Prothena Corporation PLC

NASDAQ:PRTA

Earnings Call Analysis

Strong Cash Position and Promising Trials

The company ended 2023 with $621 million in cash, strengthening its financial stability. They are progressing with PRX012 in a phase I trial, aiming for a dose that would permit entry into a registration-enabling study. Birtamimab's AFFIRM AL trial remains pivotal, with FDA approval pending results that demonstrate a significant impact on all-cause mortality (p ≤ 0.1). Revenue growth for the next year is expected to be flat, as management focuses on strategic priorities rather than short-term revenue maximization, while operating margin is forecasted to improve slightly.

Favorable Financial Performance in 2023

Prothena Corporation has reported financial results for 2023 that were better than expected, with a net cash used in operating and investing activities of $136.7 million, below the guided range of $148 million to $161 million. Additionally, the company saw a net loss of $147 million, which was also favorable compared to the forecasted $153 million to $171 million. As of December 31, 2023, Prothena's financial position was strong, with $621 million in cash and equivalents, surpassing the guidance of $600 million. The company maintains a straightforward capital structure with zero debt and roughly 53.7 million outstanding shares as of February 9, 2024.

2024 Financial Outlook

Looking toward 2024, Prothena anticipates a net cash usage within the range of $208 million to $225 million for operating and investing activities. By the year's end, the company expects to have about $405 million in cash, cash equivalents, and restricted cash. The projected net loss for the year is estimated to be between $229 million and $255 million, which factors in roughly $51 million in non-cash share-based compensation expenses.

Upcoming Clinical Milestones

Prothena is poised for significant developments, with potential clinical readouts from four ongoing trials expected in the next 12 to 18 months. Milestones include results from the AFFIRM AL Phase III trial of Birtamimab for amyloidosis, Phase I data for PRX012 as a treatment for early Alzheimer's disease, Phase IIb PADOVA trial outcomes for prasinezumab in Parkinson's disease, and Phase II results for NNC6019 treating ATTR cardiomyopathy. These catalysts underscore the company's efforts to bring new treatments to market, reinforcing Prothena's dedication to becoming a fully integrated commercial biotechnology entity.

Earnings Call Transcript 2023-Q4

[Operator]

Good day, ladies and gentlemen, and welcome to the Prothena Biosciences Fourth Quarter and Full Year 2023 Financial Results Conference Call. My name is Krista, and I will be your coordinator for today. [Operator Instructions]

I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Prothena. Please proceed.

[Unknown Executive]

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 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 Presentations 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. And 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 III for the treatment of patients with Mayo Stage IV AL amyloidosis.

Dr. Hideki Garen, 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 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 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.

[Gene G. Kinney, executive]

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 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 Protheneans 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 6. Our portfolio includes 4 wholly owned programs and 5 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 4 of our ongoing clinical programs on the next slide, PRX012, Birtamimab, prasinezumab and NNC 6 to 19. 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, and 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 I data supports advancing program into a Phase II clinical trial in 2024.

And for PRX019, 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 3 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 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 4 clinical programs that are nearing significant inflection points within the next 12 to 18 months.

First, I'll discuss our wholly owned programs, PRX-12 and Birtamimab, and then move on to our partnered programs, prasinezumab with Roche and NNC 619 with Novo Nordisk. PRX012 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.

PRX012 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 therapy, 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 AAIC demonstrating that PRX012 binds to amyloid plaques with high avidity. PRX012 is currently being evaluated in a double-blind placebo-controlled Phase I 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 I 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 MAA-stage IV 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 III AFFIRM AL clinical trial evaluating Birtamimab in patients with MAOSTAGE IV AL 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 the 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 IIb PADOVA clinical trial in patients with early Parkinson's disease. Roche completed enrollment of this trial in the first quarter of 2023, and expect to report top line data later this year.

And finally, NNC 1619 is an amyloid depleter antibody for the potential treatment of ATTR cardiomyopathy. Novo Nordisk is currently conducting an ongoing Phase II 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?

