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spk06: Good morning, ladies and gentlemen, and a welcome to the Q4 2020 Ascendance Farmer Earnings Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star, then zero on your touchtone telephone. This call is being recorded. I would now like to turn the conference over to your host, Mr. Scott Smith, Senior Vice President and Chief Financial Officer of Ascendus Pharma. Please go ahead, Jay.
spk12: Thank you, Operator. Thank you, everyone, for joining our full year 2020 financial results conference call today. I'm Scott Smith, Chief Financial Officer of Ascendus. Joining me on today's call are Yen Mickelson, President and Chief Executive Officer of Dr. Mark Bock, Head of Clinical Development and Medical Affairs for Endocrinology Rare Diseases, Jesper Hoyland, Global Chief Commercial Officer, Dr. Dana Pizzuti, Head of Development Operations, and Dr. Juha Poonanen, Head of Oncology. Before we begin, I would like to remind you that this conference call will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, our progress on our pipeline candidates and our expectations with respect to their continued progress, statements regarding our strategic plans, our goals regarding our clinical pipeline, statements regarding the market potential of our pipeline candidates, and statements regarding our regulatory filings. These statements are based on information that is available to us today. Actual results or events could differ materially from those in the forward-looking statements, and we may not achieve our goals, carry out our plans or intentions, or meet the expectations or projections disclosed in our forward-looking statements. And you should not place undue reliance on these statements. Our forward-looking statements do not reflect the potential impact of any licensing agreements, acquisitions, mergers, dispositions, joint ventures, or investments that we may enter into or terminate. We assume no obligation to update these statements as circumstances change, except as required by law. For additional information concerning the factors that could cause actual results to differ materially, please see the forward-looking statement section in today's press release and the risk factor section of our prospective supplement filed on July 9, 2020, and our annual report on Form 20F being filed today. Please note that our Transcon product candidates are investigational product candidates and are not approved for commercial use. As investigational products, the safety and effectiveness of the Transcon product candidates have not been reviewed or approved by any regulatory agency. None of the statements made on the conference call regarding our Transcon product candidates shall be viewed as promotional. On today's call, we will discuss our full year 2020 financial results and provide a business update. Following some prepared remarks, we will then open up the call to questions. I will now turn the call over to Jan Mikkelsen, our President and Chief Executive Officer.
spk01: Thanks, Scott, and good afternoon, everyone. For Ascendis, 2020 was a year to remember. We succeeded as a team and were able to meet. and in some cases exceeded all our corporate goals in 2020. I am proud to be able to say that the Ascended team was adaptive, creative and focused on achieving the goals we outlined at the beginning of last year to bring our Transcon product candidates to patients as fast as possible. For 2021, we are well positioned to continue to execute and achieve the milestones we have laid out across all of our five independent product candidates. Going back, the importance of the science, one of Ascendi's core values, is really at the center of what we do 365 days a year. Our understanding of the biology and the science It drives our drug development process. I see it again and again. If we stick to the science, understand and respect the biology, we will be successful. With our algorithm for product development focused on the patient and the unmet medical need, combined with the Transcon technology, we have a powerful platform that has allowed Ascendi's to create not just one potential blockbuster product candidate, but a portfolio of five potential blockbuster candidates in two therapeutic areas with more to come. Beginning with Transcon Growth Hormone. Throughout the development, we have kept the patient needs in mind. From the beginning, We were committed to build on the last 30 years of knowledge with daily growth hormone and other long-acting growth hormone programs. We designed our Transcon growth hormone to have a similar tissue distribution pattern, receptor activation, and exposure as seen for daily growth hormone. Once somatopine is released from the Transcon growth hormone product. For more than 30 years, multiple companies have tried to develop a long-acting growth hormone product using several different technologies, providing comparable safety, efficacy, solubility, immunogenicity, mode of action as daily growth hormone. In spite of all this effort, today all patients are still being treated with daily growth hormone in the US, Europe, and Japan. I am excited to be close to our potential regulatory approval of transplant growth hormone in the U.S. and Europe. Last June, we submitted our BLA for transplant growth hormone for the treatment of pediatric growth hormone deficiency, and we have a PDUFA date of June 25, 2021. Later in September last year, we submitted our MNA in Europe. And we expect potential improvement in the fourth quarter this year. Since our regulatory submission, I can see the payoff from our design of Transcon growth hormone and the extensive preclinical and clinical programs in our interaction with FDA and EMEA. We believe our data clearly demonstrate once-weekly Transcon growth hormone has comparable mode of action and distribution in key growth hormone responsive tissues, such as brain, bone, muscle, liver, and fat tissue, as the growth hormone substrate for daily growth hormone and industrial growth hormone. In our discussion with FDA and MIA, give me comfort that we have developed a convincing body of non-clinical and clinical data to support our belief. In December last year, we had a positive mid-cycle meeting with FDA, where they indicated the agency has no plans for an advisory committee. We continue to have a constructive dialogue. and have begun labeling discussions with the FDA. And we are looking forward to a potential regulatory approval next quarter. In Europe, our