Prothena Corporation PLC

NASDAQ:PRTA

Earnings Call Transcript 2020-Q4

[Operator]

Ladies and gentlemen, thank you for standing by and welcome to the Prothena and welcome to the Prothena Fourth Quarter and Full Year 2020 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions]

I would now like to hand the conference over to one of your speakers today Ellen Rose, Head of Communications. Please, go-ahead.

[Ellen Rose, Head of Communications]

Thank you, Michelle. And 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 8-K 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. 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 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. 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 statements. For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today, as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements.

And with that, I'd like to turn the call over to Gene.

[Gene Kinney, President, Chief Executive Officer & Director]

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 end of the year with a strong cash position. 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 III AFFIRM AL Study of Birtamimab in Mayo Stage IV 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 agreement possible and we expect to initiate the AFFIRM-AL study by mid-2021. We also announced results from our Phase 1 study of PRX004 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 Alzheimers Disease portfolio. PRX005 or anti-tau antibody being developed under our Global Neuroscience collaboration with Bristol-Myers Squibb and PRX012 our proprietary next-generation subcutaneous anti-beta antibody.

We continue to expect that the Biogen molecule aducanumab will be approved later this year and we are developing PRX012 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 2 PASADENA study of prasinezumab in patients with early Parkinson's disease.

Prasinezumab specifically targets the seed 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. Based on these results, we announced that with our partners at Roche, we are advancing prasinezumab into a late-stage Phase to be study with further details expected in the second quarter.

As someone who has devoted to 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. I'd like to start by highlighting what differentiates Prothena's proven approach our 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 in 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 caused disease. We can simplify this process into the saying epitope matters. And it certainly starts with selecting the right epitopes to target on 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 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. This unbiased and empirical methodology is highly customized for each target. In some cases we may target a cryptic epitope. In others, we made select antibodies with hyper activity, and yet in other cases we may select a neoepitope. This customized approach, depends on the unique characteristics of each target and underlying disease pathology. After a thorough evaluation of the target with advanced discovery candidates 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 result in meaningful clinical benefit for patients. And we've now achieved this across multiple programs in our pipeline. 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 test the biological hypothesis in 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. So, this slide, I want to further illustrate the concept of epitope matters, and how targeting a protein a 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 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. 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 disease, our experience in this space dates back to the development of both AN-1792 and prasinezumab. 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 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 aducanumab program, but also from recent clinical studies evaluating Eli Lilly's bamlanivimab demonstrate the targeting this region consistently results and clinical benefit, targeting other regions of the protein have not shown similar clinical benefit.

It is our confidence in this approach that led us to develop PRX012, we are advancing this molecule is the next-generation internally directed anti-beta antibody for subcutaneous administration in order to improve access to this class of potentially disease modifying treatment for patients with Alzheimer's disease. This concept has been further illustrated recently in Parkinson's disease, where prasinezumab, our anti alpha-synuclein antibody in development with Roche is the first potentially disease modifying therapeutic demonstrate signals of efficacy in the Phase 2 Pasadena Study on multiple prespecified secondary and exploratory clinical endpoints including measures of motor function in patients with early Parkinson's disease.

Prasinezumab target the C terminal of alpha-synuclein. In contrast, a different anti alpha-synuclein antibody Biogen's cinpanemab, 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 was consistent with our own Preclinical experience, which found that targeting the N-terminus with suboptimal. We adopted a different approach for the development of Birtamimab in PRX004, both of which target a cryptic epitope on their respective proteins.

With Birtamimab this led to findings of improved survival in a mouth efficacy model, which subsequently translated to an observed significant survival benefit in Mayo Stage IV Patients with AL amyloidosis in our Phase III VITAL study. PRX004, our antibody that we've 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 think the 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 is demonstrated robust and balanced immune responses to both tau and Abeta in preclinical study. And importantly these immune responses were targeted to the key epitopes that we have identified is 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 confirmations of dysregulated forms. This inherent complexity suggests that our approach is one that cannot be easily replicated.

