Q4 2020 Prothena Corporation PLC Earnings Call

Ladies and gentlemen, thank you for standing by and welcome to the Cristina fourth quarter and full year 2020 financial results Conference call. At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session to ask a question. During this session you will need to press Star then one on your telephone please be.

Unknown Executive: Please go ahead. Thank you, Michelle. Good morning, everyone, and welcome to Prothena's investor conference call to review our business progress and our fourth quarter and full year 2020 financial results and our 2021 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 8K filed today with the SEC. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will highlight Prothena's recent and 2020 pipeline progress, what distinguishes our scientific platform, and our path for sustainable growth.

Today's conference is being recorded if you require any further assistance. Please press Star then zero I would now like to hand, the conference over to one of your speakers today and.

Allen Road head of Communications. Please go ahead.

Thank you Michelle good morning, everyone and welcome to protein as Investor Conference call to review, our business progress and our fourth quarter and full year 2020 financial results and our 2021 financial guidance. Please review the press release, we issued earlier today, which is available on our website at Pristina Dot Com and is also attached to a form 8-K filed today with the SEC.

Unknown Executive: Following Gene's comments, Tran Nguyen, our Chief Operating Officer and Chief Financial Officer, will review our financial results and performance for the fourth quarter and full year of 2020 and 2021. Gene will then provide an overview of our near-term milestones. We will then open the call for Q&A and be joined by Dr. Wagner Zago, our Chief Scientific Officer, and Dr. Radhika Tripuraneni, our Chief Development Officer. Before we begin, I would like to remind you that during the course of today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statement.

On today's call Dr Gene Kinney, our President and Chief Executive Officer will highlight protein is recent and 2020 pipeline progress what distinguishes our scientific platform and our path for sustainable growth. Following gene's comments Trung Nguyen, our Chief operating Officer, and Chief Financial Officer will review, our financial results and performance.

<unk> for the fourth quarter and full year of 2020, and 2021 financial guidance Gene will then provide an overview of our near term milestones. We will then open the call for Q&A and be joined by Dr. Rajiv <unk>, our chief Scientific officer, and data and Dr. Erotica, AAA and <unk>, our Chief Development Officer.

Before we begin I would like to remind you that during the course of 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.

Unknown Executive: 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.

Release issued today as well as our most recent filings with the SEC, we disclaim any obligation to update our forward looking statements and with that I'd like to turn the call over to gene.

Gene G. Kinney: Thank you, Ellen, and thank you all for joining us this morning to review our 2020 financial results. It's been an exciting and transformational year for Prothena. As Tran will highlight shortly, we met our 2020 financial guidance and ended the year with a strong cash position.

Thank you Alan and thank you all for joining US This morning to review our 2020 financial result.

It's been an exciting and transformational year for Burkina and <unk>.

John will highlight shortly we met our 2020 financial guidance and ended the year with a strong cash position.

Gene G. Kinney: When combined with up to $140 million in potential payments stemming from our collaborations with Roche and Bristol-Myers Squibb, this enables us to fund our pipeline through key upcoming milestones. Over the past year, we've made significant progress advancing new medicines with the potential to change treatment paradigms in multiple indications. In our rare peripheral amyloid disease portfolio, we recently announced plans to initiate the Phase 3 AffirmAL study of bricamumab in Mayo Stage 4 patients with AL amyloidosis under a special protocol assessment or SPA agreement with FDA at the unprecedented P value of 0.10. The significant survival benefit observed in our vital study made this FAA agreement possible, and we expect to initiate the FIRM-AL study by mid-2021.

And when combined with up to $140 million and potential payments stemming from our collaborations with Roche and Bristol Myers Squibb. This enables us to fund our pipeline through key upcoming milestones.

Over the past year, we've made significant progress advancing new medicines with the potential to change treatment paradigms and multiple indications.

And our rare peripheral amyloid disease portfolio.

We recently announced plans to initiate the phase III affirm a L study of <unk> and Mayo stage four patients with al Amyloidosis under a special protocol assessment or Spa agreement with FDA at the unprecedented P value of 0.10 and the.

And the significant survival benefit observed and are vital study made the spa agreement possible and we expect to initiate the firm a L study by mid 2021.

Gene G. Kinney: We also announced results from our Phase 1 study of PRX4, including improvements in neuropathy and cardiac function in patients with ATTR amyloidosis, and we expect to advance this program into a Phase 2-3 study in the fourth quarter of this year. In our neurodegenerative disease pipeline, we advanced two programs in our Alzheimer's disease portfolio: PRX5, our anti-tau antibody, being developed under our global neuroscience collaboration with Bristol-Myers Squibb, and PRX12, our proprietary next-generation subcutaneous anti-A-beta antibody.

We also announced results from our phase one study appear explore including improvements in neuropathy and cardiac function and patients with <unk> amyloidosis, and we expect to advance this program into a phase two three study and the fourth quarter of this year.

And our Neurodegenerative disease pipeline, we advanced two programs and our Alzheimer's disease portfolio peer X five our anti Tau antibody being developed under our global neuroscience collaboration with Bristol Myers Squibb, and <unk> 12, our proprietary next generation subcutaneous anti a beta antibody we can.

Gene G. Kinney: We continue to expect that the Biogen molecule, aducanumab, will be approved later this year, and we are developing PRX12 to offer a next-generation treatment in order to enhance patient compliance and access. Last year, we also announced the results from part one of the phase two Pasadena study of prasonezumab in patients with early Parkinson's disease. Prasonezumab specifically targets the C-terminus of alpha-synuclein and is the first anti-alpha-synuclein antibody to demonstrate significant slowing of motor progression and improvements on imaging biomarkers consistent with disease modification.

And you to expect that the Biogen Malik molecule and you can't imagine will be approved later this year and we are developing purex 12 to offer and next generation treatment in order to enhance patient compliance and access.

Last year, we also announced the results from part one of the Phase II Pasadena study oppressed and other mab and patients with early Parkinson's disease.

Perhaps in other maps, specifically targets the C terminal of Alpha Snoopy, and and as the first anti alpha nuclear and antibody, which demonstrates significant slowing of motor progression and improvement on imaging biomarkers consistent with disease modification.

Gene G. Kinney: Based on these results, we announce that, with our partners at Roche, we are advancing Prasonesmeb into a late-stage Phase IIb study with further details expected in the second quarter. As someone who has devoted the better part of my career focused on advancing medicines for progressive neurodegenerative diseases, I was particularly encouraged by the consistent signals of efficacy observed in this proof-of-concept study. This is an exciting time for our company.

Based on these results, we announced that with our partners at Roche, we are advancing press and as mab into a late stage phase II <unk> study with further detail is expected in the second quarter.

And someone who has devoted the better part of my career focused on advancing medicines for progressive Neurodegenerative diseases, I was particularly encouraged by the consistent signals of efficacy observed in this proof of concept study.

This is an exciting time for our company.

Gene G. Kinney: I'd like to start by highlighting what differentiates Prothena's proven approach, how it positions us as a leader in developing therapies for diseases caused by protein dysregulation, and how we are well-positioned for an extraordinarily productive future. Our unique approach starts with science. Specifically, our deep scientific understanding of how protein dysregulation contributes to the cause and progression of devastating rare peripheral amyloid and neurodegenerative diseases. This stems from our decades of foundational work in protein biology and an understanding of the dynamic aspects of protein dysregulation, which subsequently informs our selection of targets. We apply our proven protein dysregulation platform to specifically target the pathogenic forms of the proteins that cause disease. We can simplify this process into the saying, "epitope matters."

I'd like to start by highlighting what differentiates protein has proven approach how it positions us as a leader and developing therapies for diseases caused by protein Dysregulation and how we are well positioned for an extraordinarily productive future.

Our unique approach starts with science.

Specifically, our deep scientific understanding of how protein dysregulation and contributes to the cause and progression of devastating rare peripheral amyloid and neurodegenerative diseases.

This stems from our decades of foundational work and protein biology, and and understanding of the dynamic aspects of protein Dysregulation, which subsequently informs our selection of targets.

We apply our proven protein dysregulation platform to specifically target the pathogenic forms of the proteins that cause disease.

We can simplify this process into the same epitope matters and it certainly starts with selecting the right epitopes to target on a pathogenic protein.

Gene G. Kinney: And it certainly starts with selecting the right epitopes to target a pathogenic protein. Beyond identifying the optimal epitope, we also engineer our molecules to interact with that epitope in a way that is most likely to intercept or halt the underlying disease process. We do this by designing molecules with a bias toward the pathogenic forms of the protein. Specifically or selectively targeting the toxic protein species in order to alleviate their detrimental effects while leaving the native or healthy form of the protein unaffected is important in order to maintain normal healthy biological function.

Beyond identifying the optimal epitope, we also engineer of molecules to interact with that epitope and a way that is most likely to intercept or halt the underlying disease process.

We do this by designing molecules with a bias towards the pathogenic forms of the protein.

Specifically or selectively targeting the toxic protein species in order to alleviate their detrimental effects, while leaving the native or healthy for them and the protein unaffected is.

Important and order to maintain normal healthy biological function.

Gene G. Kinney: This unbiased and empirical methodology is highly customized for each target. In some cases, we may target a cryptic epitope. In others, we may select antibodies with hyperavidity. And yet, in other cases, we may select a neoepitope.

This unbiased and empirical methodology is highly customized for each target.

And some cases, we may target, a cryptic epitope and others, we made select antibodies with hyper avidity and yet in other cases, we may select and neo epitopes.

Gene G. Kinney: This customized approach depends on the unique characteristics of each target and the underlying disease pathology. After a thorough evaluation of a target, we advance discovery candidates only after we have demonstrated consistent and robust biological outcomes in preclinical development. But an optimized molecule is only useful if you can influence the biology in a way that results in meaningful clinical benefits for patients. And we've now achieved this across multiple programs in our pipeline.

This customized approach depends on the unique characteristics of each target and underlying disease pathology.

After a thorough evaluation of a target with advanced discovery candidates. After we have demonstrated consistent and robust biological outcomes and preclinical development.

But and optimized molecule is only useful if you can influence the biology, and a way that results and meaningful clinical benefit for patients.

And we've now achieved this across multiple programs and our pipeline.

Gene G. Kinney: Our ability to consistently translate our science into clinical proof of concept is an important distinguishing feature of Prothena today. Key to this consistency is knowing how to design a comprehensive clinical program that tests a biological hypothesis in the right patient populations with the right outcome. Our growing pipeline includes therapies with blockbuster potential for diseases with enormous unmet medical needs that lack disease-modifying approaches. And importantly, we enjoy a strong capital position that provides a foundation to fund our growing pipeline.

And our ability to consistently translate our science and the clinical proof of concept is an important distinguishing feature of protein at today.