M&A submission for Transcon-Globetamol last September followed the agreement with PEPCO to our proposed pediatric investigation plan, or called PIP. covering the non-clinical and clinical development of transcon growth hormone in children down to age of 6 months. To our knowledge, no other growth hormone or growth hormone analog has an approved PEEP. Our expectation for potential approval of the MNA in the 4th quarter of this year is unchanged. But our innovation did not stop with the design of our drug substance. As part of our effort to address the unmet medical need, we have also developed an autoinjector for the administration of transcon growth hormone, providing wound temperature stability and a small injection volume via a 31G needle. We introduced the transcon growth hormone autoinjector into the Phase III enlightenment trial where it is currently being successfully used by over 160 subjects in the U.S. with accumulated use of more than 225 device years. We expect the Transcon-Globetamone Autoinjector will be available to patients at the same time as the potential commercial logs. Going forward, we are developing an integrated connective health program that links the Transcon growth hormone autoinjector with an app and provides information for the patient and caregivers related to adherence and doses. The pediatric growth hormone market is an established market in the U.S. and Europe with several daily growth hormone products. But we also know that drugs don't work in patients who don't take them. Even modest lack of adherence leads to suboptimal outcomes and potentially to drop out of therapy. In fact, we see that almost all pediatric patients in the U.S. stop therapy after three to four years of treatment. We have submitted for publication a manuscript based on claims data. demonstrating that the problems of adherence and lack of treatment are potentially much worse than reported in published literature. I often get asked if we think we can expand the current market with Transcontinental. These new data describing lack of adherence and lack of treatment tell me that there is a potential big opportunity to improve patient care by improved adherence, persistence, and penetration, which will lead to better outcomes for patients and better outcomes for the society. So far, I have talked about U.S. and Europe, but we are not stopping there. Ascentis is a global company with a global thinking addressing unmet needs for a worldwide population. In Japan, we filed a clinical trial notification last year to initiate the phase 3 right trial for pediatric growth hormone deficiency. In China, in 2018, we formed Vision Pharmaceutical with an investor group to develop Transcon endocrinology rare disease product in Greater China. Vision continues to execute on its Phase 3 clinical trial of transcon growth hormone in children with growth hormone deficiency and will initiate clinical development for transcon PTH and transcon CMP soon. Moving to label expansion. We have the global Phase 3 foresight trial underway for adult growth hormone deficiencies. The primary objective of the foresight trial, from a regulatory perspective, is to demonstrate efficacy compared to placebo. However, the most important comparison is to data growth hormone, which is included as a third arm in the foresight trial, where we plan to randomize 240 subjects one to one to one. I'm often asked, Why is adult growth hormone deficiency so important? What do you get out of the foresight track? Growth hormone deficiency is not just about height. In children, height emerged as the primary regulatory endpoint. Since adults are not growing in height, the primary regulatory endpoint is to measure the metabolic consequence of growth hormone deficiency, to measure change in trunk fat, Only if a once-weekly growth hormone therapy is equivalent or better to daily growth hormone in both the pediatric and adult growth hormone deficient population, then it will provide all the endocrine benefits of daily growth hormone. We believe from our Phase III pediatric programs that Transcon growth hormone can provide all these endocrine benefits. Combined with a success in adult growth hormone deficiency phase three trial. We believe we will continue to differentiate from all once we do growth hormone product candidates. We expect to complete enrollment of the foresight trial by late 2021 or early 2022. Moving to Transcon PTH. I've never seen a product like this before. A product that not only can address short-term symptoms of the disease by restoring biochemical control and the quality of life for a patient, but also potentially can address the long-term complication of the disease as well. Hypoparathyroidism, HP, is a condition which affects more than 200,000 patients just in the US, Europe, and Japan. Similar to growth hormone deficiency, where the problem is absent or insufficient amount of the respective hormone, in this case for HP PTHs. In chronic and post-surgery HP, in around 75% of all cases, the parathyroid glands, the organs that produce PTHs, have been damaged or destroyed, and the body cannot be stimulated to produce sufficient amount of PTHs. Therefore, the only way PTH can be restored to normal physiological level is by PTH hormone replacement. Transcon PTH is designed to replace the hormone at physiological levels and restore the patient to normal health. When we speak to patients suffering from HP, we hear over and over again about how poor the quality of life is. how they had to stop going to work, all worried about calcium crashes and making it to an emergency room. These are the short-term symptoms driven by lack of serum calcium control and physiological PTH levels. In addition to the short-term effect, HB patients have multiple long-term complications as insufficient kidney function, cardiovascular risk, and abnormal bone turnover. As Transcontinental PTH is designed to restore PTH to physiological levels 24 hours a day, we will expect to normalize serum calcium to improve short-term symptoms. We also expect to normalize kidney function and normalize bone health to reduce long-term complications. So what have we seen? With our six-month open-label extension, or OLE, we saw all mean summary and subdomains SF-36 quality of life scores being normalized. Later this month, we will present data at an oral presentation at ENDU, where you will see results for the first time from our HP disease-specific patient-reported outcome instrument after six months in the OLE. Since then, all 