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spk11: are in a listen-only mode. We will be facilitating a question and answer session towards the end of today's call. If at any time during the call you require assistance, please press star, then zero, and a coordinator will be happy to assist you. I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Perthena. Please proceed.
spk16: Thank you operator. Good afternoon and everyone and welcome to today's call to review Procena's business progress, fourth quarter and full year 2023 financial results and 2024 financial guidance. Please review the press release we issued earlier today, which is available on our website at Procena.com and is also attached to a form 8-K filed today with the SEC. In addition, we are using supplemental slides, which are available on our investor website events and presentation section. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will provide opening remarks, including an overview of Prothena's corporate and development strategy. Then Brandon Smith, our Chief Operating Officer, will provide an update on our pre-commercial progress for our wholly-owned Britannimab program, which is in phase three for the treatment of patients with Mayo stage four ALN mitosis. Dr. Hideki Garan, our Chief Medical Officer, will provide an update on our ongoing clinical programs. John Nguyen, our Chief Financial Officer and Chief Strategy Officer, will then discuss our 2023 financial results and 2024 financial guidance before turning it back to Gene for closing remarks, at which point we will open up the call for a Q&A session. Before we begin, I would like to remind you that during today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statement. For discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today, as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. With that, I'd like to turn the call over to Gene.
spk08: Thank you, Mark, and thank you all for joining us today to review our 2023 financial results and business highlights. Let's begin on slide five. Our mission at Prothena is to create transformational therapies addressing significant unmet medical needs for the millions of patients and their loved ones that are affected by devastating diseases caused by protein dysregulation. That mission is enabled by our deep scientific expertise, which serves as a unifying thread connecting our corporate strategy, our portfolio development, and the dedication that propels Prothenians every day. We continue to advance our mission, which has fueled our robust late-stage clinical pipeline, moving us closer to becoming a fully integrated commercial biotechnology company. As a result of our commitment to our mission, we have created a robust portfolio of therapeutic drug candidates targeting both neurodegenerative and rare peripheral amyloid diseases, as shown on slide six. Our portfolio includes four wholly-owned programs and five partner programs. This intentional mix allows us to advance a fulsome portfolio by leveraging the benefits of working with key strategic partners on some programs while still maintaining the full upside potential for our wholly-owned programs where we feel that we have unique insights and expertise. I'll discuss four of our ongoing clinical programs on the next slide, PRX12, Pertamumab, Presinezumab, and NNC6019. But first, I'd like to highlight the exciting progress across our earlier stage programs. In July of 2023, we presented compelling preclinical results in a late-breaker poster presentation at AAIC for PRX123, our dual A-beta-tau vaccine program. And by year-end 2023, PRX123 received IND clearance and fast-track designation from the FDA. Our ongoing neuroscience R&D collaboration with BMS made meaningful advancements in 2023 and into this year. BMS 986446, formerly PRX005, is a potential best-in-class antibody for the treatment of Alzheimer's disease that specifically targets a key epitope within the microtubule binding region of tau. In 2023, BMS opted into the global rights for this program with an additional milestone payment of $55 million and announced that the Phase 1 data supports advancing the program into a Phase 2 clinical trial in 2024. And for PRX19, a potential best-in-class antibody for the treatment of neurodegenerative diseases, we recently received FDA clearance for the IND application for this program as well. This is the second of three programs in our BMS collaboration. We remain well-funded to execute on our strategic objectives, taking us well beyond our upcoming clinical readout. As you will hear about in more detail later in this call, we ended 2023 with a strong cash position of $621 million. Moving now to slide seven. Our clinical expertise and differentiated approach enables us to advance best-in-class and or first-in-class therapies that have the potential to transform the treatment landscape for protein dysregulation diseases. Today, I'd like to focus on the four clinical programs that are nearing significant inflection points within the next 12 to 18 months. First, I'll discuss our wholly-owned programs, PRX12 and Bertamamab, and then move on to our partnered programs, Pracinezumab with Roche and NNC6019 with NovoNordisk. Pier X-12 is our next generation investigational treatment for Alzheimer's disease, which targets a key epitope at the amino terminus of amyloid beta with high binding potency. Pier X-12 was designed with the patient in mind, and we believe it has the potential to be best in class, transforming the treatment of Alzheimer's disease by meaningfully reducing treatment burden associated with the currently available anti-beta