Global Blood Therapeutics, Inc.

Greetings, and welcome to the Global Blood Therapeutics' fourth quarter and full year 2021 conference call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the 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 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 fourth quarter and full year of 2021, and to provide a business update. I'm Stephen Emmergut, 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 R&D. During today's call, Ted will give an update on our progress in Q4 and the full year. Jeff will review our financial results. DJ will give an update on the Ospreyda launch. Kim will discuss our pipeline. And then Ted will give a few closing remarks before we open the line for questions. Earlier this afternoon, we issued a press release announcing GBT's financial results and business progress for the fourth quarter and full year ended December 31st, 2021. 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 annual report on Form 10-K, as well as in today's press release. Copies of our SEC filings and press releases can be obtained from the investors page for our company website at gvt.com. The forward-looking statements made on this call are only as of the time they are made and 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. I'll now turn the call over to Ted.

Thank you, Stephen, and good afternoon, everyone. 2021 was a year of significant advancement and growth for GPT as we made progress on our goal to transform the lives of patients with sickle cell disease. More healthcare providers and patients are aware of OxyPrida and using it to address the root cause of this terrible disease. And in December, our broad label got even broader. It now covers patients as young as four years old. Outside the U.S., we advanced our regulatory efforts and launch preparations in Europe while gaining valuable experience through our early access program. And we are very pleased with the progress on our robust late-stage pipeline. Going forward, our focus is on driving Ocfrida adoption, advancing our pipeline, and supporting the patient community. The fundamentals of OxFighter are strong. Every quarter since launch, we have grown the net number of patients on therapy. Physician and patient feedback continues to be very positive, and we continue to have broad payer coverage. Our key initiatives to increase adoption include executing on our pediatric launch, continuing to invest in our DTC campaign, in developing more real-world evidence of clinical benefit. And in the European Union, we just received full marketing authorization for OXPREDAT, making it the first and only therapy approved to treat the hemolytic anemia of sickle cell disease. This is an exciting and long-awaited milestone for patients, physicians, the sickle cell community, and GBT. We will now work towards launching in Germany, beginning reimbursement discussions in France, and educating healthcare providers across Europe. In the UK, we have submitted for marketing authorization and anticipate a potential approval by mid-year. Importantly for the UK, OXPRATA was granted EAMS designation, which provides two key advantages. First, patients that meet the eligibility criteria can gain early pre-licensed access to Oxbrita. Second, medicines under EAMS that receive marketing authorization by the MHRA, as well as a positive assessment by NICE, benefit from accelerated NHS England commissioning. While we work through the process in the EU and UK, we are working to build momentum with early access programs with patients enrolled in France, the UK, and Germany, markets where the majority of sickle cell patients live. Our strategy continues to address sickle cell through various therapeutic approaches, and we believe our R&D program is the most comprehensive in the industry. We are focused on aggressively advancing the development of Enclaquimab and GBT-601, both of which remain on track. And our research team is exploring additional therapeutic targets in SCD and other red blood cell disorders. GBT's mission and commitment to underserved communities is stronger than ever. We've talked a lot about COVID-19, and its outside impact on the sickle cell disease patient community. In 2021, we established the GPT Foundation, which extends our corporate giving in areas of critical need and strategic importance. We have and will continue to expand our investment in the SCD community and overall health equity. We will continue to meet patients where they are to support their overall health and well-being. We expect that our initiatives will gradually contribute to new prescription rules over 2022. We are also hopeful that the COVID-19 environment will improve. We've recently seen encouraging trends in new prescriptions as cases began to drop. We are hopeful that these trends will continue And our team is working extremely hard on all the factors that are within our control. Longer term, we remain optimistic for the future, given the tremendous unmet need in this disease and the compelling clinical data on Oxypride and our pipeline. With that, I will turn the call over to Jeff to review our fourth quarter and 2021 results.

