Prothena Corporation plc (PRTA) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Prothena AD/PD Investor Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your host today, Ellen Rose, Head of Communications. Please go ahead.

Thank you, Sarah. Hello, everyone, and welcome to Prothena's investor conference call to review new results from our pipeline that were selected for oral presentations this week at the 15th International Conference on Alzheimer's and Parkinson's diseases, or AD/PD. On today's call is Dr. Gene Kinney, our President and Chief Executive Officer, will provide introductory remarks. Following Gene's comments, Dr. Phil Dolan, Senior Director and Head of Exploratory Research at Prothena, will present new preclinical data describing PRX005, our anti-tau immunotherapy for the potential treatment of Alzheimer's disease. Dr. Radhika Tripuraneni, our Chief Development Officer, will then highlight the new data from prespecified subgroup analyses from the Phase II PASADENA study of prasinezumab in patients with early Parkinson's disease being presented at AD/PD by our colleagues at Roche. Gene will then make closing remarks, and we will open the call for Q&A. For Q&A, we will be joined by Dr. Wagner Zago, our Chief Scientific Officer; and Tran Nguyen, our Chief Operating Officer and Chief Financial Officer. The slides from this webcast can be found on the Investors page of our website in the Events and Presentations section. Before we begin, I would like to remind you that during the course of today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. With that, I'd like to turn the call over to Gene.

Thank you, Ellen, and thank you all for joining us today to discuss new data that we highlighted this week at AD/PD on 2 programs in our neurodegenerative portfolio. We're excited to have presented for the first time preclinical data on PRX005, our novel anti-tau antibody for the potential treatment of Alzheimer's disease that is being developed as part of our worldwide global neuroscience collaboration with Bristol-Myers Squibb. As Phil will describe shortly, we have employed our unbiased and empirical protein mapping and antibody screening strategy to elucidate a key epitope within the microtubule binding region of tau. Our preclinical data demonstrates that PRX005 completely blocks tau internalization and robustly reduces tau pathology and downstream behavioral deficits when tested in multiple in vitro and in vivo models. We expect to file an IND and initiate a Phase I study of PRX005 in the third quarter of this year. In addition to these data on PRX005, our colleagues at Roche presented new analyses from the Phase II PASADENA study of prasinezumab in patients with early Parkinson's disease. Prasinezumab is the first anti alpha-synuclein antibody to significantly slow progression on measures of Parkinson's disease. Primary results from Part 1 of PASADENA were presented last year at the Movement Disorder Society Congress, demonstrating signals of efficacy on multiple prespecified secondary and exploratory clinical endpoints, including measures of motor function and biomarkers. This included a 35% reduced decline in motor function versus placebo at 1 year by central rating, as measured by the MDS-UPDRS Part III endpoint. This prasinezumab benefit was confirmed by site rating, bradykinesia subscore, digital measures of motor function and delayed time to clinically meaningful worsening of motor progression. At AD/PD this week, new prespecified analyses were presented, demonstrating that prasinezumab had an even greater effect on slowing clinical decline in subgroups that exhibit faster disease progression. As we've discussed in the context of many other clinical studies, to demonstrate the beneficial effect of an intervention designed to slow the course of the disease, there must be adequate disease progression in the placebo arm. In patients with early Parkinson's disease, progression in a 1-year time frame is most evident on MDS-UPDRS Part III relative to other components of the UPDRS scale. And as Radhika will discuss, we've now disclosed new data that demonstrates an even greater effect of prasinezumab on various measures within faster progressing subgroups, which provided the opportunity to assess an effect with a higher signal to noise. Roche also presented new data from the smartphone-based digital health technology tool utilized in PASADENA, which remotely and continuously monitored symptoms of Parkinson's disease. These results were consistent with a potentially disease-modifying effect of prasinezumab and show a divergence of slopes demonstrating less bradykinesia progression with prasinezumab as measured by this method. These new data further support the potential of prasinezumab for the treatment of Parkinson's disease. And as announced last year, Roche and Prothena plan to advance prasinezumab into a late-stage Phase IIb study called PADOVA in the second quarter of this year. PRX005 and prasinezumab are immunotherapies discovered through our proven protein dysregulation scientific platform, which specifically targets pathogenic forms of proteins that cause disease. This platform differentiates Prothena and positions us as a leader in the development of therapies for rare peripheral amyloid and neurodegenerative diseases caused by protein dysregulation. The development and preclinical testing of PRX005 exemplifies our highly methodical process. We first identified the optimal epitope to target on a pathogenic protein and then engineer molecules that interact with that epitope in a way that is most likely to intercept or halt the underlying disease process. After thorough evaluation of a target, we advance discovery candidates, such as PRX005, only after we have demonstrated consistent and robust biological outcomes in a variety of preclinical disease-relevant models. We've now advanced several molecules in our pipeline based on this scientific platform. Across multiple programs, this approach has led to investigational therapies that influence biology in a way that results in meaningful clinical benefit for patients. The idea that targeting the optimal epitope with an appropriately engineered molecule can result in clinical benefit is clearly illustrated by prasinezumab. As we'll review today, prasinezumab, which targets the C-terminal of alpha synuclein, continues to demonstrate promising clinical results in patients with Parkinson's disease. In contrast, a different anti alpha-synuclein antibody, Biogen's cinpanemab, which targets the N-terminus of the protein, was recently discontinued from development due to lack of efficacy in a Phase II proof-of-concept study. This finding was consistent with our own preclinical experience, which found that targeting the N-terminus was suboptimal. The ability to consistently translate our science into clinical proof-of-concept is a distinguishing feature of Prothena today. Our growing pipeline includes therapies with blockbuster potential for diseases with enormous unmet medical need that lack disease-modifying approaches. And importantly, our strong capital position provides a foundation to fund our growing pipeline as we transition to becoming a fully integrated research, development and commercial organization. This year marks the 15th AD/PD conference, and I believe I've been to just about all of them. In all these years, I've never been as confident as I am today that we are on the cusp of a meaningful advance in the treatment of Alzheimer's and Parkinson's. I'm optimistic that approval of Biogen's aducanumab as the first disease-modifying therapy for Alzheimer's is likely. But this is just the first step. What will be needed to treat the more than 35 million people around the world with this devastating disease are approaches like PRX012, our more potent next-generation subcutaneous anti-ABeta antibody. In Parkinson's, available therapies are purely symptomatic with no treatments that target the underlying cause and progression of the disease. We believe that prasinezumab can change this and offer a paradigm shift in the treatment of Parkinson's disease, the most common neurodegenerative movement disorder. We're very pleased to highlight new data from these 2 programs, which we look forward to advancing as potential new therapies for Alzheimer's and Parkinson's disease. So with that introduction, I'll turn the call over to Phil. Phil?