therapies. Based on our market research, We understand that a treatment with similar efficacy and safety to currently approved anti-beta therapies, but delivered as a once-monthly at-home subcutaneous treatment, has potential to be the dominant player in the market. In 2023, we presented compelling preclinical data at ADPD and at AAIC, demonstrating that PRX12 binds to amyloid plaques with high avidity. PRX12 is currently being evaluated in a double-blind placebo-controlled phase 1 trial. with the goal of identifying an optimal dose level or levels for a registration-enabling trial. The preclinical data, combined with the initial clinical data from our ongoing phase one trial, are supportive of a once-monthly subcutaneous treatment with a potential best-in-class profile. Pertamumab seeks to address the high risk of early mortality that remains an urgent unmet medical need for patients with Mayo Stage 4 AL amyloidosis. through its differentiated depleter mechanism, which is designed to clear accumulated amyloid and neutralize toxic light chain aggregates that are thought to cause organ dysfunction and failure. We are conducting the confirmatory phase three of FIRM-AL clinical trial, evaluating for Tamumab in patients with Mayo Stage 4 AL amyloid doses under a special protocol assessment or SPA agreement with the FDA with a primary endpoint of all-cause mortality at an unprecedented significance level of 0.10. We expect top-line results between the fourth quarter of 2024 and the second quarter of 2025. Pracinezumab is an antibody for the potential treatment of Parkinson's disease, designed to target a key epitope within the C-terminus of alpha-synuclein, and is the focus of a worldwide collaboration with Roche. Roche is currently conducting the Phase IIb Padova clinical trial in patients with early Parkinson's disease. Roche completed enrollment of this trial in the first quarter of 2023 and expects to report top line data later this year. And finally, NNC6019 is an amyloid depleter antibody for the potential treatment of ATTR cardiomyopathy. Novo Nordisk is currently conducting an ongoing phase two signal detection trial in patients with ATTR cardiomyopathy. The trial has fully recruited its patients with top-line results expected in the first half of next year. This is an exciting year of clinical trial execution for both Profina and our strategic partners. As we look ahead, we are also thoughtfully building out our commercial leadership and market insights for Bercamimab. So, to provide a little more context on our pre-commercial efforts, I will now turn the call over to Brandon. Brandon?
spk09: Thanks, Gene. Moving to slide nine.
spk02: As we continue executing on our ongoing confirmatory phase three of FIRM-AL clinical trial, we are focused on building out our commercial capabilities to support Bertamamab as our first potential commercial product. Among patients with AL amyloidosis, a rare, progressive, and fatal disease, newly diagnosed individuals with significant cardiac involvement, such as male stage four, are at the highest risk for early mortality. This remains a serious unmet need for patients and their families. Pertamumab is the only candidate to have shown a survival benefit in patients with Mayo Stage 4 AL amyloidosis in a randomized clinical trial, our previous Phase 3 vital trial. The ongoing confirmatory of FIRM-AL trial was designed based on a spa agreement with the FDA to approve Pertamumab at a p-value of less than or equal to 0.1 for the primary endpoint of all-cause mortality. Showing an early and sustained impact on mortality is a powerful differentiator, and if approved, we are confident that Bertamibab will be welcomed as a major advancement in the field and a key treatment option. Moving to slide 10. The market dynamics for Bertamibab as our potential first commercial product are quite compelling. Our plan is to independently commercialize Bertamumab, and we believe that we will be able to efficiently reach prescribers for advanced patients with a focused commercial presence. This is a rare disease patient population with a targeted call point or hematologist with support from specialized cardiologists and a primary treating specialist. KOLs in the community at large recognize the urgent need for treatments that improve survival in patients with AL amyloidosis who are at high risk for early mortality. Based on epidemiology studies, we estimate there are over 20,000 patients with Mayo Stage 4 AL amyloidosis across the major markets, including the United States, Europe, China, Brazil, and Japan. This is further supported by our claims data analysis to identify patients who are actively receiving treatment for AL amyloidosis in the United States. Based on this, we believe there are approximately 4,000 Mayo Stage 4 patients in the U.S., In addition, our U.S. and European market research indicates that approximately 75% of patients are treated in approximately 500 centers of excellence and amyloidosis specialty centers, usually within academic hospitals. Our team continues to build upon the existing relationships we've established with KOLs and experts in the field through our extensive clinical programs for Bertamometh. We will continue to collaborate with these KOLs and experts, along with the organizations that publish treatment guidelines, such as NCCN and the International Society of Amyloidosis, to ensure they are fully aware of and informed about Pertamilab. This includes continuing to present our data at top medical congresses and publications in peer-reviewed journals. Today, we are building our commercial leadership team thoughtfully as we prepare for launch.
