Prothena Corporation plc (PRTA) Q4 2023 Earnings Report, Transcript and Summary

Good day ladies and gentlemen and welcome to the Prothena Biosciences Fourth Quarter and Full Year 2023 Financial Results Conference Call. My name is Crysta and I will be your coordinator for today. At this time, all participants are in a listen-only mode. We will be facilitating a question and answer session towards the end of today’s call. [Operator Instructions] I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Prothena. Please proceed.

Thank you, operator. Good afternoon, everyone and welcome to today’s call to review Prothena's business progress, fourth quarter and full year 2023 financial results and our 2024 financial guidance. Please review the press release we issued earlier today, which is available on our website at prothena.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 Birtamimab program which is in Phase 3 for the treatment of patients with MAYO Stage IV AL Amyloidosis. Hideki Garren, our Chief Medical Officer will provide an update on our ongoing clinical programs. Tran 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 the call up 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 statements. For a 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.

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 5. Our mission at Prothena 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 disregulation. That mission is enabled by our deep scientific expertise, which serves as a unifying trend connecting our corporate strategy, our portfolio development and the dedication that propels opinions 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 candidate targeting both neurodegenerative and rare peripheral amyloid diseases as shown on Slide 6. Our portfolio includes four wholly-owned programs and five partnered 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 insight and expertise. I'll discuss four of our ongoing clinical programs on the next Slide, PRX012, Birtamimab, Prasinezumab and NNC6019. But first I'd like to highlight the exciting progress across our earlier-stage program. In July of 2023, we presented compelling preclinical results in a late breaker poster presentation at AAIC for PRx 1, 2, 3, our dual Aβ-tau vaccine program and by year-end 2023, PRX 123 received IND clearance and Fast Track designation from the FDA. Our own going Neuroscience R&D collaboration with CMS 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 the key episodes within the microtubule binding region of tau. In 2023, CMS 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 readouts. As you will hear about more detail later in this call, we ended 2023 with a strong cash position of $621 million. Moving now to Slide 7. 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 Birtamimab, and then move on to our partnered program Prasinezumab Roche and NNC6019 with Novo Nordisk. PRX12 is our next-generation investigational treatment for Alzheimer's disease, which targets the key epitope that the Amino Terminus of amyloid beta with high binding potency. PRX12 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 data 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 ADPD and AAIC demonstrating that PRX12 binds the 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 our registration enabling trial. The preclinical data combined with the initial clinical data from our ongoing Phase 1 trial are supportive of a once monthly, subcutaneous treatment with a potential best-in-class profile. Birtamimab seeks to address the high risk of early mortality that remains an urgent unmet medical need for patients with mayo stage IV AL Amyloidosis. Through its differentiated depleter mechanism, which is designed to clear accumulated amyloid and neutralized toxic light chain aggregates that are thought to cause organ dysfunction and failure. We're conducting the confirmatory Phase AFFIRM AL clinical trial evaluating Birtamimab in patients with MAYO Stage IV Amyloidosis 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 second quarter of 2025. Prasinezumab 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 2b PADOVA clinical trial in patients with early Parkinson's disease. Roche completed enrollments 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 2 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 Prothena and our strategic partners. As we look ahead, we are also thoughtfully building out our commercial leadership and market insights for Birtamimab so to provide a little more context on our pre-commercial efforts, I will now turn the call over to Brandon. Brandon?

Thanks, Gene. Moving to Slide 9. As we continue to executing on our ongoing confirmatory Phase 3 of AFFIRM AL clinical trial, we are focused on building out our commercial capabilities to support Birtamimab as our first potential commercial product. Among patients with AL Amyloidosis are are progressive and fatal disease newly diagnosed individuals with significant cardiac involvement such as MAYO stage IV are at the highest risk for early mortality. This remains a serious unmet need for patients and their families. Birtamimab is the only candidate to have shown a survival benefit in patients with MAYO stage IV for AL Amyloidosis in a randomized clinical trial, our previous Phase 3 VITAL trial. The ongoing confirmatory AFFIRM AL trial was designed based on a SPA agreement with the FDA to approve Birtamimab 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 Birtamimab will be welcomed as a major advancement in the field and a key treatment option. Moving to Slide 10. The market dynamics for Birtamimab as our potential first commercial product are quite compelling. Our plan is to independently commercialize Birtamimab 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 where hematologists with support from specialized cardiologists and a primary treating specialist. KOLs in the community at large recognized the urgent need for treatment that improved 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 IV AL Amyloidosis across the major markets including 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 IV patients in the U.S. In addition, our US and European market research indicates there are 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 for KOLs and experts in the field through our extensive clinical programs for Birtamimab. 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 Birtamimab. This includes continued 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. I'll now turn it over to Hideki to review our clinical programs.