Key to this consistency is knowing how to design a comprehensive clinical program that test a biological hypothesis and the right patient populations with the right outcome measures.

Our growing pipeline include therapies with blockbuster potential for diseases with enormous unmet medical need that lack disease modifying approaches.

And importantly, we enjoy a strong capital position that provides the foundation to fund our growing pipeline.

Gene G. Kinney: With this slide, I want to further illustrate the concept of epitope matters and how targeting a protein at different regions or epitopes results in very different biological outcomes. Here, we highlight five protein targets in our portfolio, which are ordered by their length. We have found that targeting epitopes represented by the green areas along the protein results in observations of biological activity in preclinical studies and or in clinical efficacy measures. We discovered the benefit of targeting these epitopes by first systematically mapping the length of the protein to assess how targeting different epitopes impacts multiple disease-relevant biological outcomes.

So with this slide I want to further illustrate the concept of epitope matters and how targeting of protein at different regions or epitopes results and very different biological outcomes.

Here, we highlight five protein targets and our portfolio, which are ordered by their lane.

We've found that targeting epitopes represented by the green areas, along the protein results and observations of biological activity in preclinical studies and or on clinical efficacy measures.

We discovered the benefit of targeting these epitopes by first systematically mapping the length of the protein to assess how targeting different epitopes impacts multiple disease relevant biological outcomes.

Gene G. Kinney: This approach is absolutely central to our platform and is what enables the design of novel molecules that aim to alleviate the detrimental effects of pathogenic proteins in multiple dysregulated states. Let's start with Alzheimer's. Our experience in this space dates back to the development of both AM 1792 and the Bapinuzha Massacre.

This approach is absolutely central to our platform and it's what enables the design of novel molecules that aimed to alleviate the detrimental effects of pathogenic proteins and multiple Dysregulation states.

Let's start with Alzheimer's disease.

Our experience in this space dates back to the development of both and 17 92 and Bapineuzumab.

Gene G. Kinney: Our preclinical and clinical research has consistently indicated that potentially disease-modifying antibodies that target the N-terminus of the A-beta protein, shown here in green, could more effectively block the toxic effects of both soluble and insoluble forms of beta-amyloid than antibodies that target other areas of the protein, which are exemplified in red. Recent clinical results are consistent with this view. Data not only from the Aducanumab program but also from recent clinical studies evaluating Eli Lilly's Denanumab demonstrate that targeting this region consistently results in clinical benefit. Targeting other regions of the protein has not shown similar clinical benefit. It is our confidence in this approach that led us to develop PRX12.

Our preclinical and clinical research has consistently indicated that potentially disease modifying antibodies that target the N terminus of the a beta protein shown here and green.

More effectively blocked toxic effects of both soluble and insoluble forms of beta amyloid and antibodies that target other areas of the protein which are exemplified in red.

Recent clinical results are consistent with this view.

Data not only from the <unk> program, but also from recent clinical studies evaluating Eli Lilly's day, Nana Mab Derma.

Demonstrate that targeting this region consistent results and clinical benefit targeting other regions of the protein have not shown similar clinical benefit.

It is our confidence and this approach that led us to develop purex 12.

Gene G. Kinney: We are advancing this molecule as a next-generation, N-terminally directed anti-A-beta antibody for subcutaneous administration in order to improve access to this class of potentially disease-modifying treatments for patients with Alzheimer's disease. This concept has been further illustrated recently in Parkinson's disease, where prasonezumab, our anti-alpha-synuclein antibody in development with Roche, is the first potentially disease-modifying therapeutic to demonstrate signals of efficacy in the Phase II Pasadena study on multiple pre-specified secondary and exploratory clinical endpoints, including measures of motor function in patients with early Parkinson's.

We are advancing this molecule is the next generation and terminally directed anti a beta antibody for subcutaneous administration in order to improve access to this class a potentially disease modifying treatment for patients with Alzheimer's disease.

This concept has been further illustrated recently and Parkinson's disease, where perhaps and as a map our anti alpha nuclear and antibody in development with Roche is the first potentially disease modifying therapeutics demonstrates signals of efficacy and the phase II Pasadena study on multiple pre specified secondary and exploratory clinical.

And points.

Including measures of motor function in patients with early Parkinson's disease.

Gene G. Kinney: Crassonesimab targets the C-terminus of alpha-synuclein. In contrast, a different anti-alpha-synuclein antibody, Biogen's synpanimab, which targets the N-terminus of the protein, was recently discontinued from development due to lack of efficacy in a Phase II proof-of-concept study. This finding is consistent with our own preclinical experience, which found that targeting the N-terminus was suboptimal.

Kras and hazmat targets the C terminal of Alpha's nucleus, and contrast, a different anti alpha nucleon antibody, Biogen, and Panama, which targets the and terminus of the protein was recently discontinued from development due to lack of efficacy and a phase II proof of concept study.

This finding was consistent with our own preclinical experience, which found that targeting and Terminix was suboptimal.

Gene G. Kinney: We adopted a different approach for the development of Brutamimab and PRX4, both of which target a cryptic epitope on their respective proteins. With Britannimab, this led to findings of improved survival in a mouse efficacy model, which subsequently translated to an observed significant survival benefit in Mayo Stage 4 patients with ALM loidosis in our Phase 3 vital study. PRX4, our antibody that was shown preclinically to specifically bind to pathogenic forms of the TTR protein, translated into positive clinical observations on neuropathy and cardiac function in patients with ATTR amyloidosis in our phase one study.

We adopted a different approach for the development of per Tamara and I happened to your explore.

And of which target a cryptic epitope on their respective proteins.

With pertain a map this led to findings of improved survival in a mouse efficacy model, which subsequently translated to an observed significant survival benefit and Mayo stage four patients with al amyloidosis, and our phase III vital study.

Per explore our antibody that we've shown pre clinically to specifically bind to pathogenic forms of the of the TCR protein translated into positive clinical observations on neuropathy and cardiac function in patients with <unk> amyloidosis, and our phase one study.

Gene G. Kinney: We think this story will play out again with Tau, another protein implicated in Alzheimer's disease. Specifically, we believe that targeting the microtubule binding region will be key to intercepting the pathological progression of tau that underlies Alzheimer's pathology. Understanding where and how to target these pathogenic proteins was also critical in the design of our multi-immunogen active vaccine, which has demonstrated robust and balanced immune responses to both Tau and Abeta in preclinical studies.

We think that story will play out again with Tau another protein implicated in Alzheimer's disease.

Specifically, we believe that targeting the microtubule binding region will be key to intercepting the pathological progression of Tau that underlies Alzheimer's pathology.

Understanding where and how to target. These pathogenic proteins was also critical and the design of our multi immunogen active vaccine, which has demonstrated robust and balanced immune responses to both tau and a beta and preclinical studies and importantly, these immune responses were targeted to the key epitopes that we have.

Gene G. Kinney: Importantly, these immune responses were targeted to the key epitopes that we have identified as relevant for both of these proteins. And we recently presented preclinical data on this program at CTAD. As you can see from this slide, disease-related proteins vary widely in terms of their length and their potential conformations of dysregulated forms. This inherent complexity suggests that our approach is one that cannot be easily replicated.

<unk> is relevant for both of these proteins and we recently presented preclinical data on this program at Sea Ted.

And you can see from this slide disease related proteins vary widely in terms of their linked and their potential confirmations of dysregulation forms.

This inherent complexity suggests that our approach is one that cannot be easily replicated.

Gene G. Kinney: One of the key distinguishing features of Prothena today is that we have translated science from our internal discovery engine into positive clinical outcomes for patients as measured by objective clinical endpoints across multiple programs. For example, across several indications, we've seen that targeting the appropriate epitope with the optimal binding strength and in the context of the right study design in the right patient population can result in meaningful clinical benefit. Our rare peripheral amyloid portfolio includes Tamimab for AL amyloidosis and PRX4 for ATTR amyloidosis.

What are the key distinguishing features of foreseen. It today is that we have translated science from our internal discovery engine into positive clinical outcomes for patients as measured by objective clinical endpoints across multiple programs.

Across several indications we've seen at targeting the appropriate epitope with the optimal binding strength and and the context of the right study design and the right patient population can result in meaningful clinical benefit.

A rare peripheral amyloid portfolio include per Tamara, Matt for a L amyloidosis and pure X four for a T T R amyloidosis.

Gene G. Kinney: These molecules have differentiated mechanisms of action from the standard of care therapies, which have not demonstrated an improved survival benefit for patients with advanced cardiac disease at high risk for early mortality due to amyloid deposition. The depleter mechanism of Britamomab and PRX-4 directly targets and clears the toxic amyloid that deposits in the heart and other vital organs. Earlier this month, we announced our plan to initiate the Confirmatory Phase III Affirm AL Study of Britamimab in AL amyloidosis.

These molecules have differentiated mechanisms of action from the standard of care therapies, which have not demonstrated and improve survival benefit for patients with advanced cardiac disease at high risk per early mortality due to amyloid deposition.

The depleter mechanism of per Tamara map and purex for directly target and clear the toxic amyloid that day part debt deposits in the heart and other vital organs.

Earlier this month, we announced our plan to initiate the confirmatory phase III affirm a L study and per Tamara Mab and al amyloidosis.

Gene G. Kinney: Affirm AL is being conducted under a SPA agreement with FDA to enable registration at an unprecedented p-value of less than or equal to 0.10 on the primary endpoint of all-cause mortality in Mayo Stage 4 patients. We were able to reach agreement with the FDA on this SPA because of the significant survival benefit observed in our previous vital studies, where we demonstrated a 59% relative risk reduction in all-cause mortality in Mayo Stage 4 patients over nine months.

Affirm a L is being conducted under a spa agreement with the with F. D. A to enable registration at an unprecedented P value of less than or equal to 0.10 on the primary endpoint of all cause mortality and Mayo stage four patients.

We were able to reach agreement with the FDA on this fall because of the significant survival benefit observed in our previous vital study, where we demonstrated a 59% relative risk reduction on all cause mortality and Mayo stage four patients over nine months.

Gene G. Kinney: In December, we reported results from our Phase I study of PRX4 in ATTR amylases. In this study, after only 9 months of treatment with PRX4, in eligible patients, we observed less progression on neuropathy than expected, and in several patients, we observed improvement. We also observed important improvement on global longitudinal strain, a key measure of cardiac systolic function in all eligible patients.

In December we reported results from our phase one study of <unk>, four and a T T R amyloidosis.

And this study after only nine months of treatment with Parex floor and eligible patients we observed less progression on neuropathy than expected and and several patients we observed improvements.

We also observed important.

Moving on global longitudinal strain a key measure of cardiac systolic function and all eligible patients.

Yeah.

