Q4 2019 Earnings Call

Good afternoon, ladies and gentlemen, and have also seen if which you know fourth quarter and full year 2019 financial results conference call. At this time all participants are in listen only know would meet or we will conduct a question and answer session and instructions will follow with this time if any.

Operator: Good afternoon, ladies and gentlemen, and welcome to the Prothena fourth quarter and full year. At this time, all participants are listening. Later, we will conduct a question and answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star then zero on your touchtone telephone. As a reminder, this conference call is being recorded. I would like to turn the call over to your host, Mr. Randy Fawcett, Senior Vice President of Finance and Operations. Please go ahead. Thank you, Jonah.

One should require assistance during the conference. Please press Star then zero on your Touchtone tell the selling as a reminder, this conference call is being recorded.

Like the turned to countries a richer host Mr., Randy Fossett Senior Vice President Finance and offering Shane. Please go ahead.

Thank you Jonah good afternoon, everyone and welcome to protein as Investor Conference call to review, our fourth quarter and full year 2019 financial results and business progress as well as our 2020 financial guidance.

Randy Fawcett: Good afternoon, everyone, and welcome to Prothena's Investor Conference Call to review our fourth quarter and full year 2019 financial results and business progress, as well as our 2020 financial guidance. Please review the press release we issued earlier today, which is available on our website at prothena.com and is also attached to a Form 8K filed today with the SEC. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will discuss our pipeline programs and corporate progress. Following Gene's comments, Tran Nguyen, our Chief Operating Officer and Chief Financial Officer, will review our financial results for the fourth quarter and full year of 2019 and this year's financial guidance. Gene will then provide an

Please review the press release, we issued earlier today, which is available on our website <unk> Dot com and is also attached to a form 8-K filed today with the FCC.

On today's call Dr., Jean kidney, our President and Chief Executive Officer will discuss our pipeline program and corporate progress following genes comments trying to win our Chief operating officer, and Chief Financial Officer will review, our financial results for the fourth quarter and full year of 2019, and this year's financial Guy.

Jean will then provide an overview of upcoming milestones and open the call for Q and a.

Operator: Overview of Upcoming Milestones and Open

Operator: on the call for Q&A.

Randy Fawcett: All for Q&A. Before we begin, I'd like to remind you that during the course of today's presentation, we will be making statements regarding Prothena's future expectations, plans, and prospects that constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements are based on estimates, projections, and assumptions that may prove not to be accurate, and actual results may differ materially from those anticipated due to known and unknown risks, uncertainties, and other factors. For a discussion of the risks associated with our forward-looking statements, please see our press release issued today, as well as our most recent Form 10-Q filed with the SEC and also the Form 10-K we will soon be filing with the SEC. We disclaim any obligation to update our forward-looking statements. With that said, I'd like to turn the call over to Gene.

Before we begin I'd like to remind you that during the course of today's presentation, we will be making statements regarding protein as 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.

<unk> form 10-Q filed with the FCC and also the form 10-K, we will soon be filing with the FCC, we disclaim any obligation to update our forward looking statements.

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

Gene G. Kinney: Thanks Randy, and thank you all for being on our call today for a discussion of our pipeline and the upcoming milestones we're looking forward to in 2020 and beyond. During the past year, we've continued to advance our pipeline focused on neuroscience and diseases caused by misfolded proteins. These are areas where our deep domain expertise intersects with an unmet and often increasing medical need, and we are applying our capabilities against novel targets with the potential to change the course of many of these devastating conditions. Our diverse pipeline is based on our expertise in neuroscience and the ability to integrate insights around brain function, as well as the biology of protein misfolding and how to optimally target toxic confirmation. We leverage these areas of expertise to identify and design novel approaches that aim to impact the underlying pathogenesis across several disease states. We're also leveraging our neuroscience expertise and relationships through our business development efforts, where we continue to evaluate external opportunities to potentially expand our neuroscience pipeline. We ended 2019 with a balance sheet that enables continued development of our clinical, preclinical, and discovery programs through key milestones, and we're excited about the breadth and progress of our pipeline.

Thanks, Randy and thank you all for being on our call today for a discussion of our pipeline and the upcoming milestones were looking forward to and 2020 <unk> and beyond.

During the past year, we've continued to advance our pipeline focused on neuroscience diseases caused by Misfolded proteins.

These are areas, where our deep domain expertise intersects with an unmet and often increasing medical need and we're applying or capabilities against novel targets with the potential to change the course of many of these devastating conditions.

Our diverse pipeline is based on our expertise in neuroscience and the ability to integrate insights around brain function as well as the biology of protein folding and how to optimally talk target toxic confirmations.

We leveraged these areas of expertise to identify and design novel approaches the aim to impact the underlying pathogenesis across several of these days.

We're also leveraging our nurse ice expertise and relationships through our business development efforts, where we continue to evaluate external opportunities to potentially expand our nurse ours pipeline.

We ended 2019 with the balance sheet that enables continued development of our clinical or preclinical and discovery programs through key milestones and we're excited about the breadth and progress of our pipeline.

Gene G. Kinney: I want to start by providing an update on the clinical programs, Prasonesimab and PRX4. Presinezumab, currently in a Phase 2 clinical trial, 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 Prasneva.

I want to start by providing an update on the clinical programs, perhaps another man empiric for.

Perhaps another man currently in a phase two clinical trial is an investigational monoclonal antibody for the treatment of Parkinson's disease and other synucleinopathies.

In 2013, we entered into a worldwide development commercialization collaboration with Roche for present doesn't matter.

Gene G. Kinney: Parkinson's disease is the second most common neurodegenerative disease, affecting an estimated 7 to 10 million people worldwide, and its incidence continues to increase based on an aging population. Parkinson's disease is characterized by the neuronal accumulation of aggregated alpha-synuclein in both the central and peripheral nervous system, which results in neurodegeneration and a wide spectrum of progressive motor and non-motor symptoms that are persistent throughout the course of the 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, or constipation, are also common in disabling. Current treatments for Parkinson's disease only address a subset of the symptoms. Levodopa and dopamine agonists are primarily directed at managing their early motor symptoms, but these agents become less effective over time and do not address the underlying cause of... Presinezumab is being developed as a first-in-class approach with the goal of reducing clinical decline in Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disease affecting an estimated seven to 10 million people worldwide and its incidence continues to increase based on an aging population.