Thank you, Ted. Total net revenue from sales of Oxypride was $56.1 million for the fourth quarter of 2021. Fourth quarter revenue increased by approximately $15 million or 36% year over year. 2021 revenue was $194.7 million, an increase of approximately $71 million or 57% year over year. On a sequential basis, fourth quarter revenue increased by 8% from the third quarter. This sequential growth primarily driven by the continued increase in the net number of patients on Oxbrita, including demand from existing and new patients, and slightly higher inventory purchases by distributors. On an absolute basis, levels of inventory increased, reflecting the growing patient base. Days of inventory on hand in the fourth quarter was approximately four days higher than the third quarter, representing about $2 million in revenues. Gross to net was approximately 16%, around a 1.5% increase from the third quarter, primarily related to higher Medicaid accruals in the current quarter. Now, turning to expenses. Cost of sales for the fourth quarter was $1 million, and for the full year was $3 million, compared with $1 million and $2 million for the fourth quarter and full year 2020, respectively. Cost of sales for the fourth quarter was 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 oxidized sales were incurred prior to FDA approval, and thus were recorded as an R&D expense. R&D expense for the fourth quarter of 2021 was $59 million, and for the full year was $212 million, compared with $41 million and $155 million for the same periods in 2020, respectively. The increase in R&D expense in the fourth quarter was primarily due to higher costs related to our 2 and Clacomab Phase III studies, which included the $5.3 million clinical milestone payment triggered by enrollment in our Phase III studies, as well as the advancement of our preclinical, Oxbrider, and GBT601 programs. SG&A for the fourth quarter was $79 million, and for the full year was $267 million, compared with $59 million and $211 million for the same periods in 2020, respectively. The increase in SG&A expense in the fourth quarter was primarily due to increased employee-related costs, including non-cash stock compensation, and expenses supporting the commercialization of Vox Brida, including the rollout of new materials, our direct-to-consumer advertising, and readiness activities related to our launch for younger children. Other factors driving this increase were our measured expansion into Europe, and the initiation of multiple investigator-sponsored studies. Net loss for the fourth quarter was $88 million, and for the full year was $303 million, compared to $62 million and $248 million for the same periods in 2020, respectively. Basic and diluted net loss per share for the fourth quarter was $1.36 per share, and for the full year was $4.81 per share, compared with $1 per share $4.04 per share for the same period in 2020, respectively. We ended 2021 with cash, cash equivalent, and marketable securities at $735 million, compared with $561 million at the end of 2020. This includes the addition of approximately $384 million during the fourth quarter in net proceeds from financing activities. Next, I'll walk you through some of the dynamics to think about when modeling revenue for 2022. If the pandemic begins to subside, we anticipate higher growth in Oxbrita new prescriptions for the 12 and older population in the second half of the year. While we're excited about the launch for younger children, we expect the new prescriptions and revenue growth will be gradual until the majority of patients have coverage, which we anticipate by mid-year. The label expansion represents approximately 16,000 incremental patients for a total addressable population of greater than 100,000 in the US. Following EU approval, we are now focused on access and reimbursement, particularly in the UK, France, and Germany, where the majority of patients are located. This will take time. We expect revenue from Europe will be de minimis in 2022, growth ramping up in 2023. Now for 2022 expenses. For cost of sales, we anticipate that we will utilize the remainder of our fully expensed inventory in the second half of the year, and we'll see an incremental step up in expense in the fourth quarter. For SG&A and R&D expenses, we expect higher than incremental growth in 2022 as compared to 2021. For SG&A, the increase year-over-year will be driven by continued investment in the commercialization of Oxbrita, including our launch for younger children, our measured expansion into Europe, and support for further investigator studies. For R&D, the increase year-over-year will be driven primarily by our clinical studies for EnclaqMap, as well as continued investment in Oxbrita studies in GBT601. We anticipate that both SG&A and R&D expenses will be more heavily weighted to the second half of the year. Specific to the first quarter of 2022, we anticipate revenues in the range of $54 to $56 million, driven primarily by the impact of Omicron and inventory dynamics. Inventory levels are anticipated to decrease as distributors work down the inventory built up from Q4, similar to our experience in the first quarter of 2021. And, gross to net is expected to increase incrementally from Q4, driven primarily by higher copay assistance and greater 340B utilization. Importantly, in Q1, we've seen improvement in demand trends that we anticipate will drive revenue growth in Q2 and the remainder of the year. In summary, we've delivered strong revenue growth in 2021 and have several catalysts to drive revenue growth in 2022. In addition, we continue to be well-positioned with a strong balance sheet, allowing us to make key investments in future growth. 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 on adoption, and payer coverage, which speaks to the access environment for Oxbrita. First, new prescriptions. There were approximately 800 new prescriptions during the quarter, reflecting the impact of the Delta variant early in the quarter and the holidays. During Q4, there continued to be fewer interactions between providers and patients compared to pre-pandemic levels, and less engagement between providers and our field teams as compared to Q3. Specific to Omicron, we saw an impact in January, though I am pleased with how our team continues to adapt to the changing environment, and demand and access dynamics have improved as infections have recently declined. As a result, we believe new prescriptions in the first quarter will incrementally increase compared to the fourth quarter. We believe the key leading indicators that are predictive of a return to sustained growth are improvements in industry-wide new-to-brand prescriptions and our patients' healthcare visits returning to pre-pandemic levels. While we have not yet seen a meaningful improvement in these indicators, we remain optimistic about Oxbride's growth potential and have initiated new programs to drive growth and adherence. One of the most significant new opportunities is the pediatric label extension, and new formulation approved by the FDA in mid-December. This represents approximately 15% of the total patients in the United States. Importantly, the new once daily oral dosage form allows Oxbrida to be dispersed in a liquid which is suitable for young children. It gives me great pride to have the opportunity to help healthcare providers treat children down to four years of age, to start to address their disease early, and potentially prevent further damage. Following the FDA approval, we worked quickly to train our teams, update our materials, and get the new formulation into the distribution channel. One of the key positives for the pediatric launch is that we can leverage most of the people, processes, and learnings that we've had in place for the last several years. This is illustrated by the following data, which speaks to the strong position that we are starting from. 95% of the kids aged four to 11 with sickle cell disease live in the geographies already covered by our current sales force. Drilling down, around two-thirds are being treated by prescribers who were already on our target list, and with the addition of around 200 new prescribers with the expanded label, this increases to around 75%. Viewed from another perspective, this younger age group is two times more likely to be treated in a sickle cell disease specialty treatment center as compared to adults. which is a more efficient model for our team to engage. In early January, our team was engaging with healthcare providers to educate them on the label expansion and train them on administering the new formulation and working with payers to secure coverage. The early feedback from the launch has been positive, and our surveys from mid-January indicate that around two-thirds of providers who are aware of Oxfrida know that it is now approved for younger children. This increases to more than 80% among pediatric hematologists who are the primary focus of our teams. We are pleased that we achieved this broad awareness in the first few weeks of launch. We are seeing early traction with some providers already writing prescriptions and starting their younger patients on Oxbrita across many states. To support the pediatric launch, we seamlessly added a pediatric patient and family to our DTC campaign and updated our Oxbrita website. While it is still too early to measure how the campaign translates into pull-through to new prescriptions, we are exceeding our target audience reach and made incremental investments in November to expand its impact in reaching patients and healthcare providers. We are leveraging geo-segmentation by zip code and other tactics that help focus our impressions on our target audiences. As a result, in the first five months of the campaign, we achieved approximately 20 million impressions and 2.7 million unique viewers. To complement our DTC campaign, we continue to focus on education. In December, we launched a new series of virtual education sessions for providers focused on sickle cell disease pathophysiology and the fundamental understanding of the root cause of sickle cell disease. Understanding these fundamentals is critical to conveying the value of OXPRIDA and initiating patients on therapy. We are also educating providers on the importance of improving oxygen delivery and reducing hemolysis, and we're educating patients on the potential impact of low hemoglobin. In the fourth quarter, we continued to make progress improving new prescription conversions. We are seeing good utilization of our Cover My Meds program, and Q4 data shows impressive turnaround times and adjudication rates, ultimately leading to getting patients on medicine faster. During the quarter, Oxbrita adherence, which includes compliance and persistence, continued to be within the range of our prior quarter and analogs, and we are continuing to see some patients that previously discontinued therapy restart. Around the end of the year, we launched two new patient support features for GBT Source Solutions, our patient hub. First, it will now send email newsletters timed to a patient's journey and provide information on how to access and use the hub. and the ongoing support provided by the nurse adherence program. Second, patients can now opt in to receive mobile messaging to support engagement with the hub. We hope to see these new tactics increase engagement and reduce discontinuations. Our market research also continues to support the strong fundamentals of Oxbrita. For example, post-ASH, half of the healthcare providers surveyed who attended the conference recalled Oxbrita's real-world evidence on VOCs, transfusions, and hospitalization. Over half of current prescribers surveyed indicated that this new data will significantly increase their usage, and for non-prescribers, more than 90% said that this data will motivate them to prescribe. In terms of patients, our market research built in January shows that sickle cell disease patients' treatment habits were significantly interrupted by COVID, including the Omicron variant. Many patients and caregivers reported feeling less comfortable seeking care, with many delaying or shifting their appointments to telemedicine. Looking at Oxbride use, we continue to see a broad range of patient characteristics, such as 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 decreased compared to Q3 due to the holidays and lingering impact of the Delta variant on the healthcare ecosystem. In many cases, our team had inconsistent access to in-person meetings and had to leverage virtual tools instead. Against this backdrop, we still added about 100 new prescribers in the quarter, bringing our total number to nearly 2,000 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, we continue to have broad payer coverage for the 12 and older patient population, with more than 90% of covered lives having access in the United States, and our focus is on making it easier for physicians to prescribe and patients to receive Oxprida. In addition, our team is supporting the pediatric launch by engaging with payers to educate them on the expansion of Oxbride's approved label. We are already seeing prescriptions for these patients covered through the prior authorization process with many payers. The majority of decisions have been positive, and the few denials have been administrative in nature. We believe we can achieve broad coverage for the 4 to 11 age group by mid-2022, faster than we did with the adolescent and adult population. And with that, Kim will now talk about the developments in our pipeline.