58 subjects have now completed 12 months of treatment on Transcon PTH without any additional dropout, which gives me confidence that these subjects are continuing to see the quality of life benefit with a safe once-daily PTH injection. In addition to the great data on quality of life, Transcon PTA also demonstrated normalization of key biochemical parameters related to long-term complications. After six months in the OLE, mean 24-hour urinary calcium excretion fell on average 57% compared to baseline. Almost all subjects demonstrated a normalization or improvement in urinary calcium excretion. On measures on bone health, HP patients typically have low bone turnover, and as a consequence, abnormal dense bone compared to people without HP, particularly the trabecular bone. As expected, as we restore physiological PTH level, we saw bone turnover increases with the initiation of transcon PTH treatment, resulting in a trend towards normalization of the abnormal dense bone, particularly the trabecular bone. So what is next for Transcon PTA-8? During the second quarter of 2021, we plan to provide 12-month OLE data. We expect to see continued normal quality of life, sustained reduction of HP symptoms, continued normal serum calcium, continue normal level of urinary calcium, and continue normal bone turnover. As part of extending our global reach for this potential life-changing therapy, during the second quarter, in addition to the 12-month PTH Forward update, we plan to submit a clinical trial notification for a trial evaluating transcone PTH for adults HP in Japan. Later this year, in the fourth quarter, we plan to report top-line results from the part-way trial. At phase three, randomized, double-blinded, placebo-controlled trial, investigating the safety, toolability, and efficacy of Transcon PTH in adults with ASP. The trial is expected to enroll 76 subjects as sites in North America and Europe. We are pleased by the data that we have generated so far, and we believe the data support a profile for Transcon PTH to be a potential first-line therapy for HP. We are confident we can truly make a difference in the life of HP patients. Turning to Transcon CMP, we are conducting two double-blind placebo-controlled phase 2 trials in children aged 2 to 10 years old. The first, the ACCOMPLICE trial, is a dose escalation trial of 12 to 15 subjects in each cohort, conducted mainly in North America and Europe. The second is the ACCOMPLICE China trial, which is a cohort expansion trial of at least 60 subjects conducted in China. Beeson received approval from the Chinese Center for Drug Evaluation to conduct the accomplished China trial with a design for dose expansion at an effective dose determined from the accomplished trial. Combined, these two studies will enroll more than 120 subjects, age 2 to 10, to be followed for 12 months in a double-blinded manner. Both Accomplice and Accomplice China will remain blinded until the 20-month follow-up is completed. Once completed, we will have robust clinical data from two independent, randomized, double-blinded placebo-controlled trials. We plan to provide a Transcon-CMP clinical program update in the fourth quarter of 2021. Finally, In endocrinology, we announced today that centers will have a chairman presentation at the end of 2021 annual meeting. This will include an oral presentation of the six-month open-label extension from the Path Forward trial for transcortin PTAs, as I mentioned. In our second therapeutic era, we hosted our first Oncology R&D Day back in November to share our vision on how to use transcon systemic and intratumoral technology to establish a new paradigm for treatment of cancer. We think we can develop an entirely new treatment paradigm in oncology using transcon technologies and address all steps of the immunity cycle. We are applying the same product development algorithm in oncology as we have successfully used in endocrinology, applying Transcon technology to clinical validated parent drugs and biological pathways. For Transcon TLR78 agonist, an IND was submitted in December 2020 to initiate the Phase 1-2 Transcen IT 101 trial during the second quarter of 2021. following monotherapy dosing. We plan to initiate dose escalation in combination with a checkpoint inhibitor. Initial monotherapy dosing results are expected in the fourth quarter of 2021. For Transcon AL2 Beta-Gamma, earlier this year we reported potential best-in-class preclinical data. Our transcranial 2-beta gamma is designed to have best-in-class potency receptor bias combined with a long half-life of around 22 hours and a low Cmax concentration. In non-human primary study, we have observed a highly biased potent activity with sustained exposure leading to best-in-class immune cell expansion with minimal effect of eosinophils. IL-5 or IL-6 and vascular leak marks. Based on this data, we believe transcon IL-2 beta gamma has the potential to become a backbone agent in oncology treatment. We expect to submit an R&D or similar for transcon IL-2 beta gamma in the third quarter of 2021. I sincerely believe that our goals of building a fully integrated global biopharmaceutical company gets one step closer each day. 2020 was a great year, a year to remember for Ascentis, as we advanced our endocrinology rare disease and oncology product candidate. In 2021, we look forward to achieve additional successes as we advance our pipeline ahead and closer to patients with unmet medical needs. We are continuing to apply our algorithm to build a pipeline in oncology and are committed to entering a third therapeutic era. This is how we will achieve sustainable growth. Not by advancing just one program, but succeeding with multiple potential blockbuster programs in multiple therapeutic areas in multiple geographies. Now, let me turn We call over to Scott for a financial review before we open up for questions.