Thanks, Gene. I'm happy to join you today to present the work we shared at AD/PD in an oral presentation titled, Microtubule Binding Region-specific Antibody PRX005 Prevents Pathological Tau Progression via a Blockade of Neuronal Internalization. To start, there are a number of key studies and observations that support an anti-tau immunotherapy for the treatment of Alzheimer's disease. The progression of tau pathology in Alzheimer's, as defined by histopathology and PET studies, has indicated that progression of pathological lesions correlates well with clinical symptom progression. In addition, the regions of the brain most affected by tau pathology are those that are most responsible for learning and memory. A number of studies performed in vitro and in vivo have supported the concept that this tau progression and transmission can be explained by the release of pathogenic tau in the extracellular space. PRX005 acts by binding with high affinity to the microtubule binding region or MTBR of tau, and was designed to reduce neurotoxicity, prevent cell-to-cell transmission and promote clearance of extracellular tau. As Gene described, we employ an unbiased and empirical protein mapping method to target pathological proteins that cause disease. In applying our scientific platform to tau, we tested a great number of high affinity antibodies targeting different regions along the tau protein in a variety of in vitro and in vivo efficacy models. At the left side of this slide, you see a small subset of these antibodies diagrammed against various tau domains. This approach resulted in our discovery of a region that acted as a hotspot for both inhibition of tau internalization and neurotoxicity. In this figure, different regions of the protein are color coded, and the y-axis represents tau internalization in the cellular model following application of an antibody targeting the indicated region. Reduction of the signal indicates that internalization has been inhibited and the red triangles represent antibodies that also demonstrated reductions in tau induced toxicity. When the results of these assays were examined, 1 specific area of tau found to be the most effective region to target within the microtubule binding domain that is depicted in light blue, and this is where PRX005 binds. Results from experiments using the murine version of PRX005 are displayed at right. At top, you see that PRX005 completely blocks tau internalization in a cellular assay, and that inhibition occurs at substoichiometric ratios. At bottom, we show the treatment of rat primary neurons with murine PRX005 protects against tau-induced neurotoxicity. This was measured using 2 different cytotoxicity assays. I'll pause here to note that recently announced results from a different anti-tau antibody, AC Immune's semorinemab, which targets the N-terminus of the tau protein did not meet the co-primary or secondary efficacy endpoints in a Phase II study. This finding was consistent with our own experience, which found that targeting the N-terminus of tau resulted in suboptimal efficacy in preclinical models. A number of additional studies have further validated the importance of the tau MTBR region in the development and progression of Alzheimer's pathology. Importantly, the presence of tau fragments containing MTBR and extracellular fluids has been confirmed in patients and is associated with disease. In particular, our recent study from Randy Batman's lab at Washington University, examined fragments of tau in CSF and determined that MTBR fragments positively correlated with cognitive deficits in patients with Alzheimer's to a greater extent than other assessed biomarkers. The presence and importance of the MTBR in the progression of Alzheimer's disease has been further confirmed by the lab of Kaj Blennow and others. The reason the MTBR would be a critical region involved in the regulation of cell-to-cell transmission is explained by the mechanism of tau internalization, which has been described in a number of studies. NMR interaction studies indicate that tau interacts with heparan sulfate proteoglycan over a broad interface and this interaction is critical for both tau secretion and uptake. Thus, an antibody that binds the MTBR may prevent pathogenesis by blocking these steps. And in fact, as you can see in the graph on the right, that's what we see. PRX005 potently blocks the binding of tau to an HSPG analog. PRX005 was derived from our scientific platform using our unbiased screening method to select an epitope that results in binding to all forms of pathogenic tau, specifically phosphorylated tau and nonphosphorylated tau, and importantly, all 6 splice isoforms, to an equivalent degree. This meaningfully differentiates PRX005 from other anti-tau antibodies previously studied or currently in development. We also tested PRX005 against an array of Alzheimer's donor tissue samples and demonstrated reactivity to pathological features in all samples, and the examples are shown here on the right. For in vivo validation of efficacy, we use both of the commonly used paradigms and therapeutic evaluation of tau antibodies, treatment in aging transgenic mice and a model of seeding and spreading induced by injections of tau aggregates purified from Alzheimer's brains. We elected to use both models in our evaluation of efficacy in part due to recent reports that different mechanisms may be involved in tau secretion and internalization. By utilizing models that include either the introduction of pathology by exogenous but disease-relevant aggregated tau or by tau spontaneously secreted and transmitted from neurons, our evaluation covered both of these potential mechanisms. Here, you can see the results from a long-term passive administration study in which transgenic mice that exhibit accumulation of tau pathology in the brain stem and display a resulting motor impairment are treated with the murine form of PRX005. Treatment begins at the initiation of tau accumulation into aggregates in neurons. After the treatment period, mice are analyzed on both pathological and behavioral endpoints. In the graphs, you can see the results of this treatment. The effects of the murine form of PRX005 is depicted in red and is compared to vehicle and a nonreactive isotype control. In the behavioral graph to the left, mice treated with the murine form of PRX005 demonstrated functional benefit in a test designed to measure the motor impairment caused by tau pathology. The graph on the right demonstrates that treatment with PRX 5 results in a significant reduction of tau pathology as measured by 2 different tau markers when compared to either vehicle or the antibody control. As mentioned, our seeding model included unilateral injection of AD-derived brain extracts into the brains of PS19 mice with measurement of pathology in the ipsilateral and contralateral hippocampi. Systemic treatment with the murine form of PRX005 resulted in reduced pathological development in both hemispheres, confirming efficacy of PRX005 in blocking tau uptake and transmission in this tau seeding model. An important point to mention is that in these in vivo studies, we used a murine form of PRX005 that has full effector function, which is the equivalent of the humanized PRX005 IgG1 antibody. We determined that a full effector function antibody not only promoted the faster clearance of tau aggregates in vitro versus a reduced effector antibody, but also it led to better efficacy in vivo. This is an important point an antibody with reduced effector function resulted in a suboptimal profile. Thus, we are confident that with the combination of targeting the right epitope and ability to rapidly clear pathogenic tau, PRX005 has a higher probability of slowing clinical decline in Alzheimer's disease versus other tau antibodies. To summarize, our epitope mapping and selection process included antibodies spanning the tau molecule and indicated a particular region within the MTBR was optimal for prevention of tau internalization and toxicity. PRX005, which arose from these efforts, demonstrated a superior profile in a number of in vitro assays, which translated in in vivo efficacy experiments. The superior performance in the number of in vitro and in vivo assays supports the advancement of PRX005 for the potential treatment of Alzheimer's disease. I'd like to thank our coauthors for all of their efforts and acknowledge the contributions of our collaborators at Bristol-Myers Squibb. With that, I'll turn the call over to Radhika, who will provide highlights on the new data from the PASADENA study of prasinezumab that were also presented at AD/PD.

