and gene therapy and CRISPR that once you get to certain levels of non-sickling hemoglobin, the disease mitigates dramatically. So really the concept here is to figure out if we can get to these high levels of modification, 30 plus percent, with a very low dose that would be compatible with a once daily pill. So that's really the concept that we're trying to prove. And we do think that we'll be in a strong position to make that conclusion or not at ASH. So we feel good about that. With regard to accelerated approval, what I've always said in drug development is get some data, talk to the FDA, and you'll have a good discussion. Rather than going to the FDA with a bunch of hypothetical and having a terrible discussion, that's been my career. So right now, we are really focused on getting some data so that we understand Oxprida, and then we will go and have a thoughtful discussion with the FDA about our development strategy, and then we will tell you about it. But we really don't want to put the cart before the horse to start talking about our development strategy before we know, quite frankly, pretty much about the drug. So we're just trying to proceed with this in a very thoughtful way so we can give you good feedback I will tell you that I personally, at this point, am not leaning toward an accelerated approval strategy. I'm more focused on a full approval strategy. I think that may be possible if we get the kind of efficacy profile that we anticipate we may. But again, that's really a statement that I'm making on the basis of no data, but simply speculation about what the data might look like. Understood. Thanks so much.

The next question is from Alicia Young from Cantor. Please go ahead.

Hey, guys. Thanks for taking my question, and congrats on the award, the pre-gallon. That's awesome. I guess, again, continuing on 601, I apologize. You know, it seems like with a single dose, you showed 25%. It seems like with multiple doses, obviously, there'll be more. how do you think that translates into VOC reduction? And is that something that you think now is kind of more important than it was with Oxbride or does it have the same level of importance from a regulatory standpoint?

Yeah, it's a good question, Alethea. And I'll invite Kim to follow on and add anything to this. What I would say is that I think we've demonstrated already with Oxbride that the science is actually as you would predict. That is, polymerization of sickle hemoglobin is causing sickling and red blood cell destruction and anemia. If you intervene with Oxprida and reduce the polymerization, you can see very quickly that the red cell destruction declines as measured by the hemoglobin rising, as well as all the elements of hemolysis declining. So this we already know We also know that if you look at the VOCs in a dose-response manner in the HOPE study, the VOCs decline. We did not design that study and power that study around p-values, but the apparent effect is very clear of that. As you give more oxbrita, the VOCs go down. The other thing that, again, we published, is that the higher your hemoglobin went, the lower your VOC went. In other words, they were inversely related. Hemoglobin rise correlated with VOC decline. And if you think about it, this all makes sense because this is a disease which is fundamentally driven by polymerizing to cohemoglobin, A drug which interrupts that should decrease red cell destruction, should create a more healthy vasculature with less inflammation over time, with less of the vaso-occlusive events that are associated with the disease. So I think all the science actually fits together very well. And we would expect, once we get to bigger studies with 601, if we're modifying more hemoglobin, we would expect the hemoglobin levels to be higher. and the VLC reductions to likely be lower. We have to prove all that, and we know we need to prove all that. But the science has been actually remarkably consistent.

Great. Thank you.

The next question is from Mark Breidenbach from Oppenheimer. Please go ahead.

Hey, good afternoon. Thanks for taking my question. Just very quickly for me. I'm wondering if we're actually going to see multi-dose hemoglobin occupancy data in sickle cell patients in the ASH presentation, or is it just going to be healthy volunteers, or is it just going to be single-dose hemoglobin occupancy? And then maybe I'm wondering if we can get DJ to just comment on any major differences between your pediatric launch strategy versus what you've already been doing in adults. I'm just trying to get a sense for how much of an overlap there is in terms of target health care providers and things of that sort. Thank you.

Kim, do you want to talk about the ASH-601 multidose? And DJ would take the question about pediatric launch.

Yes, Mark. Thanks for that question. I think that it's our intention to show multiple ascending dose data in individuals with sickle cell disease and healthy volunteers.