spk12: Thanks a lot, Jan. Turning to our financial results for the full year ended December 31, 2020. We reported a net loss of 419 million euro or 8.28 euro per basic and diluted share compared to a net loss of 218 million euro. or 4.69 euro per basic and diluted share during 2019. Now let me run through some components of these results. Research and development costs for 2020 were 260.9 million euro compared to 191.6 million euro during 2019. R&D costs in 2020 reflect continued advancement of our pipeline with the primary drivers of the increase including an overall increase in personnel-related and R&D infrastructure costs, and for trans-con growth hormone, or lanapeg somatropin, costs were higher due to buildup of prelaunch inventories, as well as increased clinical trial activities. As a reminder, we currently expense manufacturing costs of lanapeg somatropin as R&D in advance of our anticipated product launch. At the time of product approval, a portion of these R&D costs may be reversed and capitalized as inventory, which will result in a one-time benefit to R&D costs. For Transcon PTH, costs were higher primarily due to device development and increased clinical trial costs. For Transcon C&P, costs were higher primarily due to increased manufacturing and clinical trial costs. And finally, for oncology therapeutic area, Costs were higher due to increased manufacturing and preclinical activities primarily related to Transcon TLR78 Agonist and Transcon IL-2 Beta Gamma. Selling, general, and administrative expenses for 2020 were 76.7 million euro compared to 48.5 million euro during 2019. These higher costs primarily reflect an increase in personnel-related IT and other infrastructure costs. as well as expenses associated with the continued build out of our commercial capabilities. Finance income and expenses in 2020 included a foreign exchange rate loss of 78.9 million Euro compared to a gain of 7.7 million Euro in 2019, primarily related to unrealized losses on translation of our US dollar holdings of cash and marketable securities to Euros. We ended 2020 with cash, cash equivalents, and marketable securities, totaling 834.1 million euro. As of December 31, 2020, Ascendus had 53,750,386 ordinary shares outstanding. Subsequent to year end, on January 8, 2021, we invested $12.5 million in Visa and Pharmaceuticals' $150 million Series B financing. Following the financing, we own approximately 44% of Visans issued and outstanding shares. As a result of this transaction, we expect to recognize a non-cash gain in the first quarter of 2021 of 42.3 million euro. Turning to 2021, we expect our expenses to increase as we continue to build our commercial capabilities and prepare for launch, advance our endocrinology rare disease pipeline, expand our activities in oncology, and continue to invest in the TransCon technology platform, including for Lanipeg-Somatropin, build up of commercial inventory ahead of potential launch, execution of commercial pre-launch and launch activities, investment in expanding commercial manufacturing capacity to support anticipated future demand, continued execution of the Foresight trial, a global phase three randomized controlled clinical trial in adult GHD, An execution of the RITE trial, a Phase III randomized controlled clinical trial in pediatric GHD in Japan. For Transcon PTH, continued execution of the Phase II Path Forward trial, which continues to retain 58 subjects in the open-label extension. An execution of the PATHWAY trial, a North American and European Phase III randomized controlled clinical trial in adult HP. For TRANSCON-CNP, execution of the clinical program, which includes two randomized placebo-controlled Phase II clinical trials in achondroplasia, the ongoing ACCOMPLISH trial, and the ACCOMPLISH-CHINA trial, which is being conducted through our strategic investment in Visa Pharmaceuticals. And lastly, in our oncology therapeutic area, execution of the TRANSCENDED-101 clinical trial for our TRANSCON-TLR78 agonist, and advancing the TransCon IL-2 Beta Gamma Program into clinical development. We expect other SG&A expenses, in addition to Lanipeg's Somatropin commercial prelaunch and launch activities, will include continued investments in personnel, systems, and infrastructure to support our rapidly progressing portfolio and growing organization. For 2021, we remain on track for hitting our corporate milestones. For lonapeg somatropin, these include with a PDUVA date of June 25th, 2021, we anticipate approval for pediatric GHD in the second quarter, followed by commercial launch in the third quarter. And we anticipate European Commission approval for pediatric GHD in the fourth quarter. For Transcon PTH, we plan to file a clinical trial notification for our Japanese phase three trial and adult HP in the second quarter followed by reporting top-line results for the Phase III pathway trials in North America and Europe for adult HP. For Transcon-CNP, we expect to provide a clinical program update in the fourth quarter. For Transcon-TLR78 agonist, after dosing in the monotherapy part of the Transcend IT 101, we plan to initiate the dose escalation part in combination with a checkpoint inhibitor in the second quarter. and plan to present initial Transcend IT 101 results in the fourth quarter. And finally, for IL-2 Beta Gamma, we plan to submit an IND or similar filing in the third quarter. Before we open up the call for questions, I want to make some points about our anticipated commercial activities for Lona Peg Somatropin in 2021. During Q2 this year, we anticipate approval for pediatric GHD on the PDUFA date of June 25th. Then during Q3, we expect to have product available in the U.S. for pediatric GHD. During Q3, once product is available, we anticipate beginning to provide access to lanopaxomatropin for pediatric GHD patients by onboarding patients through our dedicated patient hub, and we do not expect to have placement on commercial formularies at that time. Finally, during Q4, we anticipate European Commission marketing approval for pediatric GHD. We plan to provide guidance on the timing of launch in Europe later this year. With that, operator, we're ready to take questions.
spk06: Ladies and gentlemen, if you have a question at this time, please press the star and then the number one key on your touchstone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. Your first question comes from Michelle Gilson from . Your line is open.
spk02: Thank you for taking my questions. I guess the first one, can you maybe discuss the cadence for Transcon GH of getting onto the formularies? You know, how does that happen over the course of a year? And then my second question, for Transcon PTH, from a safety perspective, Is there a difference between replacing PTH at physiological levels in hypoperipatients, I guess at the doses you're evaluating, versus adding pulses of PTH to stimulate an anabolic effect? And then, I guess, at the doses that you're evaluating for transcom PTH, would you expect there to eventually be a black box warning or limitation on duration therapy like there is for Forteo, given these different effects on the bone?
