Good day, ladies and gentlemen, and welcome to the Prothena Fourth Quarter and Full-Year 2018 Financial Results Conference Call. [Operator Instructions]. As a reminder, this conference call may be recorded. I would now like to turn the conference over to your host, Ms. Ellen Rose. Ma'am, you may begin.

Thank you, Valerie. Good afternoon, everyone, and welcome to Prothena's investor conference call to review our fourth quarter and full-year 2018 financial results and business progress, as well as our 2019 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 a Form 8-K filed today with the SEC. Speaking on today's call to discuss our 2018 pipeline programs and corporate activities, we have Dr. Gene Kinney, our President and Chief Executive Officer; Dr. Radhika Tripuraneni, our Chief Development Officer; and Dr. Wagner Zago, our Chief Scientific Officer. In addition, Tran Nguyen, our Chief Operating Officer and Chief Financial Officer, will review our financial results for the fourth quarter and full year of 2018 and 2019 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 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. And with that, I'd like to turn the call over to Gene.

Thank you, Ellen, and thank you all for being on our call this afternoon. I'm joined today by members of our management team to discuss 2018 and the upcoming milestones we are looking forward to in 2019 and beyond. But before we begin talking about specific activities, I'd like to first acknowledge the talent and dedication of our employees who drive our ability to execute our ambitious goal to help patients with devastating neurological diseases. During 2018, we welcomed new members to Prothena, including Radhika, and several key positions that strengthen our capabilities. I want to start our conversation today by recognizing the many individuals who have made significant contributions to Prothena through the years and thanking our employees for their ongoing commitment to advancing our science. During the past year, we have sharpened our focus in neuroscience, an area where we have deep domain expertise. Today, we are applying that expertise in innovative ways against novel targets with the potential to change the course of a spectrum of neurological diseases. As we continue to advance our broad pipeline of clinical and discovery stage programs, we remain committed to presenting and publishing our scientific -- in scientific forums at each stage of our work. We do this to raise awareness of our programs and also to advance the science and deepen the understanding of the disease areas we work in. We ended 2018 with a balance sheet that enables continued development of both our clinical and discovery programs through key milestones. In a moment, I'll turn the call over to Radhika and Wagner for a review of our pipeline, but I want to first provide you a brief update on NEOD001. In 2018, we discontinued our NEOD001 development program in AL amyloidosis. And of course this was enormously disappointing. We…

Hello, everyone. Thanks for the introduction, Gene. Today I will cover our two clinical stage programs, concizumab and PRX004. Concizumab, formerly known as PRX002 or RG7935, is in a Phase 2 clinical trial and is an investigational monoclonal antibody for the treatment of Parkinson's disease and other synucleinopathies. In 2013, we entered into a worldwide development and commercialization collaboration with Roche for concizumab. Parkinson's disease is the second most common neurodegenerative disease that affects an estimated 7 to 10 million people worldwide and its incidence continues to increase based on an aging population. Parkinson's is characterized by the neuronal accumulation of aggregated alpha-synuclein in both the central and peripheral nervous systems that results in neurodegeneration and a wide spectrum of progressive motor and non-motor symptoms that are persistent throughout the course of the disease. While the disease is most commonly known for motor symptoms such as bradykinesia, stiffness and tremor, non-motor symptoms, such as cognitive deficits, fatigue, sleep disturbances, constipation or hyposmia are also common and disabling. Current treatments for Parkinson's disease only address a subset of symptoms. Levodopa and dopamine agonists are primarily directed at managing the early motor symptoms, but these agents become less effective over time and do not address the underlying cause of the disease. Prasinezumab is being developed as a potentially first in class approach to slowing the underlying progressive neurodegeneration. Our antibody targets alpha-synuclein, a protein that is widely understood to be intricately involved in the onset and progression of Parkinson's disease. There is genetic evidence for a causal role of alpha-synuclein in Parkinson's diseases. Mutations in the synuclein protein sequence or duplication or triplication of the relevant gene lead to overproduction of alpha-synuclein and may facilitate alpha-synuclein aggregation and formation of intracellular pathology. The scientific community has also increased its understanding of how…

