Prothena Q4 2023 Earnings Call Transcript

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Provided by Quartr
February 15, 2024

There are 14 speakers on the call.

Operator

Good day, ladies and gentlemen, and welcome to the Prothena Biosciences 4th Quarter and Full Year 2023 Financial Results Conference Call. My name is Christa, 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

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

Speaker 1

Thank you, operator. Good afternoon, and everyone, and welcome to today's call to review Profina's business progress, 4th 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 ks filed today with the SEC. In addition, we are using supplemental slides, which are available on our website's Events and Presentations section. On today's call, Doctor.

Speaker 1

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 rutanimak program, which is in Phase 3 for the treatment of patients with Mayo Stage 4 AL amyloidosis. Doctor. 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 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 and A session.

Speaker 1

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 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.

Speaker 2

Thank you, Mark, and thank you all for joining 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 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.

Speaker 2

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 Folsom 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, PRX12, pertamumab, prasinezumab and NNC6019. But first, I'd like to highlight the exciting progress across our earlier stage programs.

Speaker 2

In July of 20 23, we presented compelling preclinical results in a late breaker poster presentation at AAIC for PRX-one hundred and twenty three, our dual abeta tau vaccine program. And by year end 2023, PRX-one hundred and twenty three received IND clearance and fast track designation from the FDA. Our ongoing neuroscience R and D collaboration with BMS made meaningful advancements in 2023 and into this year. BMS-nine hundred and eighty six thousand four hundred and forty six, formerly PRX-five, 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, CMS opted into the global rights for this program with an additional milestone payment of $55,000,000 and announced that the Phase 1 data supports advancing the program into a Phase 2 clinical trial in 2024.

Speaker 2

And for PRX-nineteen, a potential best in class antibody for the treatment of neurodegenerative 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 $621,000,000 Moving now to Slide 7. Our clinical expertise and differentiated approach enables us to advance best in class and or 1st in class therapies that have the potential to transform the treatment landscape for protein dysregulation diseases.

Speaker 2

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, PRX12 and bercamumab, and then move on to our partnered programs, prasinezumab with Roche and NNC-six thousand and nineteen with Novo Nordisk. PRX-twelve 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. PRX12 is 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 currently available anti beta therapies. Based on our market research, we understand that a treatment with similar efficacy and safety 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.

Speaker 2

In 2023, we presented compelling preclinical data ADPD and AAIC demonstrating that PRX12 binds to amyloid plaques with high avidity. PRX-twelve 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 1 trial are supportive of a once monthly subcutaneous treatment with a potential best in class profile. Pertamimab seeks to address the high risk 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 3 Affirm AL clinical trial evaluating brittemimab in patients with Mayo stage 4 AL amyloidosis Under a special protocol assessment or SPA agreement with the FDA with the primary endpoint of all cause mortality at an unprecedented significance level of 0.10.

Speaker 2

We expect top line results between the Q4 of 2024 and the Q2 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 PDOVA clinical trial in patients with early Parkinson's disease. Roche completed enrollment of this trial in the Q1 of 2023 and expects to report top line data later this year. And finally, NNC-six thousand and nineteen is an amyloid depleter antibody for the potential treatment of ATTR cardiomyopathy.

Speaker 2

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 PROFINA and our strategic partners. As we look ahead, We are also thoughtfully building out our commercial leadership and market insights for bertamimab. So to provide a little more context on our pre commercial efforts, will now turn the call over to Brandon.

Speaker 2

Brandon?

Speaker 3

Thanks, Gene. Moving to Slide 9. As we continue executing on our ongoing confirmatory Phase 3 AFFIRM AL clinical trial, we are focused on building out our commercial capabilities to support bertamimab as our first potential commercial product. Among patients with AL amyloidosis are rare, progressive In fatal disease, newly diagnosed individuals with significant cardiac involvement such as Mayo Stage 4 are at the highest risk for early mortality. This remains a serious unmet need for patients and their families.

Speaker 3

Pertamimab 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 Affirm AL trial was designed based on a spot agreement with the FDA to prove pertemvab at a p value of less than or equal to 0.1 for the primary endpoint of all cause mortality. Showing an early Sustained impact on mortality is a powerful differentiator and if approved, we are confident that bretalement will be welcomed is a major advancement in the field and a key treatment option. Moving to Slide 10. The market dynamics for bertamimab as our potential first commercial product are quite compelling.

Speaker 3

Our plan is to independently commercialize bertamimab 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 hematologists with support from specialized cardiologists are the primary treating specialists. KOLs in the community at large recognize the urgent need for treatments that improve survival in patients with AL amyloidosis We're 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.

Speaker 3

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.

Speaker 3

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 protamimab. This includes continuing to present our data at 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 Nadekke to review our clinical programs.