spk01: Thanks, Michelle. So before I potentially turn it over to Jesper, I couldn't potentially take a little of the PTH question that you take up. And let me just repeat what we're doing with transplant PTH related to bone structure. If you have an untreated HB patient that have a higher bone density because you basically have an unnational low bone turnover because you have not the physiological PTH level of PTH. And if you look on the serum level of PTH, it's well documented in the literature that you basically see and basically a curve that have a peak to drop about 30% during the entire 24 hours cycle. And what we saw in the six months open labelled extension data, what we saw that when we restored physiological PTH level, we basically activated the normal bone turnover that you see in a normal human being that has no issue related to potential lower level of PTH. We saw that by accelerating and a higher level of both the anabolic and catabolic bone markers, but still being placed in what we call the higher level of the normal levels. And what we saw was the associated consequence of that. We also saw that this bone density that is abnormal dense because it actually have a structure that basically are not like a normal bone because it has no bone turnover, start to be normalizing. So therefore, we saw that a trend to approaching the normal level, which are in set score, is defined as zero. That is what we observed in the six months data. This is a continued process where we saw the main effect on trabecular bone. If we basically looked on cortical bone, that was not the same kind of decline in Z-score. It was basically stable because they don't have the elevated high density that you basically see specific for trabecular bone structure. What we saw with our bone markers, what we saw in our bone density, is just following exactly as what we have expected from the physiology of restoring a normal PTH level. In our interaction with FDA and EMEA, our first discussion related to PTH and effect as an anabolic compound was when we discussed should we basically conduct a CARC study. A CARC study is basically a study that has been done for all other PTH products to my knowledge. We got a clear answer back from justification and scientific justification that there was no need to do it because what you are applying in the Transcon PTH product is just a normalization of PTH level and not generating what I call a super physiological PTH level that you do with a classical compound of PTH that is being used as a therapeutic agent in osteoporosis. I believe there is a fair chance that we can avoid any kind of REMS program, because what we continue to see with our clinical data, and remember at the date of filing we will have 18 months, so we basically can follow this for one month. We expect to have such a strong data packet that we can provide what we see is just a normalization of this. hopeful that the science will continue to play in so we can be in a position that we can do a scientific justification saying there's no need for a REMS program. And also, we're also seeing now that if you look on the osteoporosis compound, that the black box has been removed for Forteo. And also, that is a basic and US because in Europe they are not believing that the preclinical finding you take with osteoporosis or osteosarcoma for a short-acting PTH is relevant for humans. So from that perspective, I think we have a strong scientific justification to avoid both a black box warming and a REMS program. The other part which also is scientific justification is that patients have been on pump where they're using either Forteo or Napire for multiple, multiple years. And just recall, if you use a pump system with either Forteo or PTH-34, you basically have an IV injection for 8 to 12 times in a subcutaneous tissue in one hour. This will provide a flat, flat, flat continuous exposure inside the plasma compartment. And when you look on long-term case studies, even in children, pediatrics, you see normal growth there. So I don't believe there is any kind of scientific justification that it's possible to, that there's a lot of discussion, basically have a meaningful impact on the bone structure. Jesper, will you talk about how we are addressing and ensuring we have the optimal place for our market assets?
spk13: Absolutely, Jan. Michel, thank you very much. Basically, for Lonapeg Somatropene, our key focus is market access for the commercial market. The commercial market represents roughly 180 million Americans, and it represents the also mainly 75% of the market is via the three big PBMs. And that's the way that you negotiate with the PBMs for market access is basically they send out their requests during the summer months. And then the final call you could say for addressing the market access for 2022 basically comes in, in the last week of August, beginning of September. So basically, we have a golden opportunity to be first on the market with the loaner pegs from a tropene as we are anticipating the PDUVA date on the 25th of June. And therefore, we will be negotiating with the three big VVMs market access for 2022. And we do believe that we will have a good market access for 2022 on the basis of that we will be the first in the long-acting segment potentially with the loaner pegs from a tropene. I hope that answered your question. Thanks, Jesper.
spk02: Thank you so much. And congratulations on the new year.
spk11: Thanks, Paula.
spk06: And your next question comes from the line of Jessica Sy from JPMorgan. Your line is open.
spk04: Hey, guys. Good afternoon. Thanks for taking my questions. This one might be for Dana. Can you tell us whether the necessary pre-approval inspections have taken place yet for trans-county growth hormone and your expectations for those being completed prior to the PDUFA given any COVID travel issues? I know you said multiple times on the call that you guys expect approval in 2Q, so it sounds like maybe things are on track there, but that's the first question. And then second, kind of building on the last question, thinking ahead to the 12-month open-label extension data for the PTH Phase II trial coming up in 2Q, can you talk about what you would expect to see on BMD at the 12-month time point and what that means for the product. I guess more specifically, at what point do you expect to have clinical data that will demonstrate that the normalization that you're seeing in BMD early on does not overshoot and lead to below normal BMD? Thank you.
spk11: Male Speaker 1 So, Dana, would you take the first question? Male Speaker 2 Yes. As far as the inspections go, we're finally starting to see a bit of movement from the FDA in terms of their activity. In fact, we've recently had a GCP inspection at a site for our number one enroller of growth hormone. So that was completed last week. As far as the manufacturing inspection goes, we are still in communication with the FDA about when that would be scheduled. And there are a couple of opportunities in terms of alternate approaches that are available. So we still feel that we sort of can address these issues before it has any impact on the PDUFA date. But we're also noticing that FDA is doing more manufacturing inspections outside the U.S. as COVID is somewhat subsiding in certain places.
spk01: Okay. I think just going back to your second question, and I think we need to take it into this perspective as my initial comments to Michelle. Because there we basically lay out that what we're seeing now is just a normalization of the bone structure that you expect to do when you actually are coming into a replacement therapy and observing that you're providing PTAs and physiological levels. And you can also see the differentiation between trabecular and cortical bone. If you look in the data, you can see where we expect to see the biggest remodeling areas on trabecular bone. And we're also seeing the right structure coming in of the bone. So from my perspective is that I cannot see any worry about that because that is not normal biology And we have children that have been 10 years on an infusion pump growing up with normal bone structure on an infusion pump. We have adults that are sitting five to six years on an infusion pump and observing all the same thing. And I think everyone that just has a clear understanding about an infusion pump and insulin and other things like that will acknowledge there's a total flat curve you provide with an infusion pump. So I really am lost in the logic of where it's coming in, because what we're just seeing is a normal biology, which we see on a lot of other elements. We see the same thing with urinary calcium. We see the loss of soft tissue classification. We see expecting all the normal physiology. I cannot change physiology. If you want to have a hormone replacement therapy, then you need to expect to see the outcome of being a normal human being.
