Prothena Corporation plc (PRTA) Q4 2017 Earnings Report, Transcript and Summary

Good day ladies and gentlemen. And welcome to the Prothena Fourth Quarter and Full Year 2017 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Later, we’ll conduct a question-and-answer-session and instructions will follow at that time. [Operator Instructions] As a reminder, this call may be recorded. I would now like to introduce your host for today’s conference, Mr. 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 on our website at prothena.com, and is also attached to a 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 of 2017, and 2018 financial guidance. Gene will then provide an overview of the 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 provision 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 would like to turn 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 are 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 a 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 continued 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 two 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 protein misfold, aggregate, circulate through the body and deposit its amyloid in vital organs, most commonly in heart and kidney but also peripheral nerves and other organs. These circulating soluble aggregates and deposited amyloid can cause dysfunction 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 the clonal 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 failure. For patients who undergo these plasma cells 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 a safe and well-tolerated therapy that can improve organ function and survival by directly neutralizing circulating soluble aggregates and clearing deposited amyloid 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 1/2 study at the American Society for Hematology Annual Conference in 2016, including favorable safety and tolerability as well as improvements across three organ systems. And we are currently running two pivotally designed studies of NEOD001 in patients with AL amyloidosis and cardiac dysfunction, PRONTO, a Phase 2b study; and VITAL a Phase 3 study. In 2017, we completed enrollment in both of these studies and in fact both of these studies were overenrolled. Our Phase 2b 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 the 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 dysfunctions. 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 the 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 Six-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 is 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 the direct relationship between misfolded soluble life 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 life 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 the NT-proBNP secretion is increased by misfolded soluble light chain via mechanism dependent upon heme oxygenase-1 catalytic activity. The 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 provide a direct biological link between the misfolded protein and NT-proBNP elevation in patients with AL amyloidosis. Furthermore, these data indicate 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 improve 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 2b 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 a 125 people in 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 topline 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 3 global registrational, 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 Six-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 six 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 will provide additional update 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 a 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 protein 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 fiber formation which most commonly affect the heart and nervous system. There is also wild-type, a non-hereditary form of ATTR which involves cardiomyopathy. PRX004 selectively binds to amyloid, or disease 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 1 study that we plan to initiate in patients with ATTR amyloidosis by the middle of this year. The Phase 1 study has been designed as an open label 3+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 -- having the ability to demonstrate 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 a neurodegenerative disease that affects an estimated 7 to 10 million people worldwide, making it the second most common neurodegenerative disease after Alzheimer’s. The disease is characterized by the neuronal accumulation of aggregated alpha-synuclien in the central and peripheral nervous system that results in a wide spectrum of worsening progressive motor and non-motor symptoms and are persistent throughout the disease. While the disease is most commonly known for motor symptoms classically associated with Parkinson’s disease, non-motor symptoms such as loss of sense of smell, sleep disturbances or gastrointestinal matelote 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 subset of the symptoms typically related to motor impairment. Symptomatic therapies do not target the underlying cause of the diseases 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 [ph] involved in the onset and progression of Parkinson’s diseases. 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 1b 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 presented by Dr. Joseph Jankovic of the Baylor College of Medicine in the late-breaking therapeutic strategy session at the 13th International Conference on Alzheimer’s and Parkinson’s Disease. The study demonstrates 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 emergent 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 a rapid dose and time-dependent reduction of free serum alpha-synuclein of up to 97%, a statistically significant result that was maintained following two 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% of PRX002 relative to serum across all dose levels. These data further supported our selection of the two doses to be used in the Phase 2 study that we believe target and saturate the aggregated pathogenic forms of alpha-synuclein in the brain. The Phase 2 clinical study of PRX002 or RG7935 in patients with early Parkinson’s disease was initiated in the second quarter of 2017. The start of this 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 toward exciting and important milestones. But we are also thinking 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 the pipeline of innovative therapies to sustain long-term success. In November last year, during our R&D Day, we raised the curtain on some of our discovery programs that leverage our more than three decades of CNS experience, dating back to our when our scientists conducted some of the foundational science in the field of misfolded proteins and their potential cause or 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 Elan Pharmaceuticals and now at Prothena are part of the Prothena team today and their work continues to deepen our understanding of neurodegenerative diseases, and new and improvements ways to target the underlying pathology with potentially disease modifying approaches. Antibodies may be effective as disease modifying therapy through several potential mechanisms including neutralization or disaggregation 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 thoughtful relation. What we have discovered over many years of research in this space is that extensive upfront work in two 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 optimal preference or using a avidity to pathogenic forms of these toxic proteins. In 2017 at our R&D Day event in November, we highlighted two programs in our discovery pipeline, tau and ALECT2 where we are putting with this expertise and 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 the 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 is been with Prothena since inception. Wagner is an exceptional scientist and he leads the team of prolific 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 would 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 2017 as compared to a net loss of $48.9 million and $160.1 million for fourth quarter and full-year 2016. Net loss per share was $1.24 and $4.07 for the fourth quarter and full-year 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 quarter and full-year 2017 was share-based compensation expense of $7.4 million and $26.8 million compared to $5.2 million and $24.9 million for fourth quarter and full-year of 2016. We reported total revenue of $0.2 million and $27.5 million for fourth-quarter and full-year of 2017 as compared to total revenue of $0.2 million and $1.1 million for 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 up $30 million for the initiation of Phase 2 PASADENA study of PRX002. R&D expenses totaled $33.5 million and a $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 non-cash 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 costs 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 non-cash 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 2b 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 non-cash share-based compensation expense. With that I’ll turn the call back over to Gene to summarize our upcoming milestones for 2018. Gene?