Speaker 4

Thank you, Brandon. Let's continue with ptimenlab and review the results of our previous vital trial, which we're publishing in ASH peer reviewed journal Blood last year. Importantly, we observed a survival benefit in the subset of approximately 30% of the patients who are categorized as male stage 4 baseline. A capital I 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 birtimimab, reflecting approximately 60% relative reduction of all cause mortality at a P value of 0.021.

Speaker 4

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-thirty six. Turning to Slide 13. 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 physicians in the field, we actively engaged with the FDA to align on the path towards regulatory success with ritamimab. A SPA was agreed to between PASENA and the FDA for the 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 0.10 on a primary endpoint of all cause mortality. This is a time to event trial and patients are randomized 2 to 1 on bertamimab plus standard of care or placebo plus standard of care.

Speaker 4

At the end of 2023, based on a predetermined number of mortality events, we were able to estimate that top line results of Affirm AL will be available between the Q4 of 2024 and the Q2 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 PRX-twelve, our potential best in class anti amyloid beta treatment Starting on Slide 14. We believe that PRX-twelve 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.

Speaker 4

TRX12 was intentionally designed with the antibody attributes required to achieve a similar or better efficacy and safety profile to currently approved anti VAS therapies with a clear differentiation as being administered in a much more convenient and accessible once monthly at home subcutaneous treatment. TRX12 is a humanized IgG1 monoclonal antibody designed to provide a longer half life than approved anti abatement With low immunogenicity, we've demonstrated high retoolant binding, high affinity and ability and a slow off rate allowing for consistent target engagement, all of which are optimal for 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, ASANT-one is our 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 8 participants per Single setting dose cohort randomized 3 to 1 to receive a single subcutaneous dose of PRX-twelve or placebo and doses ranging from 70 milligrams to 400 milligrams.

Speaker 4

Moving on to the multiple ascending dose cohorts on 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 3 to 1 to receive PRX12 or placebo, once monthly for 6 months in multiple ascending dose levels. The objectives of the trial are twofold. One is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics PRX-twelve in patients with early Alzheimer's disease.

Speaker 4

And 2 is to find the optimum dose level or levels for registration enabling clinical trial. There are a couple of key aspects to the NADD trial design that I'd like to highlight today. Participants are assigned to 2 groups cohorts based on APO E4 status, which we refer to as A cohorts or B cohorts. Participants in the 8 cohorts are either APOE4 non carriers or heterozygous carriers. Each of these 8 cohorts is evaluating approximately 32 participants with early Alzheimer's disease and doses ranging from 45 to 400 milligrams.

Speaker 4

In addition, we are evaluating APO E4 homozygous carriers With separate B Cords, we're approximately 12 participants with early Alzheimer's disease in doses ranging from 45 to 200 milligrams. Following the 1st 6 months, which is placebo controlled, participants previously taking PRX12 at placebo are eligible to receive an additional 6 monthly doses of PRX12 in an open label extension. We have completed all stat cohorts

Speaker 2

and the double blind portion of the

Speaker 4

initial 70 milligram NAD A cohort. The Phase 1 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 PRX-twelve and expect to update you later this year. Turning now to prasinezumab on Slide 17. Prasinezumab, 1st anti L plus Nuclein antibody to demonstrate slowing the progression on measures of Parkinson's disease in Phase 2 trial.

Speaker 4

Our partner Roche previously presented data from the Phase path to the trial, trinprazolizumab reduced 1 year motor progression by 35% as measured by the MDS 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 compares 3 year progression of motor science in the pacificin of prasinezumab population with a propensity score balance cohort of real world data from the Parkinson's Progression Markers Initiative or PPMI. The prasinezumab population fell 63% slowing progression as measured by the MDS UPDRS Part 3 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 disease. Roche has advanced prasinezumab into the Phase 2b PDOVO trial, which is a double blind placebo controlled trial evaluating 586 patients with early Parkinson's disease.

Speaker 4

Participants are randomized 1 to 1 to receive prasinezumab or placebo every 4 weeks for at least 18 months. Roche announced they have completed enrollment in the Q1 of 2023. The primary endpoint is time to clinically meaningful progression on motor signs of the disease as assessed by a 5 point or greater increase in the MDS UPDRS Part III from baseline. This disease progression may be correlated to meaningful worsening on the clinical global pressure improvement scale. Roche expects to report top line data from the PDOVO trial later this year.

Speaker 4

Moving to MNC-six thousand and nineteen on Slide 18. MNC-six thousand and nineteen is being developed by Novo Nordisk As a potential 1st 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. NMC-six thousand and nineteen is thought to deplete both deposited amyloid circulating non native TTR to prevent further deposition to improve organ function. This mechanism in action has the potential to provide betasent for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs. NOLA Nordisk is progressing this an ongoing double blind placebo controlled signal detection Phase 2 clinical trial.