Yeah, Mark, this is DJ. Regarding the pediatric pending potential approval and launch, so we're in full-fledged launch preparation mode, as you would expect. The good news is 97% of the patients between 4 and 11 years old in the United States are in geographies where we already have sickle cell therapeutic specialists. The vast majority of the physicians that treat those patients are also already in our target list and being called on. We are expanding our target list by about 200 sickle cell specialists at approval, and those represent the incremental 200 physicians that are really only focused on younger kids and don't have anyone currently 12 and older, so there'd be no reason to be in our current target list. So it's a very small group of expansion, and we've already got relationships with the vast majority of other pediatric hematologists. So we feel really good about that and leveraging that and Of course, they have some experience with Oxbrida over the last couple of years in the 12 and older. But the preparation on many fronts is the same in terms of great work by our payer access teams, preparing the payers, having those meetings, making sure we can get broad coverage as quick as possible. Our patient support services and educational initiatives that we plan to launch with are all being developed. So all of those things are consistent with what we did with the 12 and older launches, but will be, of course, geared towards the kids. And then, of course, we have a new formulation. So it's a great opportunity for us to do some education around the new formulation and creating some materials to make sure the caregivers and the kids themselves have that education.

Terrific. Thanks so much.

The next question is from Paul Choi from Goldman Sachs. Please go ahead.

Thank you and good afternoon everyone. My question is on 601 and with regard to what insights you have so far from the sickle cell patients that you've dosed. The abstract indicates baseline hemoglobins in a relatively wide range, but do you feel you have visibility on what the appropriate patient population would be for your next stage study here at this point? do you think about 601 still as being applicable to severe patients with extremely low hemoglobin, or do you think about it potentially as a more narrowly defined patient population? Thank you very much. Yeah.

So it's a great question, Paul. I mean, I think of these drugs the way I think about hypertension. I really don't want to wait on you to have a heart attack or a stroke to begin treating you. And that's what we're trying to do in sickle cell disease. It's been a disease, quite frankly, where treatment has been reactionary, and we still are in the situation we were in a couple of decades ago. People are dying in their 40s. You're probably not going to change that if you have a reactionary approach. So the whole point of developing disease modifiers is to intervene – essentially when people are still normal, uh, try to correct the anemia. Uh, and in children, you may be able to do that very early and you may be able to do it reliably in children. If you intervene early, um, uh, and keep them normal, uh, as opposed to wait for their hemoglobins to go down to six or eight or nine, that's not normal. And you accumulate disease when you're, when you're running around with those levels. I mean, we know already, um, that 15%, somewhere in the range of 10 to 15% of kids have suffered silent ischemic strokes in the first decade of life. So I'm not sure why we'd be content with that if we could do something about it. Okay, thank you very much.

The next question is from June Lee from Truist Securities. Please go ahead.

Hi, thanks for taking our questions. I have a couple, but do you have any idea as to what percent occupancy you need to hit to extract the most therapeutic benefit while avoiding potential side effects? What percent do you think you'll start to run into certain weird oxygen hemoglobin interaction issues potentially?

Yeah, it's a great question, June. And ultimately you have to do the clinical work, right, to figure this out. But one of the reasons that we do all this toxicology work before we go into humans is to try to get an understanding of what are the likely consequences and risk of the drug. So you can look for that when you're actually doing your clinical studies. So we've done an extensive amount of work preclinically with 601, and the truth is it's very well tolerated. We actually modify 100% of the hemoglobin, and it does not hurt animals. So will that be true in humans? I don't know. I don't think we'll likely dose to 100% modification because coming back to your earlier question, we know people with sickle cell traits have 50% roughly sickling hemoglobin and they have a normal life expectancy. And that would imply we don't need to modify 100% of the hemoglobin. If we simply modified roughly half of the hemoglobin, you would predict that we might be able to convert people into more of a sickle cell trait phenotype, and that would be a huge medical advance. So we still need to understand exactly what the threshold is. Kim, you may want to elaborate on persistent expression of fetal hemoglobin. Some of those data indicate that you may not need to get to 50%, but we certainly have kind of set 30% and higher as a target that we think we want to prove that we can easily get to with 601.

Yeah, I think you stated that well, Ted. We know through studies of individuals with physical and hereditary persistence of fetal hemoglobin that you get 30% fetal hemoglobin levels and you're at a relatively asymptomatic state. I think it is a nice conservative approach to estimate the between 30% and 50% hemoglobin modification that we may be getting there with

Got it. Just if I could squeeze in one question. Since you mentioned disease modification, you know, if you start earlier with the pediatric population, do you have an opportunity to show benefit in organs other than the brain? I read that the spleen may be damaged in these patients earlier on. Is there an opportunity in other organs that may be more accessible? Thank you.

Well, that's a great question for Kim, since she was involved in the baby hug study, which is where I think you're going.