spk04: Great, thank you.
spk01: We just follow the science. And that is what we're doing. I cannot change science. I can follow and adapt to science.
spk06: And your next question comes from the line of Alicia Young from Cantor. Your line is open.
spk08: Thanks for taking my question, and congrats on all the progress. I just wanted to flip maybe two questions One, just clarifying on the formulary, maybe I missed it. Do you think that you'll have kind of a broad formulary that could include adults and some of the other growth hormones? And then the second one is just in oncology, you know, as you continue to kind of do work there, you know, do you feel like there's one target between IL-2 or TLR-7 that has kind of a, you know, greater target risk, or do you kind of feel like it's somewhat equal and you have, you know, a fair amount of confidence in both? Thank you.
spk01: Jasper, I actually think that what you're now addressing is part of our important launch strategy. And you know, for every product, one step is to getting approved. And we have seen actual product being approved now in the U.S. without being launched because there is not what I call an associated launch strategy where the product actually is meaningful to launch. So what you're addressing is the key element in our entire launch strategy. And this is where we have a huge comfort in what we're doing because we're not only feeling that we are providing a best-in-class product opportunity, but we're also providing into the first-in-class growth hormone deficiency market for the pediatric children. So, Jesper, do you have anything further to add?
spk13: Yeah, of course. Just to add that in the initial phase, we anticipate to get the pediatric indication, which is the vast, vast majority of the market. whereas the adult indication only represents 10% to 12% of the market. So we will enter into the lion's share of the market with a pediatric indication.
spk01: And going back to oncology, you saw we built up a pipeline of three independent product opportunity endocrinology rare disease. We will continue to build up our pipeline in oncology. What we have with our two... hopeful clinical programs now in three to four months from now. We really have a paradigm shift how to treat tumor. And what we really want to do with a tumor is make a kickstart. We want to kickstart the hemogenic response into a solid tumor. This is how we think. And at the same time, we come with what we believe could be a next step. generation of how to do immunological stimulation. We've seen the success of checkpoint inhibitor, but we've also seen the limitation. When we see how potent our transcon IL-2 beta gamma is, it's a really unique compound. And this is why we see and build on the entire immunological understanding from Juha and his entire group. is to build more product opportunities. So we basically are a fully integrated oncology company with all the aspects of the immunological immune cycle, where we've addressed all pathway. And this is our vision, how we want to be a major player in that segment too. Johan, do you have other comments?
spk07: I think just to add that I think we believe that they both have very unique properties will have a unique opportunity in the treatment of cancer. They obviously are very different product profiles, one being intratumoral administration, one being systemic. We expect them to also work very effectively together. They're hard to compare with each other, but I think our point really is that they both have their unique spot in the treatment of cancer and will also work additively when treating these patients?
spk01: So I think the visionary thinking we have and why we believe we wanted to be a player in oncology, even if we would think that it's so different environment compared to rare disease endocrinology, we believe of the power of the transplant technology that give us such a major advancement to make highly differentiated product opportunity basic no one else can make. And by doing that and built on our algorithm on basic validated target, validated parent drug, we also believe we can be in the same successful way in our development. And when we go to the third product opportunity, we basically build on what we have done in Transcon IL-2 Beta Gamma, Transcon TLR-7A. That would be a strong synergy, what we're doing in the third one. This is how we want to think how we want to make a paradigm shift.
spk08: Great, thank you.
spk06: And your next question comes from the line of Joseph Swartz from SVB Learing. Your line is open.
spk05: Thank you for your opening remarks. But I was just wondering if you could just elaborate a little bit more on the program. How did you choose your ACCOMPLISH study doses and how have you designed your ACCOMPLISH China study in order to leverage your findings in the ACCOMPLISH study in the US and EU trial? And how should we interpret these two results when they emerge later in 4Q?
spk01: We just lost the beginning of it, but I believe that what you're referring to is our Transcon-CNP program.
spk05: Oh, yeah, that's correct, Transcon-CNP.
spk01: Yeah, I think that is what you're referring to. And I actually believe that we're having a major effort now to understand this, I think, important disease. We know how CNP has functioned. We have known that for 50, 20 years. We know the biology and the science behind it, and that is what has directed our two programs with Transcon-CMP. We are now in a position that we have a unique product opportunity with Transcon-CMP, which can provide a continuous exposure for up to one week with one single dose. And we know we can do it in an extremely safe manner. And we do it now in two independent product opportunities. to independent clinical trials. But what we really want to do is not only look at one single parameter. We are aiming to go down to the newborn children as fast as possible. We were, because of our unique safety profile, managed to start already at age two. And we are dedicated to move it down as early as possible, as fast as possible, down to newborn children because we know If we want to address co-morbidity, some of them are irreversible happening in a very, very early state. And that is really what we want to do. Mark is leading a major effort in Ascentis, how really to expand the program involving a lot of different co-morbidities. And I do not know, Mark, if you can say a few words how you also use our huge national history study now and try to integrate the development in co-morbidities and try to develop that in a unique clinical development plan so we potentially can address not only height but also the other comorbidities.
spk10: Sure. I can say a few words. Thanks, Yen. So we have an ongoing natural history study which is providing us very valuable information. And, you know, one of the things we find when we talk with individuals with achondroplasia is the height is not the biggest issue that they want us to look at, but rather a lot of the comorbidities, issues with foramen magnum, issues with otitis media, issues with airway. And so for us, it's been very important not just to be prepared to look at height, but to really understand the comorbidities better. And we are using the natural history study to try to gain information about the comorbidities, frequency, time of occurrence, and to give us enough information to, you know, successfully study them in a clinical trial. So I think that's what Yan's alluding to, and it's actually providing us, even early on, what we think will be useful information. Thanks, Yan.