Thank you, DJ, and good afternoon, everyone. On today's call, I will provide an update on our key real-world evidence studies for Oxbrider, our efforts to expand its geographic reach, and our pipeline. Following GBT's strong ash in December, our medical science liaisons have been proactively sharing the updated analysis of Symphony claims data covering more than 3,100 sickle cell disease patients ages 12 and older, which was just published. Interim data from the retro registry and the durability of response and safety data for the long-term use of Oxbrita from the open label extension of the phase three hope study. From my perspective as a clinician, this data is extremely impressive. It is not surprising to hear the impact that this data is having based on the market research that DJ summarized, and we are excited to continue delivering on this front with our ongoing and planned studies. For the retro registry, the data set now includes 230 patients submitted from nine U.S. sites. The data collection period closed at the end of 2021 and we are now working to analyze the data and plan to submit the results for presentation at medical meetings this year. The Prospect Registry is currently enrolling patients with a goal of including 1,000 patients from 40 sites, and we anticipate the first results from this five-year study will be available in late 2022. Of note, the Prospect Registry has been updated to collect data from patients in the 4 to 11 age group. And again, from a clinician perspective, I want to reiterate my excitement that Oxprida is now available to younger patients. I also heard directly from many of my pediatric hematologist colleagues across the country, letting me know how thrilled they were to have a new treatment option. I believe early intervention is critical for our patients, and this is an important step towards the goal of making sickle cell disease a well-managed condition. This month, we initiated two randomized, double-blind, placebo-controlled, multicenter trials studying Ocbrita's treatment effect on neurocognitive function in pediatric and adolescent patients and cerebral blood flow in adults and adolescent patients. We believe these studies will further add to the evidence supporting the safety and clinical benefits that Ocbrita can provide. Before I get to the pipeline, I want to quickly touch on our regulatory approval in the European Union. This is an important step in our global expansion plan as we take steps towards the opportunity to reach more than 350,000 sickle cell disease patients around the world over the next several years. As we make progress against this goal, we will continue to explore strategies to bring up Sprita and future therapies to patients in limited resource geographies such as Africa and India. Now let's turn to the pipeline. For Enclacimab, our P-selected inhibitor for reduction of VOCs, we are enrolling patients in our two phase three studies collectively named THRIVE. One is evaluating the reduction of VOCs over a 48-week treatment period based on Enclacimab's potential 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. The other phase three study is evaluating the 90-day VOC readmission rates following an initial VOC hospitalization, which tragically occurs in around 50% of patients. This study and opportunity are unique to Enclacomat. further supporting its best-in-class potential. Turning to GBT601, our next-generation hemoglobin polymerization inhibitor that we believe has potential to be a best-in-class therapy. We presented compelling proof-of-concept data at ASH as follows. Doses were well-tolerated with no safety signals detected. Our target of greater than 30% mean hemoglobin occupancy was achieved with a 100 milligram daily dose. We saw corresponding improvements in hematological parameters, and we saw improved red blood cell health as demonstrated by oxygen scan data. We are extremely pleased with these results, particularly regarding GBT601's increased potency. Because of this increased potency, some have raised theoretical concerns about impaired oxygen offloading to tissues. On the contrary, the totality of clinical and real-world data suggests improved oxygen delivery with Oxbrita and GBT-601. Specifically, GBT-601 is more potent than Oxbrita with regards to its anti-polymerization activity and much lower dose requirements. but is not more potent with regards to oxygen affinity. At the annual EHA meeting in June, we aim to share more data on these points, including, for example, sickle cell disease patient EPO levels from the GBT601 Phase 1 study. We also aim to share new preclinical data that we believe further supports its safety and efficacy profile. We are on track to initiate a GBT601 Phase 2 study by mid-2022. This study will evaluate daily dose levels intended to achieve higher average hemoglobin occupancy than we saw with the 100 milligram daily dose in our Phase 1 study. And we also plan to dose over a longer period of time. We believe this will lead to higher average occupancy, and hemoglobin increases, and importantly, consistently improve the red blood cell health of patients to resemble that of a sickle cell trait individual. We believe this has potential to provide a functional cure and a once-daily pill. Our goal is to present new sickle cell disease patient data from the planned Phase II study by end of year. I am so proud of the progress we're making, not only expanding access to Oxbrita, but also meaningfully advancing the pipeline. I will now 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 entering a period with multiple new growth opportunities for Oxbrita, both in the U.S. and internationally. We have a robust pipeline, which we are working aggressively to advance. And we remain laser-focused on our mission to help patients with sickle cell disease, not only by discovering, developing, and providing access to new medicines, but also through a variety of initiatives to support the broader SCD community. On this note, We want to bring awareness to an initiative we are working on with GBT's SED Health Equity Council. We are collaborating to advocate for federal legislation to address the unmet needs of patients by significantly increasing the funding and support for treatment, research, and education. The centerpiece would be more federal funding specifically for STD treatment centers to improve access to care for patients. I want to thank the Health Equity Council members for their dedication and support to this issue. With that, we will now open the call for questions.

