Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Thank you for standing by, and welcome to the Jazz Pharmaceuticals Rylaze Investor Update Conference Call. [Operator Instructions] As a reminder, today's call is being recorded. I would now like to turn the conference to your host, Ms. Andrea Flynn. Ma'am, you may begin.

Thank you. Good afternoon, everyone, and thank you for joining us today for a discussion on the FDA approval and U.S. commercial launch of Rylaze, formerly known as JZP-458. The slide presentation accompanying this webcast is available on the Investors section of our website. Investors may also reference the press release we issued on June 30 regarding the FDA approval of Rylaze. On the webcast today are Bruce Cozadd, Chairman and Chief Executive Officer; Dr. Rob Iannone, Executive Vice President of R&D and Chief Medical Officer; and Kim Sablich, Executive Vice President and General Manager of North America. We're also pleased to have an external pediatric oncologist, Dr. Luke Maese from the University of Utah - Huntsman Cancer Institute and Primary Children's Hospital, joining us today. In addition, Anne Borgman, Jazz Hematology and Oncology Therapeutic Head; and Dan Swisher, President, will participate in the Q&A portion of the webcast. On Slide 2, I'd like to remind you that today's webcast includes forward-looking statements, which involve risks and uncertainties that could cause actual events, performance and results to differ materially. We encourage you to review the statements contained in our latest SEC disclosure document, which identify certain factors that may cause the company's actual results to differ materially from those projected. We undertake no duty or obligation to update our forward-looking statements. With that, I'll now turn the call over to Bruce.

Thanks, Andrea. So I'm going to start on Slide 4. We are exceptionally pleased that FDA approved Rylaze on June 30, which enables us to deliver this critical therapy to acute lymphoblastic leukemia and lymphoblastic lymphoma patients in the United States. Our goal since the inception of this program has been to provide a high-quality recombinant erwinia-derived asparaginase with reliable supply that meets the critical needs of ALL and LBL patients, and we are excited that we are able to do just that. The availability of Rylaze gives patients who start a chemo regimen that contains asparaginase the opportunity to complete the course of treatment even if they experience a hypersensitivity reaction to E. coli-derived asparaginase. Now let's move to Slide 5, which shares our agenda for today's call. We'll share an overview of ALL and discuss our regulatory and commercial strategy for Rylaze moving forward. We have the privilege being joined by pediatric oncologist, Dr. Luke Maese, who will provide background on the current standard of care for ALL patients; the critical role that asparaginase treatment plays in reaching optimal outcomes; and the need for erwinia-derived asparaginase treatments like Rylaze. Our Chief Medical Officer, Rob Iannone, will review the data that supported the Rylaze approval and our development plans to evolve the U.S. label in the near term and to bring Rylaze to patients outside of the United States. He will also provide an overview of the Rylaze manufacturing and CMC process that enables us to deliver reliable, scalable supply of erwinia-based asparaginase, which has historically been a challenge. Executive Vice President and General Manager of North America, Kim Sablich, will follow with an overview of our commercial strategy, and then we'll open the webcast for Q&A. Moving now to Slide 6. I'm very proud of the work our entire organization has done to prioritize the development of Rylaze, highlighting our commitment to addressing the needs of underserved patients. Like our sodium oxybate therapy, Xywav, we have brought Rylaze from concept to commercial readiness, which underscores our expanding R&D capabilities. Rylaze has also showcases the significant contribution that our technical operations and CMC groups are making toward our evolution to become an innovative, high-growth global biopharmaceutical company. As we continue to progress new and innovative therapies for our pipeline, we have the capability to explore and optimize formulations and manufacturing processes to best meet the needs of patients. I'm excited to announce that Rylaze is now commercially available. Our team did an outstanding job compressing the time lines from approval to getting supply into the distribution channel so that patients would have access. Looking now at Slide 7. It has been a collective effort to advance this therapy to approval, beginning with a cross-functional team at Jazz, who have worked tirelessly to get Rylaze to patients. Our manufacturing and CMC teams have done an incredible job developing a modern recombinant manufacturing process that enables reliable and scalable supply, and we are confident that we will be able to meet current and future demand. And I'm so proud of our clinical team who've taken this molecule from first-in-human trials to approval in around 2.5 years, meeting an urgent patient need. In addition to the amazing work by our team, I want to take this opportunity to recognize the organizations and individuals who also contributed to bringing Rylaze to patients. Our clinical trial program was conducted in collaboration with the Children's Oncology Group, or COG, whose members are acutely aware of the need to have erwinia-derived asparaginase therapy available to their patients. For those of you not familiar with COG, it is a National Cancer Institute-supported clinical trial group and the world's largest organization devoted exclusively to child and adolescent cancer research. COG is made up of more than 10,000 experts in childhood cancer at more than 200 leading children's hospitals, universities and cancer centers around the world. More than 90% of the 16,000 children and adolescents diagnosed with cancer each year in the United States are cared for at COG member institutions. The COG leadership team, clinical trial investigators and site coordinators were instrumental in helping us execute the Rylaze clinical trial program. Their support of and enthusiasm for this program helped to drive fast time line and bring this much needed therapy to patients as quickly as possible. This leads me to the collaborative nature of our interactions with FDA. Rylaze was part of FDA's Real-Time Oncology Review, or RTOR Program, an initiative designed for delivery of safe and effective cancer treatments to patients as early as possible. RTOR allows for increased interaction and regular communication with FDA, which was critical to advancing our BLA through the review process so we could make Rylaze available to patients. Most importantly, I want to thank all of the patients and families who participated in our clinical trial program. Receiving a cancer diagnosis is an overwhelming emotional experience, which is quickly accompanied by an influx of information. The decision to join a clinical trial is a courageous one. Without the trust and participation of patients and families like those in our Rylaze trial, we cannot advance care for people living with cancer. Patients and their families are what is driving this program and inspiring our team. I'm fortunate that the [ Darling ] family, whose daughter Leighton was part of the Rylaze clinical trial, was willing to share their story with us in the following video. Their experience speaks to why we are so thrilled to be able to deliver Rylaze to patients. Now a note, for those of you on the webcast who have the slide presentation in full screen view, you will need to exit out of full screen in order to see the video on your screen. Operator, please start the video. [Presentation]

Now that was a very powerful message from the [ Darling ] family, and again, so grateful for their participation. Now it's my pleasure to introduce Dr. Luke Maese, Associate Professor of Pediatrics, University of Utah Huntsman Cancer Institute. Dr. Maese is also a member of the Children's Oncology Group and was an investigator in the Rylaze clinical trial program. Dr. Maese?

