Prothena Corporation PLC (PRTA) 2017 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Prothena Fourth Quarter and Full Year 2017 Financial Results Conference Call. (Operator Instructions) As a reminder, this call may be recorded. I would now like to introduce your host for today's conference, Ms. Ellen Rose, Head of Communications. Ma'am, you may begin.

Thank you, Skyler. Good afternoon, everyone, and welcome to Prothena's investor conference call to review our fourth quarter and full year 2017 financial results and business progress as well as our 2018 financial guidance. Please review the press release we issued earlier today, which is available at our website at prothena.com and is also attached to our Form 8-K filed today with the SEC.

Speaking on today's call, we have Dr. Gene Kinney, our President and Chief Executive Officer, who will discuss our 2017 highlights as well as corporate and pipeline accomplishments; and Tran Nguyen, our Chief Financial Officer, who will review our financial results for the fourth quarter and full year 2017 and 2018 financial guidance. Gene will then provide an overview of upcoming milestones and open the call for Q&A.

Before we begin, I'd like to remind you that during the course of today's presentation, we will be making statements regarding Prothena's future expectations, plans and prospects that constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements are based on estimates, projections and assumptions that may prove not to be accurate, and actual results may differ materially from those anticipated due to known and unknown risks, uncertainties and other factors.

For a discussion of the risks associated with our forward-looking statements, please see our press release issued today as well as our most recent Form 10-Q filed with the SEC and also the Form 10-K we will soon be filing with the SEC. We disclaim any obligation to update our forward-looking statements.

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

Thank you, Ellen, and thank you all for joining us this afternoon. It's a pleasure to be here today to discuss our 2017 and recent accomplishments and the upcoming milestones we're looking forward to this year and beyond.

On today's call, I'll highlight the progress we've made on our clinical programs, talk briefly about our key accomplishments and then turn it over to Tran for review of our 2017 financial results and 2018 financial guidance.

Before we begin talking about the continued progress we've made across the company, I'd like to first acknowledge our talented and committed employees whose efforts drive our ability to steadily advance our programs. During 2017, we welcomed new team members into the company, who are working on everything from our earliest discovery efforts against novel targets to the growing part of the organization involved in planning for the potential registration and commercialization of NEOD001. It's an honor to work alongside these talented and committed folks every day.

We have ambitious goals, and while I'm the one who gets to talk with you about our accomplishments, none of what we do would be possible without the truly unwavering dedication of our team to apply high scientific rigor and best drug development practices toward developing innovative new therapies for patients.

With that, I'll turn to an overview of some of the key events we accomplished during 2017 and highlight our upcoming milestones in 2018 and beyond. As you know, we focus primarily in areas of science where we have deep domain expertise, protein misfolding, and are applying that expertise against targets in neuroscience and orphan disease categories.

In 2017, we continued to advance each of our clinical and discovery programs and continue to raise awareness of our novel antibodies through the presentation of scientific results. We ended 2017 with a balance sheet that enables continued development of both our clinical and discovery programs to key milestones as we seek to deliver differentiated therapies to patients through a growing commercial focus.

To put our progress in context, I'll first provide a high-level review of our pipeline programs and start with our most advanced program, NEOD001, a monoclonal antibody for the potential treatment of patients with AL amyloidosis. There are 2 broad categories of amyloid disease, those in the periphery and those in the central nervous system. AL amyloidosis is a rare peripheral amyloid disease, which is systemic, progressive and typically fatal due to organ dysfunction. While there are other types of systemic amyloidoses, including ATTR and ALECT2 amyloidosis, patients with AL amyloidosis represent the majority of the systemic amyloidoses. In AL amyloidosis, light chain proteins misfold, aggregate, circulate through the body and deposit as amyloid in vital organs. Most commonly in heart and kidney, but also in peripheral nerves and other organs. These circulating soluble aggregates and deposited amyloid can cause dysfunctions and ultimately organ failure. There are no proved treatments for AL amyloidosis. And for the vast majority of patients, current treatment is limited to the use of cytotoxic chemotherapeutic agents used in multiple myeloma. These agents aim to control the hematologic burden of the disease by targeting monoclonal plasma cells, which produce the light chains. These cytotoxic agents are often poorly tolerated and patients may become refractory to their effect and/or relapse.

In addition, none of these agents target the soluble aggregates and deposited amyloid that drives organ dysfunction and failure. For patients who undergo these plasma cell-directed chemotherapeutic treatments, a significant majority do not achieve adequate organ benefit even if they achieve hematologic response by decreasing production of light chains. This is important because it exemplifies the principle in amyloid disease that simply focusing on decreasing new protein production may be insufficient to provide patient benefit in many cases. In the context of AL amyloidosis, for example, it is clear that hematologic response in the absence of organ response is of limited value to this patient population. The nature of the disease means that patients do not get better without intervention and will experience progressive organ dysfunction that typically leads to death. For example, when AL amyloid builds up in the heart, it leads to a progressive restrictive cardiomyopathy with associated cardiac dysfunction. As such, there remains a significant unmet need for safe and well-tolerated therapy that can improve organ function and survival by directly neutralizing circulating soluble aggregates and clearing deposited amyloids from organs.

NEOD001 is an antibody being developed as a disease-modifying therapy for AL amyloidosis that specifically targets the amyloid that drives organ dysfunction and failure. As an immunotherapy, NEOD001's proposed mechanism of action is the neutralization of misfolded light chain in circulation and through immunotherapy-mediated clearance or phagocytosis of the amyloid deposited in organs. NEOD001 is the first immunotherapy directly targeting AL amyloidosis to receive fast-track designation from the U.S. Food and Drug Administration.

We presented final results from our 69-patient Phase I/II study at the American Society for Hematology Annual Conference in 2016, including favorable safety and tolerability as well as improvements across 3 organ systems. And we are currently running 2 pivotally designed studies of NEOD001 in patients with AL amyloidosis and cardiac dysfunction.

PRONTO, a Phase IIb study; and VITAL, a Phase III study. In 2017, we completed enrollment in both of these studies and, in fact, both of these studies were overenrolled. Our Phase IIb PRONTO study remains on track for top line results in the second quarter of this year. PRONTO is a global registration directed randomized double-blind placebo-controlled study. Our original target enrollment of 100 patients was exceeded and 129 patients were randomized in this study, which enrolled previously treated patients with a primary diagnosis of AL amyloidosis and ongoing cardiac dysfunction. These are individuals who have received one or more prior courses of plasma cell-directed therapy.

Despite the fact that their disease is stable from a hematologic perspective, they continued to have cardiac dysfunction. The patients in PRONTO received a 24-milligram per kilogram infusion every 28 days and were randomized on a one-to-one basis to receive either NEOD001 or placebo. The primary endpoint of the PRONTO study is cardiac best response over 12 months as defined by the consensus criteria that measure a change in NT-proBNP. The criteria were developed and are currently used in clinical practice by physicians who treat patients with AL amyloidosis.