Parkinson's diseases characterized by the Nurown accumulation of aggregated Alpha synuclein in both the central and peripheral nervous systems, which results in neuro degeneration, and a wide spectrum of progressive motor and non motor symptoms that a persistent throughout the course or disease.

Well the diseases, most commonly known for motor symptoms, such as Brady, Tunisia, stiffness and tremor non motor symptoms, such as cognitive deficits fatigue sleep disturbances or constipation or also common in disabling.

Current treatments for Parkinsons disease, only address a subset of the symptoms.

Lover Dopant Doberman agonists are primarily directed at managing their early motor symptoms, but these agents become less effective over time and do not addressed the underlying cause of the disease.

Press and as a map is being developed a first in class approach with the goal of reducing clinical decline in Parkinson's disease.

Gene G. Kinney: Our antibody targets alpha-synuclein, a protein that is widely understood to be integrally involved in the onset and progression of Parkinson's. Alpha-synuclein is the major constituent of Lewy bodies, a pathogenic hallmark of Parkinson's disease and other synucleinopathies. And there's genetic evidence for a causal role of alpha-synuclein in Parkinson's. Genetic abnormalities in the alpha-synuclein gene, such as duplications, triplications, or point mutations that cause autosomal dominant forms of Parkinson's, are thought to lead to the overproduction or modifications of the alpha-synuclein protein that facilitate aggregation and formation of intra The scientific community has also increased its understanding of how cell-to-cell transmission of alpha-synuclein potentially initiates the spread of pathogenic forms of this protein through different regions of the brain. Research has shown that pathology originating in one region of the brain or even in the periphery may spread to other regions as the disease advances. And in fact, the progression of Parkinson's disease symptoms is reflected in the areas of the brain where alpha-synuclein pathology has developed. Presinezumab aims to impact the underlying disease progression by preferentially targeting the pathogenic forms of alpha-synuclein and blocking this cell-to-cell transmission. Our research in this space dates back many years.

Our antibody targets Alpha Synuclein, a protein that is widely understood to be integrally involved in the onset and progression of Parkinson's disease.

Alpha Synuclein is the major constituent of when we bought a pathogenic hallmark for Parkinsons disease, and other significant offices and there's genetic evidence for calls her role of Alpha Synuclein in Parkinson's disease.

Genetic abnormalities in the Alpha Synuclein gene such a duplications trip occasions or point mutations that caused autosomal dominant forms of Parkinson's a boat to lead to the overproduction or modifications of alpha synuclein protein that facilitate aggregation and formation of intra cellular pathology.

The scientific community has also increased its understanding of how cell to cell transmission of alpha synuclein potentially initiate the spread of pathogenic forms of this protein through different regions of the brain.

Research has shown that pathology originating in one region of the brain or even in the periphery may spread to other region. That's the disease advances and in fact, the progression of Parkinson's disease symptoms is reflected in the areas of the brain Alpha Synuclein pathology has developed.

Personnel isn't that aims to impact the underlying disease progression, but preferentially targeting the pathogenic forms of alpha synuclein and blocking the cell to cell transmission.

Our research in this space that dates back many years.

Gene G. Kinney: The effects of immunotherapy with the murine form of prasonezumab demonstrated that it crossed the blood-brain barrier, decreased intraneuronal alpha-synuclein pathology, and protected synapses from degenerating, resulting in improvements in both motor and cognitive behavior in multiple preclinical models. In 2018, JAMA Neurology published results from our Phase 1b double-blind, placebo-controlled, multiple ACE-ending As described in the publication, in addition to acceptable safety and tolerability across all dose levels, presinesimab demonstrated target engagement in serum and dose-dependent CNS penetration that supported advancing to the ongoing Phase 2 Pasadena study with the two dose levels being evaluated. We believe these dose levels are sufficient to target and saturate the aggregated pathogenic forms of alzheimer's.

The effects of immunotherapy with the Mirinform oppressed and as a mad demonstrated that cross the blood brain barrier decreased entered in Toronto Alpha Synuclein pathology and protected synopses from degenerating, resulting in improvements in both motor and cognitive behavior in multiple preclinical models.

In 2018, Jama neurology publish result from our phase one be double blind placebo control multiple ascending dose study, which assess the safety Tolerability pharmacokinetics immunogenicity are pressing doesn't matter in 80 patients with Parkinson's disease.

As described in the publication in additional in addition to acceptable safety and Tolerability across all dose levels personnel, the Matt demonstrated target engagement in serum and dose dependent CNS penetration that supported advancing to the ongoing phase two Pasadena study with a two dose levels being evaluated.

We believe these dose levels are sufficient to target and saturate the aggregate pathogenic forms of alpha Synuclein and the brand.

The phase two Pasadena study or perhaps it doesn't matter in patients with early Parkinson's disease is a two part clinical study that enrolled 316 patients and is being conducted by our colleagues <unk>.

Gene G. Kinney: The Phase 2 Pasadena Study of Prasonezumab in Patients with Early Parkinson's Disease is a two-part clinical study that enrolled 316 patients and is being conducted by our colleagues at Roche. The last patient visit in Part 1 of the study took place toward the end of 2019. As such, we expect to report top-line results from Part 1 of the study this year.

The last patient visit in part one of the study took place toward the end of 2019 as such we expect to report topline results from part one of the study this year.

As a reminder of the study design part one is a randomized double blind placebo control three arm study that is designed to evaluate the efficacy and safety oppressed and as a matter in patients at 52 weeks in.

Gene G. Kinney: As a reminder of the study design, Part 1 is a randomized, double-blind, placebo-controlled, three-arm study that is designed to evaluate the efficacy and safety of prasonesomab in patients at 52 weeks. In part 1, patients are randomized on a one-to-one-to-one basis to receive one of two active doses of prasonezumab or placebo via intravenous infusion every The dose levels being assessed are 1,500 milligrams in the first presinezumab arm and, depending on body weight, either 3,500 or 4,500 milligrams in the second presinezumab arm.

In part one patients randomized on a one to one to one basis to receive one of two active dose is a process and as a man or placebo via intravenous infusion every 28 day.

The dose levels being assessed or 1500 milligram in the first crescent as a my arm and depending on bodyweight, either 3500, or 4500 milligrams and the second Crescent doesn't matter arm.