Thanks, Bruce, for that introduction. I appreciate the opportunity to talk to you all today about acute lymphoblastic leukemia and the role that asparaginase therapy plays within this devastating disease as you just heard from Leighton and her family. So moving to Slide 9. We'll first talk about acute lymphoblastic leukemia, or ALL, as it's also known. And on to Slide 10. ALL is defined as a malignant clonal disease of the bone marrow, where early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. And while it occurs across the age spectrum, it is most notable as the most common cancer of childhood, with about 3,000 children diagnosed every year with this disease. As you can see in the pie chart on your right, ALL makes up about 20% of all cancer diagnoses in patients ages 0 to 19. And while it does occur in adults, it is at much lower rates. As you can see, delineated in the line graph with age at diagnosis on the X-axis and rate per 100,000 people on the Y-axis. And so as ALL is more common in children, many of the treatment advances and paradigms have come from pediatric research and pediatric-focused trials. And so given my background in pediatrics itself and the fact that ALL treatment is often driven by pediatric innovations, just remember that we'll, over the next 10, 15 days, we'll be focusing primarily on ALL from a pediatric angle. And so moving to Slide 11 then. As far as incidence rates go, you can see in the graph on the left, there does appear to be an increased number of ALL cases in children over the past 35 years within the United States. In regards to outcomes within the pediatric age range as seen in the graph on the right, ALL is second only to brain in CNS tumors in terms of absolute mortality numbers, with a death rate of close to 4 per 1 million. But what you also noticed about this graph is the steep slope of the curve in ALL and how it has dropped over the past 35 years, with the mortality rate for this disease decreasing by more than half. And if you go to Slide 12, a graph here depicting this a little bit more visually-pleasing, you can see that the survival percentages according to the generation of treatment protocol by years are conducted. And so we've gone from a survival rate of less than 10%, as you can see from 1968 to 1970 to now, in the past decade, over 90% of patients diagnosed with ALL will achieve a long-term cure. And I've made a note within this graph that in the 1970s is when asparaginase was incorporated into therapy, and you can appreciate the noted jump in treatment in this decade. And asparaginase was certainly one of the reasons why this happened, and we'll talk about this in a little bit more detail coming up shortly. So if you go to Slide 13 then. So how we advanced treatment and improved our curates over the last 70 years. So this has been accomplished, as Bruce alluded to, through collaboration and cooperation, which really is the foundation of diagnosis and treatment of all pediatric cancer. So there are 3 major cooperative groups in the U.S. who study ALL treatment on a wider scale, and these are: the COG, or the Children's Oncology Group, as Bruce mentioned; there's also the Dana-Farber Cancer Institute; and the St. Jude Children's Research Hospital. So these 3 groups, while separate, also contain a great amount of crossover collaboration. Case in point, institutions participating in these 3 cooperative groups all enrolled patients on a pivotal Phase II/III study of Rylaze, which Dr. Iannone will be providing greater detail on shortly. So in the table below, which I took from the National Comprehensive Cancer Network pediatric ALL guidelines are the general chemotherapeutic treatment backbones of each of these cooperative groups. And so the cooperative group is indicated in the left-hand column of the table, and then it's further broken down by phase of treatment. So in the middle column, there is the induction therapy, which is the initial cycle of therapy of ALL in the last 4 to 6 weeks. And then we have the -- on the far right-hand column, consolidation therapy, and this includes treatment that follows induction and extends for another 2-plus years. So within this table, you have the description of all the different drugs that are used in these phases. And while you note, there is variability between the groups and the phases, there is also a tremendous amount of overlap. And as we then transition now from a discussion of ALL to a more focused discussion of asparaginase, I highlighted or boxed in the importance of this medicine throughout each group's treatment regimen throughout the different phases of therapy. So moving to Slide 14 then. We'll turn our discussion to asparaginase. And on Slide 15, I thought a brief overview of the science of asparaginase would help -- be helpful in providing a context to our discussion. So L-asparaginase is produced in the animals, plants and microorganisms. It hydrolyzes asparagine into aspartic acid and ammonia, which depletes the circulating pool of serum, asparagine. So this prolonged deprivation of this amino acid, asparagine, leads to reduced protein synthesis and initiation of cell death and has been -- and which has been shown several times and is indicated in the top figure, you see in the blue and green, normal healthy cells have the ability to intrinsically produce asparagine via asparagine synthetase, this is on the left. And in contrast, leukemic blasts or lymphoblast, the green box there on the right, these lack or have low levels of synthetase, which then results in selective killing of leukemia itself. And then in the bottom right, there's a graph with a table, which I took from a really -- from a seminal paper that was done in the '60s by a professor named J. D. Broome at Cornell. And what he did was he performed some very elegant experiments demonstrating evidence that L-asparaginase of actually guinea pig serum is responsible for antilymphoma effects. And while we don't use guinea pig serum anymore, as we'll get into in a little bit, Broome here did measure asparaginase activity in the 1960s, and this has continued to become a very important part of asparaginase management itself. And so continuing on Slide 16 with Broome's work then, measurement of asparaginase effectiveness through therapeutic drug monitoring is really a hallmark of leukemia therapy. And while asparaginase, as the name implies, depletes asparagine, on the surface, one would think that this would be the ideal method of measuring effectiveness. But unfortunately, the measurement of asparagine is notoriously difficult due to some of the challenging biochemical properties of asparagine. And so it's really not able to be reliably done outside of a very controlled and specialized setting, i.e., for our purposes, it's not commercially available measuring asparagine itself. So as Broome displayed in the '60s, serum asparagine activity, or SAA, as it's often known, has continued to be the surrogate measurement for asparagine -- for asparaginase effectiveness. So while this is quite technical, I think it's really important to have some understanding of this as much of what Dr. Iannone will detail shortly revolves around this concept of SAA levels. And so what level then is considered therapeutic? Well, back in the 1980s, the study on rhesus monkeys, actually, in combination with some humans, demonstrated adequate asparagine depletion corresponded with an SAA level of greater than or equal to 0.1 and have showed, taking this figure on the right from a paper in the early 1980s, which demonstrated this. And so this really -- this was the first demonstration of activity level and corresponding it with asparagine in the modern age. And so this value of 0.1 has continued then to be the benchmark for SAA level for therapeutic activity. And so moving to Slide 17 then. It's important to understand that there are multiple forms of asparaginase, and it's important to understand these differences, and Leighton and her family kind of alluded to those -- these in the video. But the first distinction is to know the difference between the E. coli and the non-E. coli-derived products. So on native E. coli-derived -- well, a native E. coli product, Elspar, which is in that second column there on the left on the table, was the first developed. It is not currently supplied in the U.S. The other 2 E. coli-derived products, Oncaspar and Asparlas, are the first line asparaginases currently utilized in the U.S. These are long-acting products, meaning one dose lasts 2 to 3 weeks. So moving then to the right of the table, on the right 2 columns, we have listed here the 2 non-E. coli-derived products, which are short-acting, meaning they require multiple doses over a period of weeks to equal the long-acting products. So Erwinaze, which up until June 31, 2021, was the only FDA-approved second-line asparaginase, these manufacturing difficulties with this product have resulted in a global shortage of this medication since 2016. And this is what Leighton and her -- and were referring to. And then Rylaze, which was FDA-approved 3 weeks ago based on data from an ongoing pivotal Phase II/III trial, which Dr. Iannone will inform us on in just a short while. So these drugs are utilized as second-line agents in a proportion of ALL patients who experienced a hypersensitivity reaction, as Leighton did, to the E. coli-based products. And so we'll discuss hypersensitivity in a bit more detail shortly. But I previously referenced the importance of asparaginase, and you all remember the improved survival curves that coincided with the introduction of the drug. But what sort of data exists specifically looking at the effect of asparagine depletion on outcomes in ALL? And so the next 2 slides will talk about that. So Slide 18, the initial studies investigating asparaginase within ALL therapy were first done in the late '70s. And these studies were performed by several different consortiums inside and outside the United States. While they looked at different doses and different dosing regimens, regardless of what dose they were investigating, regardless of the study question across all of these 4 trials, there was great statistical improvement in either remission rates or survival rates, as you can see in that last column and the principal finding on the table displayed on the slide. So these early studies then establish the benefits. And then as one would expect, right, the next -- the follow-up question would be, what -- if there is beneficial results from a little bit of asparaginase would even more of a good thing be better? And so on Slide 19, over the many years, the different -- there's been many different cooperative groups who've looked at actual intensification of asparaginase therapy or increasing the dosage or increasing the amount of this drug throughout therapy. As you can see there, detailed in this review and was put out about a decade ago, the intensification of this drug correlated with improved survival across 7 different studies within 6 different cooperative groups. And again, this spans cooperative groups in the United States and outside of this country. So while we know that asparaginase improve outcomes, it is important, like any drug, there are side effects, and it is important to have some knowledge of these effects as they do impact whether or not a patient is able to receive the prescribed course of therapy, right? So in Slide 20, we'll talk a little bit about these toxicities. And here, I've listed the 4 main toxicities of asparaginase. These include hypersensitivity, pancreatitis, thrombosis or blood clotting, hepatotoxicity or liver toxicity and then some other cursory toxicities of note, which we are also keenly aware of. So in the bar graph on the right, you can get an idea of some of the commonly reported toxicities with the incidents and percentage on the X-axis. It breaks -- this graph here breaks down the approximate percentage of toxicities and compares it from between the pediatric-age patients 0 to 14 and adults and adolescents greater than age 15. And as you see, though, at the bottom of the graph, hypersensitivity to asparaginase is much more common in the pediatric population. And for the purposes of our discussion today, as Leighton and her family introduced us to and really, any discussion with asparaginase, an understanding of hypersensitivity is really important when talking about asparaginase itself. So on Slide 21, as I mentioned before, these drugs are produced from foreign proteins. And because of this, these carry with them some strong immunogenicity factors. And this immunogenicity leads to significant rates of hypersensitivity or allergic reaction potentiality. So in clinical practice, it's often a difficult side effect to deal with as there are a variety of manifestations of hypersensitivity. So you have the more common simple rash, which is very easy to deal with, to a more extreme scenario, which is much more rare, where you get a full-on anaphylactic reaction where a patient will have difficulty breathing. So here I've given some approximate hypersensitivity rates through the 3 forms of asparaginase on the left, and these are the 3 forms that we discussed earlier. So you can see there's a significant variability, which is a function of the population tested, the number of doses the patient may receive and some of the other drugs they may be on. But then, importantly, on the right, is a review of the hypersensitivity rates for PEG-asparaginase, specifically. And remember, this is a long-acting first-line agents that we use in ALL treatment. So across a variety of cooperative groups over the past 25 to 30 years, this -- we detailed these hypersensitivity rates. And so historically, about 10% to 15% of patients will experience a hypersensitivity to a long-acting E. coli product. So in this scenario, though, that Leighton described to us of a hypersensitivity reaction to an E. coli-based product, it's important to have second-line asparaginase agents available for patients. And unfortunately, as we referenced previously, there has been a historical shortage of these agents. So knowing the importance of asparaginase in therapy and in light of the prolonged shortage of second-line products, colleagues in line within the Children's Oncology Group specifically looked at this question. So do patients who are unable to receive asparaginase, be it long-acting or short acting, having fewer outcomes to those who can complete treatment? And this -- on Slide 22, study was published very recently, and what they found to answer this question is yes, yes, they do. So patients who received all of their doses of PEG or long-acting doses of asparaginase, along with the patients who are able to complete their prescribed courses with short-acting product, had statistically significant superior disease-free survival when compared to those patients who are not able to receive their asparaginase course, whether this bit was due to a lack of available product or some other toxicity that precluded completion of prescribed kit therapy. So this then reinforced the importance of asparaginase and in particular, the need for available second-line products for patients who are unable to use the pegylated versions of the product. And so then in summary, on Slide 23, ALL is the most common cancer of childhood and hopefully, imparted on you that we've done a great job over the past century of improving these survival rates. This is large in part due to asparaginase and its incorporation into therapy itself. But knowing that there are side effects from these medications, it's important to have second-line options available for patients. So with that, I really appreciate the opportunity, and I'll turn it back over to Bruce.