Speaker 4

The trial has completed recruitment Inova estimates primary completion in the first half of twenty twenty five. Now I'd like to turn the call over to Tran for a discussion of our 2022 financial performance our 2024 financial guidance. Sean?

Speaker 5

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 BMS-nine hundred and eighty six thousand four hundred and forty six, formerly known as PRX-five, for $55,000,000 In terms of our 2023 financial performance relative to guidance, we had net cash used in operating and investing activities of 136 $700,000 which was favorable to our guidance range of $148,000,000 to $161,000,000 Net loss was $147,000,000 which was favorable to our guidance range of $153,000,000 to $171,000,000 As of December 31, 2023, Prothena had $621,000,000 in cash, cash equivalents and restricted cash, which is favorable to our guidance of $600,000,000 As of February 9, 2024, Prothena had approximately 53,700,000 ordinary shares outstanding.

Speaker 5

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 2020 For net cash used in operating and investing activities to be between $208,000,000 $225,000,000 We expect to end the year with approximately $405,000,000 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 $229,000,000

Speaker 3

to $255,000,000

Speaker 5

which includes an estimated $51,000,000 of non cash share based compensation expense. With that, I'll turn the call back over to Gene to discuss our upcoming milestones. Gene?

Speaker 2

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 Fresenians for their ongoing commitment to advancing protein dysregulation science to make a real impact for the patients and families we serve.

Speaker 2

As we look ahead, we're excited to have meaningful catalysts across our programs The potential clinical readouts from 4 ongoing clinical trials within the next 12 to 18 months, which include top line results from our confirmatory AL Phase 3 trial evaluating bertimimab in patients with Mayo Stage 4 AL amyloidosis clinical data from our ongoing Phase evaluating TRx12 as a potential best in class treatment in early Alzheimer's disease top line results from the Phase 2b PDOVA trial evaluating Prasinezumab for Parkinson's disease being conducted by Roche and finally clinical data from a Phase 2 signal detection trial evaluating NNC-six thousand and nineteen 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 I 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 and A. Operator?

Operator

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

Speaker 6

Yes. 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'm 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.

Speaker 6

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 2,005 or 2025?

Speaker 2

Yes. Thanks for the questions, Charles. I appreciate them. So I think first just with respect to timeline, 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 PRX-twelve, 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.

Speaker 2

And I think in terms of your question around enrollments in the various cohorts, maybe I can ask Hideki to address that question. Hideki?

Speaker 7

Yes. Thanks, Gene. So yes, enrollment has been Very strong in our PRX-twelve Phase 1 trial, the high level of interest in once monthly subcuant antibodies treatment. And important to note that the Data Safety Monitoring Board has a loss of clearance of 45 to 400 milligrams And we're proceeding well towards this plan. And so this will allow us to fully explore those funds curve.

Operator

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

Speaker 8

Hey, thanks for the update and congrats on the progress. We have another question about the PRX-twelve 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?

Speaker 8

And How will it impact your next steps for 2012? Thank you.

Speaker 2

Yes. Thanks, Jay. Thanks for the question. Well, maybe I can just start with the 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, Rebecca, you can just speak a little bit about that period.

Speaker 7

Yes. So each patient Within each cohort, it's allowed to enroll in open label extension for 6 months as you mentioned. And again, very strong enrollment and people are very excited about the once monthly subcu dose.

Speaker 5

And here we won't have as Suneeti is 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 PRX12, which we are capturing both safety, tolerability and of course PK as our pharmacodynamic measurement.

Operator

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

Speaker 9

Hi guys. Thanks so much for taking my question. Just wanted to 0 in on the comparable ARIA rates that we're seeing between the 70 milligram dose of 12 and placebo. So when you consider how subcutaneous bapinezumab had less ARIA rates compared to its IV version. And while lekanimab subcu had About equal ARIA rates versus the IV version, how do you reconcile this?

Speaker 9

And given that the engineering of 12 was optimized off of bapenizumab, do you foresee

Speaker 2

Yes. 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.

Speaker 2

And as you say, I think there is evidence across the anti amyloid Feel that there is an 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 different between antibodies. And I think that's what we're seeing. So you're making the point between bapanezumab And lekanamaban, I think, those are astute observations. As you say, with the bafenuzumab work, I think as approximately equivalent exposures on an The basis were managed to be attained, what was observed at least in the published literature was lesser ARIA with that molecule with lecanumab data, a little bit more comparable.

Speaker 2

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 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.

Speaker 7

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, There's placements as well as ARIA rate consistent with placebo. And the data that allows us to provide a therapeutic index to explore the full dose 1 curve with 1 monthly subcu dose.

Speaker 7

And we again, just to remind, we have the ability of up to 400 milligrams And all

Speaker 10

these cohorts are actively enrolled.

Operator

Your next question comes from the line of Nina Bittritto Garg from Deutsche Bank. Please go ahead.