spk09: I'll now turn it over to Neku to review our clinical programs. Thank you, Brandon.
spk07: Let's continue with butaminib and review the results of our previous vital trial, which were published in the ASH peer-reviewed journal, Blood, last year. Importantly, we observed a survival benefit in the subset of approximately 30% of patients who were categorized as Mayo Stage 4 baseline. The Kappa-Meier curve illustrating this separation is shown here on slide 12, demonstrating an early and sustained benefit. In this high-risk group, We observed a survival benefit favoring Bertamumab reflecting approximately 60% relative reduction of all-cause mortality at a p-value of 0.021. This was further supported by meaningful and significant improvements in function as measured by 6-minute walk tests and quality of life as measured by SF36. Turning to slide 13, to expand on Brandon's earlier remarks, based on our extensive analysis of the vital data, as well as further confirmation of the data with external statistical experts and leading physicians in the field, we actively engaged with the FDA to align on the path towards regulatory success with Britannumab. A spot was agreed to between Prisina and the FDA for the confirmatory phase three affirmed AL clinical trial to be conducted in patients with AL amyloidosis categorized as male stage four baseline. with a pre-agreed-upon significance level of alpha less than or equal to 0.10 on a primary endpoint of all-cause mortality. This is a time-to-event trial, and patients are randomized two to one on vertemimab plus standard of care or placebo plus standard of care. At the end of 2023, based on a predetermined number of mortality events, we were able to estimate that top-line results of REFIRM-AL will be available between the fourth quarter of 2024 and the second quarter of 2025. We very much look forward to the results of this trial, moving us one step closer to getting this treatment to patients and families in need. Let's discuss PRX12, our potential best-in-class anti-amyloid beta treatment, starting on slide 14. We believe that PRX12 can be a best-in-class anti-amyloid beta treatment for early Alzheimer's disease. In order to achieve this target product profile, we need to establish efficacy, convenience, and safety. CRX-12 was intentionally designed with the antibody attributes required to achieve a similar or better efficacy and safety profile to currently-approved antiviral therapies, with a clear differentiation as being administered in a much more convenient and accessible once-monthly, at-home, self-contained treatment. PRX12 is a humanized IgG1 monoclonal antibody designed to provide a longer half-life than approved anti-AVG treatments with low immunogenicity. We have demonstrated a highly potent binding, high affinity and validity, and a slow off-rate, allowing for consistent target engagement, all of which are optimal for a once-monthly subcutaneous treatment. The ongoing PRX12 phase 1 trial, which we will discuss on slide 15 and 16, is designed to demonstrate a potential best-in-class profile in the clinic. Moving to slide 15, Ascent 1 is our double-blind, placebo-controlled, single-sending dose clinical trial evaluating PRX12 in healthy volunteers and participants with early Alzheimer's disease. The trial enrolled approximately eight participants per single-sending dose cohort, randomized three to one to receive a single subcutaneous dose of PRX12 or placebo, and doses ranging from 70 to 400 milligrams. Moving on to the multiple ascending dose cohort from slide 16. Ascent 2 is our double blind placebo controlled multiple ascending dose clinical trial evaluating PRX12 in people with early Alzheimer's disease. Each MAD cohort is randomized three to one to receive PRX12 or placebo once monthly for six months in multiple ascending dose level. The objectives of the trial are twofold. One is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of PRX12 in patients with early Alzheimer's disease. And two is to find the optimum dose level or levels for a registration-enabling clinical trial. There are a couple of key aspects to the NAD trial design that I'd like to highlight today. Participants are assigned to two groups of cohorts based on ATOL E4 status. which we refer to as A cohorts or B cohorts. Participants in the A cohorts are either ApoE4 non-carriers or heterozygous carriers. Each of these A cohorts is evaluating approximately 32 participants with early Alzheimer's disease in doses ranging from 45 to 400 milligrams. In addition, we are evaluating ApoE4 homozygous carriers with separate B cohorts for approximately 12 participants with early Alzheimer's disease. in doses ranging from 45 to 200 milligrams. Following the first six months, which is placebo-controlled, participants previously taking PRX12 or placebo are eligible to receive an additional six monthly doses of PRX12 in an open-label extension. We