[Unknown Executive]

Thanks, Gene. Moving to Slide 9. As we continue executing on our ongoing confirmatory Phase III 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 rare, 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 AL amyloidosis in a randomized clinical trial, our previous Phase III VITAL trial.

The ongoing confirmatory AFFIRM AL trial was designed based on a SPA agreed with the FDA to approve Birtamimab and 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 in 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 for hematologist with support from specialized cardiologists or the primary treating specialists. 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 IV 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 IV 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 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 continuing to present our data at top medical congresses and publications in peer reviewed journals. Today, we are building on our commercial leadership team thoughtfully as we prepare for launch.

I'll now turn it over to [indiscernible] to review our clinical programs.

[Unknown Attendee]

Thank you, Brandon. Let's continue with Birtamimab and review the results of our previous VITAL trial, which were publishing the ASH peer-reviewed journal blood last year. Importantly, we observed a survival benefit in the subset of approximately 30% of the patients who were categorized as Mayo Phase IV baseline.

[indiscernible] curve illustrating the separation is shown here on Slide 12 demonstrating an early and sustained benefit. In this high-risk group, we observed a survival benefit favoring Birtamimab reflecting approximately 60% relative reduction of all cost 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 SF-36.

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 the external statistical experts and leading positions in the field, we actively engage with the FDA to align on the path towards regulatory success with Birtamimab. [indiscernible] was agreed to between Patina and the FDA for the confirmatory Phase III AFFIRM A clinical trial to be conducted in patients with AL amyloidosis, categorized as [indiscernible] Stage IV baseline, with a pre-agreed upon significant level of alpha less than to 0.10 on the primary endpoint of all-cause mortality. This is a time-to-event trial and patients are randomized 2:1 on birtamimab with 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 the firm 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 1 step closer to getting this treatment to patients and families in need.

Let's discuss PRX012, our potential best-in-class anti-amyloid beta treatment starting on Slide 14. We believe that PRX012 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.

PRX012 was intentionally designed with the antibody attributes required to achieve a similar or better efficacy and safety profile to currently approved anti-bad therapies, with a clear differentiation as being administered in a much more convenient and accessible once-monthly at-home of [indiscernible] treatment.

PRX012 is a humanized IgG1 monoclonal antibody designed to provide a longer half-life than improved anti-agents with low immunogenicity. We've demonstrated highly potent binding, high-fleet and a slow off-rate, allowing for constant target engagement, all of which are optimal for once monthly subcutaneous treatment. The ongoing PRX012 Phase I 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. [indiscernible] is our double-blind, placebo-controlled, single tend-dose clinical trial, evaluating PRX012 in healthy volunteers and participants with early Alzheimer's disease. The trial enrolled approximately 8 participants per single sending dose cohort, randomized 3:1 to receive a single subcutaneous dose of PRX012 or placebo and doses ranged from 70 to 400 milligrams.

Moving on to the multiple setting dose cohorts on Slide 16. ARSAT 2 is our double-blind, placebo-controlled, multiple ascending dose clinical trial evaluating PRX012 and in people with early Alzheimer's disease. Each MAD cohort is randomized 3:1 to receive PRX012 for placebo once monthly for 6 months in multiple-ascending dose levels.

The objectives of the trial are twofold. One is the value to safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics, PRX012, in patients with early Alzheimer's disease. And 2 is to find the optimal dose level or levels for registration-enabling clinical trials.

There are a couple of key aspects to the NAD trials that I'd like to highlight today. Participants are assigned to 2 groups of cohorts based on APOE4 status, which we refer to as A cohorts or B cohorts. Participants in the A cohorts are either APOE4 noncarriers 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 A4 homozygous carriers with separate decors for approximately 12 participants with early Alzheimer's disease in doses ranging from 45 to 200 milligrams. Following the first 6 months, which is consumer controlled, participants previously taken PRX012 placebo are eligible to receive an additional 6-month fleet doses of PRX012 and automate extension.

We have completed all sat 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 PRX012, and expect to update you later this year.