Thanks, John. 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 potential submission of a marketing authorization application for NEOD001 to European Regulatory Authorities. This year for NEOD001, we remain on track with the Phase 2b 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 2 PASADENA study. And for PRX004, we expect to initiate the Phase 1 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 thank you certainly for joining the call. So this time, we'll open the call for questions. So, Skyler?

[Operator Instructions] Our first question comes from Christopher Marai with Numora. Your line is now open.

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

So maybe I can start Chris and Tran probably can jump in here. But I think in terms of the PR around PRONTO, clearly what we're going to trying to do is as soon as we have the top line results, to try and communicate those as quickly as possible. So clearly that will be the initial data sets that we get that will include the primary outcome measures as well as secondary outcome measures, and we'll include some important cuts around safety and tolerability as well. So, we should be able to -- we're anticipating to report that out. Obviously, there will 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, we're really dictated a little bit when we can get the abstract in what meetings, we would target. But clearly, we'd look to something in the hematology space.

Sure. Are certainly those mid-year conferences really pushing it with respect to the timeline?

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'll be looking to get into scientific conferences rapidly as possible.

And then just secondly on the TTR program, obviously, the trial the Phase 1 here is in patients including and looks like some wild type patients with an expansion component. How should we think about the design and the objectives of the trial? You've highlighted the potential looks like to see data on reduction in and I guess circulating TTR, misfolded to TTR that is. So should this be really thought as that scenario piece of data as the Phase 1 program for NEOD001?

Yes, I think it's a great question thanks for it. So let me just kind a say, what we said about that Phase 1 design. So the primary purpose is the 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 pharmacodynaimc assay as well. And just to describe that assay in a little bit 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 as the normal form of transthyretin is the tetrameric so 4 units. We worked with a group that have identified some of those key interface regions by solving the structure of that tetrameric. 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 suggest that our antibody do not see the tetrameric, but do see anything else in terms of the misfolded than non-native forms. So what we have done is we have used our stable of antibodies to build an essay to look in patient blood, and what that basically does, it uses two antibodies, one is the capture antibody which specifically picks up these non-normal forms of TTR, and then we have detection or signaling antibodies that come in and actually signal off of that and that gives us slight signal which is quantifiable. And what we've shown today that is hereditary TTR patients, we can measure in a meaningful way and increase in that that specific non-normal form of TTR. So what's fundamentally different about this and everything has been done before is everybody -- prior to this is look to the total TTR form, whether it’s a normal forms or the abnormal forms. We are specifically focused on the abnormal forms. And so, what we will be doing is in our initial studies, we will be employing that assay and we will 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 our future conversations as we get into these trials and start to designing what that full expansion data set will look like and/or even into Phase 1b or Phase 2 study.

And then just lastly, should we think about that expansion set as sort of similar to that NEOD001 expansion set in many ways you know those key clinical endpoints are on similar timelines?