Yeah, I think that this is an excellent question. One of the things that is impressive about a proactive rather than a reactive approach to treatment is the possibility of preserving organ function. And so the younger that we can get into age groups faster, I think we'll be able to look at preservation of organ function. And the spleen, as you know, is one of the organs where we see dysfunction relatively early in life, which is why so many children need to be placed on penicillin early in life. So I agree with you that we may be able to really look at organ preservation, and the spleen is an optimal organ to start with.

The next question is from Gregory Renza from RBC Capital Markets. Please go ahead.

Hey, good afternoon, Ted and team. Congrats on the progress, and thanks for taking my question. Ted, maybe just to follow up on some of DJ's commentary, just curious if you could perhaps comment on some of those market dynamics you're seeing into the end of this year with respect to the new prescriptions. If I recall, I think, DJ, you mentioned just the best leading indicator being those clinical interactions Perhaps you could just elaborate further, especially with respect to that typical lag time that we're seeing and how you see that playing out when it comes to actually converting patients to start therapy. Thank you very much.

Yeah, Greg, thanks for the question. Yeah, that's right. So we've seen some really great dynamics lately in the marketplace with regards to the pandemic, right? We got past the Delta variant surge, but in Q3, we are right in the middle of it. So in August and September, there was significant increases, not only in infection rates, but if you look at the ICU bed utilization, for example, in key sickle cell states like Florida, Texas, and Georgia, all top five sickle cell states, they had over 90% of their ICU beds in use during Q3 because of the surge. Certain states like Texas and Florida, the number two and number three sickle cell states, hit all-time highs for infections in Q3, uh, of the entire pandemic. So all of this impacted negatively on patient visits and that included sickle cell patients. So the two things that we look at, um, are not only are our people being vaccinated and unfortunately the CDC website still show African-Americans are lagging behind, uh, other races in terms of vaccination rates in this country, although it's going the right direction, more and more people are being vaccinated. Um, But what's most important to us is when did people feel confident in going back into the healthcare system at the rates they were before the pandemic? Unfortunately, they weren't there in Q3. In Q3, it actually got a little bit worse. So the two parameters we look at are industry-wide new to brand metrics, which is basically new prescriptions of drugs in the United States. And if you look at the kind of industry audits on that, it's well below pre-pandemic level still, and Q3 was worse than Q2. And then the other thing we look at is a sickle cell disease-specific audit that we do. We look at the claims databases for sickle cell patients, and that's where we get insights into are they actually seeing their healthcare providers at the same rate they were, and that is still below pre-pandemic levels and got a little bit worse in Q3 because of the surge. So we're hopeful in Q4 things will start to turn around. We look at those audits once a quarter. So we'll look at it again in Q4. But in Q3, that was a clear headwind for us.

The next question is from Matthew Harrison from Morgan Stanley. Please go ahead.

Great. Good evening. Thanks for taking the question. Sorry to dwell on 601, but you'll get another one from me here. So I guess what I was hoping to do was you previously presented a lot of data in mice, and specifically in that data in mice, you're able to normalize hemoglobin in those mice, irrespective of dose. Obviously, it takes longer with lower doses. So my question would just be the data that we're going to get at ASH, do you think you have long enough follow-up to be able to pour out that data in humans? Yes. or do you think you're going to need longer follow-up to be able to see that? Thank you.

Hi, Matthew. And I think actually I read your note on 601 earlier today, and I thought you made a lot of excellent points in your note. With regard to your question, I think the real thing that we want to educate people to focus on is the modification, because we actually know what modification translates into. But there is going to be variability. The nice thing about lab animals is that they're basically the same. And these lab animals, we began to treat very early in the disease. We didn't wait for these lab animals to be equivalent of 10 years old and accumulated organ damage. We intervened very, very early. So I think that in an individual case, That's very young. It may be possible to have a tight of correlation between the modification and the hemoglobin response. But I will tell you, just based on what we've already published, is that you get quite a bit of intersubject variability with the same level of modification. So I don't think we have the patient in in our initial study to really focus you so much on proof of concept With hemoglobin, it's really proof of concept with modification and relying upon the enormous body of data that says that on average, as you achieve higher levels of modification, you will achieve higher hemoglobin response. And we think lower VOCs and more favorable outcomes in every regard. But we're not going to have enough patients, obviously, to look at things like VOC and even Hemoglobin is variable enough that I would really educate people to focus on the modification more than anything else. Now, we're also going to be doing some other studies, which are probably more correlated with modification, like the Lorca analysis as well. And we'll be presenting all of that data as well.