Gene G. Kinney: Eligible patients were not expected to require dopaminergic-based therapy or need a change to their stable MAO-B inhibitor regimen for at least 52 weeks. Part two of the study is a 52-week blinded extension phase in which patients from the placebo arm of the study were re-randomized to one of two active doses of prasonezumab on a one-to-one basis so that all participants are on active treatment. Patients who were originally randomized to an active dose will continue at that dose level for the additional 52 weeks.

Eligible patients were not expected to require dopaminergic based therapy, where needed changed their stable maybe inhibitor regimen for at least 52 weeks.

Part two of the study is it 52 week blinded extension phase in which patients from the placebo arm of the study we're re randomize onto one of two active doses of <unk>, none of them out on a one to one basis.

So that all participants are on active treatment.

Patients who were originally randomize to an active dose will continue at that dose level for the additional 52 weeks.

Gene G. Kinney: In Part 2, patients are allowed to use concomitant dopaminergic therapy. However, any patient who medically requires initiation of dopaminergic therapy or change in regimen of a MAO-B inhibitor during Part 1 of the study will have their subsequent data censored for the primary endpoint analysis. You can view additional details on this study at clinicaltrials.gov. The primary endpoint of this study is the change from baseline in the Movement Disorder Society Unified Parkinson's Disease Rating Scale, or MDS-UPDRS, total score of Sections 1, 2, and 3 at the completion of Part 1 at Week 52. For the primary endpoint, the study was designed with 80% power at a one-sided alpha of 0.1 to detect a 37.5% benefit in each treatment group versus placebo at week 52.

In part to patients are allowed to use concomitant dopaminergic therapy.

Any patient medically requires initiation of dopaminergic therapy or change in regimen of a may be inhibitor. During part one of the study had their subsequent data censored for the primary endpoint analysis you can view additional details on the study a clinical trials dot Gov.

The primary endpoint of this study is the change from baseline in the movement disorder Society unified Parkinson's disease rating scale or MBS you Pdrs total score of sections, one two and three at the completion of part one at week 52.

For the primary endpoint. The study was designed with 80% power at a one sided outflow of your 0.1 to detect a 37.5% benefit in each treatment group versus placebo at week 52.

Gene G. Kinney: Key secondary endpoints, in addition to safety and tolerability, include DATspec images. This imaging approach detects presynaptic dopamine transporter protein in the brain and is considered a biomarker of functional dopaminergic neuron termination. That SPECT is used as a diagnostic tool for Parkinson's and also has been used in clinical studies to monitor neurodegeneration of dopaminergic nerve terminals, which is thought to underlie disease progression. In addition to DatSpec, there are multiple exploratory endpoints, including those derived from a digital biomarker smartphone application. The digital biomarker smartphone application was piloted in our Phase 1B study and demonstrated that daily testing with the app generates reliable, clinically valid data in patients with Parkinson's disease. In Pasadena, these initial learnings were built upon to develop a digital platform.

Key secondary endpoints in addition to safety and Tolerability include aspect imaging.

This imaging approach detects pre synaptic don't mean transporter protein in the brain and is considered a biomarker a functional dopaminergic neuron terminals.

That's back is used as a diagnostic tool for Parkinson's and also has been using clinical study to monitor mnner nerdy generation of dopaminergic nerve terminal, which is thought to underlying disease progression.

In addition to death back there are multiple exploratory endpoints, including those derived from a digital biomarker smartphone application.

The digital biomarker smartphone application was piloted in our phase one study and demonstrated the daily testing with the App generates reliable clinically validated in patients with Parkinson's disease.

In Pasadena. These initial learnings were built upon to develop a smartphone app. The comprehensively measures core signs of Parkinson's disease remotely and continuously meetings throughout the day and not only in the clinical setting where it or certain time points and objective VM smartphone centers.

Gene G. Kinney: University of California, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, San Diego, We expect to assess the Phase II study results by evaluating multiple endpoints, including the primary endpoint and select secondary and exploratory. Now I'd like to highlight a second clinical stage program, PIRX4, for the potential treatment of ATTR embolism. Pyrrex-4 is an investigational antibody designed to specifically target MIST-TTR without affecting the native or normal tetrameric form of the protein. MIS-TTR is the term we use to describe non-native forms of the transtyretin or TTR protein that likely underlie both hereditary and wild-type ATTR amyloidosis. ATTR amyloidosis is a peripheral amyloid disease characterized by deposition of TTR amyloid in vital organs.

The digital testing encompasses measures designed to assess donation Pos Roland rest tremor manual dexterity Brady can easily on balance.

We expect to assess the phase two study result by evaluating multiple endpoints, including the primary endpoint and select secondary and exploratory endpoints.

Now I'd like to highlight a second clinical stage programs here explore for the potential treatment of eight TTR amyloidosis.

Hi, Eric scores, an investigational antibody designed specifically target Miss TTR without affecting the native or normal petroamerica form of the protein.

Ms TTR the term we used to describe non native forms of of the transfer written or TTR protein that likely underlie both hereditary and wild type a TTR amyloidosis.

Hey, TTR amyloidosis is a peripheral amyloid disease characterized by deposition of TTR amyloid and vital organs.

Gene G. Kinney: It is rare, progressive, and often fatal. ATTR amyloidosis can be hereditary when caused by a mutation in the TTR gene, or it can occur sporadically. In both forms of the disease, patients can experience a spectrum of clinical manifestations affecting multiple organs, most commonly the heart and or the nervous system. The TTR protein is produced primarily in the liver and, in its normal tetrameric form, serves as a transport carrier for thyroxin and retinal binding protein, which is a transporter for vitamin A, and it's also implicated in neuroprotective functions. It is generally accepted that, at the time of diagnosis, affected organs in both hereditary and wild-type ATTR patients contain extracellular amyloid. These deposits, together with soluble non-native conformations of TTR, are believed to cause organ dysfunction.

Is rare progressive and often fatal.

Hey to DRM like doses can be hereditary when caused by a mutation in the TTR gene well wild type when it occurs sporadically.

In both forms of the disease patients can experience a spectrum of clinical manifestations affecting multiple oregons, most commonly the harder and or the nervous system.

The TTR protein is produced primarily in the liver and then it's normal such dramatic form serves as a transport carrier first Iraq's and retinal binding protein, which is a transporter for vitamin day, it's also implicated in or protective functions.

It is generally accepted that at the time of diagnosis affected organs in both hereditary and while <unk> eight TTR patients contained extra cellular amyloid deposits.