Thank you, Radhika. As Gene stated, we have ambitious goals. And in addition to the clinical stage programs that Radhika discussed, we are advancing our leading neuroscience discovery pipeline to drive long-term value. I am delighted to talk with you today about some of the work of our research group. Driven by our team's scientific expertise and compassion to patients, we are investigating new potential targets and therapeutic modalities to develop therapies for devastating diseases. The discovery pipeline is currently comprised of antibody approaches that target proteins implicated in pathogenesis of several neurodegenerative diseases. We apply our understanding of the biology to identify and optimally target proteins implicated in diseases and design unique and important antibodies to these proteins. Having the resources and flexibility to accelerate a diversified pipeline of investigational therapies is also critical, and in 2018, we entered in a strategic scientific research and development collaboration with Celgene that helps us achieve this. The collaboration leverages each company's core expertise in protein homeostasis and protein clearance to target the underlying cause of the many neurodegenerative diseases that have devastating consequences on society. The goal of collaboration with Celgene is focused on 3 discovery stage programs: tau, TDP-43 and a third undisclosed target. All 3 of these targets are implicated in a range of neurodegenerative diseases that currently have no disease modifying therapies, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, or ALS, chronic, traumatic encephalopathy, and progressive supranuclear palsy, among others. There is strong consensus that the type of sequential cell-to-cell transmission that Radhika described earlier for Parkinson's disease may also underlie the progression of several other neurodegenerative diseases. For example, transmission of pathology between different brain regions has also been proposed in Alzheimer's disease with beta amyloid and tau. More recently, cell-to-cell transmission of TDP-43 pathology has…

Thanks, Wagner. Today we reported favorable 2018 cash burn from operating and investing activities of approximately $30 million versus our updated 2018 guidance of $40 million to $50 million, where these figures included $110 million of cash provided by operating activities associated with the Celgene collaboration. This favorability was primarily driven by lower than expected expenses related to the NEOD001 program, including discontinuation costs and the company's reorganization, which were approximately $70 million versus our 2018 guidance of $80 million to $85 million. In 2018, we reported a net loss of $22.5 million and $155.6 million for the fourth quarter and full year of 2018 as compared to a net loss of $47.8 million and $153.2 million for the fourth quarter and full year of 2017. In 2018, net loss included a restructuring credit of $1.6 million for the fourth quarter of 2018 and restructuring charges of $16.1 million for the full year associated with the discontinuation of the NEOD001 program in April 2018. Net loss per share was $0.56 and $3.93 for the fourth quarter and full year of 2018 as compared to a net loss per share of $1.24 and $4.07 of the fourth quarter and full year of 2017. Included in the net loss for the fourth quarter and full year of 2018 was non-cash share-based compensation expense of $4.2 million and $27.0 million compared to $7.4 million and $26.8 million for the fourth quarter and full year of 2017. We reported total revenue of $0.2 million and $1.0 million for the fourth quarter and full year of 2018 from our collaboration with Roche as compared to total revenue of $0.2 million and $27.5 million for the fourth quarter and full year of 2017. The decrease in revenue for the full year was primarily due to achievement…

Thanks, Tran. So as we move forward in 2019 and beyond, we expect continued progress in our pipeline and look forward to coming back to you as we have data to report. Turning to a summary of our R&D milestones, prasinezumab, the Phase 2 PASADENA study is fully enrolled, and we now expect the last patient last visit in Part 1 of the study to occur at the end of this year. Based on this timing, we expect top line results from the study to be available in 2020. For PRX004, the Phase 1 study is progressing, and we expect to report preliminary safety, tolerability and pharmacodynamic data from the lower dose cohorts in the fourth quarter of this year. We're also making important advances in our discovery pipeline. We expect to initiate cell line development of lead candidates for both our tau program that is partnered with Celgene and our proprietary abeta program in 2019. And for our abeta program, we also expect to highlight preclinical data in the fourth quarter of this year. So at this time, we'll open the call for questions. Valerie?