Speaker 11

Hey guys, thanks for taking my question. So 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 The patients so far, so both the 8.4 non carriers and the 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 204100 and why you selected 204100 for both SAD and MAD. I know you had talked a lot about selection of 70 mg as being based off of the C app similar to the average to 10 mgs take aducanumab, but just wondering how we should think about the higher doses? Thanks.

Speaker 2

Yes. Thanks, Nina, for the question. Maybe I can start and then Hideki can Again, jump in here. I think, 1st 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 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.

Speaker 2

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 Hideki indicated. Hideki?

Speaker 7

Yes. Thanks, Gene. So as you mentioned, we're continuing to explore the doses in the Phase 1 study and that's the purpose of Phase 1 study is. And just to remind you, in the 7 milligram, we did see the encouraging AML reduction and consistent ARIA rates with placebo. And that allowed us to really explore the full dose transfer 45 all the way up to 400 milligram.

Speaker 7

And again, just to remind you the XTRA has high volume potency once they subcu administration and potentially best in

Speaker 4

class in the TAEA data.

Operator

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

Speaker 6

Hi, team. This is Jung Woo on for Yas. Thanks for taking our question. Just kind of diving more into the details of the ARIA rates. Given that you're enrolling both APOE4 homozygotes and heterozygotes, we know that this drives sometimes differences in ROA rates.

Speaker 6

How do those factors your expectations regarding both safety and efficacy across these populations?

Speaker 2

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.

Speaker 2

And obviously, as we talk about ARIA rates, we're being specific 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 months of treatment were consistent with placebo. I think you're the point you're making about testing separately 8.4 homozygous 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.

Speaker 2

And one of the lessons I think that's become clear is that APOI4 homozygosity does tend to lead itself to a higher ARIA rate and in the context clinical trials that can lead to in some cases missed dosing or skipped dosing. Obviously, that's less than ideal as we 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 APO4 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. 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.

Speaker 2

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 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.

Operator

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

Speaker 4

Thanks for taking my question. 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, Trying to get better safety and any color would be helpful. Thanks.

Speaker 2

Yes. Maybe I 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.

Speaker 2

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.

Speaker 2

As we saw the 1st 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. Please go ahead.

Speaker 4

Hey, guys. Thanks for the question.

Speaker 12

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

Speaker 4

you have

Speaker 12

expected ARIA in that type of range in the drug arm, given you have very low exposure, Whereas the IV drugs, including OTEMB have already have rates that are around 12% to 20%. So if you could tie those 2 together and What is the drive confidence today for those listening that you can go to 200 milligrams in 3 times the dose and still thread the needle? Thank you.

Speaker 2

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.

Speaker 2

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 Good indicators 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, the 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 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 and being permissive from a therapeutic index perspective to continue to explore this Folsom exposure response relationship range.

Operator

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

Speaker 10

Hi, thanks for taking the questions. I guess I want to switch gears here and just ask a question about prezniizumab. 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.

Speaker 2

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 2 PASADENA study.

Speaker 2

And importantly, relative to the PPMI demographic matched group, it showed a 63% slowing of progression As measured by MDSU PTRS 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, I mean, at least on the MDS UPDRS Part III scale, 117 less percent less progression than that PPMI database group. And in fact, even on the activity of daily living scale, the MDSUPDRS Part 2, a 39% slowing of or less progression than that PPMI data group. So we're very interested in this. Obviously, the NOVA study is fully enrolled as per Roche.

Speaker 2

This is a large study that 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, 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 obtain.

Speaker 5

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 Roche believes to be clinically meaningful. They're also working on other clinical 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.

Operator

And we have time for one more question today and it comes from Ananda Ghosh from H. C. Rainwright, please go ahead.

Speaker 13

Yes. Hi. 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 PRX-twelve program. So what has been how do we think at The EUC, the Cmax and relative fractional occupancy, when you are looking at data which comes from lekaneumab subcutaneous The CTAD data and with respect to your idea on the PRIORIX12 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?

Speaker 13

Thank you.

Speaker 2

Yeah. No, I appreciate the question. And, yeah, it's an important question. And you talked about mukanumab and aducanumab and I think they're relevant as immunoterminous targeting anti A beta antibodies. And I think what we See with those antibodies as you look through the Phase 2 data set and into the Phase 3 data set is relationship between removal of plaque and the dose response, so exposure relationship.

Speaker 2

So, and in the case of lekanumab 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 denanimab 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.

Speaker 2

Although 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 events, 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 difference 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 1 trial, so that we can better characterize relationship between PRX12 exposure and our e rates. And we think that, as we Collect additional dose level cohort data.

Speaker 2

And as we think about future substantive data updates, We would be able to talk in more detail about what that means specifically for PRX12.

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.

Speaker 2

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.

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Earnings Conference Call
Prothena Q4 2023
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