Secondary endpoints include the physical component score of the quality of life measure short form 36 and the functional 6-minute walk test. NT-proBNP is a widely clinically validated cardiac biomarker that has been shown in numerous retrospective and prospective studies to predict survival in patients with AL amyloidosis following intervention. Demonstrating a significant effect on cardiac response, as measured by NT-proBNP, along with supporting secondary clinical outcomes, has the potential to expedite our development timeline and provide an opportunity to engage with European regulators.

In 2017, we sought to further elucidate the underlying biology that makes NT-proBNP such a clinically valuable biomarker in predicting survival in AL amyloidosis. Specifically, our research team generated new preclinical data that demonstrated a direct relationship between misfolded soluble light chain toxicity to cardiomyocytes and increased NT-proBNP production. These new findings were presented at the Heart Failure Society 21st Annual Meeting last year, and our research demonstrated that misfolded soluble light chain induces oxidative stress and leads to an increase in expression of the oxidative response marker, heme oxygenase 1, in cardiomyocytes.

The research further showed that NT-proBNP secretion is increased by misfolded soluble light chain via a mechanism dependent upon heme oxygenase 1 catalytic activity. This misfolded soluble light chain exhibited dose-dependent binding to cardiomyocytes suggesting that the observed effect is driven by the direct interaction between misfolded soluble light chains and cardiomyocytes.

Taken together, these results support the finding that misfolded soluble light chain induces cardiomyocyte toxicity and provides a direct biological link between the misfolded protein and NT-proBNP elevation in patients with AL amyloidosis.

Furthermore, these data indicates that the role of NT-proBNP in AL amyloidosis is differentiated and unique from other forms of heart failure and support the relationship that has been reported between lowering of NT-proBNP and improved survival in patients with AL amyloidosis.

We believe this is an exciting and important piece of the scientific story that will provide a valuable part of our total NEOD001 data package. As you know, the Phase IIb PRONTO study remains ongoing. And before I leave the topic, I want to provide you some background on our operational readiness around this key milestone.

Many of you on the call today have been following our story since we were a 30-person company. Today, we have more than 125 people on our team who have brought their expertise and knowledge to bear on our programs. Our team is well-prepared for the year ahead. Marty Koller, our former Chief Medical Officer, has returned in a consulting role and will work with Sarah Noonberg as she continues to support us during her transition and the rest of the medical team remains in place and focused as we prepare for PRONTO top line results.

In addition, throughout the past year, we hired key positions in functions across the organization, including safety, quality, pharmacovigilance, manufacturing, compliance and commercial. And as an organization, we have been focusing on critical activities, including preapproval inspection readiness, filing readiness, CMC supply planning, market access and commercial strategy. This team and these activities are keeping us well prepared and on track for potential regulatory submission and commercialization.

Turning now to the VITAL amyloidosis study. We also completed enrollment in this study during 2017. Our original target enrollment of 236 patients was exceeded and 260 patients were randomized in this Phase III global registration double-blind placebo-controlled study enrolling newly-diagnosed treatment naïve patients with AL amyloidosis and cardiac dysfunction.

The patients in VITAL receive a 24-milligram per kilogram infusion every 28 days and were randomized on a one-to-one basis to receive either standard of care therapy with or without NEOD001. The primary composite endpoint in this study is event-based with all-cause mortality or cardiac hospitalizations as qualifying events.

Secondary clinical endpoints include the SF-36 and 6-minute walk test. This study is designed to support full global regulatory registration. In November of 2017, we updated guidance that we expect to achieve the last event needed for the primary analysis in the VITAL study in the second half of 2019. At the time of our November update, the patients in the VITAL study had all been enrolled for 6 months and more than half had been enrolled for more than 12 months. Ultimately, longer-term mortality rates beyond 12 months will continue to inform our timing projections, and we will continue to evaluate blinded events as the study progresses. And we'll provide additional updates no later than the middle of this year.

Now keeping with the theme of peripheral amyloid disease, I'd like to next highlight our program for ATTR amyloidosis, PRX004. PRX004 is an investigational monoclonal antibody designed to specifically target and clear the misfolded forms of the TTR amyloid protein found in the disease known as transthyretin amyloidosis or ATTR amyloidosis. Similar to AL amyloidosis, ATTR amyloidosis is a rare progressive and often fatal disease characterized by deposition of aggregates of misfolded proteins or amyloid in organs such as the heart and/or peripheral nerves.

In ATTR amyloidosis, the precursor protein, transthyretin or TTR, is produced primarily in the liver. In its normal tetrameric form, TTR serves as a transporter for thyroxine and vitamin A and has also been implicated in neuroprotective functions.

ATTR amyloidosis can have a hereditary component and the disease most often manifests with cardiomyopathy and/or polyneuropathy. In the hereditary forms of this disease, the body makes a mutant form of the TTR protein. To date, more than 100 reported types of TTR mutations have been reported that promote amyloid fibril formation, which most commonly affect the heart and nervous system.

There's also wild type, a non-hereditary form of ATTR, which involves cardiomyopathy. PRX004 selectively binds to amyloid or diseased forms of the transthyretin protein. As demonstrated in preclinical data we published in 2016, PRX004 has unique biological activity that may lead to the prevention of deposition and enhancement of clearance of ATTR in patients with either wild type or hereditary ATTR amyloidosis. And because the epitope that is targeted by PRX004 is hidden while in tetrameric form and only exposed in the misfolded form of TTR, we see absolutely no reactivity in normal tissue.

In 2017, we continued to advance the program by producing clinical supplies for our Phase I study that we plan to initiate in patients with ATTR amyloidosis by the middle of this year. The Phase I study has been designed as an open label 3 plus 3 dose escalation study to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of PRX004.

Finally, I'd like to highlight an exciting aspect of our work in ATTR amyloidosis, which is the highly sensitive assay we have developed that detects and measures circulating forms of the misfolded TTR in patient plasma. We have tested this assay across multiple forms of the TTR mutation and have found that there is an increase in the amount of misfolded TTR in the plasma patients with hereditary ATTR.

Having the ability to demonstrate that in blood -- or having the ability to have demonstrated that in blood, those misfolded forms are present should allow us to quantify in our clinical studies how PRX004 impacts this toxic form of the misfolded protein.