Thank you, Brandon. Let's continue with Birtamimab and review the results for previous VITAL trial, which we’re publishing at ASH peer-reviewed Journal, Blood last year. Importantly, we observed a survival benefit in the subset of approximately 30% of patients who are categorized as a male stage IV bassline. The capital MAYO curve illustrating the separation is shown here on Slide 12 demonstrating an early and sustained benefits. In this high risk group, we observed the survival benefits facing Birtamimab reflecting approximately 60% relative reductions of all-cause mortality at a p-value of 0.021. This was further supported by meaningful and significant improvements in functions as measured by six-minute walk test and quality of life as measured by SF-36. Turning to Slide 13, expand on Brandon's earlier remarks, based on our extensive analysis of VITAL data, as well as further confirmation of the data with external statistical experts and leading physicians in the field, we actively engage with the FDA to the line on the path towards regulatory success for Birtamimab. A SPA was agreed to between Prothena and the FDA with a confirmatory Phase 3 AFFIRM AL clinical trial to be conducted in patients with AL amyloidosis categorized as MAYO Stage 4 baseline with a pre agreed upon significance level of alpha less than or equal to zero point one zero on a primary endpoint of all-cause mortality. This is a time to event trial and patients are randomized two to one on Birtamimab as 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 but before Mayo would be available between the fourth quarter of 2024 and second quarter of 2025. We very much look forward to the results for this trial moving us one step closer to getting the 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 PRX12 could 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 escapades convenience and safety. PRX12 was intentionally designed with the antibody attributes required to achieve a similar or better efficacy and safety profile to currently approved anti-immuno therapies. With the clear differentiation as being administered in a much more convenient and accessible once monthly, at home, subcutaneous treatment. PRX12 is a humanized IgG1 monoclonal antibody designed to provide a longer half-life and improved anti-immuno treatments with low immunogenicity. We’ve demonstrated a high potent binding, high affinity and avidity and a slow off rate allowing for considered target engagement, all of which are optimal for once monthly subcutaneous treatment. The ongoing PRX12 stage 1 trial, which we would discuss on Slide 15 and 16 is designed to demonstrate a potential best-in-class profile into clinics. Moving the Slides 15, Phase 1 is a double-blind placebo-controlled single ascending dose clinical trial evaluating PRX12 in healthy volunteers and participants with early Alzheimer's disease. The trial enrolled approximately eight participants per single ascending dose cohorts, randomized 3 to 1 to receive a single subcutaneous dose of PRX12 or placebo and doses ranging from 70 to 400 milligrams. Moving on to the multiple setting dose cohorts on Slide 16. Ascent 2 is our double blind placebo-controlled multiple ascending dose clinical trials evaluating PRX12 in people with early Alzheimer's disease. Each match cohort is randomized 3 to 1 to receive PRX12 or placebo once monthly as six months in multiple ascending dose levels. The objectives of the trial are twofold. One is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics of PRX 12 in patients with early Alzheimer's disease. And two is to find the optimum dose level or levels for registration enabling clinical trial. There are a couple of key aspects to the MAD trial design that I like to highlight today. Participants are assigned to two groups of cohorts based on APOε4 status which referred to as A cohort or B cohort. Participants in the A cohorts are either APOε4 non-carriers or heterozygous carriers. Each of these A cohorts is evaluating approximately 32 participants with early Alzheimer's disease and doses ranging from 45 to 400 milligrams. In addition, we are evaluating APOε4 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 of placebo are eligible to receive an additional six monthly doses of PRX12 in an open-label extension. We've completed all cohorts and the double-blind portion of the initial 70 mg MAD A cohort, The Phase one 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 Prasinezumab on Slide 17, Prasinezumab is the first Anti-alpha-synuclein antibody to demonstrate slowing the progression on measures of Parkinson's disease and Phase 2 trial. our partner Roche previously presented data from the phase two PASADENA trial showing Prasinezumab reduced one year motor progression by 35% as measured by the MDS-UPDRS Part III, a scale of motor dysfunction and comparison to placebo. Roche continues to provide meaningful updates on the ongoing open-label extension clinical trial 12 including recently at the Movement Disorder Study Congress in August. Roche compares three year progression of motor science and the Prasinezumab population with a propensity score balance cohort of real-world data from the Parkinson's progression markers initiative or PPMI The Prasinezumab population saw 62% slowing progression as measured by the MDS-UPDRS Part III in the early start Prasinezumab population, as compared to the real world data cohort. These data continues to support Prasinezumab potential effects of delaying motor progression in Parkinson's disease. Roche has advanced Prasinezumab into the Phase 2b PADOVA trial, which is a double-blind placebo-controlled trials evaluating 586 patients with early Parkinson's disease. Participants are randomized 1 to 1 to receive Prasinezumab or placebo every four weeks for at least 18 months. Roche announced they've completed enrollment in the first quarter of 2023. The primary endpoint is time to clinic meaningful professional or motor signs of the disease as assessed by a five point or greater increase in the MDS-UPDRS Part III from baseline. This disease progression may be correlated to a meaningful worsening on the clinical global pressure and fluid scale. Roche expects to report top-line data from the PADOVA trial later this year. Moving to NNC6019 on Slide 18 NNC6019 has been developed by Novo Nordisk as a potential first-in-class amyloid depleter 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 depositions to improve organ function. This mechanism of action has a potential benefit for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs. Novo Nordisk is progressing this program an 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. And now I'd like to turn the call over to Tran Nguyen for a discussion of our 2022 financial performance and our 2024 financial guidance. Tran?