These deposits together with soluble non native confirmations of TTR are believed to cause organ dysfunction.

Gene G. Kinney: Newly available therapeutics for ATTR amyloidosis have demonstrated clinical benefit by impacting the biological pathway leading to the formation of amyloid deposits. These approaches are designed to reduce production of native forms of the TTR protein or bind to tetrameric TTR and slow dissociation. However, neither of these approaches target MIST-TTR or tissue-deposited amyloid directly. While these new therapies represent great advances for patients with ATTR amyloidosis, we believe, based on the available clinical data to date, that a large unmet medical need remains for two groups of patients. The larger group are patients diagnosed with wild type or hereditary ATTR and cardiac, particularly in New York Heart Association class three or four.

Newly available Therapeutics Ray TTR amyloidosis have demonstrated clinical benefit by impacting the biological pathway, leading to the formation of amyloid deposits.

These approaches are designed to reduce production of native forms of the TTR protein or buying to Tetra Merrick TTR and slowed association.

However, neither of these approaches target Miss TTR were tissue deposit at amyloid directly.

Well these new therapies represent great advances for patients with a TTR amyloidosis, we believe based on the available clinical data to date that a large unmet medical need remains for two groups of patients.

The larger group, where patients diagnosed with wild type or hereditary TTR in cardiac dysfunction, particularly in New York Heart Association class three or four.

Gene G. Kinney: For these patients, a more rapid and or greater survival benefit remains to be demonstrated. The other unmet need is for hereditary ATTR patients whose peripheral neuropathy is not responsive to treatment with therapies that have silenced their mechanisms of action. Pyrex IV was designed to target MIST-TTR directly by binding to an epitope on the TTR protein that is exposed when the native form of the tetramer dissociates. This epitope continues to be exposed during misfolding of the protein.

For these patients and more rapid and or greater survival benefit remains to be demonstrated.

The other unmet need it for hereditary TTR patients, whose peripheral neuropathy is not responsive to treatment therapies that assignments are mechanisms of action.

Pyrrhic score was designed to target Miss TTR directly by binding towards epitope on the TTR protein that is exposed when the native form of the Techmer dissociate.

This epitope continues to be exposed during this building of the protein the biological goal following treatment periods for it to deplete the deposit amyloid and circulating mid TTR to improve organ function.

Gene G. Kinney: The biological goal following treatment with PRx4 is to deplete the deposited amyloid and circulating missed GTR to improve organ function. PRX4 has been shown in preclinical studies to promote clearance of amyloid fibrils through antibody-mediated phagocytosis, to inhibit amyloid fibril formation, and to target soluble aggregate forms of MIST-TTR. We believe this differentiated depleter mechanism of action could be developed as a monotherapy for the treatment of ATTR amyloidosis and might also complement existing therapeutic approaches that either stabilize or reduce production of the native TTR tetra. Our ongoing phase one study of PRX4 is designed as an open-label, multi-center, 3 plus 3 dose escalation study to determine the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of PRX4 in patients with hereditary ATTR amyloidosis with peripheral neuropathy who may also have cardiomyopathy.

Parents for has been shown in preclinical studies to promote clearance of amyloid fibrils through antibody mediated phagocytosis to inhibit amyloid fiber formation and to target soluble aggregates forms of Miss TTR.

We believe this differentiated depleter <unk> mechanism of action could be developed as a monotherapy for the treatment of eight TTR amyloidosis, and Mike also complement existing therapeutic approaches, which either stabilize or reduce production of the native TTR techmer.

Our ongoing phase one study appearance for is designed as an open label multi center three plus three dose escalation study to determine the safety Tolerability pharmaco kinetic and Pharmaco dynamic properties appearance for in patients with hereditary TTR amyloidosis with peripheral neuropathy, who may.

I also have cardio my office thing.

The study includes the use of our proprietary Miss TTR I biomarker assay that measures target engagement through changes in the level of unbound Miss TTR in plasma.

Gene G. Kinney: The study includes the use of our proprietary MIST-TTR biomarker assay that measures target engagement through changes in the level of unbound MIST-TTR in plasma. In the escalation phase of the study, patients received Pyrrhx 4 intravenously once every 28 days for up to three infusions. Six dose levels are being evaluated, 0.1, 0.3, 1, 3, 10, and 30 milligrams per kilogram. Eligible patients who complete the escalation phase can enroll in a long-term extension phase of the study and receive up to 15 additional infusions of PRX4 every 28 days. At the end of 2019, we reported interim data from the escalation portion of the Phase 1 study of PRX4 in patients with hereditary ATTR amyloidosis. In the interim analysis, 15 patients in the dose escalation phase of the study had each received three infusions in dose level cohorts 1 through 5, representing 0.1, 0.3, 1, 3, and 10 milligrams per kilogram.

And the escalation phase of this study patients receive pyrrhic for intravenously. Once every 28 days for up to three infusion.

Fixed dose levels are being evaluated 0.1, 0.313, 10, and 30 milligrams per kilogram.

Eligible patients who complete the escalation phase can enroll in a long term extension phase of the study and receive up to 15 additional infusions, appearing for every 28 days.

At the end of 2019, we reported interim data from the escalation portion of the phase one study appear export in patients with hereditary TTR amyloidosis.

In the interim analysis 15 patients in the dose escalation phase of this study at each received three infusions and dose level cohorts, one through five representing 0.1, 0.313, and 10 milligrams per kilogram.

Direct for was found to be generally safe well tolerated demonstrated pharmacokinetic profiles consistent with that of NRG, one monoclonal antibody.

Gene G. Kinney: PRX4 was found to be generally safe and well tolerated and demonstrated pharmacokinetic profiles consistent with that of an IgG1 monoclonal antibody. Target engagement was demonstrated by a dose-dependent decrease in plasma levels of unbound MIST-TTR, which is the molecule not captured by PRx4, as measured by our MIST-TTR assay. For the three patients at the 10 milligrams per kilogram dose level, which was the highest dose level reported in the interim analysis, the maximum observed reductions in missed TTR levels, which occurred within 24 hours of the first infusion, were 54%, 66%, and 76%. And, as expected, because PRx4 is designed to recognize an epitope exposed only on the MIST TTR species, there was no apparent impact on levels of normal tetrameric. Of the 15 patients from cohorts 1 through 5, 12 patients were eligible for the long-term extension and were enrolled as of December 2019.