spk01: So what is Mark designing is that we can integrate that knowledge into our clinical development now.
spk05: Okay, great. Thank you. And then my next question is on transcon PTH. Based on our conversations with endocrinologists, some docs prefer to see T-scores over Z-scores in adults. And our question is, you know, do you have plans to present this and how does that compare to T-scores?
spk01: T-score and Z-score are completely different in depending benchmark measuring. Z-score is to a normal population and this is also what we're using in growth hormone deficiency when we talk about height. You typically use a Z-score because that is the most relevant one. When you talk about osteoporosis compound, you often use a T-score because this is where you basically are trying to compare what was optimal for the person. But I think that is not really the aim of this here. We also can look on the T-score. It's basically providing the same guidance and the same thing that we see with the S-score. But as we have a hormone replacement therapy, it's typical what you want to do. You want to do a normalization of all different elements of the body to be as a normal human being. This is the definition of hormone replacement. If you go to osteoporosis, you want to redo, reset what you call a national decline in some of the bone structure. And this is why you're some way referring into a T-score. But this is coming from a demographic perspective. That is not building on a patient population that has a complete different dense bone structure than what you see in other places because it's a dense structure that is happening to what we call a non-national process where you're basically just building up a dense bone structure because you have no turnover. That is not the same thing to have a healthy bone structure. No one is ever claiming that the bone structure you have in an HB patient is healthy, even if it's more dense, because it's an old bone structure. So I think it's not meaningful to compare to a T-score. Sure, we have the data. We have looked at it. What is meaningful for hormone replacement therapy is compared to a Z-score.
spk05: Okay, great. Thank you for that.
spk06: And your next question comes from the line of Anita Deshaun from Berenberg Capital. Your line is open.
spk03: Hi, good afternoon. Thank you for taking my questions. Just a couple here. Could you please remind us the sort of timeline in terms of the pediatric phase three trial that would commence in Japan? And so I know you have applied for the CTN. when is it sort of likely to, you know, you're going to get the green signal to go ahead. And then in terms of the HP Phase III trial, would there be any change to the trial design itself in terms of inclusion or exclusion criteria of patients based on your six-month data?
spk01: I think the first question is reflecting our pediatric growth hormone deficiency trial or RITE trial. Mark, could you give us the status of a right trial that you have extensive experience in Japan?
spk10: Yes, absolutely. I actually spent 10 years of my career living and working and doing clinical research in Japan. And similar to the U.S., once you file a CTN, unless they object, then two to four weeks later you can start your study. And so that's usually not rate limiting. The approval is usually not rate limiting. But in any case, that study is actually going ahead and is in the screening phase. So, you know, so I think it's, you know, there's no roadblocks to continuing the development in Japan.
spk01: I think from a company perspective we will be in a unique position because it looks like all our product opportunities in three different indications, pediatric growth hormone deficiency, adult growth hormone deficiency and HPE will nearly be aligned for approval nearly in the same time period. What I actually think is a unique situation for us to find an optimal way to make a commercial effort in this region will typically involve Japan, South Korea, and other major countries outside Greater China in that region.
spk03: Okay. And then as far as the Phase III HP trial, would there be any changes in the trial design based on the six-month data?
spk01: Related to the six months data we have disclosed in our open label extension, we will basically have the same patient population coming into the trial as we saw in our phase two trial. That will not be, I actually think this, Mark, you can correct me, I think it's a little bit broader this time because there is a patient population as HDH1 patients. that we also have included it because they will hugely benefit to have a normal physiological level of PTH like a post-surgical one. So this kind of patient population also being opened up in the phase three trial. And we also believe that it's important that they have an opportunity to get an optimal PTH treatment with a physiological PTH level 24 hours. And from that perspective is we actually are having the other changes basic in where we looked about what was really difficult in the phase 2 trial and why we always look on screenings failure. Why do we have screenings failure? What is the drive of the screening failure? And we actually realized it was really, really difficult for an HB patient just to have a normal serum calcium 8.3. It was hard just by standard of care, taking activated vitamin D, taking calcium supplement to make them up to 8.3. You know the normal calcium is typically in the 9. In a trial here we have between 8.3 and 10.3. But we are in a position that we basically lower the entry criteria so you can go down to 7.8 to be part of the trial. And it was basically to ensure that all this patient group, which was impossible basically to be in a position to titrate up to that. Mark, do you have other elements or things I have forgotten?
spk10: Yeah, I mean, there's a few other subtle differences between phase. Basically relying on what we learned in phase two and going to phase three. So in phase two, again, for the first efficacy trial, the dose was fixed for the first four weeks and then allowed to titrate. In phase three, we're allowed to titrate from the beginning, which makes It makes clinical sense. And in Phase 2, the upper dose limit was lower than what we're allowing in Phase 3 based on what we've learned in Phase 2. So there's a few small things. And then the other is that in Phase 2, we validated a disease-specific quality of life instrument that will then be used in Phase 3 as an outcome measure. So I think those are the primary differences between the two trials.
spk03: Thanks, Mark. Great. Thank you. Sure.
spk06: And your next question comes from the line of Rene Wooders from Camden. Your line is open.