Gene G. Kinney: Turning to the neurodegenerative disease programs in our Alzheimer's disease portfolio, we believe that interventions that target both Tau and Abeta have the potential to reduce the clinical decline in, or prevent the onset of, Alzheimer's disease. As such, our pipeline is advancing programs for both antibodies and vaccines. Our two most advanced preclinical programs are our anti-tau antibody, PRX5, and our anti-A-beta antibody, PRX12. We look forward to sharing preclinical data on PRX5 at an oral presentation at ADPD in March. We've tested a large number of antibodies to epitopes along the tau protein and found that those that target the microtubule binding region more effectively block the binding of tau to neurons and prevent downstream neurotoxic effects.

Turning to the Neurodegenerative disease programs, and our Alzheimer's disease portfolio, we believe that interventions that target both tau and a data have the potential to reduce the clinical decline in or.

Or prevent the onset of Alzheimer's disease.

As such our pipeline is advancing programs for both antibodies and vaccines.

Our two most advanced preclinical programs are our anti Tau antibody pair at five and our anti a beta antibody pair at 12.

We look forward to sharing preclinical data on purex slides and an oral presentation and 80 P D and March.

We have tested a large number of antibodies to epitopes, along and Tau protein and found that those that target the microtubule binding region more effectively block the binding of tau to neurons and prevent downstream neurotoxic effects.

Gene G. Kinney: Understanding this biology increases our confidence in selecting and evaluating PRX5 as a clinical candidate, and we look forward to sharing our preclinical data at ADPD. Last year at CTAB, we presented data on PRX12, our next generation, high-potency anti-A-beta antibody. TRX12 has higher binding strength to amyloid than aducanumab, with as much as an 11-fold greater affinity, and it also recognizes beta pathology to a greater extent, demonstrating more extensive plaque area binding at lower antibody concentrations.

Understanding this biology increases our confidence and selecting and evaluating <unk> five as a clinical candidate and we look forward to sharing our preclinical data at ADP D.

Last year at G tab, we presented data on pure X 12, our next generation high potency anti a beta antibody.

Current 12 has a higher binding strength and amyloid and as you can imagine with as much as and 11 fold greater affinity and also recognized as a beta pathology to a greater extent demonstrating more extensive plaque area binding at lower antibody concentrations.

Gene G. Kinney: We are developing PRX-12 for subcutaneous administration to improve access to this class of treatment for patients with Alzheimer's disease. And I'll conclude by highlighting the results from the Phase 2 Pasadena study of prasonezumab in patients with early Parkinson's disease that we announced last September. In Parkinson's, existing treatments are symptomatic and only address a subset of symptoms. There are currently no treatments available that target the underlying cause of the disease to slow its progression.

We are developing Parex 12 for subcutaneous administration to improve access to this class of treatment for patients with Alzheimer's disease.

I'll conclude by highlighting the results from the Phase II Pasadena study, a press and as a mab and patients with early Parkinson's disease that we announced last September.

And Parkinson's is existing treatments are symptomatic and only address a subset of symptoms. There are currently no treatments available that target the underlying cause of the disease to slow its progression.

Gene G. Kinney: Presinezumab is designed to block the cell-to-cell transmission of the aggregated pathogenic forms of alpha-synuclein that are the hallmark of Parkinson's disease, thereby slowing clinical decline. In Pasadena, treatment with prasonezumab resulted in a significantly reduced decline in motor function of 35% versus placebo at one year and delayed time to clinically meaningful worsening of motor progression. This 35% reduction of clinical decline over just 12 months is particularly noteworthy relative to Alzheimer's disease, where aducanumab has demonstrated a reduced cognitive decline of approximately 22% over 18 months.

And as Matt is designed to block the cell to cell transmission of the aggregated pathogenic forms of Alpha nucleon that are the hallmark of Parkinson's disease, thereby slowing clinical decline.

And Pasadena treatment with price and as Matt resulted and significantly reduce decline and motor function of 35% versus placebo at one year and delayed time to clinically meaningful worsening of motor progression.

This 35% reduction of clinical decline over just 12 months is particularly noteworthy relative to Alzheimer's disease, where as you can imagine as demonstrated reduce cognitive decline of approximately 22% over 18 months.

Gene G. Kinney: In Pasadena, we also observed improvements in imaging biomarkers and signals of efficacy consistent with disease modification across multiple pre-specified secondary endpoints. The programs that I've just described address diseases where there are no approved disease-modifying treatments. Each of these programs has the potential to become blockbuster therapies in areas of extraordinarily high unmet need. Our rare peripheral amyloid disease portfolio addresses two orphan disease market opportunities. We are developing Britamimab and PRX4 in targeted patient populations at high risk for early mortality with a particularly urgent unmet medical need for improved survival.

And Pasadena, we also observed improvements on imaging biomarkers and signals of efficacy consistent with disease modification across multiple pre specified secondary endpoints.

Our programs that I've just described.

The address diseases, where there are no approved disease modifying treatments.

Each of these programs have the potential to become blockbuster therapies and areas of extraordinarily high unmet need.

A rare peripheral amyloid disease portfolio addresses two orphan disease market opportunities.

We are developing per camera map and peer at four and targeted patient populations at high risk for early mortality with a particularly urgent unmet medical need for improved survival.

Gene G. Kinney: Our neurodegeneration portfolio addresses Parkinson's and Alzheimer's, which are the two most common neurodegenerative diseases. Since the occurrence of many neurological disorders, including both Parkinson's and Alzheimer's disease, increases with advancing age, and the worldwide population is aging at a rate never before observed, the magnitude and impact of the pending health care crisis in the absence of better therapies are both predictable and alarming. As we've discussed, our proven protein dysregulation platform is our engine for sustainable growth.

Our neuro degeneration portfolio addresses Parkinson's and Alzheimer's, which are the two most common neurodegenerative diseases.

Since the occurrence of many neurological disorders, including both Parkinson's and Alzheimer's disease increases with advancing age and the worldwide population is aging at a rate never before observed the magnitude and impact of the pending health care crisis, and the absence of better therapies is both predictable and alarming.

As we've discussed our proven protein Dysregulation platform is our engine for sustainable growth.

Gene G. Kinney: This year, we expect three programs to initiate late-stage clinical studies for Tamimab in AL amyloidosis, Prasonezumab in Parkinson's disease, and PRX4 in ATTR amyloidosis. Beyond these programs, we expect Internal R&D to deliver as many as six INDs for new molecules over the next three years. A combination of potential payments resulting from our collaborations with Roche and Bristol-Myers Squibb as well as our existing robust cash position gives us the ability to fund our programs through key milestones.

This year, we expect three programs to initiate late stage clinical studies for Tim and map and al amyloidosis, perhaps and as a mab and Parkinson's disease, and pure X four and eight GTR amyloidosis.

Beyond these programs, we expect internal R&D to deliver as many as six indeed for new molecules over the next three years.

A combination of potential payments, resulting from our collaborations with Roche and Bristol Myers Squibb as well as our existing robust cash position gives us the ability to fund our programs through key milestones.

Gene G. Kinney: We expect our growing pipeline, with programs at every stage of development, to facilitate our transition to a fully integrated research, development, and commercial biotechnology company. At this time, I'd like to turn the call over to Tran for a discussion of our 2020 financial performance and our 2021 guidance. Tran? Thanks, Gene.

We expect our growing pipeline with programs at every stage of development.

Facilitate our transition to a fully integrated research development and commercial biotechnology company.

So at this time I'd like to turn the call over to try and for a discussion of our 2020 financial performance and our 2021 guidance John.

Thanks Gene today, we reported results that were in line with our 2020 financial guidance.

Tran B. Nguyen: Thanks Gene. Today we reported results that were in line with our 2020 financial guidance. Net cash used in operating and investing activities was $81 million compared to our guidance of $75 to $85 million. Net loss was $111 million compared to our guidance of $101 to $118 million. As of December 31, 2020, Prothena had $298 million in cash, cash equivalents, and restricted cash compared to our guidance of $294 to $304 million. Additionally, we continue to have no debt.

Net cash used in operating and investing activities was $81 million compared to our guidance of $75 million to $85 million.

Net loss was $111 million compared to our guidance of $101 million to $118 million.

As of December 31, 2020, casino had $298 million and cash cash equivalents and restricted cash compared to our guidance of $294 million to $304 million.

Also we continue to have no debt.

Tran B. Nguyen: Please refer to the press release issued today for further details regarding our fourth quarter and year-end 2020 financial results. Now, turning to our 2021 financial guidance. We expect our full year 2021 net cash used in operating and investing activities to be $51 to $74 million, which includes an expected $60 million milestone payment from Roche upon the first patient dosed in the previously announced late stage phase 2b study of prasonezumab. We expect to end the year with approximately $235 million in cash, which represents the midpoint of the range.

Please refer to the press release issued today for further details regarding our fourth quarter and year end 2020 financial results.

Turning to our 2021 financial guidance, we expect our full year 2021, net cash used in operating investing activities to be 51, and $2 $74 million, which includes an expected $60 million milestone payment from Roche upon first patient dosed and the previously announced late.

Page Phase <unk> study of press and other matters.

We expect to end the year with approximately $235 million and cash.

Which represents the midpoint of the range.

Tran B. Nguyen: The estimated full-year 2021 net cash used in operating and investing activities is primarily driven by an estimated net loss of $79 to $111 million, which includes an estimated $20 million of non-cash share-based compensation expenses. With that, I'll turn the call back over to Gene to summarize our upcoming milestones.

The estimated full year 2021, net cash used in operating and investing activities is primarily driven by an estimated net loss of $79 million to $111 million, which includes an estimated $20 million and noncash share based compensation expense.

With that I'll turn the call back over to gene to summarize our upcoming milestones.

Gene G. Kinney: Thanks, Tran. Before we talk about our near-term milestones, I want to first acknowledge and thank our extraordinarily talented employees for their ongoing commitment to advancing our science to help patients. We continue to operate in challenging times, and I could not be more proud to work alongside my colleagues at Prothena. I'd also like to thank the patients, their families, clinicians, and study site staff who are participating in our study. Without their support, we could not elucidate the potential value of the new medicines we are developing.

Thanks, John.

Before we talk about our near term milestones and I Wonder first acknowledge and thank our extraordinarily talented employees for their ongoing commitment to advancing our science to help patients. We continue to operate and challenging times and I could not be more proud to work alongside my colleagues at Christina.

And also like to thank the patients their families clinicians and study site staff, who participate in our studies.

Without their support we cannot elucidate the potential value of the new medicines, we are developing.

Gene G. Kinney: Over the past year, our team has delivered multiple clinical milestones, further positioning Prothena as a leader in protein dysregulation. We look forward to communicating additional R&D milestones over the next 12 to 18 months. Our firm AL study for Virtanamab, our most advanced program, is expected to initiate in mid-2021. We also expect to report the nine-month study results from the previous vital study at a future medical conference. We anticipate that Roche will initiate the late-stage Phase 2B study of prasonezumab in patients with early Parkinson's disease in the second quarter of this year.