Target engagement was demonstrated by dose dependent decrease in plasma level of unbound, Miss TTR, which is the mid TTR not captured by parents for as measured by our Miss TTR asset.

For the three patients in the 10 milligram per kilogram dose level, which was the highest dose level reported in the interim analysis. The maximum observed reductions in mis TTR levels, which occurred within 24 hours at the first infusion were 54%, 66% and 76% and.

As expected because trx four is designed to recognize epitope oh exposed only on the Miss TTR species.

There was no apparent impact on levels of normal Tetra Merrick TTR.

Oh, the 15 patients from cohorts one through 512 patients were eligible for the long term extension and were enrolled as of December 2019.

Gene G. Kinney: Of the three patients not enrolled in the long-term extension, two patients from Cohort 1 were ineligible due to early termination during the escalation phase, and one patient from Cohort 2 was ineligible based on the long-term extension screening criteria. As reported in the interim analysis, no dose-limiting toxicities were observed in the escalation phase in cohorts one through five of the escalation phase.

Of the three patients not ruled in long term extension to patients were from cohort one word ineligible due to early termination during the escalation phase and one patient cohort two was ineligible based on the long term extension screening criteria.

As reported in the interim analysis no dose limiting toxicities were observed in the escalation phase in cohorts one through five of the escalation phase one severe treatment emergent.

Gene G. Kinney: An Emergent Adverse Event was reported, which was a worsening of a pre-existing condition deemed unrelated to PRX4 by the investigator and subsequently resolved. These interim data support continuation of the Phase I study as planned, and we expect to report additional data from our dose escalation and long-term extension portions of the study later this year. Now, I'd like to briefly discuss our early stage pipeline. We have an active discovery and pre-clinical pipeline that is advancing new programs to potentially address a broad spectrum of devastating diseases. Our global neuroscience collaboration with Bristol-Myers Squibb is focused on three discovery stage programs, Tau, TDP-43, and a third undisclosed target. All three 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 supernuclear palsy, among them.

Emergent adverse event was reported which was a worsening of a preexisting conditions deemed unrelated to purex, whereby the investigator and subsequently result.

These interim data support continuation of the phase one study as planned and we expect to report additional data from our dose escalation and long term extension portions of the state study later this year.

Now I'd like to briefly discuss our early stage pipeline.

We have an active discovery and preclinical pipeline that is advancing new programs to potentially address a broad spectrum of devastating diseases.

Our global neuroscience collaboration with Bristol Myers Squibb is focused on three discovery stage programs town, TDP 43, and a third undisclosed target.

All three of these targets are implicated in a range of Neurodegenerative diseases. The currently have no disease, modifying therapies, including Alzheimer's disease, Frontotemporal dementia, amyotrophic lateral cirrhosis rail S chronic traumatic encephalopathy and progressive Super nuclear policy among them.

There's a strong consensus that the type of sequential transmission that I described earlier for Parkinsons disease. They also underlie the progression of several other neurodegenerative diseases.

Gene G. Kinney: There's a strong consensus that the type of sequential transmission that I 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 been described in ALS and frontotemporal dementia.

For example transmission of pathology between different brain regions has also been proposed in Alzheimer's disease with beta amyloid Intel.

More recently cell to cell transmission of GDP 43 pathology has been described it a less than frontotemporal dementia.

Antibodies, maybe effective as disease modifying therapies through several potential mechanisms, but we believe that preventing the uptake and seating into healthy cells is an important step in slowing or halting disease progression.

Gene G. Kinney: Antibodies may be effective as disease-modifying therapies through several potential mechanisms, but we believe that preventing their uptake and seeding into healthy cells is an important step in slowing or halting disease progression. Our extensive research in this space, as well as recent clinical developments in the field, suggests that the efficacy of a therapeutic is likely to be dependent on the binding characteristics to selected epitopes. Once complexed with pathogenic proteins, antibodies may also promote clearance of pathogenic species via, for example, phagocytosis and perivascular clearance.

Our extensive research in this space as well as recent clinical developments in the field suggests that the efficacy of a therapeutic is likely to be dependent on the binding characteristics to selected epitopes once complex with pathogenic proteins antibodies may also promote clearance of pathogenic species. The for example, phagocytosis.

And Perry vascular clearance.

The knowledge about common mechanisms of disease propagation at the molecular level and our increasing understanding of how to effectively intervene in this process enables our efforts to develop highly targeted at potent antibodies that aim to intercept the transmission process and prevent further neat nerve regeneration.

Gene G. Kinney: Knowledge about common mechanisms of disease propagation at the molecular level and our increasing understanding of how to effectively intervene in this process enables our efforts to develop highly targeted and potent antibodies that aim to intercept the transmission process and prevent further neurodegeneration. Our preclinical TAO program exemplifies our unique approach and methodology. We have tested a large number of antibodies to epitopes along the tau protein, including post-translational modifications, and found that only a few have resulted in a superior profile compared to those that have been described by other groups for their ability to block the binding of tau to neurons and prevent the downstream neurotoxin. We believe that understanding this biology and what may drive the efficacy of these antibodies is important to increase our confidence in selecting and optimally evaluating a clinical candidate.

Our preclinical tell program exemplifies our unique approach and methodology, we've tested a large number of antibodies epitopes, along the top protein, including post transplant translational modifications and found that only a few have resulted in a superior profile compared to those that have been described by other groups for their ability to block the binding Uptown and.

Her on and prevent the downstream neurotoxic effects.

We believe that understanding this biology, and what May drive the efficacy of these antibodies is important to increase our confidence in selecting and ultimately evaluating a clinical candidate.

Gene G. Kinney: Last year, we initiated cell line development of a lead candidate for our TAL program, and our IND-enabling studies are ongoing. We are applying a similar approach to generate clinical candidates against TDP-43 and the third undisclosed target that is part of our collaboration with Bristol-Myers-Brown. The collaboration with our colleagues at Bristol-Myers Squibb continues to be productive. As you may recall, Prothena is responsible for the execution of these programs through the preclinical and early clinical stages of development, dependent upon various clinical option exercise periods by Bristol-Myers Squibb.

Last year, we initiated cell line development of a lead candidate for a child program and our eye in the enabling studies are ongoing.

We are applying a similar approach to generate clinical candidate plant candidates against TDP 43, and the third undisclosed targets that is part of our collaboration with Bristol Myers Squibb.