The next question is from Monica Mercandini from Evercore. Please go ahead.

Great. Thanks for taking the question. Just on 601 as well and the data that we saw this morning, what was the time point that occupancy was measured at? Just wondering on the PK of the drug and if you'd expect this to be the peak level of occupancy even after SAD dosing. And then thinking to ASH, what's kind of the highest dose level we should expect to see in the MAD cohort at ASH? And would you consider going above 200 mgs if the occupancy levels aren't consistently above 30% at that dose? Thanks.

So Brian, you can take that.

Sure. The first part, we're talking about occupancy at the peak. So it's just because it's a single dose, what you expect with any drug that has a long half-life after multiple days of dosing, the C max to the C min actually are very similar. But with a single dose, we want to look at C max. That's the more relevant measure for us.

So just to make sure that that's very clear, what you would expect is that with multiple dosing with a longer half-life drug, that peak amount is going to be an underestimate of what the steady state will ultimately be. And over time, with a very long half-life drug, there will still be a peak and a trough, but that difference is likely to be very small with a very long half-life drug. And that's what we're expecting for the profile of Oxprida. So it really better, if you will, approximates gene modification, because you're not getting these excursions of activity, you're getting pretty much a steady state of how much of the hemoglobin is modified.

The next question is from... Pardon me. The next question is from Roger Prasad from William Blair. Please go ahead.

Hi there. This is Samia on for Raj. Thanks for taking our question. We're trying to get a better sense of the potential launch into the pediatric label. So I was wondering if you could provide any color on the current number of patients ages 12 to 17 who are already being treated. And then if you plan on providing any distinguishing commercial indicators so we can get a better sense of post-approval on how the launch is doing compared to the original label. Thanks.

So I'll ask DJ to take that. But I don't think we've actually provided numbers on the current breakdown of patients on therapy, but we have provided a breakdown on how many patients fit into each age group, and we could reassure that. I mean, logically speaking, they would look fairly similar, but we haven't provided that data in the past.

That's right. We haven't broken it out by age that way. I can tell you that, you know, we do feel we have both growth opportunities and breadth and depth of prescriptions of our target list of about 4,500 physicians that we call on a regular basis, about half, a little over half of the high potential, the highest decile physicians, kind of the specialists have written prescriptions for Oxbrita. So they still have opportunity to grow into their second group of patients. But overall, some of the mid tier and lower tier physicians, only about a third of them have written a prescription for Oxbride. Again, this speaks to access to their physicians, ability to educate their, excuse me, access to patients and the ability to educate patients during a pandemic. So we have great opportunity in both those areas. The pediatric hematologists have only written Oxbride to the extent that they have experience in 12 and older. A lot of pediatricians have a lot of kids between four and 11. So, you know, they tell us that they've got opportunity to write it for those kids that they've been really holding on to. So, you know, it's an opportunity for us, you know, soon after launch.

The next question is from Ritu Baral from Cohen. Please go ahead.

Good evening, guys. Thanks for taking the question. Kev, I wanted to ask you about, you know, the comment that you made about 601 constituting a functional cure in a pill. I know you want us to focus on occupancy, but I'm also thinking about the other biomarkers that were presented pretty early on in the voxelotor development. You know, for this mechanism, what sort of hemoglobin change what sort of LDH change, bilirubin change, could constitute reduced organ damage and other improved outcomes above and beyond just VOCs? And I'd love to ask Dr. Smith-Whitley that question, too.

Well, maybe Kim should answer it completely, but I'll start by saying that Ritu, we just don't have enough patients and enough follow-up in this study to look at any kind of clinically meaningful outcome. And I don't even think we have enough patients to look reliably at hemoglobin levels. I think you know, if you just look at the HOPE study, patients with the same level of modification had widely varying hemoglobin responses. Some people, three, four grams per deciliter. Other patients, a half a gram per deciliter. So And that's due to the individual. And the way you get around that is by having a larger sample size. But if you look, for example, at the 900 milligram dose and the 1500 milligram dose, there's a lot of overlap in hemoglobin response. But when you look at the total data, you see that the hemoglobin response was definitely better with the 1500. But it took 84 patients per arm to see that. So we're not really powered to be looking at hemoglobin quite in the way you want. We will get there. But the start really is occupancy, because we feel pretty good that occupancy, as it has with Oxypride, predicts hemoglobin and other outcomes going in the direction that you like. So, Kim, feel free to correct me.