Thank you. We will 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. 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'd 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. Our first question is from Gregory Renza with RBC Capital Markets. Please proceed with your question.

Hey, good afternoon, Ted and team. Thank you for the update today, and thanks for taking my question. Ted, maybe just starting with some of those market dynamics that DJ and Jeff alluded to, I'm just curious if you could comment a little bit further on what you mentioned at the top, which is some of the things you can control versus those which you cannot control. Certainly with Omicron peaking and maybe now on that declining trend trend, What are your thoughts on some of those recent trends that you've seen as really exemplifying how the early 2022 can look when it comes to return to interactions and also generating those new patient starts?

Hi, Greg, and thanks for the question. Well, I mean, a couple of things, obviously, we can control is our messaging, the materials that we're making available for our MSLs for our representatives, our training and educational materials. Those are things, our DTC campaign, so those are things that we are controlling and I think we're utilizing very effectively. One of the things we can't control obviously is the COVID infections, how they are impacting physicians being moved sometimes completely out of sickle cell care the rate of decline of patients actually making visits to centers. Some of those things, as we noted, have been getting better, but obviously those are things that we have no control over. But again, we're pleased to see that with COVID cases declining, we think those things are showing early signs of improving, and we think we'll continue to improve.

Great. Thank you very much, Ted.

Thank you. Our next question is from Mark Breidenbach with Oppenheimer. Please proceed with your question.

Hey, guys. Congrats on the quarter and thanks for taking the question. I'm just wondering if you have plans to break out the pediatric launch metrics separately from the adult launch data or if the numbers are going to be pulled going forward. And also, I guess I'm wondering if there's any potential to see a differentiated or maybe even improved safety profile for the dispersible formulation of Oxbride relative to the non-dispersible pills, given that I think it's only really been assessed for PKPD equivalents in healthy volunteers so far. Thanks for taking the question.

Okay. Mark, thanks for the call. Good to hear your voice. First, with regard to breaking out pediatrics versus adults, we do not plan to break them out. We would break them out if there was a difference, for example, in price. that would help you in some way. But we think it's better that we stay on the total enrollment number as a global indicator of product demand and not break it out by age group. With respect to the tolerability profile, now the tolerability profile of Oxpride has always been quite good. As I've mentioned many times, about the only real signal that we see are occasional rashes, which I don't think we'd expect to be any different as the formulation changes. That's probably a reaction to the actual chemical ingredient itself. The other thing that we've seen is about a 10% increase in diarrhea or loose stools, which is self-resolving over placebo. And would that be better? It'd probably be pretty hard to pick up a you know, something going from 10% to 5%, but maybe over time we would see something. I think the bigger issue with kids, and Kim can certainly comment on this, is kids often don't like taking medicines. And that's something that we're aware of. Anyone who makes therapies for children is aware of that. And so there does need to be education and efforts around getting kids comfortable and happy taking drugs. I'm Edison.