Thank you, Dr. Maese. That was a great overview of where we are today in treating ALL. The progress we've made over the years and the critical role that erwinia-derived asparaginase plays in the treatment paradigm. I'll begin my presentation on Slide 25. We had 2 primary objectives when developing Rylaze. First, there is a critical need to provide a high-quality erwinia-derived asparaginase treatment option that can be reliably supplied to patients whose curative therapy regimen depends on access to non-E. coli-derived asparaginase. Reliable supply has historically been a challenge. Over the past several years, supply constraints of Erwinaze, the only available erwinia-derived asparaginase product, have forced physicians to deviate from the treatment protocols, which uniformly recommended erwinia-derived asparaginase, following the hypersensitivity reaction to E. coli-derived asparaginase. And as Dr. Maese noted, delaying, reducing or missing asparaginase doses can lead to compromised patient outcomes and reduce survival rates. So our priority was to get a solution to patients as quickly as possible to avoid compromising treatment. The second goal, with the intent to improve existing erwinia-derived asparaginase therapy, was to design the Rylaze development program to provide a higher level of 72-hour asparaginase coverage between the Friday and Monday doses of a standard Monday, Wednesday, Friday dosing regimen schedule. The production of Rylaze, as outlined on Slide 26, utilizes the Pelican Expression Technology Platform. It is based on Pseudomonas fluorescens and employs a novel approach to recombinant protein production. This technology is clinically and regulatory validated platform. To produce Rylaze, erwinia asparaginase is extracted from fermented Pseudomonas fluorescens, purified and formulated into a ready-to-use solution in low particulate filling components. As noted in a recent publication in the Journal of Pediatric Blood & Cancer that reviewed the recombinant technology, there is a significant difference in the number of fermentations used per batch of Rylaze drug substance compared to Erwinaze, leading to a highly increased production efficiency of Rylaze. Notably, the use of low particulate filling components in the Rylaze process ensures a low risk of having component-related particles. Additionally, the Rylaze process results in a ready-to-use product without the need to be reconstituted in the clinic. This modern and efficient manufacturing of Rylaze provides physicians with a reliable supply of erwinia-derived asparaginase for patients with hypersensitivities to E. coli-derived asparaginases, allowing them the opportunity to complete asparaginase therapy and maximize the positive treatment outcomes. We have produced 1 year of commercial supply, and our manufacturing process is scalable to meet all future demand. I'm now going to move to our development program, beginning on Slide 27. Our preclinical and analytical work was designed to evaluate the asparaginase activity of Rylaze and determine the starting dose for our Phase I clinical trial. Per the data from our in vitro studies on the left-hand of this slide, we demonstrated comparable in vitro activity to Erwinaze in advance of moving to the Phase I healthy volunteer clinical trial. As shown in the 2 charts on the bottom right of this slide, which depict data from the Phase I healthy volunteer clinical trial, 25 milligrams of Rylaze is highly comparable to 25,000 international units of Erwinaze in terms of asparaginase activity over time. 25,000 international units per metered squared is the standard Erwinaze dose given to patients on a Monday, Wednesday, Friday schedule. These data gave us confidence to initiate the starting dose of the Phase II/III trial at 25 milligrams per metered squared. On Slide 28, we've outlined the Phase II/III clinical trial design, including eligibility and key study endpoints. Data on Rylaze is being generated in this ongoing Phase II/III single-arm, open-label, multicenter dose confirmation trial, evaluating pediatric and adult patients with ALL and lymphoblastic lymphoma or LBL, who had an allergic reaction to E. coli-derived asparaginases and have not previously received asparaginase erwinia chrysanthemi. The planned enrollment in this trial is complete. The trial is designed to assess safety, tolerability and efficacy, with the determination of efficacy measured by nadir serum asparaginase activity, or NSAA levels. As Dr. Maese noted, measuring serum asparaginase activity is the gold standard in determining efficacy. Our goal is to develop Rylaze to optimize the Monday, Wednesday, Friday dosing. And provide improved 72-hour NSAA between the Friday and Monday doses, such that patients will maintain and benefit from consistent asparaginase activity through the entire course of their therapy. Moving to Slide 29. The trial is being conducted in 2 parts. The first part made up of Cohorts 1a, 1b and 1c, assessed different doses of Rylaze using an intramuscular IM route of administration on a Monday, Wednesday, Friday schedule. Trial participants in Cohort 1a were initiated at 25 milligrams per metered squared administered by IM injection given on Monday, Wednesday and Friday. Based on safety and SAA from patients at this dose level, Cohort 1b was initiated at a higher dose, 37.5 milligrams, on the same schedule and route of administration, with the goal of ensuring that a higher proportion of patients would meet a 72-hour NSAA target of 0.1 units per mL from the Friday to Monday dose. Based on the safety and NSAA from Cohort 1b, Cohort 1c was initiated at 25 milligrams from Monday, 25 milligrams on Wednesday and 50 milligrams per metered squared on Friday. The second part of the trial was designed to confirm the 25, 25, 50-milligram per metered squared dose in schedule for the intravenous route of administration. Like Cohort 1, Rylaze was administered on Monday, Wednesday and Friday schedule. The FDA approval of Rylaze was based on data included in our BLA, which was submitted prior to the completion of all 3 IM cohorts. We anticipate submitting data from the completed Cohort 1c to support a label expansion with the Monday, Wednesday, Friday schedule and utilizing data from the second part of the study to expand the label to include IV dosing. The indication, dosage and administration information from Rylaze and the Rylaze label are on Slide 30. In consultation with the FDA and in light of the significant unmet need, we initiated a BLA submission in December of 2020 under RTOR prior to the completion of the trial. We worked closely with the FDA to expedite the review process and obtain approval as soon as possible, so that patients with ALL and LBL, the majority of whom are pediatric patients who are treated with curative intent, could have a high-quality, reliable supply of erwinia-derived asparaginase. We are thrilled that Rylaze is now approved for use as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL or LBL in pediatric and adult patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase. As Dr. Maese pointed out, it is critical for patients who have developed a hypersensitivity reaction to have access to a non-E. coli-derived asparaginase and to be able to complete their entire course of therapy. Recent data from the Children's Oncology Group retrospective analysis of over 8,000 patients found that patients who did not receive a full course of asparaginase treatment due to associated toxicity had a significantly lower survival outcomes regardless of their patient risk status. A high-quality recombinant therapy with reliable supply provides these patients who have experienced hypersensitivity to E. coli-derived asparaginase, with the best opportunity to receive all the prescribed asparaginase doses as part of a potentially curative multi-agent chemotherapy regimen. Moving to Slide 31. The trial evaluated the achievement and maintenance of NSAA greater than or equal to the level of 0.1 units per mL at 48 hours using intramuscular doses of Rylaze, 25 milligrams per metered squared. The results of modeling and simulations showed that for a dosage of 25 milligrams per metered squared intramuscularly every 48 hours, the proportion of patients maintaining NSAA above the critical 0.1 units per mL had 48 hours after a dose of Rylaze was 93.6%, with the confidence intervals -- the 95% confidence intervals of 92.6% to 94.6%. On Slide 32, I'll review safety. The most common adverse events with the incidence of greater than 15% are abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding and hyperglycemia. Patients treated with Rylaze, a fatal reaction occurred in one patient, which was infection and serious adverse reactions occurred in 55% of patients. The most frequent serious adverse reactions reported in greater than 5% of patients were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea and viral infection. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received Rylaze. Adverse reactions resulting in permanent discontinuation included hypersensitivity, which was at 6%, and infection, which was 3%. Additional details regarding Rylaze's safety findings are available in the product label. Importantly, these findings were consistent with what would be expected for an asparaginase when used as part of a multi-agent chemotherapy regimen in patients with ALL. Moving now to Slide 33. I'll review the next steps in this program. Given the significant need, we were very pleased that the FDA approved Rylaze before a Phase II/III trial was even complete. This certainly speaks to the need for Rylaze to be available to patients as quickly as possible. Now that Rylaze has approved in the U.S., we are turning our attention to analyzing additional data from the trial and submitting that information to the FDA and other regulatory bodies. Patients from Cohort 1c of this -- of the first part of this trial, which assessed Rylaze-dosed intramuscularly at 25 milligrams per metered squared on Monday and Wednesday and 50 milligrams per metered squared given on Friday, are now in follow-up, and we expect to submit a supplemental BLA to the FDA to support a label update to Monday, Wednesday, Friday dosing. Our belief is that the FDA will continue to move swiftly in its review process for Rylaze. Part 2 of the trial assessing intravenous administration of Rylaze is ongoing in support of IV dosing, which is common in Europe and other geographies. We are continuing to advance our regulatory strategy outside the U.S. and anticipate that from our current development program -- anticipate that our current development program will support regulatory filings in Europe in 2022. We are currently working with an in-country partner to advance the program for filing approval and launch in Japan as well. With reliable supply in hand, we have the ability to continue our research and development program to explore additional treatment usages, not only in ALL, but beyond. As outlined in Slide 34, we believe Rylaze is a significant and much-needed advance for our patients, and we're excited to bring this new therapy to those in critical need. Our manufacturing process allows for reliable product supply that can be scaled to meet demand, and our development plan was designed to optimally support Monday, Wednesday, Friday dosing. While Rylaze is now available in the U.S., we remain focused on collaborating with the FDA to further evolve the U.S. label to support Monday, Wednesday, Friday dosing and also continue our work to bring Rylaze for both IM and IV administration to patients around the world. I'd now like to turn the webcast over to Kim to discuss our commercial strategy.