I think we want to reserve the rights to do other adaptive designs and I think we are in discussions right now with our own team and then of course, as we go out to the side. 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 -- in each of the cohort need at least one neuropathy patient. But that being said it's kind of an all comer, so in let's just say a group or 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 that we have divide up hereditary cardiomyopathy in valve type. So I think we will come back to everyone later this year with thoughts on that, but the first key thing is to look at safety tolerability PKPD to pick doses or a dose going forward into those types of clinical outcome part of that portion of the study.

Our next question comes from Andrew Peters with Deutsche Bank. Your line is now open.

So a couple from me. I guess maybe to start off with TTR. So you've talked about 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 for first data kind of when can we really get a proof-of-concept type of look in humans for the program? And then coming to the PRONTO study, if you could just run through how you are 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 end points and the primary? And how it relates to kind of the overall clinical profile of D001?

Yes, too good questions. Andrew, thank you. So first with TTR, I guess we are just discussing at least an initial 3 plus 3 dose escalation multiple dose study. The real focus there is going to be on safety tolerability. Obviously, we'll have this pharmacodynamic data so we will 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 on clinicaltrials.gov, we have a completion date somewhere in August 2019 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 have recently had 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 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 the exact timing on that. With respect to secondary endpoints in PRONTO, I think you know 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 that in the predicted value of that for survival as it has been used in elucidating the field. Clearly, we would hope to see consistent movements of the secondary endpoint and improvement on those endpoints. To be clear, those secondary endpoint were not powered for statistical significance, so I don't think we've ever suggested that they have been, but I think you know overall what you want to see is from a weight of evidence perspective that your primary and secondary are making a cohesive story and moving together. So clearly that would give us a lot of encouragement if we saw that and obviously anything better than that is better than that.

Great, thanks. And a quick follow-up on the TTR side, you mentioned maybe some of the other programs that have shown some recent data there. I 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? And you mentioned the ability to be nimble in your trial. So, is that something that you're kind of thinking about on a forward looking basis?

Well, I think in the amyloid space, you can only think about it two ways right. You think about the de novo protein production inhibition and you've seen that in AL amyloidosis chemotherapy is used for that, you are now seeing that happen in TTR and we even saw some not the positive data on based from Merck recently. And I think you know 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 at the TTR space particularly polyneuropathy [indiscernible] [0:41:52.5] program have shown some very nice clinical benefits. But I think as well you know if you do 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 it's in the brain or CNS diseases or whether it's in the peripheral diseases. Turning off the production of new protein does not address the resident amyloid, and obviously these are amyloid diseases meaning amyloid is causing the problem, the toxicities and morbidity and ultimately mortality in these patients. And so one needs to address that resident amyloid and that's what we prefer 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 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. Your line is now open.

Two questions for you one, one is coming out of ASH. I think that there was definitely a lot more data presented on AL amyloidosis there was whole session on that. And I there seems to be some investor discussion at least around two datasets, one was another competitor antibody that seem 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 notably depth of organ response needs to prolong survival. However, there was noticeable response there. Maybe if you put those datasets here in the context for us? That's 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? Six-Minute Walk and SF 36 can be variable and hard to predict, so there has been mixed response across anyone that grows that work. So maybe just talk about what is that mean? How do you walk -- how do get investors comfortable with that scenario?

Sure, so let's kind a 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 and as much 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 little bit behind in terms of timeline. I think they indicated as far as we know that they're anticipating starting Phase 2 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 there are 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 is an opportunity to space that out more would probably not be a bad idea. I think also we can look to have 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 folk tends to be a little bit more prevalent in lambda. And so I think some informational cross-reactivity would be interesting as well and whether in fact they can also detect some of the lambda reforms. That said I have got nothing really negative to say about the antibody I think it's very encouraging and from our perspective it's further the biology that in fact we seem to be seeing as well. You had mentioned some posters I think you are talking about -- there was a poster that you're talking about depths 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 have always wanted to believe that the deeper the reduction of NT-proBNP that better would be, but frankly there is no literature on that or the substance literature. For the first time, I think they shown that. I know one question we have been asked is how comparable those patients are to our Phase 1/2 data or even our PRONTO patients. And the answer is not vary, those were newly diagnosed patients as we understand that there was a high number of stem cell transplantation 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 analysis that they did it was we observed that they did some land marking meaning some of the early mortalities may now necessarily have been captured. And so I think it's hard to derive any comparative information but I would say in terms of general biology it was encouraging to us to see that this magnitude has depth of response was in somewhere related to the overall benefit with respect to survival.