I just want to add that it's a very difficult process. population to really understand and study. When you look at individuals who have gone through curative therapies, we don't even achieve normal hemoglobin values and sometimes even not even normal LDH values, depending on the degree of mixed chimerism, but you have individuals who become symptom-free. So I think that this is something that we'll continue to learn more about as we study 601 and go through the clinical trials. But even with curative therapies, we really haven't been able to find consistency with what hemoglobins and other biomarkers mean in relation to cure.

The next question is from Yadin Suneja from Guggenheim Partners. Please go ahead.

Hey, guys. Let me ask you a question on the upcoming approval or upcoming PDUFA date from kids. I think you addressed this a little bit, but can you just talk about the goal from a reimbursement perspective, how quickly reimbursement could be achieved, and then your view in terms of uptake in kids versus adults? And then correct me if I'm wrong, I think this approval will add about 17,000 patients to the label. Can you just talk about the number exactly, how many new patients will be added? Thanks.

That's great. Thanks for the question, Yacht. Now I'll ask DJ to address those. Okay.

Yeah, Yacht. And so from a payer perspective, the good news is because we've already got approval for Oxbarida for the 12 and older, the majority of states will consider this a line extension. And because it's in pediatric patients where they clearly recognize a high unmet need, we expect the payer discussions to go even faster than it went with the 12 and older. Remember, we gave guidance in the Oxbride original launch of one year to get broad coverage, and we were able to accomplish that in three quarters. We expect this to be a bit faster than that. You know, exact dates, I can't give you. It will take a process still. you know, you have to introduce the product to them. It does have to go through some process to get reviewed even as a line extension to get on their formulary. But being a line extension for an existing product will go quicker. There are a few states that do require in their statutes, some Medicaid's that do require a full review every time a new NDC is brought to market. So those ones will be a little bit slower, more like three to six months for that review process. And then you're added to formulary. But by and large, we feel like This will be faster than we were able to accomplish in the 12 and older. In terms of size of market, yeah, you're right. 16,000 to 17,000 kids between 4 and 11 years old. It's a very sizable and important group for all the reasons Dr. Smith-Whitley talked about. Starting people earlier to protect the organs is the name of the game. So it's a sizable increase to our label. And because we're already calling on the pediatric hematologists, they're in our target list, we think the educational efforts will go even faster than they did with the older kids as well.

The next question is from Ben Burnett from Stiefel. Please go ahead.

Hey, thank you very much. I also wanted to ask a question about 601 and going back to some of the earlier discussion points around hemoglobin occupancy. And I guess maybe the way to ask this is really just what is the difference between single dose versus what we could expect from repeat dosing? And do you have available to you like what your experience was with Exprida when you dosed a single time in healthy volunteers, like what hemoglobin occupancy you achieved and then how that translated into patients with multi-dosing?

Hi, Ben. This is Ted. We actually did uh, send out some information. I think we may even have that on our website. So you can go onto the website and look at that comparison. But, but there is, uh, there is a pretty big difference between what you get with a single dose and a multiple dose. And the difference becomes even greater, uh, if the half-life is longer. Um, what I'll just say, just to make sure that we're not being subtle, uh, We feel very good that we're going to be able to get to the modifications that we want to get to. But we haven't gotten there yet, and we need to get there and show you the data. But we're feeling very good about getting to this 30-plus percent modification with very low doses.

The next question is from Danielle Brill from Raymond James. Please go ahead.

Hi, guys. Thanks so much for the question, and I will add to the list on 601 here. Another follow-up on the correlation between hemoglobin occupancy and hemoglobin improvement. I guess I'm just wondering if you can elaborate a bit on the magnitude of hemoglobin change you'd expect to see at a 30% plus hemoglobin modification level. I mean, it sounds like You think at ASH, the changes will be variable and it's small and so we can't read too much into that. But in a more like representative population, would you expect that 30% hemoglobin modification with 601 would generate similar hemoglobin effects as gene therapies that reach 30% fetal hemoglobin level? Thanks.

Well, I mean, I'll defer to Kim on this, but my way of thinking about this, Danielle, has been that if we can match the non-sickling hemoglobin levels of gene therapy, I would expect the outcomes to be similar. Now, we need to prove all of this, but that would be our anticipation. But we do know that people can, as Kim said, get curative procedures, and their hemoglobin response is sometimes very strong. And sometimes it's not as strong. And that probably has to do with the variability of the biology of that individual. Now, you can get beyond that variability by using big ends. And I'll just put it into context. In the HOPE study, where the ends were pretty big, the average modification with 1,500 milligrams was about 1.1, 1.2 grams per deciliter. With the 900 milligram dose, It was about 0.6 at first. So there was a pretty big difference. But if you look at the individual patients, you're going to see there's a lot of overlap. So if you just randomly pick six patients, you may not see much of a difference, even though we know there's quite a big difference between 900 and 1,500.