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

Our rare peripheral amyloid portfolio include birtamimab for AL amyloidosis and PRX004 for ATTR amyloidosis. 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 Birtamimab and PRX004 directly target and clear the toxic amyloid that deposits in the heart and other vital organs.

Earlier this month, we announced our plan to initiate a confirmatory Phase III AFFIRM AL Study of Birtamimab in AL amyloidosis. AFFIRM AL is being conducted under SPA Agreement with the 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 IV patients. We were able to reach agreement with the FDA on this part because of the significant survival benefit observed in our previous VITAL study, where we demonstrated a 59% relative risk reduction on all-cause mortality in Mayo Stage IV patients over nine months.

In December, we reported results from our Phase 1 study of PRX004 in ATTR amyloidosis. In this study after only nine months of treatment with PRX004 ineligible patients we observe less progression on neuropathy than expected, and in several patients, we observed improvement. We also observed improvement on global longitudinal stream, a key measure of cardiac systolic function in all eligible patients.

Turning to the neurodegenerative disease programs in our Alzheimers disease portfolio, we believe that interventions that target both tau and Abeta has 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, our anti-tau antibody PRX005 and our anti-Abeta antibody PRX012. We look forward to sharing preclinical data on PRX005 at an oral presentation at ADPD in March. We've tested a large number of antibodies to epitopes along tau protein and found that those the target the Microtubule binding region more effectively block the binding of tau neuron and prevent downstream neuro toxic effects. Understanding this biology increases our confidence in selecting and evaluating PRX005 as a clinical candidate. And we look forward to sharing our preclinical data at ADPD. Last year at CTAD, we presented data on PRX012, our next generation high potency anti-Abeta antibody.

PRX012 has a higher binding strength to amyloid than aducanumab with as much as an 11-fold greater affinity and also recognizes Abeta Pathology to a greater extent demonstrating more extensive plaque area binding at lower antibody concentrations. We are developing PRX012 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 2 pasadena study of prasinezumab in patients with early Parkinson's disease that we announced last September.

In Parkinson's as existing treatments are symptomatic and only address a subset of symptoms. There are currently no treatments available that targets the underlying cause of the disease to slow its progression. Prasinezumab 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 prasinezumab resulted in 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 Alzheimers disease. For aducanumab, we demonstrated reduced cognitive decline of approximately 22% over 18 months. In Pasadena, we also observed improvements on imaging biomarkers and signals of efficacy consistent with disease modification across multiple prespecified secondary endpoints.

Our programs that I've just described address diseases, where there are no proved disease-modifying treatments. Each of these programs have 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 Birtamimab and PRX004 in targeted patient populations at high risk for early mortality with a particularly urgent unmet medical need for improved survival.

Our energy generation 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 in impact of the pending health care crisis in 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. This year we expect three programs to initiate late-stage clinical studies, Birtamimab and AL amyloidosis, Prasinezumab in Parkinson's disease, and PRX004 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. 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 discussion of our financial performance and our 2021 guidance. Tran?

[Tran 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 million to $85 million. Net loss was $111 million compared to our guidance of $101 million 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 million to $304 million. Also, we continue to have no debt. 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 million to $74 million, which includes an expected $60 million milestone payment from Roche upon first patient dosed in the previously announced late-stage Phase II-b study of prasinezumab. We expect to end the year with approximately $235 million in cash, which represents the midpoint of the range. 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 of non-cash share-based compensation expense.

With that, I will turn the call back over to Gene to summarize our upcoming milestones.

[Gene Kinney, President, Chief Executive Officer & Director]

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.