Thanks, Phil. I'm pleased to discuss the 2 presentations by our colleagues at Roche at AD/PD. First, we'll highlight the new data from the prespecified subgroups of patients with faster progressing disease that demonstrated an even more evident slowing of clinical decline in prasinezumab treated patients. As you know, the ability to demonstrate a beneficial effect of an intervention depends on the ability to measure disease progression. Simply put, there needs to be evidence of progression in order to demonstrate a treatment effect. The PPMI natural history database has shown that progression over 1 year in an early PD population on the MDS-UPDRS total score is primarily driven by progression in Part III. This is confirmed in the placebo arm or the PASADENA study. You'll recall that in the primary results from the PASADENA study we announced last year, we saw an up to 35% slowing of clinical decline with prasinezumab on MDS-UPDRS Part III by central rating. For this new analysis, we looked at 2 faster progressing subgroups defined as those patients on the symptomatic treatment of MAO-B inhibitors and also by the sub phenotype called Diffuse Malignant, which I'll explain a bit more later. In these 2 prespecified subgroups, slowing of clinical decline with prasinezumab was even more evident on both MDS-UPDRS Part III and the PASADENA digital motor score endpoint. As a reminder, PASADENA is a 2-point -- a 2-part Phase II study. Part 1 is a randomized, double-blind, placebo-controlled 3-arm study and is designed to evaluate the efficacy and safety of prasinezumab in patients over 52 weeks. In Part 1 of the study, patients were allowed to be on stable dose of MAO-B inhibitor but were not expected to require dopaminergic therapy such as levodopa for at least 52 weeks. Part 2 of the study is a 52-week extension phase in which all patients are on active treatment. Part 2 of PASADENA is expected to complement our knowledge about safety. PPMI is a global landmark observational clinical study designed to comprehensively evaluate PD cohorts using imaging, biological sampling and clinical and behavioral assessments to identify biomarkers of Parkinson's disease progression. Here you see data from the PPMI data set that indicates that the total score of MDS-UPDRS change over 1 year is primarily driven by change in MDS-UPDRS Part III in an early stage PD population. This was confirmed by the data from PASADENA. There was minimal change in the Part I and Part II over the course of the year. And for a drug that is not symptomatic, it would be hard to see an effect on a scale that doesn't change at 1 year. So the signal-to-noise is pretty small for this population, it would require a very large sample size to show any type of signal. In contrast, there was a more robust change in Part III, where a robust signal of efficacy with prasinezumab was observed. There are various ways to define faster progressing subgroups. We prespecified these subgroups to increase the ability to detect a greater treatment effect in a proof-of-concept study. 2 subgroups were prespecified for the purpose in the PASADENA study. The first was patients on a stable dose of MAO-B inhibitors. The other was a sub phenotype of Diffuse Malignant. The Diffuse Malignant phenotype are comprised of patients scoring in the 75th percentile on motor scales and have at least 1 score in the 75th percentile on nonmotor scales or are in the 75th percentile on all 3 non-motor scales. We assessed both the endpoints of MDS-UPDRS Part III and the PASADENA digital motor score in these prespecified subgroups. As Dr. Gennaro Pagano of Roche pointed out in his presentation at AD/PD, as seeing effect on progression requires having a higher signal to noise, you should see more effect on patients that progress the most. And in fact, in line with our hypothesis, this is what we saw when we looked at the results on the MDS-UPDRS Part III in these 2 faster progressing subgroups. On this slide, you see results on MDS-UPDRS Part III by site rating. Starting on the left, are results from the total PASADENA study population of 316 patients, where slowing of clinical decline in prasinezumab pools was 25% versus placebo at week 52. And in the center, you can see approximately 40% effect in the MAO-B inhibitor group -- subgroup, and on the right, an approximately 60% effect for the Diffuse Malignant subgroup. I'll also note that in these subgroups, the change at 52 weeks in the placebo arm that you see noted in blue at the top each graph is consistent with the data from the PPMI analysis. Our hypothesis that prasinezumab was able to more evidently slow clinical decline in individuals who progressed faster was further confirmed by digital motor scores. In the total study population, slowing of clinical decline with prasinezumab pooled was 25% versus placebo, slowing of clinical decline in MAO-B treated patients was 26% versus placebo and in Diffuse Malignant subtype, it was nearly 36% versus placebo. The full presentation is included in the appendix, which is available on our website. I'll turn now to the second pressing news of our presentation that highlights new data from PASADENA gathered with Roche's remote digital monitoring technology. One of the major challenges in clinical drug development for Parkinson's disease is that fluctuating nature of the motor symptoms make it difficult to quantify disease progression and a potential drug effect based on infrequent clinic visits. Digital health technology tools may offer a potential solution to this challenge because they enable remote and therefore frequent assessments. These assessments of motor signs and severity can take place where patients live and work, increasing the ecological validity of the measurements. These sensors in smartphones and smartwatches appear to be highly sensitive to the motor manifestations and may provide highly sensitive markers of disease progression and treatment response. Roche's mobile application was piloted in our Phase I program and an improved second-generation app was deployed in the PASADENA study to measure core motor symptoms and signs of Parkinson's disease remotely, continuously and objectively. Results from the data gathered to date show that the daily quantification via this mobile app in early stage PD patients demonstrate a divergence of slopes in bradykinesia progression that favors prasinezumab. These results are consistent with the potential disease-modifying effect of prasinezumab and are in line with the results from Part I of PASADENA that we shared last year. Specifically, as shown here, there was less bradykinesia progression with prasinezumab as measured by the mobile digital app. This is measured through a number of assessments of symptoms of bradykinesia. On the left, you see results of an assessment of speeded tapping variability, an active measure of how quickly and consistently a patient can tap their finger. On the right, you see results from a passively assessed measure of hand gesture that is a component of bradykinesia. Again, you can find a full presentation from AD/PD in the appendix section. We continue to be very encouraged about prasinezumab's potential to be the first disease-modifying therapy for Parkinson's disease, and we look forward to the start of a Phase II PADOVA study quite soon. With that, I'll turn it back to Gene.