[Operator Instructions]. Our first question comes from Christopher Marai of Nomura.

I was wondering if you could comment a little bit on the fourth quarter update on your TTR program, specifically around the pharmacodynamic data that you might be presenting. I understand that you're going to be able to give us some information on mis-TTR, but perhaps not over knockdown levels. Could you maybe contrast and compare the type of PD readout that we might see there versus some of the more knockdown oriented PD data that we've seen for other agents? Thank you.

Yes. Thanks for the question, Chris. Maybe I can start, and Radhika, you can jump in as well. So yes, I think it's an important distinction that you're making, Chris. I think most of what we've seen in the field has really been measurements of total TTR level. And as you can imagine, at least by our estimations, the bulk of that signal would be driven by the native forms of TTR, in other words, the tetrameric form of the protein. I'm not sure I'm aware of anyone that would argue that the tetrameric form of TTR is disease causing or is involved in the pathogenesis disorder. I think most believe that it's on the destabilization of that tetramer where those monomers then start to misfold, re-aggregate in an abnormal confirmation, and that's the part of the pathway that actually leads to disease. So the distinction then with what we're calling our mis-TTR assay is that to the best we've been able to establish thus far is it does not detect that normal tetrameric form of TTR. But what it specifically tends to see is the mis-forms, i.e. those monomer breakdown products through to the different misfolded forms that are soluble and circulating in blood of patients, in particular in the plasma. And so clearly we'll be using that in multiple ways this year, as Radhika kind of indicated in her remarks. We want to use it within the program, and then we think it will be important with respect to pharmacodynamic activity and understanding something about dose selection to move forward. But also as additional agents come into the marketplace and have a broader commercial uptake, understanding how the mis-TTR pool is changing in patients treated with those types of approaches will be very important as well, we believe. So maybe Radhika, do you want to speak a little bit about just how that's employed in the program and what we might expect this year?

Sure. Just as a reminder, this is a Phase 1 study and it's a 3 plus 3 dose escalation study in which there are a total of 6 cohorts. What we are hoping to share at the end of this year is data from the lower dose cohorts in the elements, as Gene and I have previously outlined, safety, tolerability, PK and of course the PD. The PD aspect, or the pharmacodynamic aspect, is definitely the mis-TTR that we're focused on analyzing. In contrast, and as Gene sort of indicated, the other compounds that are now commercially available target native TTR production, as such knockdown total TTR, whereas ours we hope will indicate based off the results that would actually reduce mis-TTR and actually leave total TTR levels normal. Now, we'll have to wait until the end of the year to actually see all that data and we look forward to sharing it with you, but we believe that's the key differential element. So in contrast, we're also having an additional effort which we sort of call as out of our study workstream where we're working with clinicians to obtain samples for patients who are also on therapeutics that might see what effect, if any, they may have on mis-TTR. And we believe that the combination of looking at those two data sets would give us a very good strategic perspective of how to best proceed with a PRX004 clinical development.

Okay. And just maybe one quick follow up, if I may. Given the unknowns I suppose currently about the commercial opportunity in TTR, how might you guys look at running a clinical program there? Are you -- where is the focus? Obviously there's two different cardiac subsets, as well as the polyneuropathy, and we'd be curious to hear your thoughts about where you might want to bring your asset. And then perhaps in terms of line of therapy or not stage of disease where your TTR drug might be most applicable. Thank you.