have completed all STAT cohorts and the double-blind portion of the initial 70-milligram MAD-A cohort. The Phase I clinical trial continues as planned as the initial data supports once-monthly subcutaneous treatment and dose escalation in additional cohorts. We look forward to evaluating the full exposure response relationship of PRX12 and expect to update you later this year. Turning now to Prosimizumab on slide 17. Prosimizumab is the first anti-alpha-synuclein antibody to demonstrate slowing the progression on measures of Parkinson's disease in a Phase II trial. Our partner, Roche, previously presented data from the Phase II PAS-D in the trial showing Prosimizumab reduced one-year motor progression by 35%. as measured by the MGS-UPDRS Part 3, a scale of motor dysfunction in comparison to placebo. Roche continues to provide meaningful updates on the ongoing open-label extension from the trial, including recently at the Movement Disorder Society Congress in August. Roche compared three-year progression of motor signs in the Pasadena-Prazdnitsa population with a propensity score balance cohort of real-world data from the Parkinson's Progression Markers Initiative, or PPMI. The prozumizumab population shows 63% slowing progression as measured by the MDS-UPDRS Part 3 in the early start prozumizumab population as compared to the real-world data cohort. These data continue to support prozumizumab's potential effect on delaying motor progression in Parkinson's disease. Baroche has advanced prozumizumab into the Phase IIb Padova trial which is a double-blind placebo-controlled trial evaluating 586 patients with early Parkinson's disease. Participants are randomized one-to-one to receive proznizumab or placebo every four weeks for at least 18 months. Proznan says completed enrollment in the first quarter of 2023. The primary endpoint is time to clinically meaningful progression on motor signs of the disease, as assessed by a five-point or greater increase in the MDS-UPDRS Part 3 from baseline. This disease progression may be correlated to meaningful worsening on the clinical global impression improvement scale. Roche expects to report top-line data from the PEDOVA trial later this year. Moving to NNC6019 on slide 18. NNC6019 is being developed by Novon Dornisk as a potential first-in-class amyloid depletor antibody for the treatment of ATTR cardiomyopathy. This is a rare, progressive, and fatal disease characterized by deposition of abnormal non-native forms of TTR protein and amyloid in vital organs. NNC6019 is thought to deplete both deposited amyloid circulating non-native TTR to prevent further deposition to improve organ function. This mechanism of action has the potential to provide medicine for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs. Novo Nordisk is progressing this program in ongoing double-blind, placebo-controlled signal detection phase 2 clinical trial. The trial has completed recruitment, and Novo estimates primary completion in the first half of 2025. Now, I'd like to turn the call over to Tron for a discussion of our 2022 financial performance and our 2024 financial guidance.
spk03: Tron? Thanks, Hideki.
spk04: Today, we reported financial results that were favorable to our 2023 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. As Gene mentioned during his opening remarks, our robust portfolio of wholly owned and strategically partnered programs allows us to leverage partner payments while still maintaining full upside potential of our wholly owned programs. In 2023, BMS opted in to secure their global rights for BMS 986446, formerly known as PRX-5, for $55 million. In terms of our 2023 financial performance relative to guidance, we had net cash used in operating and investing activity of $136.7 million, which was favorable to our guidance range of $148 to $161 million. Net loss was $147 million, which was favorable to our guidance range of $153 to $171 million. As of December 31st, 2023, Procena had $621 million in cash, cash equivalents, and restricted cash, which is favorable to our guidance of $600 million. As of February 9th, 2024, Procena had approximately 53.7 million ordinary shares outstanding. Additionally, we continue to have a simple capital structure with zero debt. Turning to our 2024 financial guidance on slide 21, we expect our full year 2024 net cash used in operating and investing activities to be between $208 and $225 million. We expect to end the year with approximately $405 million in cash, cash equivalents, and restricted cash, which represents the midpoint of the range. The estimated full year 2024 net cash used in operating and investing activities is primarily driven by an estimated net loss of $229 to $255 million, which includes an estimated $51 million of non-cash share-based compensation expense.
spk03: With that, I'll turn the call back over to Gene to discuss our upcoming milestones. Gene?