And also I'd like to thank the patients, their families, clinicians, and study site staff who participate in our studies. Without their support, we could not elucidate the potential value of the new medicines we are developing. 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 multiple R&D milestones over the next 12 to 18 months. Our AFFIRM AL study for Birtamimab 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 IIb study of prasinezumab in patients with early Parkinson's disease in the second quarter of this year. Prothena will earn a $60 million clinical milestone payment upon first patient dosed in this study. At the upcoming ADPD conference, new prespecified exploratory subgroup analysis from Part 1 of the Phase 2 pasadena study of prasinezumab 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. For PRX004, we expect to initiate the Phase II-III study and 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 Alzheimers disease programs has also advanced. Building on our foundational science and the discovery and development of anti-Abeta antibodies and vaccines, we continue to be highly active in this space with four programs in Alzheimers disease including antibody vaccine and small molecule approaches.

One of these programs PRX005 is under our Global Neuroscience collaboration with Bristol-Myers Squibb. We expect to file an IND for PRX005 in 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 AD, PD in March.

And finally, we expect to file an IND in the first quarter of 2022 for our anti-Abeta antibody PRX012. So, we are 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?

[Operator]

[Operator Instructions] Our first question comes from the line of Jay Olson with Oppenheimer. Your line is open. Please, go-ahead.

[Jay Olson, Oppenheimer]

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 prasinezumab and cinpanemab. 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 Kinney, President, Chief Executive Officer & Director]

Yes, thanks for the questions, Jay. So, very important question. So, obviously, what we're highlighting in today's discussion is the clearly where you target these proteins in parts, very different biological outcomes. And we spend a lot of time in the preclinical space really exploring these proteins to understand the optimal way of targeting not only where to target them. What the appropriate epitope is, where in the sequence but also are there post-translation 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 in part an approach where we bias our molecule 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.

In the case of prasinezumab that was done by using a technique, where we really look for an antibody that had high preference for the aggregated forms of the protein over the non-aggregated forms of the protein and using very specific genetic and quantitative analysis, have been able to show that that selectivity or preferences over 400-fold. And so we think that's a key component as well.

And so 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 only antibodies that target at the N-terminus and maybe Wagner I can ask you to speak a little bit about just our experience in that space.

[Wagner Zago, Chief Scientific Officer]

It's a little challenging to make a direct comparison between cinpanemab and prasinezumab other than the epitope. But simply because the data around cinpanemab sparks [ph], it is published later, but it's really hard for us to make those really comparison. But, we can say is that we spent many years screening the entire of synuclein protein and what we found in very early in the program is that there was a consistency for antibodies that target the C terminal portion of alpha-synuclein, a runway of prasinezumab find [ph] there is a consistency in terms of efficacy for those antibodies. And the other antibodies that target the N terminal portion of alpha-synuclein did not show that consistency. We consider a suboptimal in fact efficacy when we did see efficacy.

So, we focus on the C terminal portion as Gene indicated one step is to define the right epitope. But the qualities of the antibody, the targeted is also very important, and binding with the highest buying strength possible that region and as selective or specific as possible to the pathogenic forms and sparing what we considered normal biological forms. It was part of the selection of prasinezumab.

So, prasinezumab has a picomolar, we are talking about study picomolar affinities who aggregated alpha-synuclein. That's very important when you consider the blood-brain barrier phenytoins [ph] of antibodies. And we selected our prasinezumab based on that Affinity, the epitope we confirmed in multiple and more models. The efficacy, but also that dose response of antibody and interesting enough in the clinic with prasinezumab, we confirmed that the occupancy that we expected for the target in the CNS translated in the two doses that we selected, a priority has been such a rating of the target showing equivalent efficacy in our Phase II. So, we are very happy, it was a very successful transition of translation of our Preclinical very rigorous preclinical exploration into a clinical evidence of tendering the disease progression.

[Jay Olson, Oppenheimer]

Thank you. That's super helpful. And then as far and since you have two super high quality partnerships and now a growing number of wholly-owned assets in the clinic or about to enter the clinic, would you consider partnering Birtamimab or any of their other wholly-owned assets?