spk14: Hi, guys. Thanks for taking my questions. I guess two from my side. So first one on transcone growth hormone. Now that you have the two years data, can you remind us how long you are planning to continue following up these patients? And what will you do with this data? And do you anticipate to submit these data to the regulators as well? And second question is on Transcom PTH. Great to see that still almost all patients are on therapy in the open label extension part. Maybe moving, jumping a few steps ahead towards commercialization. What are the lessons you learned from NetPara? Why do you think Transcom PTH will be commercially more successful? Thanks.
spk01: Okay. Yes, thanks a lot. Thanks a lot for the question. The first one is basically addressing what do we do in the flight and the trial that we continue on in our phase three where we have the open label extension for both from the flight and the high trial which are continue on it. And currently we see patients coming to a situation that they are basically reaching final height. We are in a position we will continue this open label extension trial. So we basically can continue to collect unique information about how we basically are providing a treatment where every child have an opportunity to achieve their expected height, not only height, but also other elements like body composition and other things like that that we're measuring. And we think that is a really important thing. We are running our trial in multiple countries and we hope and expect still to continue in most of this country. But Mark, you're sitting with all the past commitments now here. And perhaps you can give a short update about what we expect to continue to execute. Summary, we'd like to continue to give you data for this important trial.
spk10: Sure. Do you want me to add a couple of comments, Jan?
spk01: Yeah.
spk10: Yeah, okay. So, you know, if you know the Enlightened trial, which is the combined ongoing study from flight and height, is continuing, and, you know, and as Jan said, we're getting very nice data on it. Some of the patients are indeed, you know, getting towards their near-adult height. Others have some room to go. I think, you know, at least for the time being, the study is continuing, and I would expect, you know, both clinicians and regulators may have some interest in having some longer-term data, and so At this point, I think it's premature to make a commitment on how long we'll continue, but it is certainly continuing for now and delivering valuable data. I think over the next month, we'll have a better idea about what longer-term data we want or would need to collect, but certainly it's ongoing now and really still giving very useful information.
spk01: So I think addressing your question, what is the learning from that power. Even if you develop a product like adjunct to stand-up care, there is still a huge need for such a product. And then you can nearly imagine what the need would be when you have a hormone replacement therapy and not just an adjunct therapy. That is the differentiation. We are competing in two different segments. One is an adjunct therapy. we are positioning Transcon PTAs as a hormone replacement therapy addressing all aspects of the disease, both short-term symptoms, long-term complications. That is the main difference between the two products. This is like an apple and an orange in my view.
spk14: Okay. Thank you very much.
spk06: And the last question comes from the line of Yehan Zhu from Wells Fargo Securities. The line is open.
spk09: Hi. Thanks for taking my questions. So a couple on a CNP program and a couple on a PTH program. So for the CNP program, to identify a dose to move forward into the Accomplished China Trial, do you need to wait until all for blinded dose cohorts in the U.S.-EU accomplished trial to be completed, or could you unblind each dose cohort as you go? And then any plan to open a U.S.-EU dose expansion trial for the CMP program? Thanks.
spk01: Great question. I think we are in a position that we aiming not to unblind it. We think it's really, really, really important not to unblind it. But we also believe that it's possible on a blinded basis to be in a position to have some good guidance that we have potential in a situation that we have an active dose. We have a lot of primary outcome we're looking in, We also have a series of biomarkers that we are addressing and other elements that could give us guidance about where we are. And this is where Mark and his team is really developing how really to look on all this data and be convinced that we have something that is meaningful to move forward in a dose escalation and dose expansion on it. And that is the task of Mark and his people to be quite sure that they're confident that we see something on a blinded basis. So we don't want to unblind the trial before everything is done. The second one, this is up to the situation. Yes, potentially we will do that, depending on that. We are in a unique position to our recent pharmaceuticals and the experience for the team in Axle to conduct this trial that we have so fast access to patients in greater China. But we're also seeing the same thing in Europe and US, in Australia and other places. So huge interest for our trial that we're not going to be limited to any kind of limitation in how many patients we want to take in. So I do not know, Mark, about our plans to potentially open up and European, U.S. arm in the dose expansion. I don't think it's something we really have decided on yet.
spk10: No, we have not discussed it for now. You know, things are going well, both in the global trial and the China trial. So, you know, it's not something we talked about so far, but certainly, you know, should it be necessary, we could talk about it, but not on the agenda right now.
spk09: Got it. And on the PTH program, what kind of interest are you seeing in the pathway Phase III trial? Are there enthusiasm due to the data you reported from the Phase II open label extension? And then is the safety database from 76 patients considered sufficient for the regulators? Thank you.
spk01: That's two questions. The first question is, how high is the understanding about what we can provide with Transcontinental PTAs throughout the HCP patient society and physicians? I've never seen anything like that before. When we see the anxious asthma, how people get their life back again. Sure, it's helping us to go out and make a broader education about it, like in the endoconference. But we already see a huge enthusiasm everywhere to be part of this trial. So I believe that when I see how Transcon PTAs is a game changer, we are addressing the life of more than 200,000 patients just in Europe, U.S., and Japan. And what we have seen, basic, by having 58 out of 58 basic continue on it, everyone has a huge, huge benefit of this treatment. And related to the safety database, I think, Dana, you can explain how we're building up a combined safety database, both from our phase two trial and also what we will see in our phase three trial.
spk11: Yes, for the sort of approval As we discussed with the agency, too, in the phase two meeting, the combination of the information from the phase two and the phase three will satisfy the criteria for the safety thresholds for the applications.
spk09: Got it. Thank you. Does that address your question? Yeah. Yeah, very helpful. Thank you.
spk06: And ladies and gentlemen, this concludes today's conference call. Thank you all for your participation and have a wonderful day. You may all disconnect.
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