spk08: Thanks, Tron. Moving to slide 23. I'd like to acknowledge and thank the patients, their families, physicians, and study site staff who participate in all our clinical trials. Without their support, we could not elucidate the potential impact of the new medicines we're developing. I'd also like to thank our talented Presidians for their ongoing commitment to advancing protein dysregulation science to make a real impact for the patients and families we serve. As we look ahead, we're excited to have meaningful catalysts across our programs with potential clinical readouts from four ongoing clinical trials within the next 12 to 18 months, which include top-line results from our confirmatory AFIRM-AL phase 3 trial, evaluating for Kamimat in patients with Mayo stage 4 AL amyloidosis, clinical data from our ongoing phase 1 trial, evaluating PRX12 as a potential best-in-class treatment in early Alzheimer's disease, top-line results from the phase 2b Padova trial, evaluating presenizumab for Parkinson's disease being conducted by Roche. And finally, clinical data from a phase two signal detection trial evaluating NNC6019 for the treatment of ATTR cardiomyopathy by Novo Nordisk. I am proud of the progress that Profina made in 2023 and continued into 2024. We are well capitalized with a robust cash position and remain focused on advancing our clinical programs as we strive to become a fully integrated commercial biotechnology company. With that, we'll now open the call to Q&A. Operator?
spk11: Good question. Please press star followed by the number one on your touchtone telephone. If your question has been answered or you wish to withdraw your question, again, press star one. Please limit yourself to one question. I repeat, please limit yourself to one question. Press star one to begin. Please stand by for your first question. Your first question comes from the line of Charles Duncan from Cantor Fitzgerald. Please go ahead.
spk18: Yeah. Hi. Good afternoon, Jean and team. You've got a lot going on and limiting to one question will be a challenge, but I'll try to do that. I wondered if you could provide a little bit more clarity on on the patient enrollment in ascent to, you know, specifically what patient or what cohorts have been enrolled, both A and B in terms of which doses. And I'm wondering if you could provide a sense of what you meant with regard to giving an update later on this year on data. Could you anticipate being possibly in a pivotal program in later part of 2005 or 2025?
spk08: Yeah, thanks for the questions, Charles. Appreciate them. So, I think first, just with respect to timeline, you know, obviously this is an ongoing trial and we plan to share additional data as that data becomes substantive. I think, you know, in terms of when we plan to give an update on PRX-12, we do plan to provide an update this year. Whether that update is to update on timing or data is something that we'll still determine. And I think in terms of your question around enrollment in the various cohorts, maybe I can ask Hideki to address that question. Hideki?
spk07: Yeah, thanks, James. So, yeah, enrollment's been very strong in our PRX-12 statewide trial. high-level interest in monthly sub-Q antibody treatment. And it's important to note that the Data Safety Monitoring Board has a clearance of 45 to 400 milligrams. And we're proceeding with all course as planned.
spk09: And so this will allow us to fully explore those response curves.
spk11: Your next question comes from the line of Jay Olson from Oppenheimer. Please go ahead.
spk14: Oh, hey, thanks for the update, and congrats on the progress. We have another question about the PRX012 MAD study. Can you talk about this six-month open-label extension, and what do you hope to learn from that? Will patients on low doses switch to high doses, and how will it impact your next steps for 012? Thank you.
spk08: Yeah, thanks, Jay. Thanks for the question. Well, maybe I can just start with a reminder that the study is double-blind placebo-controlled six months in duration with patients receiving their specified dose level of placebo once a month by subcutaneous administration. Obviously, after that six-month period, we do provide the potential for an open-label extension for patients, and maybe, Hideki, you can just speak a little bit about that period.
spk07: Yeah, so each for six months, as you mentioned. And again, very strong enrollment, and people are very excited about the one-to-one piece of Q-dose.
spk05: And here, we won't have a... As Zanetti's saying, it's not placebo-controlled, where placebo patients will now receive drugs. Of course, that will be the first time they receive it, but the other patients will continue to go on to have up to 12 months of potential treatment of PRX-12, which we are capturing both safety, tolerability, and, of course, PK, sorry, pharmacodynamic measurements.
spk11: Your next question comes from the line of Michael DeFleur from Evercore ISI. Please go ahead.
spk00: Hi, guys. Thanks so much for taking my question. I just want to zero in on the comparable ARIA rates that we're seeing between the 70 milligram dose of 012 and placebo. So when you consider how subcutaneous bapanizumab had less ARIA rates compared to its IV version, And while leucanumab sub-Q had about equal ARIA rates versus the IV version, how do you reconcile this? And given that the engineering of 012 was optimized off of bapanizumab, do you foresee similarly low ARIA rates for 012 at higher dosage? Thank you.
