Prothena Corporation plc

Ladies and gentlemen, thank you for standing by and welcome to the Procena fourth quarter and full year 2020 financial results conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press star then one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star then zero. I would now like to hand the conference over to one of your speakers today, Ellen Rose, Head of Communications. Please go ahead.

Thank you, Michelle. Good morning, everyone, and welcome to Perthena's Investor Conference Call to review our business progress and our fourth quarter and full year 2020 financial results and our 2021 financial guidance. Please review the press release we issued earlier today, which is available on our website at perthena.com and is also attached to a Form 8K filed today with the SEC. On today's call, Dr. Jean Kinney, our President and Chief Executive Officer, will highlight Perthena's recent and 2020 pipeline progress, what distinguishes our scientific platform and our path for sustainable growth. Following Jean's comments, Tran Nguyen, our Chief Operating Officer and Chief Financial Officer, will review our financial results and performance for the fourth quarter and full year of 2020 and 2021 financial guidance. Jean will then provide an overview of our near-term milestones. We will then open the call for Q&A and be joined by Dr. Wagner-Zago, our Chief Scientific Officer, and Dr. Radhika Triparaneni, our Chief Development Officer. Before we begin, I would like to remind you that during the course of today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For discussion of the risks and uncertainties associated with our forward-looking statements, Please see our press release issued today as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements. And with that, I'd like to turn the call over to Gene.

Thank you, Ellen, and thank you all for joining us this morning to review our 2020 financial results. It's been an exciting and transformational year for Prathena. As Tron will highlight shortly, we met our 2020 financial guidance and ended the year with a strong cash position. When combined with up to $140 million in potential payments stemming from our collaborations with Roche and Bristol-Myers Squibb, this enables us to fund our pipeline through key upcoming milestones. Over the past year, we've made significant progress advancing new medicines with the potential to change treatment paradigms in multiple indications. In our rare peripheral amyloid disease portfolio, we recently announced plans to initiate the Phase III AFIRM-AL study of Brachymumab in Mayo stage 4 patients with AL amyloidosis under a special protocol assessment or SPA agreement with FDA at the unprecedented p-value of 0.10. The significant survival benefit observed in our vital study made this SPA agreement possible, and we expect to initiate the firm AL study by mid-2021. We also announced results from our phase 1 study of PRX4, including improvements in neuropathy and cardiac function in patients with ATTR amyloidosis. and we expect to advance this program into a Phase II-III study in the fourth quarter of this year. In our neurodegenerative disease pipeline, we advanced two programs in our Alzheimer's disease portfolio, PRX5, our anti-tau antibody, being developed under our global neuroscience collaboration with Bristol-Myers Squibb, and PRX12, our proprietary next-generation subcutaneous anti-A-beta antibody. We continue to expect that the biogen molecule, aducanumab, will be approved later this year, and we are developing PRX12 to offer a next-generation treatment in order to enhance patient compliance and access. Last year, we also announced the results from Part 1 of the Phase 2 Pasadena study of prasinezumab in patients with early Parkinson's disease. Prasinezumab specifically targets the C-terminus of alpha-synupein, and is the first anti-alpha-synuclein antibody to demonstrate significant slowing of motor progression and improvements on imaging biomarkers consistent with disease modification. Based on these results, we announced that with our partners at Roche, we are advancing prastinezumab into a late-stage Phase IIb study with further details expected in the second quarter. As someone who has devoted the better part of my career focused on advancing medicines for progressive neurodegenerative diseases, I was particularly encouraged by the consistent signals of efficacy observed in this proof-of-concept study. This is an exciting time for our company. I'd like to start by highlighting what differentiates Prothean's proven approach, how it positions us as a leader in developing therapies for diseases caused by protein dysregulation, and how we are well positioned for an extraordinarily productive future. Our unique approach starts with science. Specifically, our deep scientific understanding of how protein dysregulation contributes to the cause and progression of devastating rare peripheral amyloid and neurodegenerative diseases. This stems from our decades of foundational work in protein biology and an understanding of the dynamic aspects of protein dysregulation, which subsequently informs our selection of targets. We apply our proven protein dysregulation platform to specifically target the pathogenic forms of the proteins that cause disease. We can simplify this process into the saying, epitope matters, and it certainly starts with selecting the right epitopes to target on a pathogenic protein. Beyond identifying the optimal epitope, we also engineer our molecules to interact with that epitope in a way that is most likely to intercept or halt the underlying disease process. We do this by designing molecules with a bias toward the pathogenic forms of the protein. Specifically or selectively targeting the toxic protein species in order to alleviate their detrimental effects while leaving the native or healthy form of the protein unaffected is important in order to maintain normal, healthy biological functions. This unbiased and empirical methodology is highly customized for