[Gene Kinney, President, Chief Executive Officer & Director]

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

[Tran Nguyen]

No, I think based on our past experience, we do believe that there is interest fully from strategic on Birtamimab given its concentrated hematology call point and to what Gene just said given that based on our market research, we are planning to commercialize Birtamimab. Basically, as we stated before, it shows that approximately 75% of the Mayo Stage IV 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 given the known diagnosed prevalence in regions such as Japan and China, we may explore some regional partnerships.

[Jay Olson, Oppenheimer]

Great, thanks for taking the questions.

[Operator]

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

[Michael Yee, Jefferies]

Hi guys, good morning. Congrats 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 on the Bristol Celgene collaboration. You talked about how you do expect to potential milestone there. Maybe just talk about how that dialog and ongoing conversations have been with that on that program, the progress and how confident you are that that Milestone will come? Maybe just talk little bit about that target program and conversation.

And then the second question is obviously there's a lot more industry interest in Abeta, 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 donanemab rather than aducanumab. And maybe just talk about your epitope just a little bit more and the comparison between those programs? Thanks.

[Gene Kinney, President, Chief Executive Officer & Director]

Yes. So, great questions Mike. So, first let's start with, I wanted to go backwards order here. So let's start with Abeta. So the PRX012 molecule does target the amino terminus of Abeta, our own research which Wagner has altered quite a bit of indicates that targeting that region gives you the optimal ability to interact with both the deposited forms that 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 want to hit both of those species in the way you hit both the species is by targeting the immuno terminus of the protein. As aducanumab, target Immuno terminus of the protein as well as does Birtamimab. Birtamimab sees specifically a post-translational modified a version of the immune terminus critically to power contaminated forms, but it is still targeting that same region. So, we think there's consistency here in terms of what we're seeing. Importantly elements of clinical design that one needs to look at as well and that is when you go to treating for drillable to mild patients and you specifically using endpoints as was the case with aducanumab using their endpoint CDR sum of boxes and also even with BAN2401 using AdCom's and their most recent donanemab study.

Those endpoint tend to be more sensitive and more geared towards Birtamimab 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 then what do you see what you tend to see is what was has been found now across those studies which is with aducanumab in the EMERGE study you saw 22% slowing a cognitive decline over the 18 month period. Something in that neighborhood with Birtamimab 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 there is good dialog with Bristol-Myers Squibb and Celgene. We enjoy the collaboration, its additive in terms of the value it brings to the program and obviously the milestone there is an option, which is their option. So, they will have to make that decision at the right time. But it is connected with the IND filing.

[Tran Nguyen]

I think that's something there. Gene, I mean, yes, our teams have been working together. There is a Governance Committee from the Joint Steering Committee. So, we in order to file an IND, you have to have a plan for phase one. And so we've been working with their team in that design because as you know, there is an ex-U.S Global right that they have at the end of Phase 1 to exercise that $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 1 design and ultimately the IND package. So as Gene just stated we'll 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.

[Michael Yee, Jefferies]

Got it. There is a joint steering and there's ongoing communication on that add some color and then Lilly's [ph] targeted specifically on epitope. So thank you for clarifying that. Thank you.

[Operator]

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

[Charles Duncan, Cantor Fitzgerald & Co.]

Good morning, Gene and Tran. I thank you for taking the question and I appreciate, I also appreciate all the platform information that you provided. I'll come back to that have a couple of questions on the platform. But first, before I do with regard to the near-term clinicals, I guess I'm wondering generally about kind of rate-limiting steps both for affirm as well as a Prasi Phase IIb.

I'm wondering if you could provide us a little bit more color on the operationalization for AFFIRM AL and when you would anticipate that? And then if you have further information on its size and then similarly with Prasi in Phase IIb. I'm wondering if you anticipate being able to provide periodic updates beyond just the initial dosing of the first patient?

[Gene Kinney, President, Chief Executive Officer & Director]

So, why don't we start with the AFFIRM AL and maybe Radhika, I can ask you to speak to kind of operationally what's happening on enroute to our opening of that study?