Turning now to prasinezumab on Slide 17. The prasinezumab, 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 trial, [indiscernible] prasinezumab reduced 1 year mode progression by 35% as measured by the MDS-UPDRS Part III, a scale of motor function in comparison to placebo.

Roche continues to provide meaningful updates on the ongoing open-label extension from the trial, including recently at the move in the [indiscernible] Society Congress in August. Roche compared 3-year progression of science and apatite 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 63% 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 continue to support prasinezumab's potential effect on delaying motor progression in Parkinson's debate.

Roche has advanced prasinezumab into the Phase IIb trial, which is a double-blind placebo-controlled trial evaluating 586 patients with early Parkinson's disease. Participants are analyzed one-to-one to receive prasinezumab or placebo every 4 weeks for at least 18 months.

Roche announced that it completed enrollment in the first quarter of 2023. The primary endpoint is timed to clinically meaningful progression of motor signs of the disease as assessed by a 5-point or greater increase in the MDS UPDRS part 3 from baseline. This disease progression may be correlated to a meaningful worsening on the global pressure Improvement Scale. Roche expects to report top line data from the PADOVA trial later this year.

Moving to NMC 601 on Slide 18. MMC 619 is being developed by Novo Doris 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 nonatopic of TTR protein and amyloid and virology.

NNC6019 is thought to deplete both deposit amyloid circulating non-native TTR to prevent further deposition in crude [indiscernible] function. This mechanism of action has the potential to ibeticine for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs.

Nova Nordisk is progressing this program in ongoing double-blind, placebo-controlled signal detection Phase II clinical trial. The trial has completed recruitment and Noble estimates primary acquisition in the first half of 2025.

And now I'd like to turn the call over to Tran for a discussion of our 2023 financial performance and our 2024 financial guidance. Tran?

[Tran Nguyen, executive]

Thanks, [indiscernible] 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 PRX005 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 million to $161 million.

Net loss was $147 million, which was favorable to our guidance range of $153 million to $171 million. As of December 31, 2023, Prothena had $621 million in cash, cash equivalents and restricted cash, which is favorable to our guidance of $600 million. As of February 9, 2024, Prothena had approximately 53.7 million ordinary shares outstanding. Additionally, we continue to have a simple capital structure with 0 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 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 noncash share-based compensation expense.

With that, I'll turn the call back over to Gene to discuss our upcoming milestones. Gene?

[Gene G. Kinney, executive]

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 impact of the new medicines we're developing. I'd also like to thank our talented Protheneans 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 4 ongoing clinical trials within the next 12 to 18 months. which include top line results from our confirmatory AFFIRM AL Phase III trial evaluating Birtamimab in patients with MaoStageIVAL amyloidosis. Clinical data from our ongoing Phase I trial evaluating PRX012 as a potential best-in-class treatment in early Alzheimer's disease.

Top line results from the Phase IIb PADOVA trial evaluating prasinezumab for Parkinson's disease being conducted by Roche. And finally, clinical data from a Phase II 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'll now open the call to Q&A. Operator?

[Operator]

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

[Charles Duncan, analyst]

Yes. Gene, you've got a lot going on and limiting to 1 question that 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?

[Gene G. Kinney, executive]

Yes. Thanks for the question, Charles. I 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 PRX012, 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?

[Hideki Garren, executive]

Yes. Thanks, Gene. So yes, enrollment's been very strong in our Phase I trail. The high level of interest in what notes treatment, And part to note that the data center monitoring Board has lost a clearance of 45 to 400 milligrams, and we're proceeding [indiscernible] as planned. And so this will allow us to fully explore the sponsor.

[Operator]

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

[Jay Olson, analyst]

congrats on the progress. We have another question about the PRX012 MAD study. Can you talk about the 6-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 '12?

[Gene G. Kinney, executive]

Yes. Thanks, Jay. Well, maybe I can just start with a reminder that the study is double-blind, placebo-controlled 6 months in duration with patients receiving their specified dose level or placebo once a month by subcutaneous administration. Obviously, after that 6-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.