Over the past year, our team has delivered multiple clinical milestones further positioning proteins as a leader and protein dysregulation.

Look forward to communicating multiple R&D milestones over the next 12 months to 18 months.

Our firm a L study for preterm and App. Our most advanced program is expected to initiate and mid 2021.

We also expect to report the nine month study results from the previous vital study at a future Medical conference.

We anticipate that Roche will initiate the late stage phase <unk> study, a press and hazmat and patients with early Parkinson's disease, and the second quarter of this year.

Gene G. Kinney: Prothena will earn a $60 million clinical milestone payment upon the first patient dose in this study. At the upcoming ADPD Conference, new pre-specified exploratory subgroup analyses from Part 1 of the Phase 2 Pasadena Study of Prasonesomab will be highlighted in an oral presentation. We further expect Roche to present results from Part 2 of the Pasadena Study at a future medical conference.

And you know, we'll earn a $60 million clinical milestone payment upon first patient dosed in this study.

At the upcoming 80 P D conference New Prespecified exploratory subgroup analyses from part one of the phase II Pasadena study of price and there's a map will be highlighted and an oral presentation.

We further expect Roche to present results from part two of the Pasadena study at a future Medical conference.

Gene G. Kinney: For PRx4, we expect to initiate the Phase 2-3 study in patients with ATTR cardiomyopathy in the fourth quarter of this year and also plan to present results from our Phase 1 study at a future medical conference. Our portfolio of Alzheimer's disease programs has also advanced. Building on our foundational science in the discovery and development of anti-A-beta antibodies and vaccines, we continue to be highly active in this space with four programs in Alzheimer's disease, including antibody, vaccine, and small molecule approaches.

For <unk> four we expect to initiate the phase two three study and patients with <unk> cardiomyopathy and the fourth quarter of this year and also plan to present results from our phase one study and a future medical conference.

Our portfolio of Alzheimer's disease programs has also advanced.

Building on our foundational science and the discovery and development of anti a beta antibodies and vaccines. We continue to be highly active in this space with four programs and Alzheimer's disease, including antibody vaccine and small molecule approaches.

Gene G. Kinney: One of these programs, PRx5, is under our global neuroscience collaboration with Bristol-Myers Squibb. We expect to file an IND for PRx5 in the third quarter of 2021, triggering a possible U.S. option payment of $80 million. Preclinical data for this anti-cow antibody will be presented in an oral presentation at ADPD in March.

One of these programs peer X five is under our global neuroscience collaboration with Bristol Myers Squibb.

We expect to file and indeed for peer at five and the third quarter of 2021, triggering a possible U S option payment of $80 million.

Preclinical data for this anti Tau antibody will be presented in an oral presentation at 80, PD and Mark.

Gene G. Kinney: And finally, we expect to file an IND in the first quarter of 2022 for our anti-A-beta antibody PAIRx12. So we're excited about the year ahead. Our team has the capabilities to drive transformational innovation for some of the most devastating diseases affecting society today, and we look forward to providing updates on our programs as they progress. So at this time, we'll open the call for questions. Michelle?

And finally, we expect to file an IND and the first quarter of 2022 for our anti a beta antibody pair X 12.

So we're excited about the year ahead, our team has the capabilities to drive transformational innovation for some of the most devastating diseases affecting society today, and we look forward to providing updates on our programs as they progress.

So at this time, we will open the call for questions Michelle.

Unknown Executive: Thank you. Ladies and gentlemen, if you have a question at this time, please press star then 1 on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. To prevent any background noise, we ask that you please place your line on mute once your question has been stated. Our first question comes from the line of Jay Olson with Oppenheimer. Your line is open.

Thank you ladies and gentlemen, if you have a question and at this time. Please press Star then one on your Touchtone telephone. If your question has been answered or you wish to remove yourself from the queue. Please press the pound key.

And any background noise, we ask that you. Please place your line on mute. Once your question has been stated.

Our first question comes from the line of Jay Olson with Oppenheimer Your and.

Gene G. Kinney: Please go ahead. Oh, hey, congrats on all the progress, and thank you for the clear explanation of your strategy and vision for Prothena. The importance of the epitope is really appreciated. And since you mentioned the differences between prosinesimab and centanimab, are there other differences between those two molecules besides the epitope? And also, any feedback on Pasadena Part 1 that you've gotten from the medical community? And then I had a follow-up question, if I could.

Your line is open. Please go ahead.

Oh, Hey, congrats on all the progress and thank you for the clear explanation of your strategy and vision for Christina.

The importance of the epitope is really appreciate it and and since you mentioned the differences between Cros and isn't Mab and Santana NAV.

Are there other differences between those two molecules. Besides the epitope and also any feedback on Pasadena part one that you've gotten from the medical community and then I had a follow up question if I could.

Gene G. Kinney: Yeah, thanks for the question, Jay. So, very important question. So, obviously, what we're highlighting in today's discussion is clearly where you target these proteins imparts very different biological outcomes. And, you know, we spend a lot of time in the preclinical space really exploring these proteins to understand the optimal way of targeting them, not only where to target them, you know, what the appropriate epitope is, you know, where in the sequence, but also, you know, are there post-translationally modified forms of the protein, are the phosphorylated forms, for example, versus, you know, different misfolded confirmations that we want to think about.

Yeah. Thanks for the questions Jay So so very important question. So obviously, what we're highlighting it and today's discussion is the clearly where you target these proteins and parts very different biological outcomes and you know we spend a lot of time and the preclinical space really exploring.

These proteins to understand the optimal way.

Targeting them, not only where to target them you know what the appropriate epitope is where and the sequence. But also are there post translational modified forms of the protein or the phosphorylated forms for example versus different misfolded confirmations that we want to think about and then ultimately we and part a and <unk>.

Gene G. Kinney: And then, ultimately, we adopt an approach where we bias our molecule in a manner that tries, as best we can, to spare the normal form and function of the protein and specifically go after the more pathological forms. In the case of prastinezumab, that was done by using a technique where we really looked for an antibody that had a high preference for the aggregated forms of the protein over the non-aggregated forms of the protein.

Where we we bias our molecule and in a manner that tries as best we can spare the normal form and function of the protein and specifically go after the more pathological forms and the case.

And as a mab and that was done by using a technique, where we really looked for and antibody that had a high preference for the aggregated forms of the protein over the non aggregated forms of the protein and using very specific kinetic and and quantitative analyses.

Gene G. Kinney: And using, you know, very specific kinetic and quantitative analyses, we were able to show that that selectivity or preference is over 400-fold. And so, we think that's a key component as well. And so, you know, maybe the thing—I can ask Wagner to speak on this, because as we were doing our characterization of antibodies against different parts of the protein, of course, we had our own antibodies that targeted the N-terminus. And maybe, Wagner, I can ask you to speak a little bit about just our experience in that space.

Have been able to show that that that selectivity or preferences over 400 volt and so we think that's a key component as well and so you know maybe the thing.

I can ask Wagner to speak on this because as we were doing our characterization of antibodies against different parts of the protein and of course, we had our own antibodies that targeted the end terminals and maybe Wagner and I can ask you to speak a little bit about just our experienced and that space.

Does it it's a little challenging to make a direct comparison between <unk> and Panama and person as a matter of other than the epitope.

Wagner M. Zago: Yes, it's a little challenging to make a direct comparison between Simpanimab and Placinesumab other than the epitope, but simply because the data around Simpanimab is so sparse, at least the published data, that it's really hard for us to make a direct comparison. But what we can say is that we spent many years screening the entire alpha-synuclein protein. And what we found very early in the program is that there was consistency among antibodies that target the C-terminal portion of alpha-synuclein around where prasenosumab binds.

But simply because the data and so.

Around symphony and mob and so sparse.

And the published data that it's really hard for us to make those ROI comparison, but what we can say is that we spend.

And many years.

Training, the entire office and Oakland.

Proteins and what we found and very early and the program or is that there was a consistency for antibodies that target. The C terminal portion of office and opening a wrong way of processing, those and that binds and there's a consistency in terms of efficacy for those antibodies and and the other antibodies that target the and terminal portion of Opus and Oak and did not show that consistently.

Wagner M. Zago: There is consistency in terms of efficacy for those antibodies, and all the antibodies that target the N-terminal portion of alpha-synuclein did not show that consistency. We consider suboptimal, in fact, efficacy when we do see a...

We have considered.

And optimal and fact efficacy when we did see efficacy. So we focus on the C terminal portion and as gene. This is gene.

Wagner M. Zago: So we focus on the C-terminal portion, and as Gene indicated, one step is to define the right epitope, but the qualities of the antibody, the targeted epitope, are also very important. And binding with the highest binding strength possible to that region, and be as selective or specific as possible to the pathogenic forms, and sparing what we consider normal biological forms, was part of the selection of procinazumab. Procinazumab has a picomolar affinity; we are talking about 40 picomolar affinity to aggregated alpha-synuclein.

Indicated one one stuff is free to find the right epitope, but the qualities of central body to target. Other Coke was also very important and binding with the highest binding strength.

<unk> Ah that.

That region and be as selective or as specific as possible to the photogenic forms and sparing and what we consider normal.

Biological forms was part of the selection of pessimism.

And as a mab has a picomolar we are talking about 40, picomolar affinity charter and get it off of Sunoco and that's very important when you considered the ball and being very penetrance of a bunch of bodies.

Wagner M. Zago: That's very important when you consider the blood-brain barrier penetrance of antibodies. And we selected procinazumab based on that affinity, the epitope, which we confirmed in multiple, And interesting enough, in the clinic with Prasenesumab, we confirmed that the occupancy that we expected for the target in the CNS translated into the two doses that we selected a priori has been saturating of the target, showing So we were very happy.

And we selected.

And as and my based on that affinity the epitope, we confirmed in multiple animal models.

The efficacy, but also the dose response of the antibodies.

And interesting and all in in the clinic with Frostiness, we confirmed that.

And the occupancy that we expected for the targets.

In the CNS.

Translated in the two doses that we selected a priority has been such a rating of the target showing equivalents efficacy and and our phase two so we were very happy with our very successful.

Wagner M. Zago: It was a very successful transitional translation of a rigorous preclinical exploration into clinical evidence of change in the disease progression. Thank you for those details. Just super helpful. And then, as follows, since you have two, Super High Quality Partners, and now a growing number of wholly owned assets in the clinic or about to enter the clinic. Would you consider partnering for Tamimab or any of your other wholly owned assets?

And transitional and translation of our preclinical very rigorous preclinical XP.