Thank you, Radhika. We are excited by these new data that further support the advancement of these 2 programs. PRX005 and prasinezumab were both discovered through our proven protein dysregulation scientific platform, which provides an engine for sustainable growth. This year, we expect 3 programs to initiate late-stage clinical studies. In addition to the Phase IIb PADOVA study of prasinezumab, we expect to initiate the confirmatory Phase III AFFIRM-AL study of birtamimab in Al amyloidosis and also a Phase II/III study of PRX004 in ATTR amyloidosis. Beyond these milestones, our internal R&D team is advancing as many as 6 INDs for new molecules over the next 3 years, including the IND submission and clinical study start for PRX005 in the third quarter of this year. A combination of potential payments resulting from our collaborations with Roche and Bristol-Myers Squibb as well as our existing robust cash position, provide us the ability to fund our programs through key milestones. Our growing pipeline with programs at every stage of development facilitates our transition to a fully integrated research, development and commercial biotechnology company. Over the past year, our team has delivered multiple clinical milestones, further positioning Prothena as a leader in protein dysregulation. In addition to the upcoming milestones for PRX005 and prasinezumab, we have a number of additional expected milestones and catalysts over the coming year, which are highlighted here. We plan to initiate our AFFIRM-AL study for birtamimab, our most advanced program in mid-2021, and also to report new analyses from the previous VITAL study at a medical conference. As mentioned previously, the start of the Phase IIb PADOVA study of prasinezumab is in the second quarter of this year. I'll note that upon dosing of the first patient in this study, Prothena will earn a $60 million clinical milestone payment. For PRX004, the initiation of the Phase II/III study in patients with ATTR cardiomyopathy is targeted for the fourth quarter of this year, and we will present results from our Phase I study at an upcoming medical conference. Our portfolio of Alzheimer's disease programs has also advanced. Building on our foundational science in the discovery and development of antibodies and vaccines, we continue to be highly active in this space, with 4 molecules in Alzheimer's disease, including antibody, vaccine, and small molecule approaches. As mentioned, we are looking forward to the IND filing and setting initiation for PRX005 in the third quarter of this year, with a potential $80 million US option payment from Bristol-Myers Squibb at IND filing. We are also looking forward to an IND filing in the first quarter of 2022 for our next generation high-potency anti-ABeta antibody, PRX012, which is being developed for subcutaneous administration. We're excited about the year ahead. Our team has the capability to drive transformation innovation for some of the most devastating diseases affecting society today. And we look forward to providing updates on our programs as they progress. So at this time, we'll open the call for questions.

[Operator Instructions] Our first question comes from the line of Michael Yee with Jefferies.

I had 2 questions from these presentations of AD/PD. One was about the learnings from this subgroup analysis and what was incorporated into the PODOVA design. Now that, that is up on clinicaltrials.gov, maybe you can just talk about the design of [indiscernible] and what were the most important learnings to help you with giving us confidence on a positive outcome? And then on tau, just a quick question. I think even in your own slides you talk about how there are some others going after this C-terminus region as well. Can you just comment on the differentiation at all relative to some of the other players -- J&J, Roche, et cetera, et cetera?

Yes. That's great. Thanks for the questions Mike. And -- so let me maybe address the first question, and I can ask Radhika to also comment. And then we can talk a little bit about just epitope selection and maybe, I think Phil can help us with that as well. So just a quick comment on some learnings. I mean I think one of the things that you'll see since this is now -- the PADOVA study is now published on clinicaltrials.gov. I think we have the NCT number in the presentation so you can take a look at that is the primary outcome measure. And so one of the things that we found to be pretty interesting is the slowing of the time to meaningful progression on motor symptoms. So this is defined as a 5-point progression on the MDS-UPDRS Part III. So clearly, having that part of the UPDRS scale progressing over that early time period in these patients early in their disease course is something that provides us with sensitivity and thinking about a time to progression type of approach also makes it a very meaningful endpoint when you think about how patients are feeling with respect to progression. But maybe Radhika, do you want to add any additional color on that?

Yes. Thanks, Gene. I think the question is definitely a fair question. Obviously, with PADOVA starting in the near future there are a fair amount of learnings that we can take. But the clear dynamic here is clearly looking at patients that are enriched in such a way that you can actually see that change in MDS-UPDRS. So I think, clearly, the fact that we're focusing on part 3 overall and as we think about a patient population, both the learnings from the subgroup as well as, in essence, the initial analysis or primary analysis that we released and shared with our partner, Roche last year, I think, are our key components. I think the plan right now is, we're looking forward to sharing additional details, more specifics probably, as I suspect that's what you're looking for on PADOVA when the study actually starts. So we'll do that in partnership with Roche at that time.

And I think, Mike...

Yes, just MAO-B inhibitors it could probably be the obvious one, right? I think that's the key takeaway in terms of speed of decline. Is that fair?

Yes. Absolutely. I think the folks that felt like they needed a symptomatic treatment in this study, although, we asked individuals in PASADENA to not be taking dopamine replacement therapy which is actually not an exclusion in the move forward PADOVA study. But clearly, patients themself that they needed MAO-B inhibitor use -- did progress more rapidly. And I think that gave us the better opportunity to evidence benefit as you're pointing out. So I think that's clear from the data. I think your other question, Mike, was around epitopes and just relative to other groups out there that might be focused in different regions and I'd point out, even as folks are focused into more of the carboxy-terminal epitopes of the tau protein. Not all of those carboxy terminal epitopes are equal. It's a protein that can be as long as 441 amino acid. There are multiple domains to think about. There are a number of companies that are in the proline rich domains, for example, and our forwarding molecules in that space. I'd also point out something that Phil kind of touched on, which is that, the role of effector competency in these antibodies is also something that we think is quite important and I'll just note that there are a number of other antibodies out there that are using IgG4, which would be expected to have a more muted effector competency in terms of the antibody. So we think getting all of that right, at least in our hands, from our preclinical work is important to make sure you have an optimal profile. But maybe let me ask Phil, if he wants to add anything to that?