[Hideki Garren, executive]

Yes. So each patient within each cohort is allowed to enroll in open label extension for 6 months, as you mentioned. And again, very strong enrollment and people very excited about the once-monthly subcu dose. And here, we will have [indiscernible] saying, it's not placebo controlled, where placebo patients will now receive drug.

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 PRX012, which we are capturing both safety and tolerability and of course, PK [indiscernible] oncoDynamic measurement.

[Operator]

Your next question comes from the line of Michael D. floor from Evercore ISI.

[Unknown Analyst]

Just wanted 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 bapinizumab had less are your rates compared to its IV version?

And while lacanumab/subcu 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 bapinizumab, do you foresee similarly low ARIA rates for 012 at higher dosage?

[Gene G. Kinney, executive]

Yes. 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 what 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 there is evidence across the anti-abeta feel that there is an exposure response relationship between -- well, certainly, it's almost on a linear basis with respect to amyloid reduction. But in the case of ARIA, a little different between antibodies. And I think that's what we're seeing.

So you're making a point between bapinuzumab and lucenumab. And I think those are astute observations. As you say, with the bapinuzumab work, I think as approximately equivalent exposures on an AEC basis were managed to be attained what was observed at least in the published literature, was lesser ARIA with that molecule with lucenumab.

It is molecule-dependent and what we need to that we need to understand that relationship. And we look forward to determining that as we explore the exposure response relationship that 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 consistency meant with placebo. And maybe I can just ask Hideki to comment on that piece.

[Hideki Garren, executive]

Yes. Thanks, Gene. So just to remind you, we're running a double-blind placebo-controlled trial. And as reported in the 70-milligram dose. That was platform as well as ARIA rate consistent placebo. And that allows us to provide therapeutic index exports a full dose sponsor with once monthly subcu dose. And we -- again, just to remind you, we have the ability to up to 400 milligrams, and all these cohorts are actively enrolled.

[Operator]

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

[Neena Bitritto-Garg, analyst]

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 [indiscernible] noncarriers and the heaters as well as 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 selection of 70 mg as being based off of the C -- similar C average to technics per kg aducanumab. But just wondering how we should think about the higher doses.

[Gene G. Kinney, executive]

Yes. Thanks, Mina, 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 just again, as a reminder, I think what we've indicated is that with the A cohort, which is the 70-milligram monthly cohort, 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, ARIA rates, as you mentioned, consistent with placebo.

What goes into informing that is, obviously, the data from a single dose study as well as the cohort of the 70-milligram cohort I'm referring to in the multiple dose study. The additional ongoing cohorts remain blinded. So those are -- 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 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 the decade indicated. Hideki?

[Hideki Garren, executive]

Yes. Thanks, Gene. So as you mentioned, we're continuing to explore the dose in a Phase I study. That's the purpose of Phase I study is. And just to remind you, the 7 delivery, we did see the encouraging [indiscernible] reduction and consistent ARIA rate with placebo and that allowed us to really explore the full dose factor of all of milligrams.

And again, just to remind you [indiscernible] had high volume from the monthly [indiscernible] subcu administration and potentially be best-in-class [indiscernible].

[Operator]

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

[Unknown Analyst]

This is [indiscernible] on for Yas. Just kind of dive more into the details of the ARIA rates. Given that you're enrolling both APOE4 homozygous and heterozygous. We know that this derives sometimes differences in ARIA rates. How does this capture your expectations regarding both safety and efficacy across these populations?

[Gene G. Kinney, executive]

Yes. No, thanks for the question. I think there's kind of 2 questions built into that 1 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 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 the 70-milligram cohort after 6 months of treatment were consistent with placebo.