Exploration into a clinical evidence of ginger and disease progression.

Thank you for the detail.

Helpful and and then it has fallen since you had two super high quality partnerships and now a growing number of wholly owned assets and the clinic or about to enter the clinic would you consider partnering per Tampa and mab or any of your other wholly owned assets.

Gene G. Kinney: Yeah, so our plans for Tamimab are to pursue a commercialization approach with that. Particularly, you know, obviously in the major markets, in particular, Jay, you know, we think that it's a very focused call point from a commercial perspective. You know, we are addressing what we think is the major unmet medical need in that space, which is to improve survival for patients that are at high risk of early mortality due to amyloid deposition in the heart, in particular. And so that would be our current plan, but maybe I'll just ask Tran if you want to speak to that further.

Yes, so our our our plans with for Tim and Nab or to pursue a commercialization approach.

With that particularly.

Obviously and the major markets in particular Jay.

We think that it's a very focused call point from a commercial perspective.

We are addressing what we think is the major unmet medical need in that space, which is to improve survival for patients better and high risk of early mortality due to the amyloid deposition in the heart and particular and so so that would be our current plans, but maybe I'll just ask try and if you want to speak to that further.

Gene G. Kinney: Yeah, no, based on our past experience, you know, we do believe that there is interest, clearly from strategics, in Bertamomab, given its concentrated hematology call point. And to what Gene just said, you know, given that, based on our market research, you know, we are planning to commercialize Bertamomab. Basically, as we stated before, it shows that, you know, approximately 75% of Mayo Stage 4 patients are treated at about 500 amyloidosis centers of excellence and specialty centers in the U.S. and Europe, which makes for a very efficient hematology sales force footprint. But you know, given the known diagnosed prevalence in regions such as Japan and China, we may explore some regional partnerships.

Yeah, No I think based on our past experience, we do believe that the debt. There is interest Cooley from strategics on for Tim and map given its <unk>.

Concentrated hematology call point and to what gene just said given that based on our.

Market research, we are planning to commercialize per town Mab.

Basically as we stated before it shows that approximately 75 per cent of the Mayo stage four patients are treated at about 500 amyloidosis centers.

Excellent and specialty centers and the U S and Europe, which makes for a very efficient.

<unk> sales force footprint.

But given the known diagnosed prevalence and regions such as Japan, and China, We may explore some regional partnerships.

Tran B. Nguyen: Great. Thanks for taking the questions. Thank you, and our next question comes from the line of Michael Yee with Jeffries. Your line is open.

Great. Thanks for taking the questions.

Thanks Jay.

Yeah.

Thank you and our next question comes from the line of Michael Yee with Jefferies. Your line is open.

Gene G. Kinney: Hey guys, good morning, congratulations on all the progress and thanks for this nice pipeline update. I had two quick questions, they both relate to early stage compounds. One is about the Bristol Celgene collaboration. You talked about how you do expect a potential milestone there. Maybe just talk about how that dialogue and ongoing conversations have been with that program, the progress, and how confident you are that that milestone will come.

Please go guys good morning.

Congrats on all the progress and thanks for the nice pipeline update I had.

Two quick questions.

They both relate to early stage compounds one is on.

The Bristol Celgene.

Collaboration you talked about how you would you expect the potential milestone there maybe just talk about.

How that dialogue and ongoing conversations have been with with that on that program. The progression and how confident you are that that milestone will come and maybe just talk about that target program and conversation.

Gene G. Kinney: Maybe just talk a little bit about that target program and conversation. And then the second question is, obviously, there's a lot more industry interest in A-beta, of course, and we're awaiting a big decision by the FDA. You made some nice comments about your epitope, can you clarify? Is your compound actually more similar to Denonimab rather than Aducanumab, and maybe just talk about your epitope just a little bit more and the comparison between those programs?

And then the second question is obviously theres a lot more.

Industry interest in a beta of question, we're awaiting and a big decision by the FDA you made some nice comments about your epitope can you clarify is your compound and actually more similar to <unk>, but rather than <unk> and maybe just talk about your epic up just a little bit more and and the comparison between those programs. Thanks.

Gene G. Kinney: Yeah, so great questions, Mike. So first, let's start with, why don't I go back in order?

Yeah. So great question. So first let's start with one and I'd go back backwards order here, so let's start with a beta so the pure X 12 molecule does target and the immunotherapy and is of a beta or our own research.

Gene G. Kinney: So let's start with A-beta. So the PRX12 molecule does target the immunoterminus of A-beta. You know, our own research, which Wagner has authored quite a bit of, indicates that targeting that region gives you the optimal ability to interact with both the deposited forms, which are the forms that you can actually see on PET imaging and what have you, but also the aggregated soluble forms, which some, I think, feel contribute to disease.

Which which Wagner has authored quite a bit of.

And you know indicates that targeting that region gives you the optimal ability to interact with both the deposited forms that you know are the forms that you can actually see on pet imaging and what have you, but also the aggregated soluble forms which some I think feel contribute to disease. So the idea. There is that you you want to hit both or.

Gene G. Kinney: So the idea there is that you want to hit both of those species, and the way you hit both of those species is by targeting the immunoterminus of the protein. Aducanumab targets the immunoterminus of the protein as well, as does Denanumab. Denanumab specifically targets a post-translationally modified version of the immunoterminus, particularly the pyroglutaminated forms, but it is still targeting that same region.

And those species and the way you hit both of those species is by targeting amino terminus of the protein.

And as you can imagine targets immune of terminals to the protein as well.

And as does banana Mab banana map C. Specifically of post translational modified.

Virginia version of the amino terminus, particularly the power Glutaminyl forms.

But it is still targeting that same region. So we think theres a consistency here in terms of what we're seeing.

Gene G. Kinney: So we think there's consistency here in terms of what we're seeing. Importantly, you know, elements of clinical design that one needs to look at as well, and that is when you go to treating prodromal-to-mild patients, and you specifically use endpoints, as was the case with aducanumab, using their endpoints, CD-R soma boxes, and also even with BAN2-401 using ADCOMs and the most recent Denanumab studies, you know, those end So selecting the right patients and using the right clinical assessment scales are equally important to being able to demonstrate clinical efficacy, in our estimation. And then what do you see?

Importantly.

Elements of clinical design that one needs to look at as well and that is when you go to treating for Jo mill to mild patients and you specifically using endpoints and as was the case.

And with the with and you can't imagine using using their endpoint CVR sum of boxes and also.

Even with the band to for a one using AD comes and the most recent Jinan and <unk> studies.

Those and point tend to be more sensitive and more geared towards those presumable tomorrow patient population, so selecting the right patients and using the right clinical assessment scales are equally important to being able to demonstrate clinical efficacy in our estimation and the.

And what do you see what your attendance tend to see is what was has been found now across those studies, which is with as you can imagine in the emerge study you saw a 22% slowing of cognitive decline over the 18 month period.

Gene G. Kinney: What you tend to see is what has been found now across those studies, which is with aducanumab. In the eMERGE study, you saw a 22% slowing of cognitive decline over the 18-month period. Same thing in that neighborhood with Denanumab as well, again, across 18 months, which we think is good consistency with respect to how we view the biology playing out here. And then finally, with X5, coming back to that, I think, you know, there's good dialogue with the bristomyoscovin cell gene.

Something in that neighborhood with Dan and Nab as well again across 18 months.

Which we think is good consistency with respect to how we view the biology playing out here.

And then finally with with X five coming back to that.

I think there's good good dialog with the Bristol Myers Squibb and Celgene, we enjoyed the collaboration it its additive in terms of the value. It brings to the program and you know.

Obviously, the the milestone there as an option which is their option. So they'll have to make that decision at the right time, but it is connected with the IND filing.

Gene G. Kinney: We enjoy the collaboration. It's additive in terms of the value it brings to the program, and, you know, obviously, the milestone there is an option, which is their choice, so they'll have to make that decision at the right time, but it is connected with the IND filing. So we're, you know, we're moving forward with that.

So where were we.

We're moving.

And I think I'll add Bob.

And I think I'll add something there gene I mean, yes, our teams have been working together.

There's a governance committee from a joint steering committee, so we and order to file an IND and you have to have a plan for a phase one and so we've been working with their and their team and that design because as you know there is and X.

Gene G. Kinney: I think I'll add something there, Gene. I mean, yes, our teams have been working together. You know, there's a governance committee.

Tran B. Nguyen: working with their team in that design. Because, as you know, there's an ex-US global right that they have at the end of phase one to exercise, that's $55 million. And so clearly, we've been focused on not just the 80 million but on the 55 million too. So we have been working with them on that phase one design and, ultimately, the IND package. So, as Gene just stated, we'll file the IND, and they have a certain time period.

U S global right that they have at the end of phase one to exercise that's $55 million and so clearly we've been focused on not just the 80 million, but on the 55 million. Two so we have been working with with them on that phase one design and ultimately the IND package. So as gene just stated we will file the IND.

And they have a certain time period to make that U S.

Option decision and we look forward to it later this year.

Tran B. Nguyen: Right, got it, yeah, there's joint steering and there's ongoing communication on that, that adds some color, and then, yeah, Lily is a P-Glue targeted specifically at the epitope too, so thank you for clarifying that.

Right got it yes, there's a joint steering and there's ongoing communication on that debt.

And that add some color and then literally as a PQ targeted specifically an epitope jokes and thank you for clarifying. Thank you correct yes.

Gene G. Kinney: Thank you.

Yep.

Charles Cliff Duncan: Thank you, and our next question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is open, please go ahead. Yeah, good morning, Gene and Quan.

Thank you and our next question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is open. Please go ahead.

Yeah, good morning, and gene and try and I. Thank you for taking the question and I. Appreciate I also appreciate all the platform information that you've provided I'll come back to that have a couple of questions and the platform, but first before I do with regard to near term clinical so I guess I'm wondering.

Gene G. Kinney: Thank you for taking the question and appreciating it. I also appreciate all the platform information that you provided. I'll come back to that, and I have a couple of questions on the platform. But first, before I do, with regard to near-term clinicals, I guess I'm wondering, generally, about the kind of rate-limiting steps, both for a firm, as well as the PRASI Phase 2B. I'm wondering if you could provide us with a little bit more color on the operationalization for Affirm and when you would anticipate that, and then if you have further information on its size. And then, similarly, with PRASI and Phase IIb, I'm wondering if you anticipate being able to provide periodic updates beyond just the initial, you know, dosing of the first patient.

And generally about kind of rate limiting steps both for our firm as well as the press see phase two be on.

I'm wondering if you could provide us a little bit more color on the.

And the Operationalization for our firm.

And when you would anticipate debt and then if you have further information on its size and then similarly with fate.

<unk> and phase two B I'm wondering if you anticipate being able to provide periodic updates beyond just the initial.