Yes. I think the only other thing I'd add is that in our scrutiny and there was a subset that we showed, we did include antibodies that cover, I won't say the identical, but a lot of very similar regions that some of the competition was in. And what we saw is that the region we ended up in had the greatest depth of response when we were looking at a number of different mechanistic underlying factors about tau internalization and propagation. So that was -- really drove our decision to target where we are and why we're probably -- at least in our hands, in our assays, quite a bit different than what's out there right now.

Our next question comes from the line of Jay Olson with Oppenheimer.

Congrats on these results. I had a question on PRX005. What is the ideal clinical outcome for this tau antibody? Is it a slowing of cognitive decline? Or would you think that from the tau reduction that you showed in your preclinical work that it's possible to actually reverse Alzheimer's symptoms? And then, assuming that an Abeta antibody gets approved in the future, would you think it would make sense to combine PRX005 with an Abeta antibody? And then I had a follow-up on prasinezumab, if I may.

Great. Thanks for those questions, Jay. Excellent questions. Yes. I mean -- so first, let's talk about a molecule like PRX005. I mean I think at the end of the day, you will be required to show a slowing of disease progression. And I think for these types of disease-modifying approaches or putatively disease-modifying types of approaches that's the base assumption is that you'll be able to slow the clinical progression of disease. Now obviously, what you'd like to see is biomarker-based evidence from a biology perspective that is concomitant with that, so that you can show that both of those things are occurring. And so obviously, you can look to CSF biomarkers, imaging-based approaches with tau, but ultimately, you want to know that you're slowing disease. I think reversal of progression is probably, at this point in time, probably not the primary goal. The primary goal is to slow the progression of disease. And I think it goes then to your next question, which is, is there a role for combination approaches that target both Abeta and tau. And we certainly believe that there is a role for that, and we think that, that's important. As we see the field evolving and maturing, we think that some of the antibodies now that are in clinical development, one of which is under review at FDA now, aducanumab, which targets Abeta, and importantly, the immune-terminus of Abeta seem to show an ability to demonstrate some benefit over -- in the case of Alzheimer's disease in 18-month period. So with the EMERGE study, for example, on aducanumab, they demonstrated a 22% slowing on CDR sum of boxes over an 18-month time point. That's a treatment paradigm that's treating patients that are prodromal to mild in their disease state. And I think if that therapy is approved, that it provides a marker in the sand with which you now need to pass in order to generate better efficacy to have a now next-generation approach. That can provide more relief for patients, a further slowing of disease progression. We think combining Abeta and tau could be one way to achieve that potentially. And then the other thing I just mentioned here in terms of a role for targeting both Abeta and tau in combination would be starting to think about moving even earlier in the disease course, thinking about secondary prevention trials and ultimately, further down the line, even primary prevention trials. And there, again, we think there's a role for targeting both of these pathologies in as much as they're both implicated in the disease process.

Great. That's super helpful. And if I may sneak in another question about the PADOVA study. According to ct.gov primary endpoint is expected November 2023. Could you maybe just walk us through the cadence of enrolling that study and how long you expect it to take for prasinezumab to separate from placebo on the primary UPDRS Part 3 endpoint. And then since it is a 575-patient study, could PADOVA become 1 of 2 registrational studies?

Sure. Maybe I can start to comment on that. Maybe, Radhika, you can help with additional information. I think what you'll find on clinicaltrials.gov is that -- the Roche, obviously, is operationally running this study. They're expecting to enroll up to 575 volunteers for this study. So these would be patients with early Parkinson's disease, patients that would be on a stable low dose symptomatic therapy of levodopa, dopamine replacement therapy. And I think the estimated study start date as listed on clinicaltrials.gov is at the end of May '21. As you indicate, I think they had a primary completion date of the study listed in clinical trials.gov of November 23. So -- and I think you'll also note that the primary endpoint is a time-to-event end point, that's really more dependent on events and how rapidly people progress, or I should say, patients progress and meet the criteria for progression, which, again, is a 5-point worsening on the MDS-UPDRS Part 3. You can get maybe a sense of that from our prior PASADENA results where we've actually talked about a delay in time to progression. We've actually presented some of those data in our prior decks, where you can see the progression on that type of scale, both from a placebo perspective as well as a prasinezumab perspective. I'll also note that in some of the secondary endpoints, there are endpoints that go out to week 76. And so obviously, if you start thinking about 76 weeks plus enrollment, with the primary completion date of November 23, you can start to put some pieces together with respect to estimated enrollment timelines. But maybe Radhika, do you want to speak further to that?

Thanks, Gene. Yes, I mean, I think clearly, we're very excited and I think the reality is that we believe the data from PASADENA is quite supportive. Our partner, Roche does a great job in obviously operationalizing the study. And I think clearly, they're well on into sort of getting the study full up and running. Our hope is that through the information that's shared through the original PASADENA analysis from fall last year as well as this additional analysis and potentially any additional information even from the Part 2, it only continues to increase the interest level. I think clearly, the field is still very much in need for a therapy. The supportive signals that we saw through the Phase II study, the PASADENA study, clearly supports additional work. So the feedback we've heard to date through our partner, Roche, is that there's a fair amount of interest and we're optimistic, but the timelines that you described are yes, the current baseline estimates that are being shared at the moment.

Our next question comes from the line of Charles Duncan with Cantor Fitzgerald.

Yes. I too will take it kind of in reverse. In terms of my question on prasinezumab, first. I'm wondering if Radhika can perhaps expound on any mechanistic rationale that there may be for MAO-B inhibitor taking patients having faster progression and therefore, seeing a better separation, is that simply a signal-to-noise thing? Or is there a mechanistic rationale that would, I guess, be invoked or you could involve to explain the faster progression in MAO-B inhibitor taking patients?

Radhika.

Sure. Thanks for the question. Yes. Thanks for the question. I'll repeat the question just to make sure I have it -- but --I think what you're asking is, is there a way in which you can explain MAO-B as sort of the patient population that, that would actually be faster progressing. I think what you're actually seeing in clinical practice and honestly, through both the PASADENA study as a nice robust study design, is you can actually see that the patients who actually progress faster need MAO-B. It's not something inherent within MAO-B. It's just that's the effect of the faster progression that these patients fundamentally have. So it almost is an illustration of that progression, even faster than perhaps and allows us to basically target that patient population as well.

So it's not a cause or effect. It's just patients taking those drugs, and therefore, you get better separation, able to see the signal?