I think your -- the point you're making about testing separately, AO4 homozygote carriers, in the 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 [indiscernible] does tend to lead itself to a higher ARIA rate. And in the context of clinical trials, that can lead to, in some cases, missed dosing or skip dosing. Obviously, that's less than ideal as we start to think forward to efficacy-driven studies in 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 I study to be a little bit more deliberate in evaluating these [indiscernible] 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 3 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, we've given some directional guidance in terms of where we are in all of those encouraging levels of amyloid reduction once monthly subcu, we believe it's 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.

[Operator]

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

[Guofang Li, analyst]

Just a quick follow-up on your dosing selection. So can you maybe talk about the rationale, including the 45-milligram dose in ASCEND 2, which was not tested in ASCEND 1? I'm trying to get a better safety and any color would be helpful.

[Gene G. Kinney, executive]

Yes. 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 really what defined it.

I think as Hideki has already mentioned, there's been a 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 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.

[Operator]

Your next question comes from the line of Michael Yee from Jefferies.

[Michael Yee, analyst]

Thanks for the question. I know there's been a lot of questions around area, and we just wanted to ask more specifically when you say consistent with placebo, was there actually 1 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 little exposure whereas the IV drugs, including what can we have ARIA rates that are around 12% to 20%? So could you tie those 2 together and what would drive our confidence today for those listening that you can go to 200-milligram and 3x the dose and still thread the needle.

[Gene G. Kinney, executive]

Thanks for the question, Mike. I mean obviously, this study is double-blind, placebo-controlled. And as we reported at the 70-milligram dose level, the ROE 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 provides is the ability to move up in 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 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 is a function of the 3 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 is very focused on area, but we'll talk about safety in general as being permissive from the therapeutic index perspective to continue to explore this exposure response relationship range.

[Operator]

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

[Jason Butler, analyst]

I guess I want to switch gears 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?

[Gene G. Kinney, executive]

Yes. No, thanks for the question. Yes. So 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 3-year open-label extension data from the prior Phase II PASADENA study.

And importantly, relative to the PPMI demographic matched group, it showed a 63% slowing of progression as measured by MDS-UPDRS Part 3. And more recently, we've seen the abstract published for the ADPD meeting, which will occur here in early March, where while that presentation hasn't happened yet, they have published the abstract.

And there, they're talking now about for your open-label data and at least on the MDS-UPDRS Part 3 scale, 117% less progression than that PPMI database group. And in fact, even on the activity of daily living, scale the MDS-UPDRS Part 2, a 39% slowing or less progression than that PPMI data group.

So we're very interested in this. Obviously, the Dova study is fully enrolled as per Roche. This is a large study that is being run with high integrity. You've got 586 patients in this study, randomized on a 1:1 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 study. And then ultimately, 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 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 obtained.

[Unknown Executive]

I think one thing to add to in terms of the time to event endpoint is that it captures a 5-point or greater increase, right, progression in the scale, which in and of itself rosettes 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.

[Operator]

And we have time for 1 more question today, and it comes from Anna Gosh from H.C. Wainwright.

[Unknown Analyst]

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 PRX012 program. So what has been -- how do we think that the AUC, the CMAX and relative fractional occupancy, when you are looking at data which comes from lecanumumab subcutaneous CTAP data? And with respect to your idea on the PRX development program. So any ideas with respect to those 3 factors will be very helpful to understand how to think about PRX development going forward?

[Gene G. Kinney, executive]

Yes. No, I appreciate the question, and it's an important question. And you talked about macanimab and aducanumab. And I think they're relevant as amino terminus targeting anti-Abeta antibodies. And I think what we see with those antibodies as you look through the Phase II data set and into the Phase III data set, is a relationship between removal of plaque and the dose response, so our exposure response relationship.

So -- and in the case of an 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 donanemab from that perspective around flat 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 is a dose effect relationship within molecule, 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. 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 cohort from our ongoing Phase I trial so that we can better characterize relationships between PRX012 exposure and RE rates. And we think that as we collect additional dose level cohort data.

And as we think about future substantive data update, we would be able to talk in more detail about what that means specifically for PRX012.

[Operator]

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.

[Gene G. Kinney, executive]

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 programs. Have a good afternoon.

[Operator]

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