The collect collaboration with our colleagues at Bristol Myers Squibb continues to be productive. It as you may recall for Sina is responsible for the execution of these programs through the preclinical and early clinical stages of development depends upon various clinical option exercise periods by Bristol Myers Squibb.

Finally, I want to provide an update on one aspect of our early stage pipeline that we have accelerated on a number of front and that is our proprietary Alzheimer's disease programs.

Gene G. Kinney: Finally, I want to provide an update on one aspect of our early stage pipeline that we have accelerated on a number of fronts, and that is our proprietary Alzheimer's disease program. Building on our foundational science in the discovery and development of anti- beta antibodies and vaccines for Alzheimer's disease, we continue to be highly active in this. As you are aware, several of our scientists were responsible for elucidating the potential causal role of misfolded proteins in Alzheimer's disease and worked on developing the first anti-beta antibodies clinically tested. Last year on this call, we discussed our ABETA discovery effort, including our proprietary novel anti-ABETA antibodies that we believe may offer significant improvements for patients and their families over what can be envisioned by those currently undergoing clinical testing.

Building on our foundational science in the discovery development of anti beta antibodies and vaccines for Alzheimer's disease, we continue to be highly active in this space.

As you're aware several of our scientists were responsible for elucidating the potential caused the role of Misfolded proteins in Alzheimer's disease and worked on developing the first anti beta antibodies clinically tested.

Last year on this call we discussed our a beta discovery effort, including our proprietary novel anti a beta antibodies that we believe may offer significant improvements for patients and their families over what can be envisioned by those currently undergoing clinical testing.

We have initiated cell line development of lead candidates and this program and expect to initiate I Indy enabling studies this year.

Gene G. Kinney: We have initiated cell line development of lead candidates in this program and expect to initiate IND-enabling studies this year. Separately, we have also initiated new discovery activities on a number of our other programs in our Alzheimer's portfolio. We are very interested in the new analysis of the larger Atacanamab dataset presented at CTAD in December from the Emerge and Engage study.

Separately, we have also initiated new discovery activities on a number of our approach our other programs in our Alzheimer's portfolio.

We're very interested in the new analysis of the larger added Kennametal dataset presented at Sicad in December from the emerging engaged studies.

Gene G. Kinney: Those data are consistent with our belief that antibodies that target the A-beta protein at an optimal epitope, and in particular, antibodies with high binding strength that broadly interact with both the soluble and insoluble pathological forms of the A-beta protein, will ultimately be a successful first step toward slowing the relentless progression of neurodegeneration in Alzheimer's. I've spoken about our work in tau and A-beta, and I want to also emphasize how closely linked we believe these two proteins are in driving the pathophysiology of Alzheimer's and their important role in disease onset and progression. Evidence suggests Alzheimer's pathology results from a complex interplay among pathogenic tau and a beta protein. Phosphorylated Tau in the brain is a well-understood hallmark of Alzheimer's pathology associated with cognitive decline.

Those data are consistent with our belief that antibodies that target a beta the a beta protein at an optimal epitope and in particular antibodies with high binding stream that broadly interact with the soluble insoluble pathological forms of the beta protein will ultimately be a successful first step toward slowing the relentless progression of nerve regeneration and.

Timers disease.

I've spoken about our work in town, a beta and I want to also emphasize how closely linked we believe these two proteins are in driving the pathophysiology of Alzheimer's disease, and they're important role in disease onset and progression.

Evidence suggest Alzheimer's pathology results from complex interplay, among pathogenic Tao and a beta proteins.

Phosphorylated town, the brain is well understood hallmark of Alzheimer's pathology associated with cognitive decline in fact research closely linked a beta to the rapid spread of tell phosphorylation.

Gene G. Kinney: In fact, research closely links ABETA to the rapid spread of tau phosphorylation. Because of this intricate relationship between pathogenic forms of these proteins, we continue to believe that both A-beta and tau play important roles in the potential treatment and prevention of Alzheimer's. Ultimately, we believe that interventions that target each and or both of these proteins have the potential to reduce the clinical decline in or prevent the onset of Alzheimer's. As such, we are conducting discovery activities for both antibodies and vaccines. We believe our team, with its scientific expertise in diseases caused by neurological dysfunction and protein misfolding, has the capabilities needed to drive transformational innovation. We look forward to providing updates on these programs as they progress. With that said, at this time, I'll turn the call over to Tran for a discussion of our financial results. Okay, Tran? Thanks, Gene.

Because of its intercut relationship between pathogenic forms of these proteins. We continue to believe that both a beta and towel play important roles in the potential treatment and prevention of Alzheimer's disease.

Ultimately, we believe the interventions that target each indoor both of these proteins have the potential to reduce the clinical decline in or prevent the onset of Alzheimer's disease.

As such we are forwarding discovery activities for both antibodies and vaccines.

We believe our team with its scientific expertise in diseases caused by neurological dysfunction in protein folding has the capabilities needed to drive transformational innovation.

We look forward to providing updates on these programs as they progress.

With that said at this time I'll turn the call over to turn for a discussion of our financial results strong.

Thanks Gene today, we reported favorable 2019 cash burn from operating and investing activities of approximately $53.5 million, which was below our updated 2019 guidance of $57 million to $65 million as of December 30, Onest 2019, patina had approximately 378.

Tran B. Nguyen: Today we reported favorable 2019 cash burn from operating and investing activities of approximately $53.5 million, which was below our updated 2019 guidance of $57 to $65 million. As of December 31st, 2019, Prothena had approximately $378 million in cash, cash equivalents, and restricted cash and no debt.

Million dollars in cash cash equivalents and restricted cash and no debt. Please refer to the press release issued today for further details regarding our fourth quarter and year end 2019 financial results.

Tran B. Nguyen: Please refer to the press release issued today for further details regarding our fourth quarter and year-end 2019 financial results. Turning to our 2020 financial guidance, we expect the full-year 2020 net cash burn from operating and investing activities to be $60 to $76 million and to end the year with approximately $310 million in cash, which represents the midpoint of the range. The estimated full year 2020 net cash burn from operating and investing activities is primarily driven by an estimated net loss of $84 to $106 million, which includes an estimated $23 million of non-cash share-based compensation expenses. With that, I'll turn the call back over to Gene to summarize our upcoming milestones. Gene.