Well, I think what you have underlying is the patients fundamentally have a faster progression in the disease and the effect is, therefore, from a clinical management tool, the physicians look for therapies. And right now, that's just one of the few therapies that are offered. So the MAO-B prescription or concomitant medication these patients are getting is an effect of that faster progression, because they have the need for everything to try to slower. So it's not necessarily that MAO-B causes the faster progression. My clinical my clinical impression is that, it's more the effect of that faster progression, right? You come into the clinic complaining and sharing your signs and symptoms and the physicians are looking to try to optimize care for that patient and the family.

Yes. That makes sense. And then the second, call it, faster progressing cohort the diffuse malignant. I'm not sure I fully understood that. So I'm wondering if you could run through what comprises that patient population. And then for both of them, if you consider the PADOVA design, is there going to be, I guess, an analysis that is to look at these particular patients that's secondary to the primary analysis.

Sure. So the disease malignant phenotype is basically patients that score depending upon the motor scales or the non-motor scales. And there's actually a really nice slide, I think, in the main data presentation from Dr. Pagano that outlines what these are, but basically, it's patients that score in the 75th percentile of the motor scales and have at least 1 score in the 75th percentile on the non-motor scale or in the 75th percentile in all 3 non-motor scales. And items like the non-motor scales could be something as simple as the autonomic dysfunction or sleep scales, et cetera, that are utilized for monitoring and observing in this patient population. So that's the kind of cohort in and of itself. And sort of the technical definition that was utilized for the sake of the subgroup analysis. With regards to PADOVA, I don't think we're ready yet to share patient populations yet that we're interested in looking. We'll have to obviously see how enrollment contributes, but that's definitely a priority for us as we think about analysis set up for PADOVA study?

Okay. That is helpful. And I appreciate it. One last question, then, jumping back up to PRX005. You did a good job of outlining and comparing in contrast to different mechanism. I guess is it just epitope or could it also be an effector function and why do you think this particular area of the protein is so important? It almost makes sense that it would do, but I'm kind of wondering why other folks have gone after other areas.

Yes. So we think it's both of those things, Charles. So appreciate the question. And I can ask Phil maybe to sneak a bit further about it. But clearly, when we think about any of these protein targets and tau is no different in that regard, you have to both target at the right place, right, because these proteins take on different conformational states as they become dysregulated. And certain areas of the protein become inaccessible during that process and some remain accessible during that process. And it's critical to interact with an area that remains accessible. Otherwise, you've got nothing to interact with. And then the second component is you have to think about the right mechanism and the mechanisms of clearance. And obviously, in this case, we believe that effector-based mechanisms in the antibody are going to be important as well. So -- but maybe, Phil, do you want to address that further?

Yes. I think you addressed is probably -- one of the parts of the question was about, who are the folks that targeted in that -- one of the components, may not necessarily be a reason, but I only touched on it lightly during the talk. But very recent data and really only in the past few months is really look at extracellular tau different fragments and one of the recent findings really was that, the reason why we're targeting is actually well present in extracellular fluid. So it could be that people were considering some of the most abundant species that were present in biofluid that they may have started and are may have been working in a different place. But in our case, I think we started with some mechanistic reasons. And you mentioned -- we covered them in the talk, and you did mention them for particular receptors that might be finding tau and kind of all [indiscernible] and really that was kind of the path we took. And it was well supported with recent data providing evidence of MTBR and CSF and in bio fluids.

Okay. Last question. And it's probably one you won't answer or won't be able to easily answer and it's for Gene or Tran. Regarding strategy, it seems to me that you have great external validation on prasi with your partner. And I'm just kind of wondering, if partnering on 005 is a nice to have or a need to have in terms of moving this drug forward, this candidate for.

I appreciate the question, Charles. And maybe I can start and Tran, if you want to add as well. I mean look, we have a really great and productive collaboration with Bristol-Myers Squibb. As you probably remember, we initially entered into this agreement with Celgene. And ultimately, as Bristol-Myers Squibb acquired Celgene, this collaboration transitioned over to Bristol-Myers Squibb. It's -- from our seat, really very much the same team. So we've enjoyed now a long-standing collaboration that's gone back a period of time. We feel like we've certainly seen value-add in the collaboration. And we would very much value continuing the collaboration on PRX005 with Bristol-Myers Squibb. It is an option, as you say, it is their decision as to whether they'll remain involved with this molecule or not. I will tell you that from our seat, if they choose to forgo PRX005, we'll be just fine with that. We think it's a great molecule. We think it has a differentiated mechanism of action on a very important target. And we think the potential synergy, as was asked earlier, with other components of our portfolio, like our Abeta molecule, could be very, very interesting as we move and continue to see the field move forward. So I think the way I'd say it is, we would very much welcome and enjoy the continued collaboration but we don't feel from a financial perspective that we absolutely need that option nor do we feel like we would be in a position where we wouldn't know what to do with this molecules. In fact, they chose not to exercise that option. But maybe, Tran, do you want to further comment?

Yes. No, absolutely. Thanks, Gene. I appreciate that. And Charles, thanks for the question. I think given the current climate regarding neurodegeneration and AD/PD here is still ongoing. We think there's a lot of clearly momentum in the space, and we would welcome the program back. I mean we clearly think we've got a best-in-class tau antibody, and we've got a best-in-class Abeta antibody. And that being said, there are very clear, capital-efficient ways to get to -- of biology in terms of determining not just target engagement, but reductions of pathology in both the tau and Abeta antibody. So again, very excited for everything that's going on right now in neurodegeneration, as you put it. And Gene already stated, we have a great collaboration with Bristol, and they've been a fantastic partner. That being said, we wouldn't mind having the 2 best antibodies in Alzheimer's, be wholly owned by us.

Our next question comes from the line of Kennen MacKay with RBC Capital.

Congrats on the data. Maybe first, I thought I'll spend a little bit more of a tauist than a baptist as it relates to Alzheimer's disease and that's kind of based on tau's intercellular location and just the relationship with neurofibrillary tangles and pathogenesis and existence of other tauopathies. It seems that it is sort of necessary and sufficient to cause pathogenesis, which maybe you can't say about beta amyloid. Certainly necessary for Alzheimer's -- beta amyloid, but not necessarily sufficient to cause the disease alone. So just -- I guess wondering, why target tau now? Is this knowledge of sort of the new protein epitope that you're chasing or post translational modifications there? Or is it more to do with some new models that made preclinical work that much more predictive of what we might see in a patient.