Thanks, Rob. I'll start on Slide 36. I'm proud of what our commercial team working together with our supply chain and regulatory teams have achieved to ensure that patients can receive Rylaze as quickly as possible following the RTOR review and approval of Rylaze. We were at commercial launch readiness prior to the approval and had expedited packaging and distribution in place to ensure that Rylaze could be shipped to patients within 15 days of approval. We expect near universal payer coverage from launch for this predominantly young patient population with such high unmet need. The Rylaze wholesale acquisition price, or WAC, is $4,390 per vial. Per vial pricing is comparable to the historic cost of Erwinaze. I'll remind you that in line with our more recently improved drugs, relative to Erwinaze, we expect improved profitability from Rylaze, with significantly reduced royalties and IP located in a favorable tax domicile. As noted on Slide 37, in the U.S., there are approximately 6,000 cases of ALL each year. And on average, around 20% of those patients will have a hypersensitivity reaction to their E. coli asparaginase treatment. Almost all patients treated under a pediatric regimen will receive asparaginase therapy, and a large majority of those patients in the U.S. will be treated in COG institutions. This is a concentrated prescriber base. We've served these physicians and patients for nearly a decade. We know them well, and at launch, we'll be focused predominantly on these existing pediatric prescribers across 280 accounts covering 90% of current asparaginase treatment. Turning to Slide 38. We heard from both Dr. Maese and Rob that completing the course of asparaginase is critical to patient outcomes and that ALL treaters have had to make very difficult treatment compromises in the face of unreliable erwinia-derived asparaginase supply. Our launch approach and messaging are built on these 2 key issues. First, we want ALL treaters to be aware that Rylaze is now available and that they now have access to a reliable supply of erwinia asparaginase, which is manufactured via an efficient and modern recombinant process. Second, we will work with the ALL treatment community to establish confidence in Rylaze as a reliable, high-quality product, giving clinicians the confidence to know that their patients who have a hypersensitive reaction to E. coli-derived asparaginase will always have the opportunity to complete asparaginase therapy. Clinicians know that completing asparaginase therapy and ensuring continued asparagine depletion are critical to patient outcomes. Our launch will be focused on reinforcing this understanding. As highlighted on Slide 39, we are taking multiple approaches to delivering this message and ensuring that every patient who needs to complete their asparaginase therapy following a hypersensitivity reaction can get Rylaze. Our existing leukemia and transplant sales force will be calling directly on our target prescriber base. In addition, our account reimbursement managers will be working with pharmacy decision makers to ensure confidence in access and reimbursement. And our regional marketing and medical teams will be engaging with thought leaders to build efficacy and gather insights on the ALL treatment landscape. These efforts will be supported by both branded and unbranded campaigns focused on our key messaging, which will be delivered through a suite of both digital media and direct contact. I'm really excited about what our teams can achieve and the resources that they have at hand to ensure that we meet our key goals of ensuring that clinicians are aware of the availability of Rylaze and are confident that with its high quality and reliable supply, they have the opportunity to complete asparaginase therapy and maximize positive patient outcomes. I'll conclude on Slide 40. Moving beyond our launch focus on pediatric oncologists, we are committed to ensuring that as many patients as possible can benefit from treatment with Rylaze. As Rob mentioned, we expect to submit our approval in Europe next year, and we're working toward an approval in Japan. Beyond this, we also see a significant future opportunity to ensure that adolescent and young adult patients are appropriately treated with asparaginase. Treatment paradigms for adolescents and young adult patients today are much more fragmented than in the pediatric market. Even beyond that, we're excited, as Rob mentioned, to be able to consider how asparaginase might benefit additional patients. I'll now turn the webcast over to Bruce for closing comments.