Turning to our 2020 financial guidance, we expect the full year 2020, net cash burn from operating and investing activities to be $60 million to $76 million end to end the year with approximately $310 million in cash which represents the midpoint of the range. The estimated full year 2020, net cash burn from operating and invest.

The activities is primarily driven by an estimated net loss of $84 million to $106 million, which includes an estimated $23 million of noncash share based compensation expense with that I'll turn the call back over to gene to summarize our upcoming milestones Jane Thanks John.

Gene G. Kinney: Thanks, John. As we move forward in 2020 and beyond, we expect continued progress in our pipeline and look forward to coming back to you as we have data to report. Before we talk about our upcoming milestones, I'd like to first recognize two groups of people who make immeasurable contributions to our ability to execute our highly ambitious goals. I want to first thank the patients and clinicians who participate in our studies, because without their support, we could not elucidate the potential value of the new medicines we're developing. I'd also like to acknowledge and thank our very talented employees for their ongoing commitment to helping patients by advancing our research. Now, turning to a summary of our R&D milestones, for presinezumab, the last patient last visit in Part 1 of the Phase 2 Pasadena study took place toward the end of 2019, and we continue to expect to report results from Part 1 of the study this year.

So as we move forward in 2020 and beyond we expect continued progress in our pipeline and look forward to coming back to you as we have data to report before we talk about our upcoming milestones I'd like to first recognized two groups of people, who make immeasurable contributions towards our ability to execute our highly ambitious goals.

I want to first thing to patients and clinicians who participate in our studies because without their support we could not elucidate the potential value of the new medicines, we're developing.

I'd like to also acknowledge and thank our very talented employees for their ongoing commitment to helping patients by advancing our signs.

Now turning to a summary of our R&D milestones for breast and as a man in the last patient last visit in part one of the phase two Pasadena study took place toward the end of 2019, and we continue to expect to report results from part one of the study this year.

Gene G. Kinney: For PRx4, the Phase I study is ongoing, and we expect to report additional detailed data, including data from the 30 milligram per kilogram cohort and data from the long-term extension portion of the study later this year. We are also making important advances in our Discovery Pipeline. We are progressing our collaboration with Bristol-Myers Squibb and expect to advance our IND-enabling activities for Tau this year. We also expect to initiate IND-enabling activities for our A-Beta program. So that said, at this time, we'll open the call for questions. Fiona?

The appearance for the Phase one study is ongoing and we expect to report additional detailed data, including data from the 30 milligram per kilogram cohort and data from the long term extension portion of the study later this year.

We're also making important advances in our discovery pipeline, we're progressing our collaboration with Bristol Myers Squibb and expect to advance our R&D, enabling activities for tell this year.

We also expect to initiate I in DNA, enabling activities for our a beta program. This year. So that said at this time, we'll open the call for questions John.

Thank you, ladies and gentlemen, if he has a question.

Operator: Ladies and gentlemen, if you have a question... Please press the star then the number one key on your touch-tone television.

Please.

Number one.

And if your question, it's been answered or you wish to move yourself from Vicki.

Operator: And if your question has been answered or you wish to remove yourself from the queue, press... Your first question comes from the line of Christopher Murray from New Morgan. Your line is open.

Yes.

Your first question comes from the line of Christopher <unk> from Jpmorgan. Your line is open.

Christopher Murray: Okay, thanks for taking the question and congratulations on the year and a great update. I appreciate that. Firstly, I was just going to hit upon perhaps PRX04 and the next data that you might release and sort of when. I'm assuming it's too late to present it at ISA later this quarter. And then secondarily, with respect to your clinical trial plan that it seems you laid out, did I hear correctly that in polyneuropathy, you'd look at patients who have progressed following Noctan agents or the RNAi or the famitis? Thank you.

Okay. Thanks for taking the question and congratulations on the year in a great update I appreciate that.

Firstly, who is just going to hit upon perhaps p. Rx. So for the next data that you might release and sort of when I'm, assuming it's too late to there's anything I say later this quarter and then secondarily.

With respect to.

You know your clinical trial plans that said it seems you laid out today, you're correct. The input Polyneuropathy you look at all patients who have progressed following dr. and agent or.

Gene G. Kinney: Thanks, Chris, for the question. So I think there are two questions there.

He already <unk> or Stamatis.

Thank you.

Gene G. Kinney: The first was timing for more data with X4. And I think, you know, there we'll be consistent with what we've done in the past. We want to make sure that we disclose additional data, notably the higher-level cohort, the 30-meg per kid cohort from the escalation phase of the study, as well as some of the early long-term extension data. And we will likely do that at a scientific conference this year. As would be typical for us, we wouldn't commit to what that scientific conference would be until we've got that abstract done and accepted, and we'd let the street know at that point in time. So we don't have much more to add to that piece.

Thanks, Chris with the question so things to question there. The first was timing for more data with export I think there.

It will be consistent with what we've done in the past we want to make sure that we disclose additional data, notably the higher level cohort 30 make particular from the escalation phase of this study as well as some of the early long term extension data.

And we would likely do that as scientific conference. This year as would be typical for us we wouldn't see we wouldn't commit to what that scientific conference would be until we've got that abstract done in and accepted and we'd let the street know at that point in time. So we don't have it much more to add on that piece I think in terms of their clinical trial plans for X four.

Gene G. Kinney: I think in terms of the clinical trial plans for X4, the way we're thinking about it at this point, and I think what we tried to communicate is where we feel the residual unmet medical need is for patients with ATTR amyloidosis. And we see two groups of patients, broadly, right? In one group, you're talking about both wild type and hereditary ATTR patients with cardiomyopathy. And there, I think, you know, there's a significant medical need to prolong survival and have a survival benefit, particularly in patients that are in a more severe cardiomyopathy state. So these would be your New York Heart Association class three and four patients. And ultimately, potentially being able to see a more rapid improvement, say something that occurred in the first 18 months, even amongst the more milder patients.

Sure I well the way we're thinking about it at this point and I think what we tried to communicate is where we feel the residual unmet medical need is for patients with HCR amyloidosis, and we see two groups of patients broadly right in one group you're talking about both wild type in hereditary TTR patients with car.

In my office, they and their I think you know theres a significant medical need.

To to prolong survival and have a survival benefit particularly in patients.

That are in a more more severe cardium up at these days. So these would be your New York Heart Association class three and four patients.