Thank you. Mark, are you still there? Yep, yep. Thank you.

Thanks, Mark.

Thank you. Our next question is from Raju Prasad with William and Blair. Please proceed with your question.

Thanks for taking the question. Just wanted to talk a little bit more, get a little more color on the metrics that you provided on kind of new prescriptions and where you see the incremental increases. And you mentioned 800 new prescriptions in the fourth quarter and potentially an incremental increase. And then the COVID kind of headwinds kind of going away in the back half of the quarter. Just wanted to see if there's any extra color that you could say. Is there any messaging that's working well with with physicians or is it kind of just COVID subsiding that's causing kind of this incremental increase as well as kind of the new prescriptions in the fourth quarter? Thanks.

Yeah, I think there are a couple of things we can speak to. One is I think Kim might pick up on some of the real world data and what you've been hearing. And maybe DJ, you could elaborate a little bit more on some of the late numbers that you've been seeing and why you think they are moving in that direction.

Yes, I think that one of the things that is really obvious to us is that we're still seeing impact from the COVID-19 pandemic. We know that Omicron surging towards the end of the year or the beginning of the year had an incredible impact on the sickle cell population, with infections in the first part of the year being so frequent that they outnumbered those for the entire calendar year previously in the pediatric population. So I think that, as Ted mentioned, with staff in the sickle cell community having to be repurposed to go to other areas, so having staff shortages, having impacts on the ability to do in-person and having to switch to telehealth really greatly impacted. And I'm hoping that we'll come out of this as Omicron continues to subside.

And maybe, Kim, you could mention the reaction to the real-world data that you've been hearing.

Yeah, I think that the real-world evidence is really resonating with the pediatric and the adult sickle cell community. We know that we had really impressive data at ASH with our symphonies claims data that showed we had decrease in pain, all-cause hospitalizations, decrease in medication use such as opioids and chelation therapy, as well as a decrease in triglycerides. I think that, alongside some of the compelling evidence for protecting the kidneys in mouse models and most recently published in humans, also is resonating with the sickle cell community.

Yeah, and I'll just add a couple of things. You know, Q4 was kind of bookend by the two surges. The beginning of Q4 had the Delta surge. The end of Q4 started in the Omicron surge. And then we had the two holidays as well. So that all kind of took its toll in Q4. Now, the Omicron surge really hasn't really shown its impact until the beginning of Q1. We had the highest infection rates in the country in December and January and the highest hospitalization rates in January. So it did have some impact in Q1. That said, the reason we have optimism about this quarter and this year is all the totality of tactics that we've rolled out and that we spoke about. We now have a track record with a DTC campaign and seeing impact with that. We have the Cover My Meds program that we started last year, and we're seeing good metrics on that. And then, of course, we have the pediatric launch that it's on its way. Now it's early. But it's on its way, and we're already seeing prescriptions written and coverage and that sort of thing. So all of those things give us confidence in the demand picture going forward. And, you know, you have to take into account things like inventory at the end of the year when you think about revenues in Q1. But from a demand perspective, that's why we have some confidence as Omicron has started to go down and these other programs have started to kick in. It's looking good from that perspective.

Great. Thank you.

Thank you. Our next question is from Alicia Young with Cantor Fitzgerald. Please proceed with your question.

Hey, guys. Thanks for taking my question. Congrats on the progress. I wanted to ask a little bit about Europe. You know, obviously, probably the core country is Germany, United Kingdom. Can you just talk a little bit about, like, the market dynamics there? I mean, I'm assuming the prevalence is maybe a little lower, but how do you think about the cadence in those particular early-stage countries versus what you saw in the United States next?

Hi, Alethea. It's good to hear your voice. So as you know, Alethea, the first country that you typically launch in Germany is because like the U.S., you have free pricing available in Germany for the first year. So Germany will be the first country that we launch in given the approval. We don't have a specific date yet, but we are obviously working feverishly to make that happen. The other two countries and the countries where the majority of sickle cell patients reside, as you know, are France and the UK. And in those two countries, after the regulatory approval, you have to get pricing approval. And that process can take typically anywhere from six to 12 months. So it really won't be until 2023 that we began to get revenue from the two geographies with the vast majority of the sickle cell patients.

Is there anything in particular about those, like, countries and, like, the cadence and how they're treated that would affect that prior launch?

I'd defer to DJ. Anything you want to add to that?

No, I mean, there's nuances in every market. I mean, the good news, it's very similar to the U.S. in terms of it's a very concentrated industry. group of patients. You know, the 17 states make up the majority of patients in the U.S., while in France and the U.K., they're centralized in certain cities like Paris and London in particular. So that does help our footprint, which we've already established in those key markets, to be very concentrated and focused in terms of our educational efforts, which are underway currently.

Thanks so much. Thank you. Our next question is from Akash Tiwari with Jefferies. Please proceed with your question.