Thanks so much, Kim. I'll close out our prepared remarks on Slide 42. Our goal since the inception of this program has been to provide a high-quality recombinant erwinia-derived asparaginase with reliable supply for ALL and LBL patients. The approval of Rylaze meets a critical need for patients. Rylaze will give physicians and patients the opportunity to start their course of asparaginase treatment with absolute confidence that they will have the opportunity to complete this critically important therapy. The approval and launch of Rylaze exemplifies Jazz today. We are evolving to an innovative global biopharmaceutical company with strong execution-focused capabilities, all the way through from concept to commercial. We've demonstrated this both through the talents of our internal team, whose drive and engagement to address the unmet needs of ALL patients is, I believe, unparalleled and whose innovation, dedication and excellence have been critical in getting us to this point so quickly as well as through our ability to successfully collaborate with outside groups to further our mission of transforming the lives of patients and their families. I've never been more excited about the future for Jazz. We continue to be impressed with the superb cultural fit between legacy Jazz and GW teams. The successful completion of our integration will only further enhance our ability to innovate and execute. With the addition of the GW pipeline and cannabinoid research platform to our own pipeline and the strategic investments we've made in growing our R&D capabilities, we will continue to improve the lives of many more patients while driving significant shareholder value. I want to close by thanking the Children's Oncology Group for their unwavering support of this important program. They have been a critical partner in getting this much needed therapy to patients. I'd also like to thank FDA who have, at all times, recognized and acted upon the significant need for ALL patients to have access to a high-quality, reliable supply of erwinia asparaginase. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

[Operator Instructions] Our first question comes from Ken Cacciatore of Cowen and Company.

Bruce, congratulations to you, the team, the collab group, patients and the FDA. We rarely see this type of interaction, and it's really wonderful to see. Question for you is, could you give us a sense of what level of demand was not being satisfied? I guess an alternative way of asking that is, could you give us an average per patient cost of treatment so maybe we can try to understand the math better given your penetration rates that you're indicating? And then wondering if you could help us size the international opportunity, do you see it as equivalent to the U.S.? And then just last question for you is, obviously, your previous partner had manufacturing issues. I guess there's 2 ways this could be dealt with. The agency could finally take action or in the commercial market, the institutions could obviously just gravitate to you. Can you talk about how you think the competitive dynamics will play out with your approval and the legacy products still available?

Yes. And thanks for your compliments to really the multiple collaborators that got us to this point. Maybe I can start by coming to Kim with a little commentary on what the demand is out there and a little bit about cost of therapy. And then, Dan, perhaps you can jump in a little bit on ex U.S. opportunity and competitive environment. Kim?