[Radhika Tripuraneni, Chief Development Officer]

Sure, Gene. Thanks for the question. It's a really exciting time for Prothena as we embark on getting the AFFIRM 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 where we're quite pleased to ultimately get this study up and running.

The standard activities as you would assume as we engage for our 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. The other dynamic to think about is we've got a long-standing relationship and when you consider the study itself and Birtamimab it's an agent in which there is a 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 regards to excitement as we get this study started.

[Gene Kinney, President, Chief Executive Officer & Director]

And I think, Charles. You also asked about the size of that study where it's two to one random. And we anticipate up enrolling up to a150 patients in total. And so as Radhika says we're excited to see that get started. On the Prasinezumab 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 IIb study, up and running.

We've talked about the idea that with that study and first patient dose that avails us of a $60 million clinical milestone in the partnership. And I think we do expect to AD, PD that there will be additional analysis of the Pasadena part one study. So, these based on pre-specified subgroups we further expect that at a future conference TVD 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 Prasinezumab.

[Charles Duncan, Cantor Fitzgerald & Co.]

Okay, that's helpful. Thank you, Gene, I do have a couple of questions and the platform, but just one more that I was thinking about with regard to AFFIRM. You mentioned the all-cause mortality in the p-value 0.1 is being unprecedented. And I guess when I think about that. It's almost 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 perspectives on that p-value?

[Gene Kinney, President, Chief Executive Officer & Director]

I think as we looked at our data from the vital study and noted what we considered certainly be a robust survival benefit Mayo Stage IV patients with a hazard ratio, you know that basically translates to a 59% relative risk reduction of all-cause mortality that's meaningful. And it shouldn't go on said that every one of those events is just really beyond quantification. I mean these are individuals, families, friends. And so 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 external statisticians in to the team to help challenges around that data, we look for ways to try and explain that data away and failing to do so we engaged not only with KLOs, 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 meeting and it was really aligned around understanding both the strength and relevance of the vital data and what would be required to move this forward from a registration perspective. So we were very happy that we came to in accord with the agency in the form of the special protocol assessment. Really that underlies what AFFIRM AL study is right. A study that, so if you want one randomization up to 150 patients enrolled and as you say with an all-cause mortality at a p-value significance of 0.10, which would enable registration path when combined with our other datasets.

[Tran Nguyen]

Maybe I'll just add one Gene, this is Tran. And 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 this out this amazing outcome. So we're very excited to be initiating AFFIRM AL later this year as Radhika has said mid ‘21. And we really do feel excited for the vital data where again you see significant survival benefit.

[Charles Duncan, Cantor Fitzgerald & Co.]

Good deal. We're looking forward to that start and believe that perhaps that set up may drive enrollments answer then our anticipated. So one platform question and that is on PRX004 12 and follow up kind of to Michael's questions regarding how the profile looks relative to aducanumab and Birtamimab. 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 any implications in terms of ARIA [ph]?

[Gene Kinney, President, Chief Executive Officer & Director]

Yes. So since Wagner is an author on a paper that basically described what ARIA [ph] is from the biological perspective, I'll let him answer this questions.

[Wagner Zago, Chief Scientific Officer]

So let me start by talking about the mechanism behind ARIA, that we think is behind. So two things, we think is contributing to these vascular observations. One is certainly the removal of Abeta from vascular itself. We think that our contributors, but also what we're seeing is during the process of black clearance from the parenchyma, not from the vasculature. During that process of antibodies, there is a mobilization of abeta from the plaques to perivascular spaces and that process of mobilization, which we believe is an important clearance mechanism in addition to the phagocytosis, that process can alter vascular permeability by changing the interaction of vascular elements with, for example, astrocytes. 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 point. And we think that that incidents of ARIA, more specifically the symptomatic ARIA, will very much depend on the Cmax, the maximum concentration of the antibody that's reached in the brain.