Hey, guys. So, look, this is more of a holistic question, but any color on why you didn't guide for Oxpride in 2022 or perhaps give mid- to long-term guidance for this product? COVID cases are back to pre-Omicron levels, and several companies have guided in 2022 while pointing out that if COVID returns, then their guidance is moot. So curious why the company didn't take that approach today. And I guess maybe on the pipeline, if we were to longitudinally follow the hemoglobin levels for the patients treated on 601 at ASH, did we see any signs of hemoglobin levels continuing to increase even after two weeks on the drug? And is there any possibility that for 601, the hemoglobin data could get better over time? And if so, when would we be getting any updated 601 data on that original proof of concept trial that we showed, that was presented at ASH? Thank you.

So maybe I'll ask Jeff to take the guidance questions and Kim, you'll take on the 601 questions. Sure. Hi, Akash.

We did actually consider at this call about potentially giving some guidance, but reflecting on history with COVID, there was just too much uncertainty. I don't think people were anticipating Delta happening in the fall of last year, and certainly Omicron wasn't on the cards looking back in January. But that doesn't preclude us from potentially doing something in the following quarter. If we do think that we're on a clear pathway, there is the potential that we could give say nine months' worth of guidance for year end for both OpEx as well as revenue. So that's not off the cards in the near term, and it's frankly our preference is to be able to do something like that.

Hi, Akash. And then for the proof of concept data, I'm just going to start with the phase one. We would theoretically say that you may see improvements in hemoglobin over time. That's going to require doing longer periods of follow-up on 601, hopefully in our phase two study. But theoretically, you may see increases over time. I want to say that we hope to have incremental data available at EHA, maybe some EPO levels on that initial cohort. And then later in the year, hoping to have more information, new information on individuals with sickle cell disease.

Thanks so much.

Thank you. Our next question is from Danielle Brill with Raymond James. Please proceed with your question.

Hi, guys. Good afternoon. Thanks so much for the question. I guess I'm just wondering if you could maybe quantify a bit more. NRX expectations for 1Q? I know you said incremental, but can you give us a sense of a range? And then how many NRX have you gotten for pediatrics so far, and was there any contribution from those, from peds in 4Q? Thank you.

Hi, Danielle. This is Ted. Good to hear your voice. I'll defer to DJ to elaborate, but I suspect the reason He said incremental is that he wanted to have some latitude and not be too specific. And I think with regard to breaking numbers out, it's been the plan, Danielle, to just report a single number and that reflects overall demand and not break it out by age group. But DJ, please feel free to add.

Yeah, I mean, this may be unsatisfying. It's just early days, right? So we're just at the beginning of this launch. The metrics we do have in hand that are promising that we talked about in the script, which are the awareness of the new dosage form is very, very high with our target audience, specifically the pediatric hematologists. So they've been anticipating and are now well aware of the approval in rapid time. So we did that survey just three weeks in the launch in January. So we feel really good about that. We are getting enrollments. Mostly really starting in January. No appreciative enrollments would be expected in Q4 because we got approval right before the holidays there. And we had, to be honest, we needed some time to get it into the channel and to the pharmacy. So really starting in January is when we started to see the enrollments. And we'll be looking at those over time. Everything is going according to plan is what I could say at this point.

Thanks, D.J.

Thank you. Our next question is from Paul Choi with Goldman Sachs. Please proceed with your question.

Hi. Good afternoon, everyone, and thanks for taking our questions. I wanted to revisit the Q1 guidance for a moment here and the range that you provided and just given what seems like, you know, positive exiting commentary here coming out of Q4 and midway through Q1. Is the range here, you know, which seems conservative to me, primarily reflecting the COVID headwinds, that you spoke to about in January, or are there additional factors that you would call out, such as you mentioned 340B as being part of the mix that you expect to abate over the course of Q1? And then how are you thinking about the contribution from those factors over the remainder of 22? Thank you very much. Hi, Paul. This is Jeff.

We do think these dynamics are somewhat unique to Q1. We did see last year, if you remember, some impact also related to the inventory buildup. We saw that and anticipate that again here for Q1. The other aspect is the gross to net, which you mentioned. The copays reset, we typically see a higher copay assistance, which reduces or increases our gross to net. That should subside in the subsequent quarters, but we will start to see I'll step up over time to probably around the 25% gross to net probably by middle of next year. But it should spike a little bit in the first quarter. The other aspect is the early impact of Omicron in the first part of the quarter here. We have seen that sort of taper down in the second quarter, and we certainly hope that we're through this quarter. sort of continual variants that come around here, and if that's the case, we would expect growth. We do think it's probably going to build up more in the second half of the year. Just typically what happens is these patients come in for a wellness visit, and then perhaps on the second visit, these patients get offered Oxypride or some other therapy for sickle cell. So that's why we're going into the second part. The other aspect of seeing an increase in the second half of the year is we expect really robust coverage on the pediatric side by the middle of the year. So that would also add to further growth in the second half of the year. Great. Thanks for the additional details, Jeff.

I'll hop back into you.

Thank you. Our next question is from Jason Gerberry with Bank of America. Please proceed with your question.

Hey, guys. Thanks for taking my questions. Just following up on the Phase II plan for 601, I'm curious if there's any latest thoughts as it pertains to trial design. I'm not sure if the sort of slight timeline shift was, you know, was there any FDA interaction? Are you thinking about this as a Phase II slash Phase III or more of a midsize dose-ranging Phase II with a placebo arm? And just a point of clarification on what we'll get at EHOC, My understanding is those patients that were dosed three weeks post their washout period, that was the extent of getting 601 treatment, not extended treatment. So when you give us the EPO data for those patients, will it only be sort of for the post three-week washout period of treatment? Just curious. Thanks.