spk08: Yeah, it's a great question, and you've got a lot built in there around the science, so I appreciate the question. I think what you're alluding to is really just how, you know, the biology of ARIA plays into dosing with these anti-amyloid agents. And as you say, I think, you know, there is evidence across the anti-A-beta field that there is a exposure-response relationship between, well, certainly it's almost on a linear basis with respect to amyloid reduction. But on the case of ARIA, a little difference between antibodies. And I think that's what we're seeing. So you're making the point between Bapinuzumab and licanumab, and I think those are astute observations. As you say, with the Baffinuzumab work, I think as approximately equivalent exposures on an AUC basis were managed to be attained, what was observed, at least in the published literature, was lesser aria with that molecule, with licanumab's data a little bit more comparable. So what that indicates to us is really that it is molecule dependent, and what we need to understand as we see multiple dose-level cohorts with our molecule, PRX12, that we need to understand that relationship. And we look forward to determining that as we explore the exposure-response relationship, as Hideki mentioned, from the 45-milligram monthly dose level through to the 400-milligram monthly dose level. With that said, I think you also kind of asked a little bit of a question there just in terms of what, you know, consistency meant with placebo. And maybe I can just ask Hideki to comment on that piece.
spk09: Yeah, thanks, Jean.
spk07: So just to remind you, we're running a double-blind placebo-controlled trial. And as reported in the 70-milligram dose, there was plaque turn as well as aria-rate consistent with placebo. And the data that allows us to provide a therapeutic index explores the full dose-to-once curve with once-monthly sub-Q dose. And we, again, just to remind you, we have the ability to dose up to 400 milligrams.
spk09: And all these cores are actively involved.
spk11: Your next question comes from the line of Nina from Deutsche Bank. Please go ahead.
spk01: Hey, guys. Thanks for taking my question. Just to kind of piggyback on the ARIA discussion here, I'm just wondering if you can tell us a little bit about was the comment on ARIA being consistent with placebo, is that true for both the cohort A and the cohort B patients so far, so both the APOE4 non-carriers and the heterozygotes as well as the homozygotes. And then I was just wondering if you could also talk a little bit about some of the differences in activity that you're expecting between the 70-mig dose versus 200 and 400 and why you selected 200 and 400 for both SAD and MAD. I know you had talked a lot about selection of 70-mig as being based off of a similar C average to 10-migs per take aducanumab, but just wondering how we should think about the higher doses.
spk18: Thanks.
spk08: Yeah, thanks, Nina, for the question. Maybe I can start and then Hideki can again jump in here. I think first with respect to your question about the data that informs what we've said about this molecule to date, which, you know, just again as a reminder, I think what we've indicated is that with the A cohort, which is the 70 milligram monthly cohort, you know, we've seen evidence of what we would characterize as encouraging reduction in amyloid data, obviously, that helps us to understand that we believe this is a once-monthly subcutaneous drug. And obviously, RE rates, as you mentioned, consistent with placebo. What goes into informing that is obviously the data from the single-dose study as well as the cohort, the 70-milligram cohort I'm referring to in the multiple-dose study. The additional ongoing cohorts remain blinded. So it is a double-blind, placebo-controlled study. I think the other question was really just around the selection of the dose levels, and I think maybe I'll just ask Hideki to speak to that, other than to say that, you know, these dose levels that are being explored are the dose levels that were anticipated to be explored, and that we are continuing to conduct this study as we had anticipated, and it's moving forward in an encouraging pace, as Hideki indicated. Hideki?
spk07: Yeah, thanks, James. As you mentioned, we're continuing to explore the doses in a phase one study, and that's the purpose of the phase one study is. And just to remind you, the 70 milligrams, we just see the encouraging amyloid reduction and consistent REO rates with placebo. And that allowed us to really explore the full dose response for 45 all the way up to 400 milligrams. And again, just to remind you, the high, extraordinary high volume pump fee, monthly sub-Q administration, and potentially the best in class in anti-abate amyloid.
spk11: Your next question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead.
spk17: Hi, Dean. This is for Yas. Thanks for taking our question. I'll just kind of dive more into the details of the ARIA rates. Given that you're enrolling both ApoE4 homozygotes and heterozygotes, we know that this derives sometimes differences in ARIA rates. How does this factor into your expectations regarding both safety and efficacy across these populations?