Yes, sure. So there are a number of questions in there, because I think first, just in terms of how we structured the program to date, clearly this initial Phase 1 study is primarily around safety, tolerability. Clearly PK is going to be important, and we are very interested in changes potentially in the mis-TTR measurements as well. We think that could inform us on a number of different levels, and obviously we need to see that data to really make any decisions on the optimal path forward. In particular, I think questions around whether you think about this on a standalone basis or whether you think about this in combination with either silencers or stabilizers I think is a very important question. And we hope to be informed by that both through the Phase 1 study results, as well as through, as part of the Phase 1, the pharmacodynamic assay results. And so I don't know that I can give you a definitive answer right now. I think the landscape is clearly evolving for TTR amyloidosis patients, which is a good thing. And clearly we believe that the mechanism of action of PRX004 is differentiated, yet still in a pathway where we know influencing that pathway leads to benefit in the disease. So we like that from a potential combination perspective, but at the same time, it doesn't necessarily rule out a future path where we also may evaluate PRX004 on a standalone basis.

Okay, thank you.

Our next question comes from Michael Yee of Jefferies.

Kolatchy Chicory [ph] on for Michael Yee. Just two questions here on our side. I guess based on your preclinical as well as your in vitro work, what level of mis-TTR reduction are you hoping to see at the low dose? And I guess on the second question is also earlier you did a great job highlighting some of the differences between your antibody approach to TTR amyloidosis in currently -- in some of the currently marketed silencing technology. I know it may be a little early, but from a clinical perspective, what do you hope to see there over time that could potentially differentiate your approach from those technologies? Thank you.

Yes. So two very important questions. So obviously, as we think about the clinical profile of the existing therapies -- Radhika, you can jump in here as well -- I think we have a lot of data now from both the Alnylam and the Akcea molecule in terms of what they do on hereditary forms of neuropathy in the disease. And of course we're learning more and more about the role of the stabilizers, particularly in cardiomyopathy patients. The recent tafamidis data I think was very interesting. And actually how some of the effects appeared both in terms of timing when we look at survival and the impact before 18 months versus after 18 months. But also when you look at some of the key secondary endpoints and some of the functional measures, maybe starting to separate in treated versus untreated or placebo patients, even at an earlier time point I think are quite interesting. The other component I'd look at in those spaces are what's happening in the maybe less severe patients relative to any of the given endpoints versus more severe patients. And I think you can start to pull out what the patient need is in those spaces. Then it becomes a relatively straightforward logic exercise to ask the question of whether either a combination approach or a standalone with PRX004 might fill some of those needs for the patient population. And obviously any clinical design would be focused on addressing those residual needs. And so those are the sorts of things we're looking for. We think this data that will come in front of us that we'll be able to see and have in front of us in terms of the commercial uptake and how these different therapeutics are used, and that will obviously also go into informing exactly how we would position PRX004 moving forward. That said, as we talked about earlier, I think it does have a differentiated and unique mechanism of action. And given where it works in the TTR pathway, we certainly see it as not being competitive to those other agents, but rather complementary on that pathway, so we think that that's important. And I don't know if Wagner, Radhika, you want to add to that, but I think it's -- we're still encouraged by where PRX004 interacts in that space.

Yes, and your question about the mis-TTR and what is our expectation. We share the results with the field, and based on the interaction of the antibody with these misfolded forms, we do expect indirect targeting of these forms. And we increase our confidence that the doses that were tested, that are being tested now in our Phase 1, I would think the ranges that we expect for our [indiscernible] approach. There are a number of elements that are won't seen humans, so we cannot fully reflect in an innovative assay. And just to say the least pharmacokinetics, clearance mechanisms, all of those could contribute to the level of occupancy and availability of those forms involved. So we will have to wait for the data coming from the clinical trials. But I think we can say with confidence that the ranges, the dose ranges that we selected for the trial are appropriate.