Thanks, Hideki. 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 the BMS 986446 formerly known as PRX5 for $55 million. In terms of our 2023 financial performance relative to guidance, we had net cash used in operating an investing activity of a $136.7 million, which was favorable to our guidance range of $148 million to $161 million. Net loss was $147 million, which was favorable to our guidance range of a $153 million to $171 million. As of December 31st 2023, Prothena had $621 million in cash, cash equivalents and restricted cash which is favorable to our guidance of $600 million. As of February 9th 2024 Prothena 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 that's on Slide 21. We expect our full year 2024 net cash used in operating and investing activities to be between $208 million 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 million to $255 million, which includes an estimated $51 million of non-cash share-based compensation expense. With that, I'll turn the call back over to Gene to discuss our upcoming milestones. Gene? Thanks, Tran. 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 impacts of the new medicines we’re developing. I'd also like to thank our talented Prothenians 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 AFFIRM AL Phase 3 trial evaluating Birtamimab in patients with MAYO stage IV AL amyloidosis, clinical data from our ongoing phase 1 trial evaluated PRX 12 as a potential best-in-class treatment in early Alzheimer's disease, top-line results from the Phase 2b PADOVA trial evaluating Prasinezumab for Parkinson's disease being conducted by Roche. And finally clinical data from the Phase 2 Signal Detection trial evaluating NNC6019 for the treatment of ATTR cardiomyopathy by Novo Nordisk. I am proud of the progress that Prothena 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 will now open the call for Q&A. Operator?

[Operator Instructions] Your first question comes from the line of Charles Duncan from Cantor Fitzgerald. Please go ahead.

Yeah, hi. Good afternoon, Gene 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 the patient enrollment in ascent 2, 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?

Thanks for the questions Charles. Appreciate them. So I think first just with respect to time line, obviously this is an ongoing trial and we plan to share additional data as that data becomes substantive. I think, in terms of when we plan to give an update on PRX12 would you plan to provide an update this year whether that update is to update on timing or data is something that we will still determine. And I think In terms of your question around enrollment in various cohorts, maybe I can ask Hideki to address that question, Hideki?

Thanks, Tran. Enrollemnt is very strong in our PRX12 Signal trial. The high [Indiscernible] for treatment and important to note that the Monitory Board has authorized a 400 mg and proceeding cohort has planned and so this will allow us to facility for the [Indiscernible]

Your next question comes from the line of Jay Olson from Oppenheimer. Please go ahead.

Oh, hey, thanks for the update and congrats on the progress. We have another question about the PRX012 MAD study. Could 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.

Yeah, thanks, Jay. Thanks for the question. Well, maybe I can just start with the reminder that the study is a 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 a Hideki can just speak a little bit about that period.

Yeah, so each patient within each cohort enroll open-label extension for six months as you mentioned. And again, very strong enrollment and people are very excited about the one [Indiscernible] placebo-controlled, where placebo patients will now receive a drug of course that will be the first – the other patients will continue to go on down to 12 months of potential treatment of PRX12, which we are capturing both safety and tolerability and of course PK and pharmacodynamic measurement.