Yes. So great question, Kennen. And kind of dissertation worthy questions. I think you're right. I mean how is that just wars I think, have been going on for some time. I'll be honest, we're a little bit more in the camp that we believe that they're on pathway. We've published data. In fact, people on this call are authors on papers demonstrating that, in fact, when Abeta binds the neuronal membrane is internalized, one of the results of that can be an abnormal phosphorylation of tau protein. So we actually think that these things aren't necessarily completely disconnected. To your point, tau pathology is thought to more closely map on a regional basis, some of the cognitive dysfunction that's seen in Alzheimer's disease. So it may be a little bit closer from a proximal state to the actual cognitive disruption. And then it comes down to your question of what's necessary versus what's efficient? And I think here is why we're also seeing Abeta studies moving into the earlier populations. So we're talking now, remember, when all the way back when, when the first anti Abeta approaches were being tested, they were being tested first in moderate patients and then mild patients. And now we're in prodromal to mild patients. And I think what we're seeing is probably the early impact of Abeta that leads to subsequent dysregulation of tau, of course, by the time patients are diagnosed. It's likely that both proteins are involved. And so in as much as growth proteins likely play a role, we think ultimately, there's a place for targeting each protein individually as well as the potential to treat via combination approaches as we've discussed. So I think it's a great question. I mean I guess, why has it taken a little bit longer to get to the tau approach? Well, I think, with tau -- we've learned a couple of things targeting Abeta. The first is that epitope matters. If you target Abeta at the immuno-terminus versus central region versus Carboxy-terminus, we know that, that results in very different biological outcomes in various biological model systems. So you have to have the right way of interacting with these proteins. That's something that was importantly learned with Abeta, which is a protein that is about 38 to 42 amino acids long. You also think about clinical study design and approach. How do we select the right patients who are most likely to advantage from these types of interventional approaches in the time period of these studies? Are we using the right clinical assessment scales that are matched to those types of patients. In this case, patients that are a little bit earlier in the disease, and I think we've seen a maturation of those clinical design elements as well as the regulatory understanding of what Alzheimer's is and what it's not. And I think what we're seeing now is a convergence of a lot of that activity and tau, of course, is a more complex protein, where Abeta 38 to 42 amnio acids, tau is a protein that can be as large as 441 amino acids, 6 different splice varying isoforms. And so understanding the right way to interact or I should say the optimal way to interact with that protein in order to produce a very robust and consistent effect takes some time. And I will tell you, we've been working on this protein and in this space for some time now, as I'm sure Phil can attest to. And so we are now satisfied based on our preclinical work that the approach that we've taken with PRX005 in our hands is the optimal approach. And so we're excited now to get that into the clinical space. As we've mentioned on the call, we plan on having an IND and a clinical study start here in the third quarter of this year and then progressing that to a place where we can learn the lessons that we've learned in the Abeta space, design the correct trial and move these molecules forward to what we hope to do is to help patients with this disease, of course.

That's awesome. If I can just squeeze in a quick follow-up question. Just going back to what you mentioned on sort of designing the right trials. And again, just thinking about what you can and can't learn from the trial. I wanted to sort of shift over to Parkinson's disease in the PADOVA trial. Years ago, when we were talking about PASADENA you had mentioned upfront, that trial was underpowered to potentially show benefit. And so again, that wasn't something that wasn't necessarily expected. And you had talked about what could be observed and what could be sufficient to lead to another trial and further development, which is obviously occurred. So just thinking about PADOVA, can you walk us through sort of what the likely outcomes are here? And really what from the sort of a statistical significance front. And then beyond that, what you and the team are looking for or your collaborations with Roche are looking for in order to advance this into a registrational trial?

Yes. No. Thank you for the question. I'll ask Radhika to also speak to this. But I think your point is well taken, and I think it goes to exactly my prior comment, right, which is, we have to learn from our prior experiences. And I think the PASADENA study, as you're starting to see was run, I think, in a way that really allowed us to drill down on the relevant types of clinical assessment scales that we could look at over in this particular case, a 52-week period, to state the thesis in a very obvious way. You can't see improvements unless you see progression or worsening on the placebo side. And so understanding what clinical assessment scales will actually allow you to see progression in placebo-treated patients over a 52-week period, of course, is critical. And as Radhika shared today, on the MDS-UPDRS, Part 1 and 2 really don't progress to a sufficient extent, in order to observe benefit over a 12-month period. And so the MDS-UPDRS Part 3 in this more early patient population is a much more sensitive scale from a signal-to-noise perspective and therefore, allows you to evidence the benefit. And so the thesis holds true, right, if you look at particular subgroups, as Radhika shared, and as was shared at AD/PD, like the MAO-B inhibitor treated patients in the diffuse malignant sub phenotype, you see more rapid progression in those individuals. And again, that enables you to see the benefit of prasinezumab to a better extent. Again, as Radhika described earlier, from a signal-to-noise perspective. So you do carry those learnings forward, right? And I think that's -- you'll see a lot of that in the PADOVA study not the least of which as has already been covered, the emphasis on the UPDRS Part III in this mild patient population. I mean I think the other thing we can say is that, when you look at the effect of MDS-UPDRS Part III across 12 months in the PASADENA study, we saw a very nice effect and a nice effect size. So when we talk about central rating, for example, in MDS-UPDRS Part III there was a 35% slowing of progression over the 12-month period. Now compare that to a comment that I made earlier in Alzheimer's disease, where the study that's currently under review by FDA in Alzheimer's with the aducanumab program showed a 22% slowing over 18 months -- or 18 months as opposed to 12 months and 35%, as we just discussed. So I think you have that kind of magnitude of effect. We had shared earlier some biological underpinnings of that. I think there was some previous data that we discussed looking at arterial spin labeling MRI-based approaches, suggestive that there's biological effects that underlie this clinical effect. And when you kind of put that together, it provides you an opportunity to start thinking about the patient population in a more expanded way. And I think allowing and having patients in PADOVA moving forward that are on stable dose of levodopa, the most commonly prescribed symptomatic treatment, which provides dopamine replacement therapy to patients, really expands the reach of this program to a variety of patients. So obviously, what I think both companies are looking for is continued indication of activity as we continue to expand the patient population here. I think you asked a very pointed question as to whether this study could be used from a registrational perspective. I mean clearly, the study is going to be run as a double-blind placebo-controlled study with high integrity so that you can never say no to that question, but at the same time, we fully anticipate that an additional Phase III or potentially 2 additional Phase III studies would ultimately be required. So let me maybe pause there and ask Radhika, if she'd like to comment further.