Now moving from the periphery and into the CNS, I'll turn to PRX002, a monoclonal antibody for the potential treatment of Parkinson's disease and other synucleinopathies. PRX002, also known as RG7935, is the primary focus of our worldwide collaboration with Roche. Parkinson's is an neurodegenerative disease that affects an estimated 7 million to 10 million people worldwide, making it the second most common neuro generative disease after Alzheimer's. The disease is characterized by the neuromal accumulation of aggregated alpha-synuclein in the central and peripheral nervous systems that results in a wide spectrum of worsening progressive motor and nonmotor symptoms and are present throughout the disease. While the disease is most commonly known for motor symptoms classically associated with Parkinson's disease, nonmotor symptoms such as loss and sense of smell, sleep disturbances or gastrointestinal motility issues, may present many years earlier. Current treatments for Parkinson's disease are primarily directed at managing the early motor symptoms of the disease mainly through the use of levodopa and dopamine agonists. But these only address the subset of the symptoms typically related to motor impairment. Symptomatic therapies do not target the underlying cause of the disease. And as the disease progresses and dopaminergic neurons continue to be lost, these drugs lose effectiveness, often leading to debilitating side effects.

PRX002 is being developed as a potentially disease-modifying approach to slow the progressive neurodegenerative consequences of this disease. PRX002 targets alpha-synuclein, a protein that is widely understood to be integrally involved in the onset and progression of Parkinson's disease. Targeting alpha-synuclein has the potential to slow or reduce the neurodegeneration associated with alpha-synuclein misfolding and/or its cell-to-cell transmission.

Last year, we presented results from the Phase Ib double-blind, placebo-controlled multiple ascending dose study designed to assess the safety, tolerability, pharmacokinetics and immunogenicity of PRX002 in 80 patients with Parkinson's disease. The results were represented by Dr. Joseph Jankovic of the Baylor College of Medicine in a late breaking therapeutic strategy session at the 13th International Conference on Alzheimer's and Parkinson's Diseases. The study demonstrated an acceptable safety and tolerability across all dose levels up to, and including, 60 milligrams per kilogram, the highest dose level tested, with no serious or severe treatment emerging adverse events in patients treated with PRX002.

In addition to achieving acceptable safety and tolerability, the study demonstrated target engagement and antibody penetration in the CNS. Specifically, the data demonstrated the rapid dose and time-dependent reduction of 3 serum alpha-synuclein of up to 97%, a statistically significant result that was maintained following 2 additional monthly doses.

In addition, we saw penetration of PRX002 in the central nervous system, which exceeded our expectations based on our preclinical experience. We observed dose-dependent increases in PRX002 in the cerebrospinal fluid and a mean concentration of 0.3% to PRX002 relative to serum across all dose levels. These data further supported our selection of the 2 doses to be used in the Phase II study that we believe target and saturate the aggregated pathogenic forms of alpha-synuclein in the brain. The Phase II clinical study of PRX002 or RG7935 in patients with early Parkinson's Disease was initiated in the second quarter of 2017. The start of the study triggered a $30 million milestone payment from Roche to Prothena.

Now I'd like to also briefly highlight some of the programs in our active discovery pipeline. As you know, we've been focused on successfully stewarding our pipeline towards exciting and important milestones. But we are also seeking a great deal about the future and how we can continue to leverage our expertise to deliver additional programs across the neuroscience and orphan disease categories where we continue to build a pipeline of innovative therapies to sustain long-term success.

In November last year, during R&D day, we raised the curtain on some of our discovery programs that leverage our more than 3 decades of CNS experience dating back to when our scientists conducted some of the foundational science in the field of misfolded proteins and their potential causal role in neurodegenerative diseases such as Alzheimer's and Parkinson's. Scientists who advanced this work first at Athena Neurosciences in the '80s, then at AlainPharmaceuticals and now Prothena, are part of the Prothena team today. And their work continues to deepen our understanding of neurodegenerative diseases and new and important ways to target the underlying pathology with potentially disease mortifying approaches.

Antibodies may be effective as disease-modifying therapies through several potential mechanisms, including neutralization or desegregation of cytotoxic forms of the protein, blocking the uptake of the pathogenic species into healthy cells and promoting clearance, and blocking post-translational modifications of the protein that occur through processes, including cleavage or phosphorylation. What we have discovered over many years of research in this space is that extensive upfront work in 2 areas is fundamental to developing antibodies that have the potential for better efficacy across all of these potential mechanisms of action.

First, it is essential to determine the optimal epitope to target because targeting different regions on proteins can drive very different efficacy profiles. And second, it's critical to engineer antibodies with the optimal preference or using avidity to pathogenic forms of these toxic proteins.

In 2017, at our R&D Day event in November, we highlighted 2 programs in our discovery pipeline: tau and ALECT2, where we are putting this expertise in selecting the epitope and engineering high avidity antibodies to work. Beyond these programs, our discovery efforts are focused on proteins, including a beta, TDP 43 and other targets in neuroinflammation that are implicated in a range of neurodegenerative or orphan diseases that have no disease-modifying therapies, including Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, chronic traumatic encephalopathy and progressive supranuclear palsy.

Our discovery team is led by Wagner Zago, our Chief Scientific Officer, who's been with Prothena since its inception. Wagner is an exceptional scientist and he leads a team of prolific and talented researchers. Their expertise has been central to our ability to build a diverse pipeline of internally discovered first-in-class therapies. And under his leadership, we have continued to steadily advance our discovery efforts. We believe our team has profound insights to apply toward new approaches in this space, and we look forward to providing updates on his work that will be an important part of Prothena's future.

So at this time, I'd like to turn the call over to Tran for a discussion of our financial results. Tran?

Thanks, Gene. First, our cash flow from operating and investing activities in 2017 was approximately $135 million, which was favorable and below the low end of our updated guidance of $142 million to $152 million.

In 2017, we reported net loss of $47.8 million and $153.2 million for the fourth quarter and full year of 2017 as compared to a net loss of $48.9 million and $160.1 million for the fourth quarter and full year of 2016. Net loss per share was $1.24 and $4.07 for the fourth quarter and full year of 2017 as compared to a net loss per share of $1.41 and $4.66 for the fourth quarter and full year of 2016.

Included in the net loss for the fourth quarter and full year of 2017 was share-based compensation expense of $7.4 million and $26.8 million compared to $5.2 million and $24.9 million for the fourth quarter and full year of 2016. We reported total revenue of $0.2 million and $27.5 million for the fourth quarter and full year of 2017 as compared to total revenue of $0.2 million and $1.1 million for the fourth quarter and full year of 2016.

The increase in revenue for 2017 was primarily due to the achievement of a clinical milestone payment from Roche of $30 million for the initiation of Phase II PASADENA study of PRX002. R&D expenses totaled $33.5 million and $134.5 million for the fourth quarter and full year of 2017 as compared to $39.8 million and $119.5 million for the fourth quarter and full year of 2016.