The next question is from John Newman from Canaccord. Please go ahead. John, your line is open. We can't hear anything, so let's move on. The next question is from Andreas Argyris from Wedbush Securities. Please go ahead.

Good evening, and thanks for taking our questions. Before I start, just a quick, I want to offer our condolences on the loss of your friend. Sorry to hear about that. Thank you, Andres. Yeah, sorry to hear. This is probably for DJ. It's not a 601 question because they all have been asked. I look forward to the update. Just, you provided some metrics on the last quarterly call, and I just wanted to kind of get an update on those. So discontinuation rate in the sense of those who discontinued and then ultimately restart, has that number increased from the 20%? And then as far as the existing prescriber patient population, the penetration into that prescriber base, has that also improved above 30%? Thanks. Yeah, thank you.

Thanks for the questions. Regarding discontinuation rates and restarts, so the adherence, which includes both the discontinuations as well as compliance, has been stable for the last several quarters. It's well within the analogs. We've always said we want to be between 50% and 70% at the end of a patient's first year, and we're well within that range. The restart has also been consistent. We've seen over the last several quarters, 20 plus percent of discontinuations restart therapy at some point in the future. And so that continued in Q3 as well. And then the prescription penetrations, we have penetrated over, I think we're at now in terms of our target list, somewhere in the mid to high 30% range penetration now. I've written a prescription for Oxbrita. We know that our highest, prescribers like the top 50 doctors are writing it for 75% of their patients. So we know what it looks like and now it's just about continuing the education and getting patient access to their healthcare providers so that we can increase those rates.

The next question is from Yanan Zhu from Wells Fargo Securities.

Please go ahead. Thanks for taking my questions. Ted, you mentioned 50% non-sickling globin in trait individuals. And in the gene therapy gene editing studies, I think the non-sickling globin level is 45%. It was pretty consistent between different studies. So my question is, is 45% kind of equivalent receptor occupancy that that can give a lot of confidence in VOC-free and other functional cure measures. Is that the right way to think about it? And also, importantly, do you think with the current study, are you confident that 45% level is something that is within the reach of the study?

Yeah, so it's a good question. Yeah, actually, we've kind of set this 30% for a reason, and we could elaborate on the reason, but it's actually, if you look at persistent expression of fetal hemoglobin, it's at around 30% that individuals with sickle cell disease begin to significantly look more normal than like they've got sickle cell disease. And I agree with you that if you look at the gene therapy data, they've seen really their most dramatic effects when they've gotten above these levels. I have not gone back and parsed out exactly what Bluebird saw, for example, when they were at 38% or 35%. But my recollection is that when they were below 30%, they weren't getting the kind of efficacy that they wanted. They had to go above 30%. But Kim, you may know this data from experience better than I do.

No, Ted, I think you stated that correctly.

So the other point I would make is that one of the things that we know about sickle cell disease is that the VOCs that patients get are probably significantly driven by inflammation. And And that's one of the reasons we're developing Inclacimab, is that it is an anti-inflammatory drug. And we expect it will be highly effective in treating VLCs. Oxybride and 601 are not anti-inflammatory drugs. So we wouldn't anticipate any significant anti-inflammatory effect. But we do expect that with our therapy, there will be a delay between initiating therapy and and the resolution of inflammation and the symptoms and outcomes associated with inflammation. I mean, one of the things about ablative therapy is that it's highly immunosuppressive. In fact, that's what you're doing. You're completely wiping out the hematologic and significantly the immune system when you do these things. So you do get a profound and immediate anti-inflammatory effect, which we will not bring with our therapies, of course. But over time, as we saw in the HOPE study, we would expect inflammation to recede and VOCs to decline.

This concludes the question and answer session. I would like to turn the floor back over to Ted Love for closing comments.

In closing, I'd just like to thank everyone for joining the call today. I also want to remind you that we look forward to seeing many of you at our R&D day next week as well as seeing any of you virtually. In the meantime, I want you all to stay safe and healthy and please feel free to reach out if there are any additional questions.

This concludes today's conference call. You may disconnect your lines at this time. Thank you for your participation.