And the dosing of the first patient.

Radhika Tripuraneni: So why don't we start with Affirm AL, and maybe Radhika, I can ask you to speak to kind of where you know operationally what's happening on en route to our opening of that study.

Yeah. So why don't we start with a firm a al and maybe erotic I can ask you to speak to kind of where you know operationally what you know what what's happening.

And route to our opening of that study.

Radhika Tripuraneni: Sure, Jean. Thanks for the question. It's a really exciting time for Prothena as we embark on getting their Pharm-AL study up and running. I think given our history in the space and our past relationship, as well as our ongoing program in the ATTR space, we're quite poised to ultimately get this study up and running. The standard activities, as you would assume, as we engage in a Phase III study in terms of site contracts and so forth, are really the main dynamic that we're working through, and we're looking forward to getting that study up and running and initiating it ultimately in mid-2021, so in the very near future.

Sure.

Thanks for the question and it's it's a really exciting time for protein as we embark on getting their firm L study up and running I think given our history in the space and our past relationship as well as our ongoing program and the ATR space, where we're quite poised to ultimately get the study up and running the standard activities as you would assume as we engage.

And as for Phase III study in terms of type contracts and so forth are really the main dynamic that where we're working through and we're looking forward to getting that study up and running and initiating and ultimately in mid 2021, and so in the very near future.

Radhika Tripuraneni: The other dynamic to think about is, you know, we've got a long-standing relationship. And when you consider the study itself, and for ChemMAD, it's an agent in which there's plenty, a significant amount of data that's already out there in addition to the post hoc analysis. So I think it really gives us a fair amount of information to communicate and engage the clinical community with. And we've seen that come through with regard to excitement as we get closer to the study.

The other dynamic to think about it is you know we've got a long standing relationship and when you consider the study itself and per ton and that it's an agent and which there's a plenty of.

A significant amount of data that's already out there. In addition to the post hoc analysis. So I think it really gives us a fair amount of information to communicate and engage the clinical community with and we've seen that come through with regards to excitement as we get the study started.

Gene G. Kinney: Yeah, and I think, Charles, you also asked about the size of that study. It's a two-to-one randomization, and we anticipate enrolling up to 150 patients in total. And so, you know, we, as Radhika says, we're excited to see that get started. On the Prasonesimab side, I think your question was just about news flow, and I think what we can say at this point is, you know, that we anticipate Roche getting the Phase 2B study up and running.

Yeah, and I think Charles you also asked about the size of that study.

It's a two to one random and and we anticipate enrolling up to 150 patients in total.

And so we as Radhika says, we're excited to see that get started.

On the press and doesn't match side I think your question was just about news flow and I think what we can say at this point is you know that we anticipate.

Roche getting the phase <unk> study up and running you know we've talked about the idea that with that study and first patient dose that available and survey a 60 million dollar clinical milestone in the partnership and and I think you know we do expect the 80 P. D that there will be additional analyses.

Gene G. Kinney: You know, we've talked about the idea that with that study and the first-patient dose, that avails us of a $60 million clinical milestone in the partnership. And I think, you know, we do expect at ADPD that there will be additional analyses of the Pasadena Part 1 study, so these are based on pre-specified subgroups. And we further expect that at a future conference, TBD, Roche will be talking about the Part 2 Pasadena study as well. So I think those are things we can look forward to just from additional information on Prasonesimab.

Of the of the Pasadena part one study so these based on Prespecified subgroups.

We further expect that at a future conference TBD.

And the Roche will we'll be talking about the park to Pasadena study as well so and so I think those are things. We can look forward to just from additional information around pressing us and them.

Gene G. Kinney: Okay, that's helpful. Thank you, Gene.

Okay. That's helpful. Thank you gene.

Gene G. Kinney: I do have a couple of questions on the platform, but just one more that I was thinking about with regard to the firm. You mentioned the all-cause mortality and the p-value 0.1 as being unprecedented. And I guess, you know, when I think about that, it's almost, you know, a challenge to think about because it's so low. And I guess, is there any other color that you can provide with regard to the discussions that you had with the agency around that? Any thoughts on that p-value for a firm?

And do have a couple of questions and the platform, but but just one more debt I was thinking about with regard to the firm you mentioned the all cause mortality and the P. Values 0.1 is being unprecedented and I guess you know when I think about that it's it's almost.

A challenge to think about because it is so so low and I guess is there any other color that you can provide.

With regard to the discussions that you had with the agency around that any any perspectives on that P value for yeah well.

Gene G. Kinney: Yeah, well,

Gene G. Kinney: I mean, look, as we looked at our data from the VITAL study and noted, you know, what we considered certainly be a robust survival benefit in Mayo Stage 4 patients with a hazard ratio that basically translates to a 59% relative risk reduction of all-cause mortality. You know, that's meaningful, and, you know, it shouldn't go unsaid that every one of those events is just really, you know, beyond quantification, right?

I mean look I think I think you know as we looked at our data from the vital study.

You know and and noted what we considered certainly be a robust survival benefit and may have stage four patients with a hazard ratio.

And that basically translates to a 59% relative risk reduction of all cause mortality.

You know that that's that's meaningful and and and you know it shouldn't go on and said that every one of those events is is just really.

Beyond quantification right. I mean these are these are individuals families friends and so you know you look at that and you don't just turn your head from net sort of data and so we spent a long time ourselves really digging into that data we brought external statisticians in to the team to help challenge around that data.

Gene G. Kinney: I mean, these are individuals, families, friends, and so, you know, you look at that, and you don't just turn your head from that sort of data, and so we spent a long time ourselves really digging into that data. We brought in external statisticians into the team to help challenge us around that data. We looked for ways to try and explain that data away.

We looked for ways to try and explain that data away and failing to do so we engage not only with kols, but also with the regulators and really the goal. There was both to understand the data, but also then to find a feasible path forward in this population and I have to say it was really a.

Gene G. Kinney: Failing to do so, we engaged not only with KOLs but also with the regulators. And really, the goal there was both to understand the data but also then to find a feasible path forward in this population. And I have to say, it was really a good collaboration with the FDA; it encompassed multiple formal and informal meetings. And you know, it was really aligned around understanding both the strength and relevance of the vital data and what would be required then to move this forward from a registration perspective. So we were We were very excited.

Good collaboration with the FDA and encompassed multiple formal and informal meetings and you know it was really aligned around understanding both the strength and relevance of the vital data and and what would be required then to move this forward from a registration perspective. So we were we were very happy.

Gene G. Kinney: I'm happy that we came to an accord with the agency in the form of this special protocol assessment, which really underlies what the AFIRM-AL study is, a study that involves two-to-one randomization up to 150 patients enrolled, and as you say, with an all-cause mortality at a p-value significance of.10, which would enable a registration path when combined with our other datasets.

You know that we came to an accord with the agency and.

In the form of the special protocol assessment.

And it really debt that underlies what the affirm a L study is a study that's two to one randomization and up to a 150 patients enrolled.

And you know as you say with and all cause mortality at a P value significance of 0.10, which would enable a registration path when combined with our other datasets, maybe I'll just add one thing gene is drawn and that simply put Charles if we didn't have this significant survival benefit in these patients.

Tran B. Nguyen: Maybe I'll just add one thing, Gene, and this is Tran, in that, simply put, Charles, if we didn't have this significant survival benefit in these patients that are at high risk for early mortality, we would not have gotten that, like what you just said, the unprecedented P-value of 0.1. We don't believe our other competitors who don't have double-blind placebo-controlled trial data can go to the FDA and have So we're very excited to be initiating Affirm AL later this year, as Radhika said, mid-21. And, you know, we really are excited for the vital data where, again, you see significant survival benefit.

And that are at high risk for early mortality, we would not have gotten that debt like what you just said the unprecedented.

P value of 0.1.

Don't believe our other competitors, who don't have double blind placebo controlled trial data can cannot it can go to the FDA and have this this out this amazing outcome. So we're very excited to be initiating a firm mail later this year as <unk> said mid 'twenty one and.

And we really do.

Excited for the vital data, where again you see significant survival benefit.

Gene G. Kinney: Good deal. We're looking forward to that start and believe that perhaps, you know, that setting may drive enrollment faster than we anticipated. So, one platform question, and that is on PRX012, and a follow-up kind of to Michael's questions regarding how the profile looks relative to, say, a catamab and to an anamab. I guess I'm wondering, beyond what you mentioned in that answer, what do you think about the implications of the design of the molecule for, say, CNS penetration, and then the potential for area? It seems like you're going to have better targeting, and therefore, perhaps even better CNS penetration. But do they have any implications in terms of area?

Good deal, we're looking forward to that and start and believe that perhaps.

You know debt setup may drive enrollment faster than our anticipated. So one platform question and that is on.

Per axis, or 12 E and follow up kind of to Michaels questions regarding how the profile looks relative to say and you can imagine and Anna Ma'am I guess I'm wondering beyond what you mentioned and that answer what do you think about the implications.

And of the design of the molecule for say CNS penetration and then the potential for area. It seems like you're going to have better targeting and and therefore, perhaps even better CNS penetration, but any implications in terms of the ARIA.

Gene G. Kinney: Yeah, so since Wagner is an author of a paper that basically describes what RA is from the biological perspective, I'll let him answer this question.

Yeah, so since since Vulgaris and author on a paper that debt basically describe what are is in the biological perspective I'll, let him answer this question.

Wagner M. Zago: Okay, so let me start by... Okay, well, the mechanism behind ARIA that we think is behind so, so, two things we think are contributing to these vascular observations. One is certainly the removal of a beta from the vascular itself. We think that that contributes, but also, what we've seen is that during the process of plaque clearance, from the parenchyma, not from the vasculature. During that process of clearance by antibodies, there is a mobilization of A-beta from the plaques to the perivascular space. And that process of mobilization, which we believe is an important clearance mechanism in addition to the phagocytosis, can alter vascular permeability by changing the interaction of vascular elements with, for example, astrocytes.

Okay.

So let me start by [laughter].

Okay, well the mechanism behind the idea that we were.

And cause behind so so.

Two things, we think is contributing and should these vast cooler.

Observations one is certainly the removal free beta from the buzzwords itself.

We think the other contributors.

But also what we've seen is that during the process of black clearance.

From the point and one off from their boss culture. During the process of growth by entrepreneurs and there is a mobilization operating data from the blocks chip Perry vossler spaces and.

And that process of mobilization and which we believe is an important clearance mechanism.

In addition to the progress at doses that process.

Ken alter vossler from a bullish and by changing the interaction of muscular elements with for example, astrocytes.

Wagner M. Zago: So all of that is to say that we believe that in order to reach clearance of plaques from the brain, you will see aria happening at certain points. And we think that the incidence of ARIA, more specifically symptomatic ARIA, will very much depend on the C-max, the maximum concentration of the antibody that's reached in the brain. And that is normally a peak.