The decrease in R&D expenses for the fourth quarter of 2017 compared to the same period last year was primarily due to lower manufacturing expense and to a lesser extent, lower clinical trial costs, which were partially offset by higher personnel costs, higher consulting expense and higher expense associated with PRX002.

The increase in R&D expenses for the full year of 2017 compared to the same period in the prior year was primarily due to higher personnel costs and to a lesser extent, higher clinical trial costs associated primarily with NEOD001, higher consulting expenses and higher expenses associated with PRX002, which partially offset by a decrease in external expenses related to product manufacturing.

R&D expenses included noncash share-based compensation expense of $3.1 million and $10.9 million for the fourth quarter and full year of 2017 as compared to $1.9 million and $7.1 million for the fourth quarter and full year of 2016. G&A expenses totaled $14 million and $48.2 million for the fourth quarter and full year of 2017 as compared to $9.6 million and $41.1 million for the fourth quarter and full year of 2016.

The increase in G&A expenses for the fourth quarter and full year of 2017 compared to the same period last year was primarily due to higher personnel cost and to a lesser extent, higher consulting expense and other expenses in 2017, which were partially offset by a reduction in share-based compensation expense related to the accelerated vesting of stock options in the comparable periods in the prior year.

Additionally, a gain was recognized from the assignment of our former South San Francisco facility lease in January 2017. G&A expenses also included noncash share-based compensation expense of $4.4 million and $15.9 million in the fourth quarter and full year of 2017 as compared to $3.3 million and $17.8 million for the fourth quarter and full year of 2016. As of December 31, 2017, Prothena had approximately $422 million in cash, cash equivalents and restricted cash and no debt.

As of February 9, 2018, we had approximately 38.5 million ordinary shares outstanding. Now turning to our 2018 financial guidance. We expect the full year 2018 net cash burn from operating and investing activities to be $175 million to $230 million and to the end of the year with approximately $218 million in cash, which represents the midpoint of the range. Of this $55 million difference between the low and high end of the cash burn range, approximately 90% is gated to the results of Phase IIb PRONTO study, which includes additional headcount and regulatory and commercial activities to support NEOD001. The estimated full year 2018 net cash burn from operating and investing activities is primarily driven by an estimated net loss of $200 million to $260 million, which includes an estimated $33 million of noncash share-based compensation expense.

With that, I'll turn the call back over to Gene to summarize our upcoming milestones for 2018. Gene?

Thanks, Tran. So as we move forward in 2018 and beyond, we expect continued momentum in our pipeline and to progress our planning activities in preparation for the potential submission of a marketing authorization application for NEOD001 to European regulatory authorities. This year, for NEOD001, we remain on track with the Phase IIb PRONTO study and expect to report top line results in the second quarter. For PRX002, Roche continues to enroll patients with early Parkinson's disease in the Phase II PASADENA study. And for PRX004, we expect to initiate the Phase I multiple ascending dose study in patients by the middle of this year. We look forward to providing updates on our programs throughout the year, and we thank you, certainly, for joining the call. So at this time, we'll open the call for questions. So Skyler?

(Operator Instructions) Our first question comes from Christopher Marai with Nomura.

I was wondering, first, if you can maybe address how we should think about data release with respect to PRONTO. Obviously, it's a material event. I was wondering whether or not we should just expect a PR some time in this business in the second quarter and then -- and how much data should we expect from that and then which potential conference then you -- or may be reasonable to expect the data to be presented at? And then I have a follow-up on the TTR program, if possible.

So maybe I can start, Chris, and Tran and [Colin] probably can jump in here. But I think in terms of the PR around PRONTO, clearly, what we're going to try and do as soon as we have the top line results is try and communicate those as quickly as possible. So clearly, that would be -- the initial data set that we get, it will include the primary outcome measure as well as the secondary outcome measure and will include some important cuts around own safety and tolerability as well. So we should be able -- we anticipate being able to report that out. Obviously, there'll be more fulsome analysis done behind that, and we would look forward to sharing that more fulsome analysis at the appropriate scientific meeting. The timing of being able to get that analysis done will really dictate a little bit when we can get the abstract and what meetings we would target. But clearly, we'd look to something in the hematology space.

Sure. Are sort of those midyear conferences really pushing it with respect to the timelines?

Well, it all comes down to abstract submission dates. And so without having those in front of me, I can't say with any certainty. But clearly, we'd be looking to get into a scientific conference as rapidly as possible.

Great. And then just secondly, on the TTR program. Obviously, the trial, the Phase I period is in patients, including, it looks like, some wild type patients with an expansion component. How should we think about that design and the objectives of the trial you highlighted, the potential, it looks like, to see data on reduction in, I guess, circulating TTR, misfolded TTR, that is. So should this be really thought of as a similar piece of data as the Phase I program for NEOD001?

Yes, I think -- yes, so it's a great question. Thanks for it. So let me just kind of say what we said about that Phase I design. So the primary purpose is safety, tolerability. Obviously, we'll be looking at PK immunogenicity. What you alluded to, and we're very excited about, is the development of this pharmacodynamic assay as well. And just to describe that assay in a little bit of detail. As I think many folks know, our antibodies are somewhat unique in that they were developed in such a way that they don't recognize the normal form of transthyretin. So the normal form of transthyretin is a tetramer, so 4 units. We worked with a group that had identified some of those key interface regions by solving the structure of that tetramer. And using that information and working with that team, we were able to target antibodies to those regions. And basically, all of our preclinical data to date suggests that our antibody do not see the tetramer but do see anything else in terms of the misfolded and non-native forms. And so what we've done is we've used our stable of antibodies to build an assay to look in patient blood. And what that basically does is uses 2 antibodies. One is to capture antibody, which specifically picks up these non-normal forms of TTR. And then we have detection and -- or signaling antibodies that come in and actually signal off of that. And that gives us this nice signal, which is quantifiable. And what we've shown to date is that in hereditary TTR patients, we can measure in a meaningful way an increase in that specific non-normal form of TTR. So what's fundamentally different about this and everything that's been done before is everybody prior to this has looked at the total TTR, whether it's the normal forms or the abnormal forms. We're specifically focused on the abnormal forms. And so what we will be doing is in our initial studies, we'll be employing that assay and we'll be asking the question of how PRX004 interacts with that specific abnormal TTR pool. And so we certainly think that will give us some interesting information. How we start to incorporate clinical endpoints later, I think, will be the subject of a future conversation as we get into these trials and start designing what that full expansion data set will look like and/or even into a Phase Ib or Phase II study.

Okay. And then just lastly, should we think about that expansion plan as sort of similar to that NEOD001 expansion plan in many ways, those key clinical endpoints on similar timeline?