Sure. So starting with demand, we're not providing an estimate for sales, but we certainly see a significant opportunity with a meaningful runway. Just for reference, global Erwinaze revenue peaked at just over $200 million before the supply shortages started, and approximately 3/4 of that revenue was in the U.S. We're incredibly pleased, as you heard today, to be able to provide Rylaze to patients in critical need. But we also recognize it's going to take some time to reestablish the market where physicians have had to adapt their practices based on lack of supply and quality issues. In addition, we look forward to restarting promotion in this space, which we had the stop previously during the supply issues, and do want to remind you that we do expect improved economics from Rylaze versus Erwinaze, both in terms of being the innovator of this therapy and having meaningfully reduced royalty expenses, but also noting that in line with our more recently developed products, that Rylaze's IP jurisdiction is more favorable in terms of the effective tax rate. So while our commercial strategy does account for the possibility of competition, we do believe Rylaze represents a clinically significant advance as the only recombinant erwinia asparaginase-manufactured product that maintains a clinically meaningful level of asparaginase activity through the entire duration of treatment. So we provided you with -- in terms of price and cost with the price per vial. Really, we think that the total cost of therapy, it's hard to get it because it's highly variable and dependent on both the patient size and the timing of the switch to Rylaze. Our WAC price per vial is comparable to the historic Erwinaze pricing by vial. If you look at our label and you really want to get a sense of the patient situation, you're going to see quite a bit of variety. You see that the median course of therapy was 3, but that at least 38% of patients received at least 4 courses of therapy. And then we saw quite a bit of a range, both in terms of ages, we saw a range of patient ages between 1 and 14, and we saw also -- I'm sorry, we saw a range of courses of therapy from 1 to 14 in an age range between 1 and 24. So you can see right there with such significant ranges on these key treatment parameters that we don't believe that an average cost of therapy is really particularly informative here.

So Kim, just to add in, this is Dan. So Ken, on the international question, Kim got to because of price differential, there's historically been a difference in terms of revenue potential with 75% in the U.S., 25% outside the U.S. It could go higher with time in terms of a number of markets we're not fully distributed. We had similar shortages. Patient impact is, of course, quite high outside of the U.S., so we're going to work very closely with the EMA to get the full package of clinical data, which will include the IV and IM data set to the EMA next year and look forward to pursuing that. And then there are certain significant markets like Japan, because of quality and supply issues, despite approval, we were never able to introduce Erwinaze, and we're working closely with an in-line partner there to bridge the data and get that to the Japanese market as well. So it's going to be a very meaningful product for us from a full hem/onc perspective. And internationally, we're looking for to support as best we can. In terms of dynamics, especially within the U.S. market and where Erwinaze is, we have the BLA. We've distributed the last of the Erwinaze. We intend to withdraw the BLA for Erwinaze. What PBL or Clinigen will do in regard to future plans, we don't have insight into. They did get some temporary product with the U.K. label that was imported during the interim between our selling the last of Erwinaze and before we had approval or product available, but that was under a temporary emergency authorization. So that's -- as far as we know with the dynamics, we'll be the only recombinant manufactured product with a year's worth of supply at the time of launch.

Our next question comes from Jessica Fye of JPMorgan.

This is Daniel for Jessica Fye. Maybe first, could you characterize the potential size of the market that you could unlock now that the supply issues have been addressed? And maybe in line with that, could you also characterize the market opportunity for patients with silent inactivation? And third one would be, would the label expansion for IM dosed on Monday, Wednesday, Friday come at the same time as IV? Or in sequence? And when could that happen?

So maybe I'll take the first part of that, Daniel. And then Rob, maybe you could address silent inactivation and next regulatory steps on broadening the label. Daniel, there was a great slide earlier in the presentation that talked about how doctors have tried to cope with lack of reliable supply of Erwinase over the last number of years, which include probably reducing the amount they use that drug to what I would characterize as a point where not every patient was probably getting optimal treatment. The ability to fully treat all pediatric patients is probably the first opportunity for the market to recover a little bit to more where it was historically before supply constraints got worse. But then there's the opportunity, as Kim mentioned, to start promoting again in the adolescent young adult market where asparaginase is not as routinely used yet has good results in those patients. And then we've got, obviously, the geographic expansion opportunities that Dan and others have covered. Rob?

Yes. So starting with the silent inactivation question, I would just say broadly, we think hypersensitivity is occurring in about 20% of patients and as Dr. Maese pointed out, tends to be more common in pediatrics. As was mentioned earlier, during the period of shortage of Erwinaze, doctors tended to accommodate their treatment in trying to persist through over hypersensitivity and wouldn't necessarily look for silent inactivation without an alternative therapy. But now that there is -- we expect that, that practice to change back to what's rational, in other words, any hypersensitivity of significance would suggest the benefit of switching, and if there's any concern around potential silent inactivation that could be tested for. In terms of timing of the label update, as we mentioned, enrollment is complete in the IM portion and is complete also for the IV portion, at least in terms of what we've planned so far. The IV patients were enrolled after the IM, so the follow-up there isn't quite as long. So we are working to get those data together and working closely with the FDA to find the fastest possible path to providing FDA with those data for a label update. And we expect, given our interactions to date, that the FDA will work very quickly to make those updates as appropriate.

Our next question comes from Jason Gerberry of Bank of America.

I guess, first is, what's the bigger lever for rebranding? Are we growing this market back to where it could be at peak levels? Is it kind of getting more patients back to full or optimal dosing? Or is it really increasing treatment rates? And then you were previously $200 million or so peak, 75% of that U.S. and I know in the past, there was some commentary that the market may have been maybe depressed by 1/3 in terms of utilization, so that would imply pricing kind of in the $270,000 to $300,000 per patient as an average. So what's wrong with that math ultimately? Wondering if you can comment on that just to get a ballpark sense of where pricing has been historically in the category on an annualized basis.

Yes. Jason, on the first part of your question, this is going to be really a much easier process for treaters moving forward, right? Before now, before Rylaze, there were more days when we were out of stock than in stock. In more recent years, people were having to monitor a supply update website and get alerts as to when therapy was available to be ordered. The ordering process itself was somewhat cumbersome. For ethical reasons, we want to make sure that every vial of the older product went to an actual patient being treated rather than being put on the shelf. So there was a lot of work that had to be done to verify that. Now it's as easy as calling and just ordering the product and knowing it will be there. That peace of mind, I think, is going to be important to treaters and to patients. And as people have that confidence that the supply will always be there when they need it, they can reverse some of these treatment practices that Rob mentioned. So I think it won't take that long before we get back to optimal treatment for patients, which is our goal. In terms of the per patient math you did, again, it's so variable based on the size of patients, from very small children up to adolescents and young adults, and the amount of Rylaze a particular patient gets depends on when in their treatment course they develop that hypersensitivity response to the frontline E. coli-derived asparaginase. So that's not a lot of value in trying to assign an average per patient. But again, our hope is to fully meet demand and then go about correctly promoting treatment among patient groups who may not have routinely been getting asparaginase therapy that could benefit from it.

Our next question comes from Gary Nachman of BMO Capital Markets.

Congrats. So first, how important is it to have the additional dosing cohorts for the uptake of Rylaze, the higher doses and also the IV? What portion of patients would opt for IV versus IM? Is it just in Europe where they would opt for it or also in the U.S. potentially? And then secondly, any reason physicians would consider using Erwinaze rather than Rylaze for new patients for all the reasons you just laid out, Bruce? And can patients switch from Erwinaze to Rylaze if their mid-treatment and supply runs out for Erwinaze?

Yes. Let me have Rob, Gary, take your question on the dosing cohorts. Maybe Dan can comment a little bit on IM IV. And Rob, maybe in your answer, you could hit on the question of going back and forth between the 2 erwinia asparaginase products.