And I think that Dr. [Lukie] at ASH 2016 had put out an oral presentation in regards to possible variables that might have driven responses in our Phase 1/2 trials. And I think it shows from that presentation that there wasn’t anything obvious. And one of those variables they looked at clearly was the type of therapy you had and I believe stem cell therapy was there along with CyBorD. It was pretty much similar across the board so it didn’t -- the goal standard didn’t see it was driving our response rate and we also looked that depth and time depth and last response things like that from hematology perspective. So that’s I tried 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 predicted those survival in terms of its relevance to clearly VITAL our Phase 3 trial that stuff ongoing. And I think that’s the first thing that we are very focused and then of course the secondary we see although there is literature out there that correlates NT-proBNP response with betterment of Six-Minute Walk distance in short form 36, but clearly the first thing is we need to know that we move 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. Your line is now open.

This is Evan on for Jeff. I know you have provided probably all you can, but any other updates on the transition of the CMO, I'm assuming that this was 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 NT-proBNP as a biomarker for approval in the United States any updated thoughts there?

So thanks, for some important questions. So first obviously we don't have anything more to share about their decision. I think I had 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 remain in place and focus on executing. And you know we don't see frankly any hiccups with respect to our operational readiness to get the top line of PRONTO and probably most importantly you know from our view that there's nothing has changed in, that was 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 of NEOD001 that hasn’t changed. You know we remain as confident as we have been. I think the other question of NT-proBNP and regulatory you know we're holding the same base assumption that we've held you know so just to restated, our assumption is that with a positive PRONTO trial with the primary coming in strong and the secondary supportive that we think we can have the productive dialogue with the European regulators around conditional approval. We're not and have not set that expectation with the U.S. regulators. Clearly depending 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 probability of success sitting here today based on the feedback that we received today.

Our next question comes from Cannon McKay with RBC Capital Markets. Your line is now open.

So with a vital primary endpoint potentially a couple to maybe even several years now, PRONTO and 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 have that having had a productive discussion with them. Can you maybe help us understand sort of where the FDA hadn't gotten comfortable with the NT-proBNP end points? And I guess with ongoing interactions from amyloid research consortium to get 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 have been when you were initially starting this trial again back in late 2015 or early 2016?

Yes, so a lot in that question. So, certainly as you know and obviously I don’t want to speak about too much about other people's who work but you can go look at the amyloidosis research consortium and 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 clinically validated. Obviously that's different than regulatory you know regulatory validation and those does 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 dataset, how we will formulate that discussion at that time. I think over engaging in a conversation about the potential usefulness of a biomarker for a registration purpose. It absent data may actually solidify certain views that we wouldn't want to solidify at this point in time. So that said, I think there will be an opportunity certainly to inform the FDA of the sponsor trial results that would be expected as any trial finishes in any clinical programs, so that's I think pretty much again. But I think then the second question would be how actively to engage to the regulators with additional discussions. And frankly again I can't really provide any assurance on that it would be largely based on the strength of that PRONTO dataset.

Right, one thing to add Cannon in terms of one part of your question was just, the continuing education that as has gone through engaging with the FDA in terms of educating the relevance of NT-proBNP within the AL amyloidosis indication of disease versus general heart failure. And 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 set.

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 has shown last year, is that life chain induces an -- 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 is almost a unique toxicity of this misfolded forms of life chain at the level of heart fail the cardiomyocytes that's unlikely do taking the dynamic effects that's you'd expect in kind of a normal chronic heart failure patients. And so, it's starts to provide a biologic rationale as to why NT-proBNP levels maybe 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 best 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 the credible argument that this is sufficiently differentiated in AL amyloidosis relatively to chronic heart failure. And so this is why that type of research is so critically important for an overall data package. And obviously in an optimistic scenario a data file.

And can you just elaborate on that data 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 that because at the time, the data really providing a direct link between NT-proBNP and the toxicities associated with amyloid chain really hasn't been established back then?.

Well, there were some data out there. I don't want to short-change the team who in or out gets our research team obviously built up research already in existence. And there were number of groups most notably, the group from Pavia, Italy, another group at a Boston that has implicated on p38 MAP kinase pathways in this biology. And that data have been known for some time. Our team kind of took and moved it forward so that we understood the relationship there between some of these path ways and NT-proBNP. So I do want to give credit where credit is due, there were number of groups that has already made that initial observation link. 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.