That's a great question. I think we want to reserve the right to do other adaptive designs. And I think we're in discussions right now with our own team and then, of course, love to go out to the sites. But I think -- but in theory, I think what you just said, yes, I think that would be something we would do, which is enroll the right patient population because, as you remember from the dose escalation portion, it's in all comers with the exception of each of in each of the cohorts, you at least one neuropathy patient. But that being said, it's kind of all comers. So in, let's just say, a group where you want to look at clinical outcomes, you do want to make sure that the cohort is focused on, let's say, hereditary neuropathy or depending on if you have to divide up hereditary cardiomyopathy and multi. So I think we'll come back to everyone kind of later this year with our thoughts on that. But the first key thing is to look at safety, tolerability, PK, PD to pick doses or a dose to bring forward into those types of clinical outcomes part of that portion of the study.

Our next question comes from Andrew Peters with Deutsche Bank.

So a couple for me. I guess, maybe to start off with TTR. So you talked about kind of the start of the MAD study around the middle of next year. Just wanted to get a sense if you could offer your view on potential timelines around either enrollment or time to first data, kind of when can we really get a proof-of-concept type look in humans for the program. And then coming to the PRONTO study. If you could just run through how you're thinking about some of the secondary endpoints. And more importantly, based on what we know about NT-proBNP in particular, how do you think about the relationship between the secondary endpoints and the primary and how it relates to kind of the overall clinical profile of D001?

Yes, 2 good questions, Andrew, thank you. So first with TTR. I think -- and I guess, we were just discussing, at least in an initial 3 plus 3 dose escalation multiple dose study, the real focus there is going to be on safety and tolerability. Obviously, we'll have this pharmacodynamic data. So we'll be excited to take a look at that as we go. It's 3 plus 3. So the exact timing is always a little difficult to predict. I mean, obviously, it depends on whether you need to expand cohorts or not. I think right now in ClinicalTrials.gov, we have a completion date somewhere in August 19 of the entire portion of that. Clearly, we'll be looking for ways to start to gain clinically meaningful endpoint information as rapidly as we can. But I can't really predict the timing of that because it will be very data dependent, not just our data, but I think also, we're going to need to understand how some other folks that are out there in the field that recently have some nice data in TTR are starting to be used so that we can design the appropriate clinical assessments. And I think that's going to be an important consideration. So we're going to have to be a little reactive in real-time to that. So when you think proof-of-concept, I guess, I automatically go to clinical endpoint. And there, I think it's just a little too early to predict exact timing on that. With respect to secondary endpoints in PRONTO, I think we've always been pretty consistent that the primary thing that obviously we're most interested in is the primary outcome, which is NT-proBNP. We believe in the predictive value of that for survival as it has been used and elucidated in the field. Clearly, we would hope to see consistent movements of the secondary endpoints and improvement on those endpoints. To be clear, though secondary endpoints were not powered for statistical significance. So I don't think we've ever suggested that they have been. But I think, overall, what you want to see is from a weight of evidence perspective that your primary and secondaries are making a cohesive story and moving together. So clearly, that's -- that would give us a lot of encouragement, if we saw that. And obviously, anything better than that is better than that.

Great. And a quick follow-up on the TTR side. You mentioned maybe some of the other programs that have shown some recent data there. Just wanted to get your sense maybe from a high level on mechanistically, what is the potential for combinations with 04 with some of those new agents? You mentioned the ability to be nimble in your trials. So is that something that you're kind of thinking about on a forward-looking basis?

I think in the amyloid space, you can only think about it 2 ways, right? You can think about the de novo protein production inhibition. And you've seen that in AL amyloidosis. Chemotherapy is used for that. You're now seeing that happen in TTR. And we even saw some not-so-positive data on base from Merck recently. And I think when you look at that side of it and you just focus on inhibiting protein production, you can see some impact. And clearly, I think if you look in the TTR space, particularly at polyneuropathy, the Alnylam and Ionis programs have shown some very nice clinical benefit. But I think, as well, if you go look in these other amyloid fields, at the impact of simply focusing or exclusively focusing on that end of the biology, there appears to be a lot of opportunity left to target the toxic moiety. Said another way, when these patients come to diagnosis, they typically already have a substantial amount of misfolded protein already accumulated on vital organ structures, whether that's in the brain for CNS diseases or whether it's in the periphery for peripheral diseases. Turning off the production of new protein does not address that resident amyloid. And obviously, these are amyloid diseases. Meaning, amyloid is causing the problem, the toxicity, the morbidity and ultimately, the mortality in these patients. And so one needs to address that resident amyloid, and that's what we purport to do with our antibodies. I think the potential for combination is real. I think it's potentially very attractive. And I think if there are reasonable opportunities to do that, moving forward, that's something that we could consider. It's not something that's being actively contemplated today though.

Our next question comes from Michael Yee with Jefferies.

Two questions for you. One is coming out of ASH, I think that there was definitely a lot more data presented on AL amyloidosis. There was a whole session on that. And I think there seems to be some investor discussion at least around 2 data sets. One was another competitor antibody that seemed to have noticeable efficacy. Maybe you could put that into context for us. And then, secondly, there was a poster up from the Mayo Clinic talking about a notably depth of organ response leads to prolonged survival. However, there were noticeable responses there. Maybe you could put those, the data sets, here in the context for us. That was the first question. And the second question was going back to secondary endpoints, what is the scenario where the secondary endpoints are somewhat mixed or hard to clearly delineate? A 6-minute walk in SF-36 can be variable and hard to predict. So there's been mixed responses across, and you're willing to (inaudible) that works. So maybe just talk about what does that mean. How do you walk -- how do you get investors comfortable with that scenario?

Yes, sure. So all right. So let's kind of walk through these. So first, you mentioned other antibodies. And I assume you're talking probably about the Caelum antibody here formerly known as 11-1F4 inasmuch as I think that's the only other light chain-targeting antibody out there. So look, first, I'll say we're encouraged by their organ responses. It shows that, obviously, directly targeting the light chain in this disease consistently produces, I think, very reasonable organ responses. And they've seen that now in cardiac as well as other organ systems as well. They did report as well, I think, a pretty reasonable safety profile. I think one would have to -- they're a little bit behind in terms of time line. I think they've indicated as far as we know that they're anticipating starting a Phase II trial maybe later this year. So we think that's great, frankly. The antibody itself, in terms of what we know about it, you can look to their data. I know their multiple dose study was once weekly IV infusion. I don't know if they're planning on staying with that infusion regimen moving forward. But I think that's something that, certainly, if there's an opportunity to space that out more, would probably not be a bad idea. I think also, we can look to how that antibody was made. As I understand it, that was focused on kappa light chain. And obviously, in the disease, lambda tends to be more prevalent in terms of causing disease, although kappa in normal folks tends to be a little more prevalent than lambda. And so I think some information on cross reactivity would be interesting as well and whether in fact they can also detect some of the lambda forms. That said, I've got nothing really negative to say about the antibody. I think it's very encouraging, and from our perspective, it's further validating the biology that in fact, we seem to be seeing as well. You had mentioned some posters. I think you're talking about the -- there was a poster that you talked about depth of organ response. So I'm familiar with one. Hopefully, we're talking about the same one, which comes from the Mayo Clinic. In that study, it was actually very encouraging from a results perspective. I think intuitively, we've always wanted to believe that the deeper the reduction of NT-proBNP, the better it would be. But frankly, there was no literature on that or no substantive literature. For the first time, I think they've shown that. I know one question we've been asked is how comparable those patients are to our Phase I/II data or even our PRONTO patients. And the answer is not very. Those were newly diagnosed patients. As we understand it, there was a high number of stem cell transplant patients in that group, which would imply that it was a more mild data set than we would typically enroll in our study. And obviously, on some of the analyses that they did, it was -- we observed that they did some landmarking. Meaning, some of the early mortalities may not have necessarily been captured. And so I think it's hard to derive any comparative information, but I'd say, in terms of general biology, it was encouraging to us to see that the magnitude of the depths of response was in some way related to the overall benefit with respect to survival.