So all of that is to say that we believe that in order to seek to reach clearance of plaque from the brain you will see our year happening at certain point, and we think that debt.

The incidence of ARIA.

More specifically the symptomatic and no we will very much depend on the <unk>. The maximum concentration of zone to body that is reached.

And in the brain and that is normally a pick.

Wagner M. Zago: If you do intravenous, you see a maximum C-max, and the antibody goes down. From our program, what we are positioning PRx12 for is to deliver it subcutaneously. So with a subcutaneous delivery, you will reduce that CMAP. [inaudible] But what we do believe is that if you don't see aria, you are not seeing clearance of the meaningful pathogenic forms of A-beta in the brain. So we are not surprised that synpanimab, denonimab, aducanumab, and BAM2401 all show aria. And we are also not surprised that the antibodies that did not show efficacy did not show aria. Again, because clearance of plaques and that perivascular

If you do intravenous and you'd see a Max and C. Max and then somebody goes down.

From our program, what we are positioning purex 12, whose true deliver subcutaneously.

So we just saw the Katanga and delivery you will reduce debt Cmos X.

But and maintained the AUC over the course of one month, so and you potentially could have even better efficacy which is underlying.

And by the AUC.

But potentially the same or even lower argued and ultra antibodies.

But what we do believe is that if you don't see are you are you are not seeing clearance of the meaningful Oh pathogenic forms of EBITDA and the brain. So we are not surprised that simple.

The net and map and I couldn't imagine then to 401 all show our year and we are also not surprised that the antibodies that did not show efficacy did not show how are you.

And again, because clearance of blocks and the pascua clearance process is an important component.

Gene G. Kinney: Yeah, and so when we think about the blood-brain barrier technologies, and you know, we've looked at many of these very closely, you know, we, you know, I think what's key is what Wagner is just talking about, you know, this issue of C-max versus AUC. And what you need to be very careful of, of course, is that you're not increasing in a very transient way concentrations in the brain. But that, you know, at the end of the day, that compromises total exposure.

Yeah, and so when we think about the blood brain barrier technologies and you know we've looked at many of these very closely you know.

You know I think what's key is what Wagner and it's just talking about this issue of C. Max versus AUC and what you need to be very careful of of course is that youre not increasing in a very transient way concentrations and the brain, but debt at the end of the day that compromises the total exposure. So so one.

Gene G. Kinney: So, one of the techniques that we subscribe to, and I think, you know, is built into PRx12, if you will, is this idea of interacting more specifically with aggregated forms of the protein, which would be more exclusively found in the brain, and thereby, you know, providing the antibodies over time with better access to that compartment. So, we think that that's an appropriate approach. It's the approach that we've taken with prastinezumab as well. And so we think, you know, for some of these types of diseases, particularly where pathology is a little bit more focused in the central compartment, that these types of approaches make sense.

Of the one of the techniques.

That we subscribe to and I think you know is is built into peer X 12. If you will is this idea of interacting more specifically with aggregated forms of the protein which would be more exclusively found in the brain and thereby providing the antibodies.

Over time with better access to that compartment.

So we think that that's an appropriate approach is the approach that we've taken with perhaps it doesn't map as well and and so we think you know for these some of these types of diseases, particularly where technology is a little bit more focused in the central compartment that these types of approaches makes sense.

Gene G. Kinney: Thank you. And our next question comes from the line of Bert Heslett with VTIG. Your line is open. Please go ahead.

Thank you and our next question comes from the line of part Hazlett with.

<unk>. Your line is open. Please go ahead.

Bert Heslett: Thank you. Thank you for taking the question. Great discussion this morning. I just have a couple of granular questions on the TAL program with regard to

Thank you and thank you for taking the question a great discussion. This morning, I just have a couple of granular ones on the Tau program with regard to Bristol.

Bert Heslett: Bristol. Just with regard to the ADPD

Bert Heslett: Data. What are the expectations for data for the upcoming program?

Well with regard to the ADP.

And ADP D data what are your expectations for data for the upcoming program.

Bert Heslett: and Then I have a couple of follow-ons.

And then I have a couple of follow ons for the.

Bert Heslett: For the

Bert Heslett: for the Bristol collaboration more generally. Yeah, so Wagner, maybe you could address some of the types of preclinical data that would be expected to be discussed at ADPD.

And the Bristol collaboration more generally.

Yes, so Wagner and maybe you can address.

Some of the types of preclinical data that would be expected to be discussed at ADT.

Wagner M. Zago: Yeah, we'll be very consistent with what we did in the past with all the programs that we have in the pipeline. So we like to publish first; we like to show our data out there and deliver it timely as well. So what you're going to see in ADPG is the first round of preclinical data that really guided us to target the MTDR portion of Tau and some in vitro data suggesting that that is the most impactful portion of Tau that can block the binding to neurons and also neurotoxic effects downstream of that binding to neurons as well.

Yes, it will be very consistent with what we did and the first with the other programs that we have and the pipeline. So we like to publish first and we'd like to sure they're out there and.

And and delivered.

Timely as well, so what youre going to see and.

And then D. P. D is our the first round of preclinical data that really guide to those two targets for them to be our portion of <unk>.

And also and some in vitro.

Data, suggesting that that is the most impactful portion of style and that can block the binding to and neurons and also neurotoxic effects.

Gulfstream should the binding Geneva, and so so so it is.

Wagner M. Zago: So it's the first round. We're going to continue releasing data as we move forward, but this is the first time that we are putting those data, as well as the superiority of the clinical candidate versus other antibodies, even within a pool of antibodies that targets the MTDR region, the superiority of PRx5 versus others.

Is the first round, we were going to continue releasing data as we move forward.

For the first time, but we are putting those there as well.

Out there and also certainly the superiority of the clinical candidate versus autoantibodies and even we're seeing.

A pool a bunch of bodies the targets that you are a region.

Superiority of their X five versus others.

Tran B. Nguyen: That's helpful to frame it. Thank you. And then just because these collaborations are so material, could you remind us of the deliverables to gain the $80 million and then the $55 million? And as you talk about the collaborative effort, are the people, are the principals that were at Celgene still involved in these discussions at Bristol-Myers? I think some are, but a little bit more color on that aspect of it would be helpful. Thank you. Yeah, so maybe, Tran, you could address just the structure of the collaboration milestones and then maybe also just a comment on how we've dealt with that in our forecast.

That's helpful to frame it. Thank you and then just because these collaborations are so material could you remind us of the deliverables to gain the $80 million and then the $55 million and as you talk about.

The.

The collaborative effort.

Other people other principles that were at Celgene.

Involved in these discussions at Bristol Myers, I think some more but a little bit more color on that aspect of it would be helpful. Thank you.

Yeah, So maybe try and you could you could address just the structure of the collaboration milestones and then.

And then maybe also just a comment on how we've dealt with that and our and our forecast.

Tran B. Nguyen: Yeah, I mean, more importantly to what you're saying Bert is that the delivery of the IND, when we file that, we deliver it to them too. There are some other documents that we send to them, but in a timely manner, and they have a certain time period after that to make their decision on their exercise of their US rights, and so we believe we are on the path to deliver all of those necessary documents for them to make their decision.

Yeah, I mean, more importantly to what what you are saying Bert is that the delivery of the eye and D. When we file that we deliver it to them too there are some other documents that we send to them, but and of <unk>.

Timely manner and they have a certain time period after that to make their decision.

And they're exercising of their U S rights and so we believe we are on path to deliver all of those necessary documents for them to make their decision.

Tran B. Nguyen: In terms of your question around you know the the players involved as you know Bristol had a CNS you know group back in the day and they don't anymore in a sense in terms of Bristol proper but when they acquired Celgene that CNS team came from Celgene and so the team that did the deal with us at Celgene are for the most part there at Bristol and key relationships still exist that Gene has and that Wagner has up and down from a joint steering committee perspective so we're you know we still have daily to weekly conversations with that team and you know we've been planning with that team in terms of our ability to be able to say we're on track to deliver the IND both submission to regulatory authorities

In terms of your question around.

The players involved as you know Bristol.

How to CNS.

The group back in the day, and they don't anymore and a sense in terms of Bristol proper, but when they acquired Celgene that CNS team came from Celgene and so there the team that did the deal with us at Celgene are for the most part there and at Bristol and key relationships still.

<unk> that.

Gene has and that Wagner has up and down from a joint steering Committee perspective. So we're we still have daily to weekly conversations with that team and we've been planning with that team in terms of our ability to build and say we are on track to deliver the indie both submission to regulatory authorities.

And also delivery too to that team to make their decision.

Radhika Tripuraneni: And Radhika, maybe you would want to comment on this as well, given that you're driving this towards the clinic.

And Roddick and maybe you would want to comment on this as well given that you're you're driving that towards the clinic.

Radhika Tripuraneni: Yeah, no, of course. I think it's been an exceptional relationship that we've had with, you know, in the beginning with Celgene and now with Bristol. So we're really thrilled to continue that collaboration, not just from the business dynamics, but of course, the scientific aspects are heavily involved in every aspect of our, you know, X5 program and have been engaged at all levels, both the formal governance meetings, and honestly, there are also, over the last couple of years, we've built a very close personal relationship with a number of individuals.

Yeah, No of course, I think it's been a it's and exceptional relationship that we've had with you now.

And the beginning with Celgene and now with Bristol. So we're really thrilled to continue that collaboration not just from the business dynamics, but of course, the scientific aspects are heavily involved in every aspect of our.

Five program and have been and.

Engaged and at all levels, both the formal governance meetings and and honestly. There's also over the last couple of years right with Delta very close personal relationship with the number of individuals. So we have a number of informal conversations as well and in the interim so they're very well versed and the progress and opportunities as we think about getting ready for that.

Radhika Tripuraneni: So we have had a number of informal conversations as well in the interim, so they're very well versed in the progress and opportunities as we think about getting ready for the IND and launching our first human study. It's been a great relationship.

And and launching our first in human study that's been a great relationship.

Tran B. Nguyen: Thanks. Look forward to The Catalyst. Appreciate it. Thank you. And our next question comes from Canon McKay with RBC Capital Markets. Your line is open. Please go ahead. Hi, thanks for taking the question here. A question on the development of Birtanomab and again, how are you thinking about ALMY doses in that market moving forward? Obviously, in male stage four.

Thanks look forward to the catalyst I appreciate it.

Thanks, Bert Thank you and our net.

Our next question comes from the line of Kennan Mackay with RBC capital markets. Your line is open. Please go ahead.

Hi, Thanks for taking the question here.

And the timing out there.

The element and again.

How are you thinking about al amyloidosis, and that market and moving.