spk08: Yeah, no, thanks for the question. I think there's kind of two questions built into that one in terms of how we're thinking about ARIA just across the entirety of the patient population. And I think the second is really just around how we think about this trial design. So let me start with ARIA. And obviously, you know, as we talk about ARIA rates, we're being specific to our patient level cohort. We are reporting data out as one would in a phase study relative to placebo. And I think that's what we indicated in our release in January, that ARIA rates in this 70 milligram cohort after six months of treatment were consistent with placebo. I think the point you're making about testing separately ApoE4 homozygote carriers in these B cohorts is something that we're learning from the field. So as we continue to iterate in this field across multiple companies, it does take a village to develop therapeutics in this space. we are learning from each other, I think, on the clinical side as well as the preclinical side. And one of the lessons, I think, that's become clear is that APOE4 homozygosity does tend to lead itself to a higher ARIA rate. And in the context of clinical trials, that can lead to, in some cases, misdosing or skip dosing. Obviously, that's less than ideal. As we start to think forward to efficacy-driven studies and registrational studies, we want doses that are optimized for the entirety of the population, not just portions of the population. So we chose, in the context of the phase one study, to be a little bit more deliberate in evaluating these APOE4 homozygote patients so that when we bring this entirety of the patient population back together in a clinical study, that we're selecting dose levels and approaches that are optimized for the entirety of the population. So that's kind of how we think about it from an ARIA perspective, and not just from an ARIA perspective, but from a therapeutic index perspective. At the end of the day, as we think about best in class for a molecule in this space, we think about three important variables, convenience, efficacy, and safety. Efficacy and safety, of course, leading to the therapeutic index. But obviously, with the convenience factor, we think that's quite important with respect to patient burden. And as we've indicated in January relative to the data that we have seen to date, You know, we've given some directional guidance in terms of where we are in all of those, encouraging levels of amyloid reduction. Once monthly sub-Q, we believe, is supported based on the data we've seen to date. It is the approach we're continuing to take moving forward in our trial as planned. And then, of course, we've just talked about the ARIA being comparable with placebo.
spk11: Your next question comes from the line of Rudy Lee from LeeRinc Partners. Please go ahead.
spk13: Thanks for taking my question. Just a quick follow-up on your dosing selection. So can you maybe talk about the rationale including the 45mg dose in ASCEND-2, which was not tested in ASCEND-1? I'm trying to get better safety and any kind of would be helpful. Thanks.
spk08: Yeah, thank you for the question, and maybe I can just take this one. I think, you know, what we're looking for is to really have a fulsome understanding of the exposure-response relationship, and we believe that evaluating dose levels, you know, from 45 milligrams to 400 milligrams provides us with a pretty comprehensive overview of that, and obviously that exposure-response relationship is something that we're interested in. both in terms of amyloid reduction, but also in terms of aria rates to understand that therapeutic index. So that's really what defined it. I think as Hideki has already mentioned, there's been very high level of interest in this study, so we've been afforded also the opportunity to include a number of cohorts, and we've been able to enroll those cohorts in a pretty favorable way. So I think that really is the rationale for it. Other than that, I would just say that these were the dose levels that we had preplanned on testing. As we saw the first dose level cohort, the 70 milligram dose level cohort data, the decision was to continue to conduct this study in the way that had been previously envisioned.
spk11: Your next question comes from the line of Michael Yee from Jefferies. Please go ahead.
spk06: Hey, guys. Thanks for the question. I know there's been a lot of questions around ARIA, and we just wanted to ask more specifically, when you say consistent with placebo, was there actually one case of ARIA in the placebo, and whether you would have expected that? And then, if so, would you have expected ARIA in that type of range in the drug arm, given you have very low exposure? Whereas the IV drugs, including what can be have already a race that are around 12% to 20%. So you could tie those two together. And one of the drive competence today for those listening that you can go to 200 milligrams and three times the dose and still thread the needle. Thank you.
spk08: Yeah, thanks for the question, Mike. I mean, obviously this study is double bind placebo controlled, you know, and as we reported at the 70 milligram dose level, the ROE rates, as you say, were consistent with placebo. And I think, you know, that's, I think the statement around where we are from a therapeutic index perspective and what we think that therapeutic index then provides is the ability to move up in dose range, as you've indicated. So I think Hideki's already mentioned that the 200 milligram dose level cohort, in fact, all dose level cohorts are active. And so we're moving forward and exploring a pool exposure-response relationship ranging all the way from 45 to 400. So I think, you know, what that should indicate is that we believe that the therapeutic index provides us with the sense that we have the potential for a best-in-class molecule. And again, for us, a best-in-class molecule, you know, is a function of the three variables, the convenience factor, which is really around patient burden, The efficacy, which in the case here, we're talking about really a reduction of amyloid. And then, of course, the safety, which I think everyone's very focused on ARIA, but we'll talk about safety in general and being permissive from the therapeutic index perspective to continue to explore this Folsom exposure-response relationship range.