The only I think additional item maybe to bring the previous response a little bit more into clinical perspective is I think there's a unique opportunity for PRX004. Obviously as a clinician, we're thrilled that there have been two recent advances. Two new therapeutics have been come onto the space particularly here in the U.S. Tafamidis shared some really impressive data that I think has us really looking at the disease space. That being said, there still is I think a clinical need, as Gene sort of alluded to, when you look at the data sets in terms of how do we better treat this patient population and something these patients who've been underserved have an opportunity and a right to ask for. And we look forward to hopefully developing a compound that sort of supports that and can deliver that for them. The reality is what you can see from compounds such as patisiran and inotersen is they are on target and on pathway as it relates to affecting the total TTR production, while ours is a bit further down in the pathway and really focuses on that non-native form, the pathogenic components that we believe, and I think many believe in the field, are actually really the issue at hand. So including that, that's also deposited in the organ, which is a bit more differentiated from perhaps the Onpattro or inotersen approaches. Now, the reality is we have to sort of see how that plays through in the clinical data, and that's something we're definitely very excited to study and look forward to sharing with you when the time is right.

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

Maybe two on the PASADENA trial. Was wondering first on the prior Phase 1 data sets of PRX002 both in healthy volunteers as well as the Parkinson's patients, was wondering sort of what you saw as the most compelling efficacy data that's been generated so far or PK/PD data. And then second, thinking about the potential outcomes of the PASADENA trial, and given the mechanistic rationale for targeting amyloid or aggregated proteins suggest that it might take quite a long time to sort of see benefit from this process. What do you think we need to see from PASADENA to justify potentially moving forward into a larger Phase 3?

Yes, very good questions. So maybe I can just start on the earlier studies. And obviously, healthy volunteer study or a 3-month study, and I think you kind of alluded to this in the second part of your question, clearly efficacy was not our focus of what we were looking at in those early studies. What we really wanted to know from the early studies was where we could go with respect to dose level, what we would see in terms of central penetration as per CSF levels, and could we actually evidence that we were engaging alpha-synuclein and do so in a way that could be done safely in patients. And so that was really the focus of the Phase 1 study. As a reminder, even the Phase 1b was a 3-month study where patients received 3 doses, and in that study, I don't remember the exact number, but a substantial number of those patients were on concomitant dopaminergic replacement therapy at the same time. So what we saw there, of course, and Radhika alluded to this in her comments, was in the blood of those patients a reduction of free alpha-synuclein I think up to a maximum about 97%, which is near complete reduction of free alpha-synuclein at the higher dose levels, which was both time and dose level dependent. And of course that's encouraging with respect to the safety profile we saw at equivalent dose levels, and so we were encouraged by that. I think the other thing that was alluded to in the comments was the idea, and I think Wagner had mentioned this, that when we look at the brain penetration levels, or the central nervous system penetration levels as assessed by CSF levels, we actually saw on a percentage basis higher levels than we…

Our next question comes from Jay Olson of Oppenheimer.

Hi, this is Matt on for Jay. Thanks for taking the question. I know you touched on it already, but could you please remind us of how the clinical profile of PRX004 could be differentiated from tafamidis, patisiran and inotersen, and how that might ultimately, depending on the data, inform your cell strategy?

Absolutely. So the last part of your question is how it informs what, I'm sorry?

Our go-forward strategy.

Go-forward strategy. Got it. Okay. So Radhika, do you want to cover?

Yes, sure. So obviously the therapeutics you're talking about employ across a full range of the pathway. And just as a reminder, before we start talking about a therapeutic, the pathway is such that the liver produces the normal functioning protein, or TTR. That protein is usually in a tetrameric form and is sort of a normal functioning protein. And many of those in the room and probably on the call, the reality is that unfortunately for these patients, particularly those whether they have a mutation or perhaps even in wild type patients, that tetramer falls apart or disassociates and accumulates either in from their monomeric formation into misfolded proteins and ultimately accumulate across various organ systems that result in dysfunction and severe disability for the patients. So with that pathway in place, you can envision a couple areas where therapeutics could play. Patisiran and inotersen are in a category that we refer to as RNAi therapies or silencers or antisense therapies where they basically target the liver and reduce total TTR production, and thereby there is a certain level of expectation or assumption that it therefore sort of stops the availability of TTR from misfolding or becoming pathogenic. Stabilizers, such as tafamidis, are intended to basically stabilize the tetramer, the normal functioning protein, and basically prevent it from falling it apart. In contrast, PRX004 works, as I mentioned earlier, a little bit more downstream on the pathway. So it's really focused on the misfolded or the non-native forms of the protein, including that which is deposited in the organ. So it directly targets those specific forms. It leaves the normal functioning tetramer alone, and the intention is that with the antibody function, that it's able to then activate and clear that misfolded protein that's within the body. So, that's sort of how I'd simply put kind of the element of differentiation. Obviously the patisiran, inotersen and tafamidis have all come with clinical data. And we look forward to sharing ours, albeit a Phase 1 study, some data from the lower dose cohorts at the end of the year that might give us some better insights as to how our clinical compound might be a bit more in play, but that's how I'd sort of describe the clinical difference between the landscape right now.