And I think that Dr. Liedtke at ASH 2016 had put out an oral presentation in regards to possible variables that might have driven responses in our Phase I/II trial. And I think it showed from that presentation that there wasn't anything obvious. And one of those variables that they looked at clearly was the type of therapy you had. And I believe stem cell therapy was there and along with CyBorD. And it was pretty much similar across the board. So it didn't -- the gold standard didn't seem like it was driving our response rate, and we also looked at depth and times and best and last response, things like that from a hematologic perspective. So I just wanted to add that. And then in terms of your other question regarding PRONTO. I mean, I think, first and foremost, Gene, I think, mentioned this previously, is that we need to show that we can move NT-proBNP. And I think that's what our primary focus is on because the reliance is that NT-proBNP is predictive of survival in terms of its relevance to clearly VITAL, our Phase III trial that's ongoing. And I think that's the first thing that we are very focused on. And then, of course, the secondary as we see, although there is literally out there that correlates NT-proBNP response with betterment of 6-minute walk distance and short from 36, but clearly, the first thing is we need to know that we moved NT-proBNP so that we -- that it supports VITAL in terms of the survival and hospitalization.

Our next question comes from Geoff Meacham with Barclays.

This is Evan on for Geoff. I know you've provided probably all you can. But any other updates on the transition of this CMO? I'm assuming that this is all voluntary and not related to data, but I've gotten a lot of questions on that. And then also, any evolution with regard to the NT-proBNP as a biomarker for approval in the United States? Any updated thoughts there?

Yes. So thanks, Evan, some important questions. So first, obviously, we don't have anything more to share about Sarah's decision. I think I mentioned in my remarks that, obviously, with Marty coming back, and we expect that transition to be very smooth. The remaining clinical and medical team remained in place and focused on executing. And we don't see, frankly, any hiccups with respect to our operational readiness to get the top line with PRONTO. And probably most importantly, from our view, there's nothing that's changed. And I heard the second part of your question around that. And so clearly, in terms of how we view the data, that hasn't changed. Our operational readiness hasn't changed. How we view the prospects in NEOD001, that hasn't changed. So we remain as confident as we have been. I think the other question in NT-proBNP and regulatory, we're holding the same base assumption that we've held. So just to restate it. Our assumption is that with a positive PRONTO trial with the primary coming in strong and the secondary is supportive, that we think we could have the productive dialogue with the European regulators around conditional approval. We have not and have not set that expectation with the U.S. regulators. Clearly, dependent upon the strength of PRONTO data, we would certainly inform and/or engage in active dialogue with the U.S. regulators to understand how they view the data. But we certainly can't handicap the probabilities of success sitting here today based on the feedback that we received to-date.

Our next question comes from Kennen MacKay with RBC Capital Markets.

So with the VITAL primary endpoint, potentially a couple to maybe even several years out, PRONTO and the NT-proBNP endpoint, I think, becomes much more important when you think about the number of AL amyloidosis patients who really are going to die between the PRONTO and VITAL trial readouts. And with the European regulators really seeming to have signed off on this and having had a productive discussion with them. Can you maybe help us understand sort of where the FDA patent gotten comfortable with the NT-proBNP endpoint? And I guess, with the ongoing interactions from the amyloid research consortium to take that through the FDA, maybe could you talk about sort of where that stands now and sort of again maybe help us understand what your interactions originally had been when you were initially starting this trial, again, back in late '15 or early '16?

Yes. So a lot in that question. So certainly, as -- and obviously, I don't want to speak too much about other people's work. But you can go look at the Amyloidosis Research Consortium, in their website, and I think they have a number of white papers and discussions about interactions with the agency. NT-proBNP reduction following intervention is fairly widely used in this field amongst physicians that treat this disease. And I think most in the field would consider it clinically validated. Obviously, that's different than regulatory validation. And those require different levels of evidence. So I think the answer to your question is, I think, really, it's going to be, in our particular case, very much dependent upon the strength of that data set, how we will formulate that discussion at that time. I think over-engaging in a conversation about the potential usefulness of a biomarker for registration purposes, absent data, may actually solidify certain views that we wouldn't want solidified at this point in time. So that said, I think they'll be an opportunity certainly to inform the FDA of the PRONTO trial results, that would be expected as any trial finishes in any clinical programs. So that's, I think, pretty much a given. But I think then, the second question would be how actively to engage with the regulators for -- with additional discussion. And frankly, again, I can't really provide any assurance on that. It would be largely based on the strength of that PRONTO data set.

Right. And one thing to add, Kennen, in terms of one part of your question was just the continuing education that ARC has done through engaging with the FDA in terms of educating them on the relevance of NT-proBNP within the AL amyloidosis indication of disease versus general heart failure. I think that's been the focus of the education and all the data that's been built around NT-proBNP and predicting survival in this disease state.

Yes, I mean, I spent a little bit of time talking about some of the basic research that we did last year. And we think it's critically important work with respect to what Tran just mentioned. So fundamentally, what the team, the research team had shown last year, is that light chain induces an oxidative stress pathway and subsequent increase in NT-proBNP production that is not likely to be in the pathway that you see in normal heart failure cases. So what we're seeing is there's almost a unique toxicity of this misfolded forms of light chain at the level of heart cells or cardiomyocytes that's unlikely due to hemodynamic effects that you expect in a kind of a normal chronic heart failure patients. And so it starts to provide a biological rationale as to why NT-proBNP levels may be higher in patients with AL amyloidosis. And more importantly, why it may be such a sensitive indicator of survival in AL amyloidosis unique from normal chronic heart failure patients or I should say, the vast population of normal chronic heart failure population. And so for us, this is very important information because absent that kind of biology, it's very hard to build a credible argument that this is sufficiently differentiated in AL amyloidosis relative to chronic heart failure. And so this is why that, that type of research is so critical and important for an overall data package, and obviously, in an optimistic scenario, a data file.