And that is normally a peak, if you do intravenous, you see a maximum Cmax and antibody goes down. From our program, what we are positioning PRX0012 is to deliver subcutaneously. So, with the subcutaneous delivery you will reduce that Cmax, but maintain the AUC over the course of one month. So, you potentially could have even better efficacy, which is underlying, which is driven by the AUC, but potentially the same or even lower ARIA than other antibodies. But, what we do believe is that if you don't see ARIA, you are not seeing clearance of the meaningful pathogenic forms of Abeta in the brain.

So, we are not surprised that donanemab and aducanumab and BAN2401 all show ARIA, and we are also not surprised that [indiscernible] that did not show efficacy, did not show ARIA. Again, because clearance of plaques and that perivascular clearance process is an important component.

[Gene Kinney, President, Chief Executive Officer & Director]

So when we think about the blood-brain barrier technologies and we've looked at many of these very closely, I think what key is what Wagner was just talking about, this issue of Cmax versus AUC and what you need to be very careful of, of course, is that you are not increasing in a very transient way concentration in the brain, but that at the end of the day that compromises the total exposure. So one of the techniques that we subscribe to and I think is built into PRX012, 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 to it, the approach that we've taken with Prasinezumab, as well. And so, we think 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.

[Operator]

And our next question comes from the line of Bert Hazlett with BTIG. Your line is open. Please go ahead.

[Robert Hazlett, BTIG]

Thank you. Thank you for taking the question. Great discussion this morning, I just have a couple of granular ones on the tau program with regard to Bristol. Just with regard to the AD/PD data, what are the expectations for the data for the upcoming program? And then I have a couple of follow-ons for the Bristol collaboration more generally.

[Gene Kinney, President, Chief Executive Officer & Director]

Yes, so Wagner, maybe you can address some of the types of preclinical data that would be expected to be discussed to the AD/PD?

[Wagner Zago, Chief Scientific Officer]

Yes, it will be very consistent with what we did in the past with the other 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 ADPD is the first round of preclinical data that really guided us to target the anti-TBR portion of tau, and some in-vitro data suggesting that is the most impactful portion of tau that can block [indiscernible] and also neurotoxic effects downstream to that as well. So is the first round, we are going to continue releasing data as we move forward, but for the first time that we are putting those there, as well, out there. And also, certainly the superiority of the clinical candidate versus other antibodies even within a pool of antibodies that targets the TBR evasion [ph], the superiority of PRX005 versus others.

[Robert Hazlett, BTIG]

That's helpful to frame it. Thank you. And then just because these collaborations are some 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 -- or the people of the principles that were at Celgene still 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.

[Gene Kinney, President, Chief Executive Officer & Director]

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.

[Tran Nguyen]

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 exercising of their US rights. And so, we believe we are on path to deliver all of those necessary documents for them to make their decision. In terms of your question around the players involved, as you know, Bristol had a CNS group back in the day and they don't anymore, in a sense, in terms of Bristol, 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 still have daily to weekly conversations with that team. And, we've been planning with that team in terms of our ability to build, say, we're on track to deliver the IND, both submission to regulatory authorities and also delivery to that team to make their decision.

[Gene Kinney, President, Chief Executive Officer & Director]

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

[Radhika Tripuraneni, Chief Development Officer]

I think it's been an exceptional relationship that we've had with 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. They’re heavily involved in every aspect of our X5 program and have been engaged in at all levels, both the formal and governance meetings. And honestly, there is also over the last couple of years, we've built very close personal relationships with a number of individuals. So, we have 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 in-human study. It's been a great relationship.

[Robert Hazlett, BTIG]

Thanks. Look forward to the catalyst. Appreciate it.

[Operator]

Our next question comes from the line of Kennen McKay of RBC Capital Markets. Your line is open. Please, go-ahead.