Sure. So in terms of the IV question, in the United States for a variety of reasons, our understanding is that IM is really the preferred route of administration, and that's why we started our development program with that. As you mentioned, that practice differs a little bit globally, with IV being used more commonly in Europe. But nonetheless, we want to ensure that we have all options available to patients, and so that's why we quickly pivoted to the IV part of that study and built it into the initial clinical trial. As to the second question around switching, I mean I think all the data presented today suggests that really, Rylaze is the product that one would want to start with. Given the quality of the product and the manufacturing process, but also what I mentioned, which is ultimately been developed to provide better coverage, whether that be at 48 hours or 72 hours given the dose optimization that we've done. Having said that, if for some reason, a patient had started on Erwinase, there'd be no reason they couldn't switch to Rylaze.

Dr. Maese, would you like to jump in with any thoughts on the question?

Yes, Bruce, thanks. I will second what Rob said. I think in terms of preferences of IM versus IV, IM is preferred in the U.S. I think a lot of it is institutionally driven, and that can be variable. But I think regardless, the point that we should emphasize is the availability. And if it's available, the route isn't going to be an issue. And if you're asking about which one would someone prefer, I think it will be an institutional-based decision as far as that goes.

Okay. Actually, just to follow up, with respect to the higher doses, do you need to have that, you think, to have maximum uptake? Or all the patients would potentially go on the 25 milligram given that's what's available at this point?

Yes. I think people are going to want to complete -- as Dr. Maese highlighted the importance of complete their full asparaginase course of treatment. And with the approval we have in hand now, that is possible for all patients, providing more flexibility in how the product is dosed with more data in the label is a near-term goal of ours. But -- as of now, the product is available and will meet the needs of all patients.

Our next question comes from Graig Suvannavejh of Goldman Sachs.

I had a couple of questions. And maybe my first, if I could, just had to do with as you think about the potential future treatment paradigm, particularly in light of some novel therapies such as CAR T, just wondering, does the potential use of Rylaze change? Or is it impacted in any way? So if you could comment on kind of future use as we get other therapies? And then perhaps a second question just regarding the hypersensitivity, just wondering if there are any differences between age groups in terms of that hypersensitivity, whether they be adult, adolescent or pediatric?

Dr. Maese, maybe I'll let you weigh in on these.

Sure. Thanks for the question. So yes, you're right, there's lots of promising new treatments for cancer and leukemia and BL-ALL in particular, which include CAR T and there's other options as well. I would say that we haven't -- we do not -- first of all, we don't know the long-lasting effects of these immunotherapeutic options. Currently, the FDA indications are for patients who have relapsed disease with -- for immunotherapeutic options and sometimes in second relapse or refractory disease. And when we think about asparaginase depletion, it's a hallmark of really initially newly diagnosed patients, and this is -- can be a killer. You have this broad range of courses throughout treatment, right? You had patients getting up to 14 courses and that's because this is what's part of the Dana-Farber consortium protocol, they use lots of asparaginase and so you got patients getting continuous asparaginase throughout treatment, whereas the COG uses different regimen, different numbers and not as many doses, as being part of the protocol, but up to 8 doses for some of these patients. And this is an upfront therapy. When you're talking about these new therapies, these immunotherapies, these are for relapsed patients, as I said, and relapsed patients oftentimes, depending on timing, such as transplant, has been the treatment for them. And CAR Ts may be replacing that, but we don't know that for sure. And regardless of how you get some patients into remission, I think it's -- whether it's with immunotherapy or with traditional chemotherapy, you just need to get the patient into remission. And what we found, there are certain patients who will still continue to respond to chemotherapy, who've relapsed. And so these patients will continue to get and need asparaginase depletion and all. And I'll mention, these patients who have relapsed have greater toxicity. They've already received lots of E. coli product. And so you do see a fair number of those patients with hypersensitivity issues and who need second-line products. So having a second-line product for relapsed patients is incredibly important and shouldn't be minimized. So I don't think that these newer therapies will really affect the use of Rylaze as much. I think what -- if you want to talk in broader strokes, we want to try and decrease the toxicity of our treatments. And however, we can do that, we will at the therapeutic community. And then as part of your second question, yes, so the hypersensitivity to E. coli-derived products do differ across the age ranges. So adults have less hypersensitivity reactions. It's not really known, probably due to certain exposures they've been throughout their lives and have not had any -- don't have -- are not having these reactions as they are older age. I will say, patients, and it was mentioned -- Kim mentioned this AYA patients, these adult -- adolescent young adult patients, they are often caught in the middle between adult programs and pediatric programs, and so they are lost a little bit. And so I do question whether or not we're recording this data and these hypersensitivity reactions in this population. The AYA patients, traditionally speaking, are ages 16 to 39. And so are we correctly capturing the data on those patients? I don't know. But certainly, you see less of these reactions as patients are older in age. And then -- yes, so I think that was it there.

Our next question comes from Esther Rajavelu of UBS.

Congrats on the approval. Maybe just a quick commentary from you in terms of the opportunity expansion here. Given the risks with E. coli-derived asparaginases and with the risk of the shortage is potentially not an issue anymore with Rylaze, do you envision a treatment paradigm where perhaps Rylaze may be used in the first line for this pediatric patient population? And then I have a quick follow-up.

Yes. So that's not historically how erwinia-derived asparaginases have been used and certainly, not in the label. Dr. Maese, I don't know if you want to add anything on that question.

Sure. That's a great question and a logical way of thinking. I think the shortage has affected a little bit of how we think of this product. But now that it's not, certainly, that would be the logical next step. I do say there are some important things to realize. And really, it's -- in my mind, it's the long-acting nature of a product. So strictly speaking, from a clinician's point of view, when you can have a patient get 1 dose of the medication that will last 2 to 3 weeks versus having to get repeated doses of a medication, it's just preferred from our perspective and from a patients' perspective. So really, it's the logistics of that more than anything else. I think if you're thinking about the other toxicities that can take place with E. coli-derived products that I went into outside of hypersensitivity to thrombosis, clotting issues, liver toxicity or pancreatitis, these side effects are present with all asparaginase products. And we're not -- it's not like these things have been compared head-to-head. And so I don't say that E. coli-derived products are better or worse than non-E. coli-derived products. In my mind, it's the length of mechanism -- the length of activity that these drugs have. So...

And Esther, just as a reminder, we have historically disclosed that we do have a program with a longer-acting erwinia-derived asparaginase as well.

And that would be a different entity or closely tied to this one? Or how would that be different?

So the goal of that R&D program is to develop product that will be dosed less frequently, as Dr. Maese just described.

Got it. So it's not a label expansion for this potentially, it's a completely different development agent?

Correct. Correct.

Okay. And then really quickly, in terms of your guidance for this year, where do you think Rylaze fits into what you've guided for the top line?

Yes. So the guidance we gave earlier in the year did contemplate that we would be bringing Rylaze to market. There was some uncertainty around timing. There was some uncertainty about how long our supply of Erwinaze would last as we came into the year with knowing we'd be distributing some. But all of our assumptions about that were built into our guidance.

Our next question comes from Jeff Hung of Morgan Stanley.