Kim, do you want to take that? Sure.

Sure. Hi, Jason. I'm going to start with the latter part of your question about the EPO levels. And I think that we'll have, remember, two phases from the MAD-1 and MAD-2. So we should have some indication for greater than two to three weeks because for the MAD-1 part of the study, we had a longer treatment period. So I do anticipate that we will have EPO levels reflecting longer than three weeks on 601. For the plans for the further development of 601, remember that we still have to finalize the protocol. We're working on a very thoughtful yet comprehensive protocol and that we need to set up a meeting with FDA in order to present our plans. Once we have those two things accomplished, I think that we can anticipate steady initiation mid-year this year in 2022. I think that when you think about what our goals are, we continue to be very thoughtful because we have the potential of getting to a good therapeutic level of hemoglobin occupancy on a relatively low dose in a single once daily pill.

Okay.

Thank you. Our next question is from June Lee with Truist Securities. Please proceed with your question.

Hi, thanks for taking our questions and for the updates. Can you tell us a little bit about the Phase 3B trial you initiated this month looking at the neurocognitive improvement? What's the objective of this study, given you already have real-world data from the Symphony Health Supporting Clinical Benefit Profile? And also, you know, the study duration of 12 weeks, how feasible do you think it is to see a cognitive improvement in such a short period of time, and what is the power and assumption of this? Thank you.

Hey, June. Thank you for those thoughtful questions. You know, that study is in 8 to 18-year-olds, and it's specifically focusing on executive functioning through the NIH toolkit. I agree that 12 weeks is a short period of time, but as you know, for executive functioning, that's more than enough time to be able to see an improvement. This goes along the lines of what we see in real world with Oxbrita use with an improvement in overall well-being pretty shortly after initiation of Oxbrita. So the goal is to really look at Delta and executive functioning over that 12-week period, but in a group, a young group of children and adolescents, where we know that we have seen changes in executive function in other studies prior.

June, are you there? Yes, yes, thank you so much.

Thank you. Our next question is from Ritu Baral with Cowan. Please proceed with your question.

Hi, guys. Good afternoon. Thanks for taking the question. I wanted to just follow up on the NRXs for the next quarter. You guys mentioned that you expect an incremental increase in Q1 and hopefully more in Q2. Is it reasonable to expect that the NRXs should be back to approaching about the 1000 level that you guys had seen last year and the year before, especially for Q1. And then what do you think will happen with compliance and dropout rates going forward as physician interactions increase, both from the sales force and patient and clinician interactions? Do you think that you could also see reductions and dropouts more, you know, a better take, so to speak, of all the programs that you have to improve compliance and persistence? Thanks.

DJ, you want to take that? Hi, Ritu.

Sure. Hi. Yeah, Ritu, we, yeah, we're... It's early, and we don't have any data to report here on Q1 yet. We're just signaling that we did see Omicron spike and then go down in Q1. So while it had an impact on the beginning of January, as you might expect, we don't think that's going to be long-lived throughout the quarter. So that gives us some optimism because we have all these other things as tailwinds helping us, namely the pediatric approval process. as well as these programs becoming much more mature and having impact as well. Things like the DTC campaign, for example. We're seeing big spikes in patient seeking education on our websites, on our social media campaigns, and that sort of thing. So all of these things are pointing in the right direction if we can just get past these Omicron spikes. So we're optimistic because the spike is over. are coming down. So that gives you an idea of why we think we can certainly do better than Q4. Q4 also has the headwind of the two holidays. So that's another reason why we might expect demand to be higher in Q1 as well. In terms of adherence rates, yeah, we look at that very closely as a chronic therapy. That's something we're always going to focus on and always going to work on. We've seen it stabilize. Q4 was no different than what we've reported before, which is a stabilization consistent with the analogs within a range that we think is common, but we're not satisfied. So we do think some of the new programs will have an impact over time. We're really excited about our ability to do proactive communications, outbound and inbound communications via text. the email through our SP partnerships and GBT source solutions, our access navigators in the field being able to proactively reach out directly to patients in certain situations and walk them through the support process. All of these things were initiated last year. We think they will have an impact on adherence going forward.

Got it. And if I could squeeze one last in, you mentioned some denials in pediatric in pediatric coverage and some negative prior off decisions, administrative in nature. Could you just elaborate on that? Thanks.

Sure. Yeah, this is just around the kind of the part and parcel with launching any product. We had similar things happen when we, in our first launch two years ago, and that is in the very beginning until the payers formally add it to formulary, they oftentimes will reject the first prescription that comes in. because it's not in their system yet. And they require a follow-up, either an appeals process, a secondary prior authorization, as well as education from our strategic account team, which are very actively engaged with the payers right now. So we are getting them paid for oftentimes through a denial process and an appeals process, but that's what you would expect in the early days. it does take us some time to get around and get all the meetings on the books for them to have a formal formulary decision. We expect that to go smoothly, by the way, and that's why we're optimistic we can do even better than we did last time.

Got it. Thanks for taking the questions.

Thank you. Our next question is from Yanan Zhu with Wells Fargo Securities. Please proceed with your question.

Thanks for the update and thanks for taking our questions. We just have a question on 601. So I think, so I was wondering in terms of trial design, sounds like you're still working on it, would you contemplate a comparator arm with Oxbrita? And also, Kim, please correct me if I heard this wrong. I thought you said data from this Phase II study can be expected by year end, initial data by year end. If I heard that correctly, what kind of follow-up would those data be and what are some of the major endpoints? I know hemoglobin levels is probably one, but what other metrics will you be looking at to analyze the potential for the drug? Thanks.