[Kennen MacKay]

Hi, thanks for taking the question here. A question on Birtamimab development and, again, how you're thinking about AL amyloidosis in that market moving forward? Obviously in Mayo Stage IV patients there’s incredible unmet medical need. But just wondering as you're thinking about the future, whether you think Darzalex will be playing a part in the treatment of those specific positions or whether really thinking about the future beyond Birtamimab, that is, whether there is anything else in development that might offer any benefit to those patients? Thank you.

[Gene Kinney, President, Chief Executive Officer & Director]

Great question, maybe Radhika do you want to start with this?

[Radhika Tripuraneni, Chief Development Officer]

Thanks for the question. It's great to see, as a clinician, any therapy that's created and ultimately approved for patients regardless of competition per-se by any means. But I think when you look at the Darzalex data and in closer detail, I think it will still be used for hematological response but there clearly have not shown in survival benefit that we think is meaningful. So obviously, hematological response of 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 Birtamimab is clear. I think the opportunity is very clear as we think about the patient population.

[Tran Nguyen]

Radhika, maybe I’ll add a little bit there. I think as we developed in this space, as you see, Ken, we have a lot of experience and we've learned a lot in terms of our own data and of course Dara [ph] data and other's data. And I think the role that our molecule plays in terms of birtamimab is that we're starting to really learn that the advanced patients especially these Mayo Stage IV Patients, they need an antibody that depletes the toxic forms out of tissue, especially the heart. And so, when you look at the Dara data from the six months, they've got great hematologic response, six months they got great organ response, but again at six months, it didn't translate into better survival. As a matter of fact, they had 25 deaths on the Dara arm plus CyBorD versus 20 deaths on the CyBorD arm at six months. So, again, those patients at high risk for early mortality they need an anti-amyloid immunotherapy like birtamimab and that's what our data was showing out. That if you look at our Kaplan-Meier curves, the Median OS for the control arm was about eight months. And you saw again, a 59% relative risk reduction in all-cause mortality. That was significant in Mayo Stage IV patients.

[Gene Kinney, President, Chief Executive Officer & Director]

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

[Operator]

Thank you. And our next question comes from the line of Tazeen Ahmad with Bank of America. Your line is open. Please, go ahead.

[Tazeen Ahmad, Bank of America]

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, 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 rate of enrollment in the study? Thank you.

[Gene Kinney, President, Chief Executive Officer & Director]

Yes. Thanks, Tazeen for the question. I'll ask is Radhika to speak on, but maybe just a quick comment, which is that when we had our webcast on birtamimab, we are fortunate to have Dr. Morie Gertz from Mayo Clinic on the phone with us. Dr. Gertz of course treats patients with AL amyloidosis and he was asked the similar question. I think just to reiterate what he said, there were really two mitigating factors there. The first is that patients with AL amyloidosis particularly, Mayo Stage IV patients because they are at such extreme risk of early mortality, that it is not considered optional, it's considered a medical emergency that those patients is seen diagnosed and treated as rapidly as possible. So, the importance of those patients coming into study sites, I think 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?

[Radhika Tripuraneni, Chief Development Officer]

Of course. Thanks, Gene. Thanks for the question. I think, as Gene noted and as Dr. Morie Gertz noted, it's very much, these are incredibly ill patients who ultimately kind of come to the punch 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 can play away and watch. But the reality, too, is when you think about COVID and then the general health care system, unfortunately, this is not the beginning of the pandemic from a public health dynamic. 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. Know now after nine or eight months, if not even a year, 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 obviously is responsible to provide that care. So the reality here is we're really talking about a holistic healthcare system that I think is going to be best suited to optimize the care for these critically ill patients. And then the other dynamics that we're trying to instill within our study is creating as much flexibility to make it as easy for these patients. Obviously, it's already a stressful time being diagnosed with AL amyloidosis and trying to comprehend all the information that comes with that. But the dynamic, 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 give us a fair amount of comfort that we'll be able to move forward with the study easily.

[Operator]

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 Kinney, President, Chief Executive Officer & Director]

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. Thank you.

[Operator]

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.