each target. In some cases, we may target a cryptic epitope. In others, we may select antibodies with hyperavidity, and yet in other cases, we may select a neoepitope. This customized approach depends on the unique characteristics of each target and underlying disease pathology. After a thorough evaluation of a target, we advance discovery candidates after we have demonstrated consistent and robust biological outcomes in preclinical development. But an optimized molecule is only useful if you can influence the biology in a way that results in meaningful clinical benefits for patients. And we've now achieved this across multiple programs in our pipeline. Our ability to consistently translate our science into clinical proof of concept is an important distinguishing feature of Perthena today. Key to this consistency is knowing how to design a comprehensive clinical program that tests a biological hypothesis in the right patient populations with the right outcome measures. Our growing pipeline includes therapies with blockbuster potential for diseases with enormous unmet medical needs that lack disease-modifying approaches. And importantly, we enjoy a strong capital position that provides a foundation to fund our growing pipeline. So, with this slide, I want to further illustrate the concept of epitope matters and how targeting a protein at different regions or epitopes results in very different biological outcomes. Here we highlight five protein targets in our portfolio, which are ordered by their length. We have found that targeting epitopes represented by the green areas along the protein results in observations of biological activity in preclinical studies and or on clinical efficacy measures. We discovered the benefit of targeting these epitopes by first systematically mapping the length of the protein to assess how targeting different epitopes impacts multiple disease-relevant biological outcomes. This approach is absolutely central to our platform and is what enables the design of novel molecules that aim to alleviate the detrimental effects of pathogenic proteins in multiple dysregulated states. Let's start with Alzheimer's disease. Our experience in this space dates back to the development of both AN1792 and Bapanuzumab. Our preclinical and clinical research has consistently indicated that potentially disease-modifying antibodies that target the end terminus of the A-beta protein, shown here in green, could more effectively block toxic effects of both soluble and insoluble forms of beta amyloid than antibodies that target other areas of the protein, which are exemplified in red. Recent clinical results are consistent with this view. Data not only from the aducanumab program, but also from recent clinical studies evaluating Eli Lilly's dinanamab, demonstrate that targeting this region consistently results in clinical benefit. Targeting other regions of the protein have not shown similar clinical benefit. It is our confidence in this approach that led us to develop PRX12. We are advancing this molecule as a next-generation N-terminally directed anti-A-beta antibody for subcutaneous administration in order to improve access to this class of potentially disease-modifying treatments for patients with Alzheimer's disease. This concept has been further illustrated recently in Parkinson's disease, where Pracinezumab, our anti-alpha-synuclein antibody in development with Roche, is the first potentially disease-modifying therapeutic to demonstrate signals of efficacy in the Phase II Pasadena study on multiple pre-specified secondary and exploratory clinical endpoints, including measures of motor function in patients with early Parkinson's disease. Pracinezumab targets the C-terminal of alpha-synuclein. In contrast, a different anti-alpha-synuclein antibody, Biogen's Synpanamab, which targets the N-terminus of the protein, was recently discontinued from development due to lack of efficacy in a phase two proof of concept study. This finding was consistent with our own preclinical experience, which found that targeting the N-terminus was suboptimal. We adopted a different approach for the development of Bertamamab and PRX4, both of which target a cryptic epitope on their respective proteins. With Bertamamab, this led to findings of improved survival in a mouse efficacy model, which subsequently translated to an observed significant survival benefit in Mayo Stage 4 patients with AL amyloidosis in our Phase 3 vital study. our antibody that was shown preclinically to specifically bind to pathogenic forms of the TTR protein, translated into positive clinical observations on neuropathy and cardiac function in patients with ATTR amyloidosis in our Phase I study. We think this story will play out again with tau, another protein implicated in Alzheimer's disease. Specifically, we believe that targeting the microtubule binding region will be key to intercepting the pathological progression of tau that underlies Alzheimer's pathology. Understanding where and how to target these pathogenic proteins was also critical in the design of our multi-immunogen active vaccine, which has demonstrated robust and balanced immune responses to both tau and A-beta in preclinical studies. And importantly, these immune responses were targeted to the key epitopes that we have identified as relevant for both of these proteins. And we recently presented preclinical data on this program As you can see from this slide, disease-related proteins vary widely in terms of their length and their potential conformations of dysregulated forms. This inherent complexity suggests that our approach is one that cannot be easily replicated. One of the key distinguishing features of Prathena today is that we have translated science from our internal discovery engine into positive clinical outcomes for patients, as measured by objective clinical endpoints across multiple programs. Across several indications, we've seen that targeting the appropriate epitope with the optimal binding strength and in the context of the right study design in the