Forward obviously in.

Canon McKay: for Patients with incredible unmet medical needs.

Stage for Covid.

And incredible unmet medical need, but just wondering as you're thinking about the future whether you think dark lots will be playing a part in that.

Canon McKay: As you're thinking about the future, whether you think Darzilek's

And the treatment of those specific patients or weather.

Canon McKay: Specific Patients, or whether really thinking about the future beyond BirtanmaMath, that is, whether there's anything else in development that might offer any benefit to those patients. Thank you.

Really just thinking about the future beyond the time and that that is whether there's anything else and development that might offer.

And any benefit to those patients. Thank you.

Gene G. Kinney: Yeah, great questions, Kenney.

Yeah, great questions getting maybe Radhika do you want to start with with us.

Radhika Tripuraneni: Maybe Radhika, do you want to?

Radhika Tripuraneni: with with those.

Radhika Tripuraneni: Yeah, no, I think, thanks for the question. It's great to see, you know, as a clinician, any therapy that's created and ultimately approved for patients regardless of, you know, competition, per se, by any means. But I think when you look at the DARLEX data in closer detail, you know, I think it will still be used for hematological response, but there it clearly has not shown any survival benefits that we think are meaningful.

Yeah, No I think and thanks for the question, it's great to see you know as a clinician any therapy, that's created and and ultimately improved.

For patients regardless of of.

Competition per se by any means but I think when you look at the Darla X data and and gluten closer detail.

You know I think it will still be used for Hematological response, but there clearly has not shown and survival benefit that we think is meaningful. So obviously can clogs correspond to the component of the ultimate management and progress of these patients but at the end of the day you want to actually maintain survival in these patients. So I think the role for part time and that is clear I think the APA.

Radhika Tripuraneni: So, obviously, hematological response is a component of the ultimate management and progress of these patients. But at the end of the day, you want to actually maintain survival in these patients. So, you know, I think the role for Birtamimab is clear. I think the opportunity is very clear as we think about the patient population.

The community is very clear as we think about the patient population.

Tran B. Nguyen: Maybe I'll, maybe Radhika, I'll add a little bit there. I mean, I think, as we have developed in this space, as you, as you see, Ken, and you know, we have a lot of experience in it, and we've learned a lot in terms of our own data and, of course, Dara and others' data. And I think the role that our molecule plays in terms of protaminab is that we are starting to really learn that the advanced patients, especially these Mayo Stage 4 patients, they need an antibody that depletes the toxic forms out of tissue, especially the heart.

Maybe I'll, maybe radhika all of that a little bit there I mean, I think I think as we developed in this space as you as you see Ken and you know we have a lot of experience and it and we've learned a lot in terms of our own data and of course, Dara and other others data and I think the role that our molecule plays in terms of <unk> is that we were starting to <unk>.

Really learned that the advanced patients, especially these may have stage four patients they need and antibody that that depletes the toxic forms out of tissue, especially the heart and so when you look at the great Dara data from the six months they've got great Hematologic response six months, they've got great, Oregon response, but again at six months.

Tran B. Nguyen: And so when you look at the great Dara data from six months, they've got a great hematologic response. And for six months, they've got a great organ response. But again, at six months, it didn't translate into better survival. Matter of fact, they had 25 deaths on the Dara arm plus Cyborg-D versus 20 deaths on the Cyborg-D arm at six months. So again, those patients at high risk for early mortality need anti-amyloid immunotherapy like protaminab.

And it didn't translate into better survival matter of fact, they had 25 deaths on the Dara arm plus <unk> versus 'twenty des on the Sideboard D arm at six months. So again those patients at high risk for early mortality, they need and anti amyloid immunotherapy like <unk> and that's what.

Tran B. Nguyen: And that's what our data was showing, that if you look at our Kaplan-Meier curves, you know, they're, the median OS for the control arm was about eight months. And so, and you saw, again, a 59% relative risk reduction in all-cause mortality that was significant in Mayo Stage 4 patients.

Our data was showing out and that if you look at our Kaplan Meier curves.

And there the median OS for the control arm was it was about eight months and so and you saw it get again, a 59% relative risk reduction and all cause mortality that was significant in stage four patients.

Gene G. Kinney: And just a reminder, in that control arm, that was with standard of care, you know, addressing the hematologic burden. So the 59% number that Tran just spoke of was on top of standard of care. So we think, you know, obviously that's important.

And just a reminder, on that control arm that was with standard of care you know addressing the hematologic burden and so so the the the 59% number that try and just spoke of.

<unk> was on top of standard of care.

So we think you know obviously that's important.

Tazeen Ahmad: Thank you. And our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is open. Please go ahead. Hi, guys. Good morning, and thanks for taking my question. As all of our companies have been reporting, we've been getting guidance for both sales as well as trial enrollment, with the caveat that people think that COVID could have an impact, and the rate of vaccinations might have an impact.

Thank you and our next question comes from the line of causing Amit with Bank of America. Your line is open. Please go ahead.

Hi, guys. Good morning, and thanks for taking my question.

And as all of our companies have been reporting we've been getting guidance for both sales as well as trial enrollment and with the caveat that people think that COVID-19 could have an impact.

And the rate of vaccinations might have an impact but as it relates to your particular study with al amyloidosis, given that it is a serious patient population and how are you thinking about any impacts from the pandemic at all and how important will it be the rate of vaccination to your internal.

Tazeen Ahmad: But as it relates to your particular study with AL amyloidosis, given that it is a serious patient population, how are you thinking about any impact from the pandemic at all, and how important will be the rate of vaccination to your internal view on rates of enrollment?

And if you on rate of enrollment and the study. Thank you.

Gene G. Kinney: Yeah, so thanks, Tazeen, for the question. I'll ask Radhika to speak about it, but maybe just a quick comment, which is that when we had our webcast on Bertamomab, we were fortunate to have Dr. Mori Gertz from the Mayo Clinic on the phone with us. Dr. Gertz, of course, treats patients with ALM leidosis, and he was asked a similar question. I think, you know, just to reiterate what he said, there were really two mitigating factors there.

Yeah. So thanks for the question and I'll ask right it gets bigger and but maybe just a quick the.

A quick comment which is that when we had our webcast on on for Tim and Matt.

We were fortunate to have Dr. Mauri Gertz from Mayo clinic on the phone with US Dr. Gertz of course treats patients with al Amyloidosis and and he was asked the similar question I think just to reiterate what he said was there were really two mitigating factors. There. The first is that patients with al amyloidosis, particularly may have stage four patients because.

Gene G. Kinney: The first is that patients with ALM leidosis, particularly Mayo Stage 4 patients, are at such extreme risk of early mortality that it is not considered optional. It's considered a medical emergency that those patients be seen, diagnosed, and treated as rapidly as possible. So the importance of those patients coming into study sites, I think, you know, really can't go understated. And then, of course, the second piece that I think he talked about a little bit was just the idea that those patients, because of that very fact, would be expected to be prioritized for COVID vaccination. So we think both of those things are mitigating factors. But maybe, Radhika, do you want to add anything?

They are at such extreme risk of early mortality that it is not considered optional it's considered a medical emergency that those patients be seen diagnosed and treated as rapidly as possible.

And so the the importance of those patients coming into the study sites.

And I think you really can't go understated and then of course, the second piece that I think he talked about a little bit was just the idea that those patients because of that very fact would be expected to be prioritized for COVID-19 vaccination. So we think we think both of those things are mitigating factors that maybe radhika do you want to do you want to add.

Radhika Tripuraneni: Yeah, no, of course. Thanks, Gene. Thanks for the question.

Yeah, No of course, thanks, Jay and thanks for the question I think it's.

Radhika Tripuraneni: I think, you know, as Gene noted and as Dr. Maury Girtz noted, it's very much true. These are incredibly ill patients who ultimately kind of come to the front of the line with regards to seeking and ultimately needing to go into these clinics or centers of excellence for care. So it's not, by any means, that it's a slow disease that you simply wait and watch. But the reality, too, is when you think about COVID and the general health care system, unfortunately, you know, this is not the beginning of the pandemic, from a public health perspective.

As gene noted and as Dr. Martin Gertz noted, it's very much true. These are incredibly ill patients, who ultimately kind of come to the punch. The line with regards to seeking and ultimately needing to go into these clinics or centers of excellence for current so it's not by any means that it's it's a it's a flow disease that you complete your wait and watch but the reality is when you think about.

With Covid and the general Health care system. Unfortunately, you know this is not the beginning of the current that Mike.

From a public health dynamics, but for the sake of these patients that's actually quite helpful. Because a lot of these institutions, particularly the centers of excellence have instituted protocols.

Radhika Tripuraneni: But for the sake of these patients, it's actually quite helpful because a lot of these institutions, particularly the centers of excellence, have instituted protocols now after nine, eight months, if not even a year, you know, and in certain cases around the world, more than a year of learning how to manage this condition and really have optimized the protocols to ensure the safety not only of the patients but also of the caregivers that accompany them along with the clinical staff that So the reality here is we're really talking about a holistic health care system that I think is going to be best suited to optimize care for these critically ill patients.

No now after nine eight months, if not even a year and and <unk>.

Certain cases around the world you know more than a year.

Learning how to manage this condition and really have optimize our protocols to ensure the safety not only have the patients but also of the caregivers that accompany them along with the.

And the clinical staff that obviously is responsible to provide that care. So the reality here is we're really talking about a holistic health care system that I think is going to be best suited to optimize the care for these critically ill patients and then the other dynamic that we're trying to and still within our study is creating as much flexibility to make it as easy.

E D for these patients I mean, obviously, it's already a stressful time being die.

Radhika Tripuraneni: But the dynamic, you know, I think between the protocol benefits that we've implemented along with the key centers of excellence and the experience of those centers gives us a fair amount of comfort that we'll be able to move forward with this study easily. Thank you, and I'm not having any further questions at this time, and I would like to turn the conference back over to Gene Kinney for any further remarks.

And diagnosed with al amyloidosis, and trying to comprehend all the information that comes with that but the dynamic and you know I think between the protocol benefits that we've implemented along with the key centers of excellence and experience of those centers I think really gives us a fair amount of comfort that we'll be able to move forward with this study easily.

Okay.

Thank you and I'm showing no further questions at this time and I would like to turn the conference back over to gene Kinney for any further remarks.

Gene G. Kinney: Great. Thank you, Michelle. And thank you all for joining us. We appreciate your interest in Prothena, and over the coming months, we look forward to sharing further updates on our programs.

Great. Thank you Michelle and thank you all for joining US we appreciate your interest and Christina and over the coming months, we look forward to sharing further updates on our programs. Thank you.

Unknown Executive: Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone have a great day.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect everyone have a great day.

[music].

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Unknown Executive: BF-WATCH TV 2021