Thank you for that question. I think that comparator arm with Oxbrita is an interesting thought. However, we really were planning on really looking at the mechanism of action and the potency of one of our sickle hemoglobin polymerization inhibitors, so wanted to really focus on 601 here as we continue to gather real-world evidence on Oxbrita. I think that your questions regarding the Phase II data are spot on. We are really looking to provide new information on individuals with sickle cell disease receiving 601 for a longer period of time. This will include, of course, you know, the usual hemoglobin occupancy, the hematological parameters, but, of course, hoping to get some early signals on other clinical endpoints. If 601 does what we want it to do, we should be able to provide hemoglobin modification to higher levels more consistently using a lower dose. And this gives us the opportunity to really consider clinical endpoints, including pain and other things that have been signals that we've detected in our real-world evidence.

Great. Thanks for the color. Appreciate it.

Thank you. Our next question is from Yatin Sunija with Guggenheim Partners. Please proceed with your question.

Just a couple questions for me. Can you just talk about how are you guys thinking about breakeven or achieving profitability? When can it be achieved or what level of sales it can be achieved? Can you also talk about the optimal capital structure? I mean, I think you have close to $600 million in debt now. I was just thinking about the capital requirements in the future. And then finally, if you can comment on the EU dynamic. You mentioned de minimis contribution in 2022. What does that mean? Is it like $1 million, $5 million, $15 million? Can you just comment there? Thanks.

Hi, Yatin. We'll ask Jeff to take that.

Hi, Yatin. Yeah, we ended the year with about $735 million in cash and cash equivalents, which I think puts us in a good place. We haven't given any specific guidance on time to break even or revenue thresholds at this point. I think we really need to see how the pandemic plays out here. Obviously, revenue is going to have a big impact on that. But what we can say is that our balance sheet is sufficient to meet our goals here. And these are long-term goals of launching in Europe, Also, making sure we have enough capital to complete the two Phase III and CLACMAP studies and into registration, as well as 601, moving that into pivotal studies and seeing a data readout there. So, you know, in totality, we think that our balance sheet is sufficient for us to be able to achieve those. And I think down the road, we look to be in a position to provide, you know, more guidance both on top-line revenues as well as, you know, expected time to profitability.

Yatin, does that answer your question? Yep, thank you.

Thank you. Our next question is from Tessa Romero with JP Morgan. Please proceed with your question.

Hey, thanks guys so much for taking the question. I think DJ gave an updated total prescriber number in his remarks. What are your expectations for growing the prescriber base for Expida this year? And how do you think... further penetration of existing prescribers versus adding new prescribers might play out in the year ahead. Thanks so much.

Yeah, Tessa, thanks for the question. You're right. We announced that we're closing in on 2,000 unique prescribers throughout the U.S. We call on about 4,500 in our target list. So as you can imagine, we still have a significant amount of prescribers to continue to educate and get started on Oxbrita. So we have growth potential there. The penetration of the patients within the prescribers, our highest decile physicians with the most patients, they have an even higher rate of adoption. Almost 60% of them have written a prescription for Oxbrita. So the ones that are most experienced certainly have the most experience with Oxbrita as well. And that makes sense. That's where we spend a lot of our time with those physicians. But now we're calling on primary care doctors, nurse practitioners that also care for patients as well to grow Oxbrita going forward. We do think Oxbrita's new indication in pediatric down to four years old does create a new opportunity. We added about 200 new prescribers to our target list that were not on there before. So that's just another group of physicians to get introduced to Oxbrita throughout this year.

Okay, great. Thanks so much for taking our question.

Thank you. Our final question is from Ben Burnett with Stiefel. Please proceed with your question.

Hey, thank you very much. I have a question around 601 and inflammation. Kim, I appreciate the comments and the prepared remarks around some of the oxygen release points. But I guess inflammation is another thing that comes up. And I would just ask, based on what you've seen so far with 601 and also Exprida, can you just talk about the timeframe that you might expect inflammation to resolve with a drug such as 601?

Thanks for the question, Ben. You know, I think this is really an opportunity for us to think about this more. And what we've seen in real-world evidence and long-term follow-up is as Oxbrita improves the red cell health by its primary mechanism with hemoglobin modification, we really see over time that pain episodes start to decrease. And as you know, a lot of what stimulates pain is that steady state inflammation in individuals living with sickle cell. So I theorize that what may be happening over time is that because Oxbrita is acting upstream on the root cause, it takes a little while for those downstream hemolysis-related inflammatory endpoints to start to change. And so I believe that this will be further explored in Oxbrita studies, either the externally sponsored or some of our internal studies, And we're definitely planning on looking at this parameter with 601.

Yeah, and I would just say just that if you look at the actual HOPE VOC data, you begin to see the curves begin to separate after probably about four to six weeks. And they continue to separate over the period of treatment. So I think that it does take some time, as Kim said, and that's something that we'll obviously be looking at with 601.

Okay, I appreciate the caller. Thank you.

Thank you. Dr. Love, there are no further questions at this time. I'd like to turn the floor back over to you for closing comments.

Well, thank you, and I'd like to thank everyone for joining our call today. We continue to hope that you all stay safe and healthy and want to

extend a welcome to you to reach out if you have any additional questions this concludes today's teleconference you may disconnect your lines at this time thank you for your participation