spk11: Your next question comes from the line of Jason Butler from Citizens JMP. Please go ahead.
spk15: Hi. Thanks for taking the questions. I guess I want to switch gears here and just ask a question about . Can you just speak to us about how we should think about magnitude of benefit or clinical meaningfulness around the primary endpoint? And then how do you envisage the product being incorporated into clinical practice? Thanks.
spk08: Yeah, no, thanks for the question. Yeah, so, you know, just maybe just a quick refresh of what Roche has already shown with this molecule. So, starting with the Movement Disorder Society data last year, where they showed the three-year open-label extension data from the prior phase 2 Pasadena study. And, you know, importantly, relative to the PPMI demographic matched group, they showed a 63% slowing of progression. as measured by MDS-UPDRS Part III. And more recently, we've seen the abstract published for the ADPD meeting, which will occur here in early March, where, you know, while that presentation hasn't happened yet, they have published the abstract. And there, they're talking now about four-year open-label data. And at least on the MDS-UPDRS Part III scale, 117 percent less progression. than that PPMI database group. And in fact, even on the, you know, activity of daily living scale, the MDSU PDF Part 2, a 39% slowing of, or less progression than that PPMI data group. So, we're very interested in this. Obviously, the PDOVA study is fully enrolled as per Roche. This is a large study that is being run with high integrity. We've got 586 patients in this study randomized on a one-to-one basis. So we're excited to see those results. I think it's based on strong science. It's based on previous clinical data. I think the way they're thinking about the endpoint is informed by the prior studies. And then ultimately, the go-forward regulatory path, and I think to your question, you know, how this will ultimately be positioned will be determined by the data and obviously also continued conversations between our partners at Roche and the regulators. And we have very high confidence that Roche will be as aggressive as is appropriate based on the data set that they obtain.
spk05: I think one thing to add, too, in terms of the time to event endpoint is that it captures a five-point or greater increase, right, progression in the scale, which in and of itself rose for these to be clinically meaningful. They're also working on other clinical, you know, functional endpoints within the trial to correlate. So, we look forward to their continued discussion with regulators and, of course, the data later this year.
spk11: And we have time for one more question today, and it comes from Anana Ghosh from HC Rainright. Please go ahead.
spk12: Yeah, hi. So, you know, just wanted to get your opinion on some of these concepts, which I don't think the street understands very well with respect to PRX O2L program. So what has been, you know, how do we think at the AUC, the CMAX, and, you know, relative fractional occupancy? When you are looking at data which comes from leucanumab, subcutaneous, you know, CTAD data, and with respect to your idea on the PRX12 development program. So, any ideas with respect to those three factors will be very helpful to understand how to think about PRX12 development going forward. Thank you.
spk08: Yeah, no, I appreciate the question. And yeah, it's an important question. And, you know, you talked about mecanumab and aducanumab, and I think they're relevant as, you know, aminoterminous targeting anti-β antibodies. And I think what we see with those antibodies, as you look through the phase two data set and into the phase three data set, is a, you know, a relationship between removal of plaque and the dose response or exposure response relationship. And in the case of licanumab and aducanumab, that relationship is close to linear. That's not true with every anti-beta antibody. Other antibodies show a much more of an all-or-none effect, and I'd point to dinanumab from that perspective around plaque clearance. I think with respect to ARIA, it's a little bit different. It is a little bit more molecule-dependent. Although, you know, that being said, there clearly is a dose-effect relationship within molecules, but between molecules, there's a little bit of a difference. And we continue to believe that ARIA is a mechanistically driven event, meaning if you're removing plaque, you're going to increase the risk of observing ARIA. But as I said, the relationship between that and different, between antibodies may be a little bit different. And so, what we need to be informed by now is our data from multiple dose-level cohorts from our ongoing phase one trial so that we can better characterize the relationship between PRX-12 exposure and our E-Rates. And we think that as we collect additional dose-level cohort data and as we think about future substantive data updates, we would be able to talk in more detail about what that means specifically for PRX-12.
spk11: Thank you, everyone. This is all the time we have today. I'll now turn it over to Gene Kinney, Chief Executive Officer, for closing remarks.
spk08: Thank you very much, operator, and I want to thank you all for joining us on the call today. We appreciate your interest in Perthena, and we look very much forward to sharing further updates on our program. Have a good afternoon.
spk11: Thank you for participating in today's conference call. This concludes the presentation, and you may now disconnect. Good day.
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