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

Yes, so when people have looked at NT-proBNP response, they done it multiple different ways, they done it at various timeframes 3 months, 6 months, 12 months. People used that response and I think what we can say is across all of those analysis without any exception that I'm aware of NT-proBNP response predict survival following intervention. 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 newly diagnosed treatment naive 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 PRONTO, i.e. patients where they previously received chemo therapy and for one reason or another they brought back in to receive more active treatment. And in those studies again a fact that seeing at various time points it tends to be a lower response rates when you look at those patient populations, but full cavies there the study tend to be lower to sample size as well, so a little less certainty around the total with the quantification of the effect side.

And our next question comes from Steven Breazzano with Evercore. Your line is now open.

Maybe one on NEOD001, maybe just outline for us what you would 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?

So I think you can look to our powering to estimate where we were at least with the placebo so clearly what we had said was we were power to see 80% power 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 1/2 data, we were always in the 50% range. So it's anywhere from 47% or 46% plus all the way to 57% or 58%. But I would say generally trending around 50%. So it's a subtraction there and you find pretty easy to see where we ended up. We think that a pretty reasonable estimation in part because in newly diagnosed treatment naive patients you tend to see cardiac response rate 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 similar in the range of 0% to 15%. And so we think, we think we've been pretty reasonable in terms of how we've estimated that placebo type. And remember as well, we overenrolled the study by about 30% giving us some additional power to see the effect there as well. Your second question.

VITAL interim.

VITAL interim, yes, I mean at present, we don't have any interims plans 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 and we would conduct that.

Our next question comes from Bill Tanner with Cantor Fitzgerald. Your line is now open.

Gene, just wonder see if you could clarify a little bit the answer to last question. The question I was going to ask you 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 range of numbers that you think is very reasonable, so the people have some rational viewpoint as to what could be real? And then I had a bigger picture follow-up, if I could.

So I mean again what you can say is you can kind of calculate it from the way we powered this study and you know we think that's reasonable. So that's kind of where we felt it was reasonable. You know, one would need to -- and well I’ll be very careful to say here is there's no exact natural history here that exactly matches the PRONTO patient population. 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 you think the extrapolation is. Again newly diagnosed treatment naive patients getting a treatment for the first time will expect the highest response rates, those range is tend to be anywhere from about 17% to 35%. You go to previously treated and of course in PRONTO we're not treating newly diagnosed treatment naive patients we're treating previously treated patients. So then you go to previously treated patients and those ranges with smaller ends with 0% to 15% of across three 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 a kind of what did we expect perspective you can get there pretty easy on the math.

Okay now that makes sense, I appreciate that. And just thinking, you mentioned the R&D presentation and some new targets and if I look at your pipeline chart from that R&D data everything below 004 is in discovery. And if you had to look at the assets there and triage them and obviously a lot of the targets and the conditions are of interest to other companies, but if you had to triage those assets in terms of you know ones you felt like you really wanted to keep ones that you might want incubate de-risk a little bit incrementally and ones that you want to partner. How should we be thinking about those advancing in an expeditious manner?

I think though you bring up a good point. I mean I think VITAL and ALECT2 and A beta and Sortilin and TDP-43, I think there's natural kind of divide that I would like targets like ALECT2 we could actually take through ourselves and ultimately commercialized due to his orphan nature and small footprint. Actually even VITAL we can think about it because there is also PSP side of it versus the Alzheimer's side of it. But I think you know in terms of VITAL and A beta and like Sortilin you would think that sometime in the future, you would you know look to do -- look to start some discussions around partnering. But that being said you want to make sure you've reached some kind of either pharmecodynamic or proof-of-concept data on them to drive more value to your program. So I think we're going reserve exactly when we would go out and get it but that being said, I think eventually we look for commercial partner at some point with those auto indications.