And can you just elaborate on that a little bit? You brought up a great point. Wondering if you could just help us understand sort of what data it was that the European regulators were sort of more recognizing of. Because at the time, the data really providing a direct link between NT-proBNP and the toxicities associated with the amyloid light chain really hadn't been established back then.

Well, there was some data out there. I don't want to shortchange the teams who -- so our research team obviously built up research already in existence. There were a number of groups. Most notably, the group from Pavia, Italy, another group out of Boston, that had implicated p38 MAP kinase pathways in this biology, and that data had been known for some time. Our team kind of took that and moved it forward so that we understood the relationship there between some of these pathways and NT-proBNP. So I do want to give credit where credit is due. There were a number of groups that had already made that initial observation linked. Yes, I mean, in terms of any unique insight that European regulators had relative to the U.S. regulators, I can't really speak to that. I don't -- I can't give you an answer off the top of my head.

Got you. And then just one more quick follow-up as it relates to doing some sort of historical comparisons throughout the trial landscape here. Can you talk a little bit about the sort of best response analysis for NT-proBNP that's been used sort of in a landscape fashion at a specific time point versus a best response over a period of time? And how that relates to the trials that you had run as well as some of the trials across the, again, historical landscape here and really, how we should think about sort of reconciling between these 2 different endpoints?

Yes, sure. So there -- so when people have looked at NT-proBNP response, they've done it multiple different ways. They've done it at various time points, 3 months, 6 months, 12 months. People have used best response. And I think what we can say is across all of those analyses, without any exception that I'm aware of, NT-proBNP response predicts survival following intervention. I think -- and when I say NT-proBNP response, I mean, by the consensus criteria, reducing NT-proBNP by at least 30% and a minimum of 300 nanograms per liter. The majority of those studies are in newly-diagnosed treatment naïve patient populations. That's where the bulk, majority of those studies are run. There are a handful of studies in relapsed refractory patients. So these would be a little bit closer to PRONTO, i.e. patients where they previously received chemotherapy and for one reason or another, they're brought back in to receive more active treatment. And in those studies, again, a fact you've seen at various time points, it tends to be lower response rates when you look at those patient populations. But for caveats there, those studies tend to be lower sample sizes as well. So a little less certainty around the total, the quantitation of the effect size.

And our next question comes from Steven Breazzano with Evercore.

Maybe one on NEOD001. Maybe just outline for us what you'd expect from the placebo arm in the PRONTO study. And is there an interim analysis in VITAL? And would you consider taking one based on the results of PRONTO?

Yes. So I think you can look to our powering to kind of estimate where we were at least with respect to placebo. So clearly, what we had said was we were powered to see -- 80% powered to see a 27.5% delta between the placebo group and the drug group. And I think if you go look at our multiple interim cuts of the Phase I/II data, we were always in the 50% range. So it's anywhere from 47 or 46 plus percent all the way up to 57% or 58%. But I'd say, generally trending around 50%. So you do the subtraction there, and you kind of -- it's pretty easy to see where we ended up. We think that's a pretty reasonable estimation, in part because in newly diagnosed treatment naïve patients, you tend to see cardiac response rates somewhere in the range of 17% to 35%, tends to be about the range. In these patients that I mentioned before, who have been previously treated and come back in on active treatment, you see response rates somewhere in the range of 0 to 15%. And so we think we've been pretty reasonable in terms of how we've estimated that placebo side. And remember as well, we over-enrolled the study by about 30%, giving us some additional power to see the effect there as well. Your second question was?

VITAL interim.

VITAL interim, yes. I mean, so at present, we don't have any interims planned on VITAL. Obviously, if there was something in the PRONTO data set that caused us to want to do that, we would let folks know when we would conduct that.

Our next question comes from Bill Tanner with Cantor Fitzgerald.

Gene, just wanted to see if you could clarify a little bit the answer to the last question. The question I was going to ask is what's the reasonable number to expect, I guess, to set expectations on NT-proBNP? So I don't know if there's a sort of a range of numbers that you think is reasonable so that people have some rational viewpoint as to what could be real. And then I have a bigger picture follow-up if I could.

Yes, Bill. So I mean, again, what I can say is you can kind of calculate it from the way we powered the study, and we think that's reasonable. So that's kind of where we felt it was reasonable. One would need -- and what I'll be very careful to say here is there's no exact natural history here that exactly matches the PRONTO patient population. So one has -- so if the question is, was our estimation a reasonable estimation? Then I think what you can do is go back to the other patient populations and ask how reasonable do you think the extrapolation is. Again, newly-diagnosed treatment naïve patients getting a treatment for the first time, we expect the highest response rates. Those ranges tend to be anywhere from about 17% to 35%. You go to a previously treated -- and of course, in PRONTO, we're not treating newly-diagnosed treatment naïve patients. We're treating previously treated patients. So then you go to previously treated patients, and those ranges with smaller ends were 0% to 15% across 3 studies. And you say, okay, well, is that a closer approximation to the PRONTO? Well, it is, except those patients were getting active treatment. And of course, on PRONTO, the placebo arm will receive placebo. So I think you can make your own determination on how reasonable that was. But obviously, from kind of what did we expect perspective, you can get there pretty easy on the math.

Okay, no, that makes sense. I appreciate that. And the just thinking you mentioned the R&D presentation and some new targets. And if I look at your pipeline chart from that R&D Day, everything below 004 is in discovery. And if you had to look at the assets there and triage them, and I would assume -- obviously, a lot of the targets and their conditions are of interest to other companies. But if you had to triage those assets in terms of, one you felt like you really wanted to keep, ones that you might want to incubate and derisk a little bit incrementally, and ones that you don't want to partner. How should we thinking about those advancing in an expeditious manner?

Well, I think, Bill, you bring up a good point. I mean I think with Tau and ALECT2 and abeta and Sortilin and TDP-43, I think there's a natural kind of divide there where like targets like ALECT2, we could actually take through ourselves and ultimately commercialize due to its orphan nature and small footprint. Even -- actually, even Tau, we can think about it because there's also the PSP side of it versus the Alzheimer's side of it. But I think in terms of Tau and abeta and like Sortilin, you would think that sometime in the future, you would look to do -- you'd look to start some discussions around partnering. But that being said, you want to make sure you reach some kind of either pharmacodynamic or proof-of-concept data on them to drive more value to your program. So I think we're going to reserve exactly when we would go out and get it. But that being said, I think, eventually, we'd look for our commercial partner at some point with those odder indications.