Yes. Thanks, Gene. I think the other dynamics when you think about PASADENA and moving from PASADENA now into PADOVA are really related to study basically fundamental study learnings, right? As we think about patient population, end points and I think clear from this analysis and from the primary analysis last fall, we're able to see that time to progression on the MDS-UPDRS Part III score is a measurable change. And more importantly, it's actually a meaningful change for the patient, which is ultimately who we're trying to support in this horrible disease. So the reality is, we think about being able to provide that change. It's in a tool that can be easily administered. And one that can clearly be analyzed and ultimately support treatment decisions for patients. So these are all aspects that we're able to pull from PASADENA, both from a study patient population, study conduct, and fundamental kind of biometric assumptions that sort of all follows the PADOVA. So there are a fair number of learnings, I think, from PASADENA that support the framework for PADOVA. And as Gene just concluded, I think the additional benefit is here. We're also talking about a larger patient population that is also one of need in this disease area. So clearly, an opportunity to address an even a greater unmet market here.

Our next question comes from the line of Bert Hazlett with BTIG.

Really informative. My question is on PRX005 and really just almost a basic biology question. Could you -- you mentioned once or twice, could you talk a little bit about the significant materiality of that -- the fact that PRX005 binds to all the splice isoforms. How meaningful is it for what you're doing now in 80? And could that potentially provide an opportunity 405 to move into other neurodegeneration settings where tau plays a role?

Yes. Great question, Bert. Thank you. So maybe I can ask Phil to speak a little bit about the splice isoforms and the differential implications of that to the biological setting. And then, I think Wagner is on the phone and maybe he can think about or speak to other potential neurodegenerative tauopathies perhaps. So Phil?

Sure. And good question. The reason that we wanted to make sure the decision was made was that we're binging kind of near or where some of that splice isoform shifting may happen. And making sure that we bound both forms is very important just to get bulker present in Alzheimer's disease. And so we did want to make sure that the binding to both isoforms are well present. That would be -- potentially impact was not impacted. And that was the case that we found that it is not through a couple of different mechanisms or excuse me, methods, either biochemical or histochemical. So we felt confident that we found all forms of tau that might be in disease. Wagner, do you want to take the next part?

Yes. I think the selection of Alzheimer's as the first indication is always one that the evidence that tau pathology might be transmitted between regions of the brain and potentially in trans-synaptic transmission is very, very strong in this disease. Now with the PET data, it's even strengthening even more and the pathology data that was generating in the past. That evidence is not as strong in other diseases like PSP, for example. We know that there is a presence of intracellular pathology in the tau pathology inside the cells is very similar to what you find in Alzheimer's, for example, with intracellular aggregation and phosphorylation. but it's unclear if the mechanism of disease in this other tauopathies is the same as Alzheimer's. It's possible that it is, and it's just a question of time in building that evidence. But the selection of Alzheimer's, certainly, it's in our mind, it's the right one to start with. I think as we build evidence with X5 in Alzheimer's, certainly, we should be exploring these other diseases and very high unmet need in that space as well. We are focusing on the blockade of cell-to-cell transmission as the most obvious mechanism of action for the antibody. And as few showed the blockade of interaction of tau with surface proteins that could be mediating that internalization really makes sense when we look at all the portfolio of antibodies that we tested and compare the ones that fail with the ones that succeed like X5 but we are not completely discouraging the possibility that some of these antibodies could also have an intracellular mechanism, and they could be internalized maybe via the tau internalization itself and they could have some intracellular effects as well. It's not as clear to us, but I'm saying that maybe, even in diseases where tau is not transmitted at the same rate as we see in Alzheimer's, potentially an antibody tau could have an effect, if it's targeting the right epitope of tau certainly. That's our learning. But also if it's engaging the right mechanisms and as Phil said, we think that the combination of the 2 being able to intercept tau in the first place but also being able to clear tau very efficiently, in combination, we think that's what gives the higher probability of success for molecule of [ X5 ]

Our last question comes from the line of Tazeen Ahmad with Bank of America.

And thanks for providing so much detail about PADOVA. Maybe one question on the study from me. You spent a lot of time talking about the rationalization of using this MDS-UPDRS Part III score as the right point to be looking at. But can you share specifically what feedback FDA gave as if A, was using it as a tracker for progression? And then as it relates to the patient population that you're enrolling, for some patients for some Parkinson's patients who take, let's say, levodopa, LID could be something that becomes an issue over time. Is it your view that these patients are early on in their disease progression and may not be exposed to the risk of LID? And if they are, what would be the protocol? Would they be allowed to take any kind of rescue medication? Or would they drop out of the study?

Yes. Thanks, Tazeen. So excellent question. Maybe I can hit the last first, which is that these patients would be early in their disease, so would not be expected to have developed dyskinetic side effects due to levodopa treatment at this point in time. So they're still going to be relatively early. So we don't anticipate that as being an issue in this study. And again, I'll ask Radhika to comment on that. And I think your question about regulatory feedback. So obviously, we wouldn't share regulatory feedback in any specific way. I think what I can say is that regulators typically care both about clinical manifestations of the disease. So in this case, you can think about motor symptoms and motor manifestations of the disease, but also how patients are feeling, how patients feel, how they function are also very important to regulators. And I think one of the noteworthy things about thinking about a delay in time to progression as defined by a 5-point increase in the MDS-UPDRS Part III is that a 5-point increase is meaningful to patients. And I think there's a number of studies out there that kind of demonstrate that linkage. But maybe, Radhika, would you want to speak further?

Yes. Just as a reminder. You have it right, Gene, in the factors of patient population is still early PD. So it's unlikely that they would have these side effects. But the general concept applies as in all clinical trials, right, the physician has to do what is appropriate with regards to the management of care, if the patient did have adverse events. So in the rare current someone did have this occurrence we would obviously allow the physician to appropriately manage the patient and then we manage it from the analysis standpoint. But this will be incredibly rare at this point.

Just -- maybe one thing I'll add Tazeen, is that the inclusion criteria is holding our 1 in 2 patients. So just to build upon what Gene just said in terms of still being early Parkinson's disease patients.

There are no further questions at this time. I would now turn the call back to Gene Kinney for closing remarks.

Great. Well, thank you, and thank you all for joining us. So we appreciate your interest in Prothena. And over the coming months, we look forward to sharing further updates on our programs. Thank you.

Ladies and gentlemen, this concludes today's conference call. We thank you for your participation. You may now disconnect.