And then maybe just last question. Gene, as relates you mentioned, with the antibody engineering obviously you're finding right epitope and trying to engineer the right ability. 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 FC receptor to get some kind of…

Yes, potentially, it depends on the target. So there will be opportunities where I think having FC for example FC gamma receptor interaction maybe 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 want to think about. So I think those are always same as we think about. For a lot these targets where you actually are want to remove the positive material, we actually like antibody recycling capabilities of full effective function antibody. We think it's important just from a circle metric perspective. You want to take advantage of normal antibody recycling and you want to actually induce macrophage to come in and phagocytes. One of the kind of interesting things about amyloid from my perspective is that these are made up of protein for the most part absent some of the hereditary mutations. And what that means is I mean it's tolerant 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 it's 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 and whatever tissue it's deposited in. And so we actually think that being able to induce phagocytosis being able to actually stimulate the main immune system to come in and clear the material actively, maybe 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 effective function. If a disease we know that not to be true then I think we think about FC engineering to kind a remove some of that function. But it's really a target-by-target discussion within the last.

Our next question comes from Jay Olsen with Oppenheimer. Your line is now open.

Two of them. The first is about PRX002. Can you please outline some of the key points of differentiation between PRX002 and the other alpha nuclei antibodies from bio optic and autoimmune?

Yes, well I can tell you that at least to my knowledge there hasn't been a lot published on those antibodies. We know it's little bit about them just from a presentations that the Biogen done around the neurimmune antibody or some of the work that BioArctic done. Just to kind of set the stage, I mean the characteristics that our antibody was selected for was first to buying to an epitope on alpha-synuclein that was found to be very important for us, some of the biologic activities that are thought to bedetrimental 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 cells of sub-transmission of alpha-synuclein. And we have been observed in some early studies that we could see some reduction of intraneural pathology of alpha-synuclein. Frank, we don’t exactly know what's driving that. But certainly there are some epitomes that do that and others that don’t. In fact in our experience, we made antibodies all different parts of the alpha-synuclein protein. You can move off the area where PRX002 interacts by just a couple of interacts. There is almost lost all biological activity. So, it's really important where you target that protein. And as much as I don’t know exactly where the Biogen molecule or the BioArctic molecules are targeting us, I can't really say much about that part of it. I think we are saying the same things though which is cell-to-cell transmission is important, aggregated side of forms of alpha-synuclein are important with respect to causing disease progression. And it's more than just a motor symptom, 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 draw direct comparisons for you. I'll just say that given our experience in the space, we started working in this space about 2003 published the first paper 2005. We feel confident that we've looked at antibodies that have lots of different ways of targeting alpha-synuclein that that targets different parts of the protein that targets different modifications of the protein. And we are pretty happy with how PRX2 acts across the entirety of the biology that we have been able to explore.

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 in last November, which I think generating a lot of interest. I was just curious about the timing can you help us to understand which of the assets in your discovery portfolio or for this alone? And then when should we expect to see some preclinical work on those compounds? And then eventually what will be the timing to those into the clinic?

So, clearly the two that we highlighted were the VITAL 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 were thought to actually play a significant role. So VITAL what we were highlighting there is that, we have a group of antibodies that to the best extent that we know target the VITAL protein in a way that’s different that everything else out there. And at least with respect to everything we have been able to do preclinical to date, it's provided targeting the VITAL protein in that way has provided us much more consistent biological effects than antibodies we have 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 likely to be third in prevalent following AL amyloidosis is first and then TTR second and then ALECT2 it 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 are starting to understand as a field the more we look for just the more folks see it in different geographic regions. And so clearly we're pushing both of those programs forward as well as some other things. We'll be continuing to generate preclinical data I’d expect you know we've always kind of pride 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 person that we're taking.

Our next question comes from Bert Hazlett with DTIG. Your line is now open.

Just coming back to 001 and PRONTO and VITAL for a second. Are there additional secondary endpoints beyond SF-36 Six-Minute Walk test that we should be considering or looking at or that you are considering that’s important as you discussed 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 endpoint but it's a different analysis. We'll be looking at some measures of persistency of effect, we’ll be doing some slope analysis for example to give us a sense of duration of effect, we'll be doing obviously these are the subset analysis not the secondaries, but for patients that have renal or and/or neuropathy at base line we’ll be looking to see if in fact dose organ systems are showing any benefit at all. Frankly I don't know what the sample size in those subset analyses would be, so I can't really set any expectations as to whether those will be meaningful or not. But you know again we saw obviously in the Phase 1/2, very nice activity across 3 organ systems, so clearly you know we want to continue to look it particularly in neuropathy and renal as we have these patients come in.

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

Great, thanks Skyler. 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.