Kim mentioned that it will take some time to reestablish the market. So can you talk about your expectations for the initial launch? Should we expect a bolus early on in the launch because of the Erwinaze shortage? Or do you think adoption will be more slow and steady? And I guess, if you're expecting a bolus, do you have a sense for how long it would take to get through the bolus?

Kim, do you want to take that? Kim, are you there?

Sorry, I forgot to come off mute. Yes, as we've emphasized, physicians have been in a tough position being forced into making tough decisions and adapting their clinical practice when patients have had a hypersensitivity reaction. We're going to be helping physicians to reestablish optimal treatment by reinforcing what you heard today about the statistical improvement in survival rates when completing the full course of treatment, educating around the importance of switching at the first sign of hypersensitivity reaction without delay. And we're going to be, at launch, focusing on existing asparaginase prescribers, predominantly those in the pediatric setting. And we also have been working with the ALL community for nearly a decade. As I said, we know this market and the health care providers and they're going to be driving awareness of the availability of the product and the reliable manufacturing and supply. Really, in terms of uptake, quite a bit of it has to do, as Bruce said, with we don't have certainty still in terms of what Erwinaze supply is going to be. That being said, we really do believe that we are -- have a strong product here in terms of being the only product that's able to provide that strong coverage over the full course of therapy.

And if I could ask a separate question. Robert mentioned that the manufacturing is scalable to meet upcoming demand. Can you talk a little bit about how long that process takes and how far in advance do you have to decide to scale up to meet upcoming demand?

Yes. I'd just say that this is a modern production technology with high throughput and capacity. The manufacturer of each lot is relatively abbreviated. And we have a good sense of what, for right now, U.S. demand is. We have a pretty good idea of what demand will be in other markets. So I don't see a lot of uncertainty in our ability to meet demand, not just in the near term, but over time.

Our next question comes from Annabel Samimy of Stifel.

They're very similar to the last questions, which is to get a little bit more specific on time it would take to reestablish the market. When you say that practices, Kim, have been adapting to the shortage of supply, have they been adapting in terms of just reducing Erwinase or using suboptimal doses of Erwinase or moving on to other types of therapies altogether? I mean if I look back on Slide 13 of the NCCN Guidelines, it looks like there's a number of different options in ALL and a number of different treatment regimens. So have they switched to other treatments altogether and then have to be convinced to switch back? Or am I thinking about it incorrectly? So that's the first question. And I know that you've sort of avoided this question quite a bit, but in terms of the AYA population and how sizable that might be, I understand that they have probably -- or the adult and AYA population has lower sensitivity or hypersensitivity, but they also have greater weight. So when you think about the market size, is there any way you can, in broad strokes, quantify that? Is it double where it could be? Is it a 1/4 of what it could be? Is it maybe triple the size? Is there any kind of idea you can give us around what a peak number could be for the population if you are able to treat AYA and adult patients adequately?

Yes. Maybe I'll let Dr. Maese weigh in on at least the first part of the question. I'm happy to come back and take the latter part.

Yes. Thanks, Bruce. I think it's a great question. So what -- so some things -- people have been doing this, again, institutionally differently. With the shortage, there was an idea that came about in the community in regards to desensitizing people to E. coli-derived asparaginase. So just as you would desensitize someone for a nut allergy or something like that, so you expose the patient to a very small amount of medication over a very extended amount of time and you titrate that up so it's a desensitization process? There's literature on that. We published a paper on that in our institution, and you saw there are several other papers out there regarding this desensitization process. And there had been success within that realm in terms of getting the medication in patients, certainly, some patients are not able to do that, not able to tolerate it. The issue with these desensitization processes is they're quite expensive. So you have to admit a patient to the intensive care unit. They may be there for a day or longer. It takes a lot of coordination from an administrative perspective, but also a pharmacy perspective in drawing up these titration of these doses. Many centers aren't -- don't have the capacity to do these things. And so it was limited to too much of -- it was limited to some of these larger centers. So that was 1 option that people utilize. The other 1 really was, like we talked about eliminating treatment, you could -- sometimes people would eliminate the doses and then give it to them later in treatment, so changed their kind of therapeutic regimen. You showed that -- you referred to that table I showed, so you can move some of these asparaginase treatments around. Now that probably affects outcomes. We have a certain devised algorithm for treatment, very protocolized, for this disease, and one of the reasons we've been able to improve cure rates. So that was the only other thing that could be done. And then unfortunately, there were scenarios where we had to make decisions about who were able to get the asparaginase and who would not be able to get it. So those were really the only ways to getting around it and has been referenced before. I can't emphasize enough the availability of the product is what's going to really make an impression in clinicians' minds. And I -- Bruce, you can -- the AYA population, I can just comment and then turn it back over to you to direct a comment with that.

Sure.

I think that this is a -- it's a tough situation. We're not sure -- you made a good point about the way -- I think what I will say from a clinician's perspective is there's been great data that's shown that patients treated on pediatric protocols in AYA population do better than patients treated on adult protocols. So we do try and get as many of those patients into our facilities, as a pediatric oncologist, treating these patients the best way we can. Now these docs and others have done really amazing work shifting adult and AYA oncologists in adapting some of our protocols to adult population. But we do our best to try and get these patients in. And here in Utah, we will treat patients up to the age of 30 with leukemia here. And again, that's variable throughout the country. So go ahead, Bruce, sorry.

Yes. No, great. Thank you for that. And just to add a little additional context, roughly 60% of the annual incidence of ALL is in pediatric, and roughly 20% is in the adolescent young adult group. So it is a smaller number of patients. And as Dr. Maese said, they're not all treated with pediatric-inspired regimens that contain asparaginase today. Each patient would get more drug, again, depending on when they develop an allergy or hypersensitivity reaction to the frontline E. coli-derived asparaginase. So potentially, more drug usage per patient. But importantly, this involves change in practice in some physicians. The adult treaters tend to be a little less coordinated than pretty phenomenal coordination we see among pediatric oncologists in terms of getting to more standardized protocols. There's a little more heterogeneity in approach. But again, it's just important to remember, we stopped promoting for this use because we thought it was unethical to try to create demand that we couldn't fill. And we also know that physicians who treat both pediatric and AYA patients were probably reserving the prior product for pediatric patients during this period of chronic shortages. So yet another reason we're really excited to take supply out of the equation is something people need to think about when trying to optimize treatment for all their patients. And I believe that was the last question. So I'm just going to conclude by saying we're excited to bring Rylaze to patients with ALL and LBL who have to have access to high-quality asparaginase with reliable supply. I would also like to thank our colleagues from Jazz for their commitment and sense of urgency. This was a great example of what we're capable of accomplishing on behalf of patients. And again, we'd like to recognize the Children's Oncology Group, FDA and the trial participants and their families for their invaluable contributions to the Rylaze development program. Dr. Maese, also, thank you again for joining us today. We look forward to providing updates across our business in early August on our 2021 2nd quarter earnings call. Until then, please stay well, and we'll now close the call.

Ladies and gentlemen, this does conclude today's conference. Have a good day. You may all disconnect.