right patient population can result in meaningful clinical benefit. Our rare peripheral amyloid portfolio includes Pertamamab for AL amyloid doses and PRX4 for ATTR amyloid doses. These molecules have differentiated mechanisms of action from the standard of care therapies, which have not demonstrated an improved survival benefit for patients with advanced cardiac disease at high risk for early mortality due to amyloid deposition. The depleter mechanism of Brutamamab and PRX4 directly target and clear the toxic amyloid that deposits in the heart and other vital organs. Earlier this month, we announced our plan to initiate the confirmatory Phase III AFIRM-AL study of bertamamab in AL amyloidosis. AFIRM-AL is being conducted under a SPA agreement with FDA to enable registration at an unprecedented p-value of less than or equal to 0.10 on the primary endpoint of all-cause mortality in Mayo Stage 4 patients. We were able to reach agreement with the FDA on this SPA because of the significant survival benefit observed in our previous vital study, where we demonstrated a 59% relative risk reduction on all-cause mortality in Mayo Stage 4 patients over nine months. In December, we reported results from our Phase 1 study of PRX4 in ATTR amyloidosis. In this study, after only nine months of treatment with PRX4, In eligible patients, we observed less progression on neuropathy than expected, and in several patients, we observed improvement. We also observed important improvement on global longitudinal strain, a key measure of cardiac systolic function in all eligible patients. Turning to the neurodegenerative disease programs in our Alzheimer's disease portfolio, we believe that interventions that target both tau and A data have the potential to reduce the clinical decline in, or prevent the onset of Alzheimer's disease. As such, our pipeline is advancing programs for both antibodies and vaccines. Our two most advanced preclinical programs are our anti-Tau antibody, PRX5, and our anti-A-beta antibody, PRX12. We look forward to sharing preclinical data on PRX5 at an oral presentation at ADPD in March. We've tested a large number of antibodies to epitopes along the tau protein and found that those that target the microtubule binding region more effectively block the binding of tau to neurons and prevent downstream neurotoxic effects. Understanding this biology increases our confidence in selecting and evaluating PRX5 as a clinical candidate, and we look forward to sharing our preclinical data at ADPD. Last year at CTAD, we presented data on PRX12. our next-generation high-potency anti-A-beta antibody. PRX12 has a higher binding strength to amyloid than aducanumab, with as much as an 11-fold greater affinity, and also recognizes A-beta pathology to a greater extent, demonstrating more extensive plaque area binding at lower antibody concentrations. We are developing PRX12 for subcutaneous administration to improve access to this class of treatment for patients with Alzheimer's disease. I'll conclude by highlighting the results from the Phase II Pasadena study of prasinezumab in patients with early Parkinson's disease that we announced last September. In Parkinson's, existing treatments are symptomatic and only address a subset of symptoms. There are currently no treatments available that target the underlying cause of the disease to slow its progression. Pracinezumab is designed to block the cell-to-cell transmission of the aggregated pathogenic forms of alpha-synuclein that are the hallmark of Parkinson's disease, thereby slowing clinical decline. In Pasadena, treatment with Pracinezumab resulted in significantly reduced decline in motor function of 35% versus placebo at one year and delayed time to clinically meaningful worsening of motor progressions. This 35% reduction of clinical decline over just 12 months is particularly noteworthy relative to Alzheimer's disease, where aducanumab has demonstrated reduced cognitive decline of approximately 22% over 18 months. In Pasadena, we also observed improvements on imaging biomarkers and signals of efficacy consistent with disease modification across multiple pre-specified secondary endpoints. Our programs that I've just described address diseases where there are no approved disease-modifying treatments. Each of these programs have the potential to become blockbuster therapies in areas of extraordinarily high unmet need. Our rare peripheral amyloid disease portfolio addresses two orphan disease market opportunities. We're developing Bertamamab and PRX4 in targeted patient populations at high risk for early mortality with a particularly urgent unmet medical need for improved survival. Our neurodegeneration portfolio addresses Parkinson's and Alzheimer's, which are the two most common neurodegenerative diseases. Since the occurrence of many neurological disorders, including both Parkinson's and Alzheimer's disease, increases with advancing age, and the worldwide population is aging at a rate never before observed, the magnitude and impact of the pending healthcare crisis and the absence of better therapy is is both predictable and alarming. As we've discussed, our proven protein dysregulation platform is our engine for sustainable growth. This year, we expect three programs to initiate late-stage clinical studies for Tamumab in AL amyloidosis, Pracinezumab in Parkinson's disease, and PRX4 in ATTR amyloidosis. Beyond these programs, we expect internal R&D to deliver as many as six INDs for new molecules over the next three years. A combination of potential payments resulting from our collaborations with Roche and Bristol Myers Squibb, as well as our existing robust cash position, give us the ability to fund our programs through key milestones. We expect our growing pipeline with programs at every stage of development to facilitate our transition to a fully integrated research, development, and commercial biotechnology company. At this time, I'd like to turn the call over to Tron for a discussion of our 2020 financial performance and our 2021 guidance. Tron?