That's really helpful. Thank you. And one second one real quick, if you can. Just some color on the timing of moving the additional development candidates into the clinic, tau, et cetera. That would be great.

I think as of today, what we're saying is we'll move tau and abeta into cell line development this year. That's what we'll initiate. As you know, antibodies from a CMC perspective take time to make clinical supply, and I think there's a time period. And actually I think as we have more to update there as we move ourselves through the CMC, we'll give more of a specific update as to when to expect it in the clinic.

Our next question comes from Robert Hazlett of BTIG.

Just one on the early phase abeta development program. Just given the experience that your team has in that field, could you just give us the sense -- I know we're going to get data later this year, but could you just give us a sense of how that program might be differentiated versus what's going on in the field? And then just strategically with that program, given the capital requirements that would be contemplated for such a program in later stage development, even though you have a ton of cash right now, is that a core asset, or could that be partnered as well?

So maybe I'll -- Bert, thank you for the question. Maybe I'll answer the second part of your question first. But from a standpoint of how do we think long term about abeta and some of the neurodegenerative indications clearly in Alzheimer's, I think what we like about the clinical program and the aspects of it in the early parts of the year is we have a PET tracer to help guide us in the early parts of our clinical trials from the Phase 1 perspective. And clearly there's some also -- like the PRIME trial from Biogen, aducanumab has given us a roadmap as to how to think about clinical outcomes in early clinical stage trials. Ultimately, I think you're bringing up a good point, but I think we'll cross that -- those are things that we'll have to evaluate as we bring in clinical data to inform us in how to move forward. But I think clearly partnering and collaborating as we've done on tau would be high potential going forward in an abeta program.

And in terms of what we think is going to be differentiating our programs, our abeta program with other programs. And you know very well that we've been intimately related to this field since the beginning since the early days, and we are extremely excited with the latest suggestions that came from aducanumab trials. And I think taking all of that together, including the outcomes from solanezumab and crenezumab recently, we are convinced that in order for an antibody to have a higher probability of changing the clinical outcome of this patient population, both removal of amyloid plaques and targeting the soluble aggregates is an important aspect. And the antibodies that we are developing now and we plan to move forward into cell line development retain those qualities. So the ability to clear plaques, the ability to target soluble aggregates in a single entity. And since we are coming back to this space, we have the opportunity to create molecules that are superior in several angles. One, it's a natural to believe that you can increase the potency of an antibody versus the antibodies that are developed by other companies. We can also increase the efficacy of these antibodies in preventing, for example, the binding of toxic aggregates to neurons. And increasing even -- now on a more basic level, increasing the pharmacokinetics of the antibodies, which the antibodies that are now currently being tested are not -- we don't believe they are optimal. So these are just examples, but we are taking the advantage of being in this stage and observing how the field is developing, taking advantage of all that information, design the absolute best antibodies with in mind not only in terms of potency, but what is meaningful for the patient population that we are trying to target and ultimately the society.

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

Thank you, Valerie, and thank you all for joining us this afternoon. We appreciate your interest in Prothena, and over the coming months, we look forward to sharing updates on our programs. Thank you all very much.

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you for your participant and have a wonderful day. You may all disconnect.