And then maybe just the last question. Gene, as it relates -- you had mentioned, the antibody engineering, obviously, finding the right epitope and trying to engineer the right avidity. I mean, is there any -- and so those are all on the binding domain part of the antibody. Is there any utility in tinkering with the FC receptor to get to kind of...

Yes, potentially. It depends on the target. I mean, so there will be opportunities where, I think, having FC, for example, Fc gamma receptor interaction, may be unnecessary for the activity of the antibody, and reducing ADCC may be helpful just in terms of any potential liability, known or unknown, around the antibody that you'd want to think about. So I think those are always things we think about. For a lot of these targets where you actually want to remove deposited material, we actually like the antibody recycling capabilities of a full effector function antibody. We think it's important just from a [cytometric] perspective. You want to take advantage of normal antibody recycling, and you want to actually induce macrophage to come in, in phagocytose. One of the kind of interesting things about amyloid, from my perspective, is that these are native proteins for the most part, absent some of the hereditary mutations. And what that means is folks are immunotolerant to these proteins. And clearly, the immune system is more geared towards sequence differences than it is to conformational structural differences. And so the immune system does not engage with amyloid all that readily. And given that, plus its extremely low energy state when it's in the amyloid fibril conformation, it makes it very hard to clear this material once it's inherent in whatever tissue it's deposited in. And so we actually think that being able to induce phagocytosis, being able to actually stimulate in the immune system to come in and clear the maternal activity, may be a very, very important part of the mechanism of action. And in as much as that's true for any given disease, we'd want to retain that effector function. If in the disease we know that not to be true, then I think we'd think about Fc engineering to kind of remove some of that function. But it's really a target-by-target discussion within the labs.

Our next question comes from Jay Olson with Oppenheimer.

I've 2 of them. The first is about PRX002. Can you please outline some of the key points of differentiation between PRX002 and the other alpha-synuclein antibodies from BioArctic in neuroimmune?

Yes. I can tell you that, at least to my knowledge, there hasn't been a lot published on those antibodies. We know a little bit about them just from the presentations that Biogen's done around neuroimmune antibody or some of the work that BioArctic's done. Just to kind of set the stage, I mean, the characteristics that our antibody was selected for was first to bind to an epitope on alpha-synuclein that was found to be very important for some of the biological activities that are thought to be detrimental in the disease process. So namely, we designed PRX002 to have a high preference with more aggregated forms of alpha-synuclein to be able to block the cell-to-cell transmission of alpha-synuclein. And we've even observed in some early studies that we could see some reduction of intraneuronal pathology of alpha-synuclein. We don't -- just to be frank, we don't exactly know what's driving that. But certainly, there are some epitopes that do that and others that don't. In fact, in our experience, we've made antibodies to all different parts of the alpha-synuclein protein. You can move off the area where PRX002 interacts by just a couple of amino acids and almost lose all biological activity. So it's really important where you target that protein. Inasmuch as I don't know exactly where the Biogen molecule or the BioArctic molecule are targeting alpha-synuclein, I can't really say much about that part of it. I think we're all saying the same things, though, which is cell-to-cell transmission is important, aggregated soluble forms of alpha-synuclein are important with respect to causing disease progression, and it's more than just the motor symptoms. This is a whole body synucleinopathy. And we think the antibodies may have activity across. So until they actually come out and publish more data, I'm not going to be able to draw direct comparisons for you. I'll just say that given our experience in this space, we started working in this space about 2003, published the first paper in 2005, we feel confident that we've looked at antibodies that have lots of different ways of targeting alpha-synuclein that target different parts of the protein, that target different modifications of the protein. And we're pretty happy with how PRX002 acts across the entirety of the biology that we've been able to explore.

Okay. Great. And then I just had a follow-on to the earlier question about your discovery portfolio, which you provided a very thorough update on back at your R&D event last November, which I think generated a lot of interest. I was just curious about the timing. Can you help us understand which of the assets in your discovery portfolio are the furthest along? And then when should we expect to see some preclinical work on those compounds? And then eventually what would the timing be to move those into the clinic?

Yes. So good questions. So clearly, the 2 that we've highlighted were the tau program and the ALECT2 program and basically highlighting both our focus in the CNS space but also our continued presence in orphan diseases, but very specifically in orphan diseases where misfolded proteins are thought to act to play a significant role. So with tau, what we were highlighting there is that we have a group of antibodies that, to the best extent that we know, target the tau protein in a way that's different than everything else out there. And at least, with respect to everything we've been able to do preclinically to date, it's provided -- targeting the tau protein in that way has provided us much more consistent biological effects than antibodies we've made to other parts of the protein or that target other forms of the protein. And so obviously -- and then ALECT2 is an emerging peripheral amyloid disease that's likely to be third in prevalence following AL amyloidosis as first and then TTR as second. And then ALECT2 looks like it will be third most prevalent in terms of peripheral amyloid diseases. So we think this is a very interesting disease as well. It's primarily renal in its presentation. And we're starting to understand, as a field, the more we look for this, the more folks see it in different geographic regions. So clearly, we're pushing both of those programs forward as well some other things. We'll be continuing to generate preclinical data. I'd expect -- we've always kind of prided ourselves on being fairly prolific in publishing our preclinical data. We don't intend to change that phenotype. I would expect even this year and into next year, you'll see data coming from those programs, primarily preclinical data, that highlights maybe some of the unique characteristics of the approach that we're taking.

Our next question comes from Bert Hazlett with the BTIG.

Just coming back to 001 and PRONTO and VITAL for a second. Are there additional secondary endpoints beyond SF-36 and a 6-minute walk test that we should be considering or looking at or that you are considering important as you discuss things with the regulators and look at the data?

Yes. So it's a good question, Bert. So we have -- certainly, it's not a different end point, but it's a different analysis. We'll be looking at some measures of persistency of effect, we'll be doing some slope analyses, for example, to give us a sense of duration of effect. We'll be doing -- obviously, this would be subset analyses, not key secondaries. But for patients that have renal or -- and/or neuropathy at baseline, we'll be looking to see if, in fact, those organ systems are showing any benefit at all. Frankly, I don't know what the sample size in those subset analyses will be, so I can't really set any expectations as to whether those will be meaningful or not. But again, we saw obviously in the Phase I/II, a very nice activity across 3 organ systems. So clearly, we want to continue to look at particularly in neuropathy and renal as we have these patients come in.

And at this time, I'm showing no further questions. I'd like to turn the call back over to Gene Kinney for closing remarks.

Okay, great. Thanks, Skylar. So I want to thank everyone for joining us this afternoon. We certainly appreciate your interest in Prothena and our programs. And over the next coming months, we look forward to sharing our advancements that we expect to propel our programs towards potential commercial availability for patients. So thank you very much.

Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.