Your next question comes from the line of Michael DiFiore from Evercore ISI. Please go ahead.

Hi guys. Thanks so much for taking my question. Just wanted to zero in on the comparable ARIA rates that we're seeing between the 70 mg dose of 012 and placebo. So when you consider how subcutaneous had less Aria rates compared to its IV version and while lecanemab 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 – and do you foresee similarly low Aria rates for 012 at higher doses? Thank you.

Yeah, so it's a great question and you've got a lot built in there around the science. So I appreciate the question. I think that you're alluding to is really just how 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 amyloid field that there is a exposure response relationship between - certainly it's almost on a linear basis with respect to amyloid reduction. But in the case of Aria a little difference between antibodies and I think that's what we're seeing. So you're making point between bapineuzumab and lecanemab and I think those are astute observations. As you say with the bapineuzumab work, I think there is approximately equivalent exposures on an AAC basis were managed to be attained what was observed at least in the published literature was lesser Aria with that molecule with lecanemab’s data a little bit more comparable. So I mean 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 at the deck you mentioned from the 45 mg monthly dose level through to the 400 mg 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 consistency meant with placebo and maybe I can just ask Hideki to comment on that piece.

Yeah, thanks, Gene. Just to remind you we're running a double-blind placebo-controlled trial and have reported in the 70 mg dose that factor as well as Aria rate consistent with placebo. And the data allows us to provide a service index explore a full dose response curve with once monthly dose. Again just to remind we have the ability to up the program and all these courses are active people.

Your next question comes from the line of Neena Bitritto-Garg from Deutsche Bank. Please go ahead.

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 APOε4 non-carriers and heterozygous as well as the homozygous, 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 mg dose versus 200 and 400 and why you selected 200 and 400 for both SAD and MAD? I know you talked a lot about collection of 70 mg as being based off of the see C average to 10 mg per [Indiscernible] but just wondering how we should think about the higher doses. Thanks.

Yeah, thanks Neena for the question. Maybe I can start then hand it to 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 just again as a reminder, I think what we've indicated is that with the A cohort which is the 70 mg monthly cohort, we've seen evidence of what we would characterize as encouraging reduction in amyloid beta. Obviously, that helps us to understand that we believe this is a once-monthly subcutaneous drug. And obviously Aria rates as you had mentioned consistent with placebo, what goes into informing that is obviously the data from a single dose study, as well as the cohorts - that 70 mg cohort I am referring to in the multiple dose study. The additional ongoing cohorts remain blinded. So there is a 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 the Hideki to speak to that other than to say that 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?

Yeah, thanks Gene. So as you mentioned we are continuing explore in a Phase 1 study and that’s the purpose of Phase 1 study is and I just remind you that 7 mg is encouraging Amyloid reduction and consistent Aria rate with placebo and that allowed us to really explore the full dose sponsor modify all of this 400 mg, And again just to remind you that high binding – once monthly subcu administration and potential be best-in-class and [Indiscernible]

Your next question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead.

Hi team, this is [Indiscernible] for Yas. Thanks for taking our questions. Just kind of diving more into the details of the Aria rates given that you're enrolling both APOε4 homozygous and heterozygous. We know that this drives sometimes differences in Aria rates. How do the - expectations regarding both safety and efficacy across these populations?

Yeah, no. Thanks for the question. I think there is 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, as we talked about Aria rates were being specific to our patient level cohorts 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 the 70 mg cohort after six months of treatment were consistent with placebo. I think your - the point you're making about testing separately APOε4 homozygous carriers in these B cohort 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 that APOε4 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 1 Study to be a little bit more deliberate in evaluating these APOε4 homozygous 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 gut 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 came to date, we've given some directional guidance in terms of where we are in all of those encouraging levels of amyloid reductions 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.

Your next question comes from the line of Rudy Li from Leerink Partners. Please go ahead.

Hi, thanks for taking my questions. Just a quick follow-up on your dosing selection. So can you maybe talk about the rationale including the 45-mg dose in ascent 2 which was not tested in ascent 1. I am trying to get a better safety and any color will be helpful. Thanks.

Yeah, maybe - thank you for the question and maybe I can just take this one. I think, what we're looking for is to really have a fulsome understanding of the exposure response relationship and we believe that evaluating dose levels, 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 that's really what defined it. I think as Hideki has already mentioned there has been very high level of interest in this study. So we've been affording 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 that really is the rationale for it. And other than that, I would just say that these were the dose levels that we had pre-planned on testing as we saw the first dose level cohort at 70 mg dose level cohort data, the decision was to continue to conduct this study in the way that had been previously evident.

Your next question comes from the line of Michael Yi from Jefferies. Please go ahead.

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 had very little exposure to whereas the IV drugs inclusion can have Aria rates that are around 12% to 20%. So, could you tie those two together and what would drive confidence today for those listening that you can go to 200 mg and three times the dose and still thread the needle. Thank you.

Yeah. Thanks for the question, Mike. I mean, obviously this study is double-blind placebo-controlled and as we reported as a 70 mg dose level. The Aria rates as you say were consistent with placebo and I think that's I think the statement around where we are from a therapeutic index perspective and what we think that therapeutic index then provide is the ability to move up and dose range as you've indicated. So I think Hideki has 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 full exposure response relationship ranging all the way from 45 to 400. So I think what that could 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 is a function of the three variables. The convenience factor, which is really around patient burden. The efficacy which indicates case here, we're talking about really reduction of amyloid. And then of course the safety, which I think everyone is very focused on Aria. But we'll talk about safety in general as being permissive from therapeutic index perspective to continue to explore this fulsome exposure response relationship rank.

Your next question comes from the line of Jason Butler from Citizens JMP. Please go ahead.

Hi, thanks for taking the question. I guess I wanted to switch gear here and just ask a question about Prasinezumab. 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.

Yeah, no, thanks for the question. Yeah, so like, 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 importantly relative to the PPMI demographic matched group, it showed a 63% flowing of progression as measured by MDS S-UPDRS Part III. And more recently, we’ve seen the abstract publish for the ADPD meeting which will occur here in early March where that presentation hasn’t happened yet. They have published the abstract and they have been talking now about four year open-label data and then based on UPDRS – the MDS-UPDRS Part III scale 117% less progression than that PTMI data base group. And that’s like even on the activity of daily living, scale of the MDS-UPDRS Part II are 39% less progression in that PTMI data group. So, we're very interested in this. Obviously the PADOVA study is fully enrolled as per Roche. This is a large study that is being run with high integrity. You 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, that the go-forward regulatory path and I think to your question, how this will ultimately be positioned will be determined by the data. And obviously also continued conversations between our partners at Rocha and the regulators and we have very high confidence that Roche will be as a aggressive as is appropriate based on the data set that they have today.

But I think one thing to add to in terms of the time to event endpoint is that it captures a five-point or greater increase right progression in the scale, which ended up self Roche for these to be clinically meaningful. They're also working on other clinical functional endpoints within the trial to correlate. So we look forward to the continued discussion with regulators. And of course the data later this year.

And we have time for one more question today and it comes from an Ananda Ghosh from H.C. Wainwright. Please go ahead.

Yeah, hi. And so just wanted to get your opinion on some of these concepts which I don't think the street understands very well with respect to the Aria focus program. So what has been, how do we think that the PUC, the C-Max and in a relative fractional occupancy when you are looking at data which comes from the kind of a subcutaneous data and with respect to your idea on the PRX drug development program. So any ideas with respect to those two factors would be very helpful to understand how to think about PRX12 development going forward. Thank you.

Yeah, no. I appreciate the question and it's an important question and you talked about lecanemab and - and think their relevance as immuno is targeting anti beta antibodies and I think what we see with those antibodies as you look to the Phase 2 dataset and into the Phase 3 data set, is a relationship between removal of plaque and the dose response. So our exposure response relationship. So and in the case of lecanemab and I 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 pointed to – 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, that being said, there clearly as if those 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 are removing plaque, you're going to increase the risk of this observing Aria. But as I said their relationship between that and difference between antibodies may be a little bit different. So what we need to be informed by now is our data from multiple dose level cohorts from our ongoing Phase 1 trial. So that we can better characterize the relationship between PRX12 exposure and Aria rates. And we think that as we collect additional dose level cohorts data and as we think about the future substantive data updates, we would be able to talk in more detail about what that means specifically for PRX12.

Thank you, everyone. This is the this is all the time we have today. I'll now turn it over to Gene Kinney, Chief Executive Officer for closing remarks.

Thank you very much operator and I want to thank you all for joining us on the call today. We appreciate your interest in Prothena and we look very much forward to sharing further updates on our program. Have a good afternoon.

Thank you for participating in today's conference call. This concludes the presentation and you may now disconnect. Good day.