And ultimately.

Potentially being able to see more rapid improvement say something that occurred.

In the first 18 months, even amongst the more milder patients.

Gene G. Kinney: I think on the other hand, when you think about polyneuropathy, what we look at here in terms of unmet need, there are a number of studies that, plus or minus, depending on the publication, show that about, you know, a third, plus or minus, depending on the publication, of patients on silence or treatment are characterized as non-responders. And, you know, there are different ways that non-responders are characterized There's no standard definition of that across the field, just to be very clear. But we see, you know, obviously, a potential need to improve treatment for those patients as well. So that's what it is.

I think on the other side when you think about Polyneuropathy, what we look at here in terms of unmet need.

There are number of studies that plus or minus show that about a third plus or minus depending on the publication of patients on silence or treatment.

Characterized as non responders and there are different ways that nonresponders are characterized there's no standard definition of that across the field has to be very clear, but we see obviously, they're being potential need.

To improve treatment for those patients as well, so thats, where we see the potential need the space and broadly when we think about further development appearance for we think the depleter mechanism of action that pyrrhic for possesses.

Gene G. Kinney: And broadly, when we think about further development of PRx4, we think the depleted mechanism of action that PRx4 possesses is something that kind of lends itself well to think about both standalone trials where we can think about PRx4 by itself, but we can also think about it as a potential additive approach to the existing therapeutic approaches in as much as the biology is complementary and not competitive.

You know is something that that kind of lends itself well to think about both standalone.

Yes.

Kind of trials, where we can think about the appearance for by itself, but we can also think about it as a potential additive approach to the existing therapeutic approaches in as much as the biology is complementary and not competitive.

Okay, Great and then just just to sort of fall off.

Gene G. Kinney: Okay, great. And then, just to sort of follow up. With respect to that polyneuropathy population, is there any indication that some of those patients may have irreversible damage and that you wouldn't be able to sort of reverse it or help them out even with your differentiated approach? And then lastly, when we think about you guys kicking off some of these trials, presumably sort of these two threes, if you will, given the OLEs started on phase one, what sort of timing should we think Thank you.

With respect to that falling off the population is.

Is there any indication that some of those patients may.

Have you reversible damage that you wouldn't be able to sort of reverse it or or help even with here.

Differentiated approach and then lastly.

When we think about you guys kicking off some of these these trials previously sort of these two threes if you will.

Given the oil you started on the phase one and what sort of timing should we think about with respect to those trials kicking off or would you wait for partnership.

Or something that aspect to get those.

Gene G. Kinney: Well, I think we will continue to look at the dose escalation data, you know, from the higher doses, and we'll look at the long-term extension data, but that being said, we'll let the data guide us in terms of ultimate timing, and clearly some of these conversations need to be done with, you know, with regulators in terms of the next steps. In terms of reaching the broadest patient population, clearly cardiomyopathy would be a major first step given the size of that opportunity, and hereditary neuropathy, you know, clearly a little bit smaller, well a lot smaller. But in terms of, you know, our belief in terms of reversal of damage in maybe sicker patients, I think we don't have exact data in ATTR patients to understand that, and even the clinical data that's being shown hasn't really borne that out in terms of where we get our confidence from is when we go back to our Neo D1 data in terms of our Mayo Stage 4, you know, patients who are the sickest patients in the AL population, you know, where in the wild, I think the median OS is about six months, and then, of course, in our trial, the control arm was about eight months, and so, you know, of course, on our treatment side, it was not reached, and I think at a nine-month period, I think we had a hazard ratio of below just 0.5.

Thank you.

Well I think we will continue to to look at these dose escalation data from the higher doses. Then we'll look at the long term extension data, but but that being said, we'll let the data guide us in terms of ultimate timing and clearly some of these conversations need to be done with with regulators in terms of the next steps.

Terms of reaching the broadest patient population clearly cardiome after the would be.

A major first step given the size of that opportunity and hereditary lofty clearly a little bit smaller of will lot smaller but in terms of you know our belief in terms of.

Reversal of damage in maybe sicker patients I think what we don't have the exact data in 80 TR patients to understand that the even though clinical data. That's that's being that's being shown hasn't really borne that out in terms of where we get our confidence front as we go back to our new D. one data in terms of our mail stage four.

Patients who are the sickest patients in a on population where in the wild I think there the media West is about six months and then of course in our trial. The control arm was about eight months and so of course on our treatment side. It was not reach in I think at a nine month.

Period, I think we had a hazard ratio below just 0.5 on calls for Todd It's right on all cause mortality. So that gives us believes that lease in some of cardio property perspective.

Gene G. Kinney: on all calls.

Gene G. Kinney: That's right, an all-cause mortality rate. So that gives us, you know, a belief that at least in, from a cardiomyopathy perspective, in a patient population, although different, that dies a lot sooner, that we were able to intervene there with an antibody with a similar mechanism, clearly, but we'll have to, you know, continue to look for data here in phase one to give us that, that, We clearly like what we showed at the end of last year last year, where we showed proof of mechanism, where we showed we could interact with the MIST-GTR, which we believe is a pathogenic species in a very,

Patient population although different.

That does a lot sooner that you know that we were able to intervene there with an antibody with a similar mechanism clearly, but we'll have to continue to look for data here in the phase one to give us that that signal, we clearly like where we'll do what we showed at the ended the year last year, where we've showed proof of mechanism where.

Weve shown we can interact with.

The Miss GTR, which we believe the pathogenic species in a very short period time.

Your next question comes from the line of Charles Duncan from country.

[laughter] base.

Gene G. Kinney: Your next question comes from the line of Charles Duncan from Canter. Hi guys, good afternoon. Thanks for that detailed update on the platform and the pipeline. I need to take another approach to trying to understand this kind of news flow, and I doubt you'll really be able to give us much granularity, but I'll give it a shot anyway. And that is, if you think about the Pasadena data, you said you'd anticipate data this year, and yet for PRX04, you qualified it by saying it would be later in the year. And so I guess I'm wondering if you anticipate updates out of Pasadena before PRX04. Yeah,

Afternoon, Thanks for that details.

Update on platform and the pipeline.

I need to take another approach to trying to understand kind of new slowing that I doubt you will really be able get much much granularity, but I'll give it to shut anyway and that is if you think about the Pasadena data you said you'd anticipate eight at this year and yeah for PR so for.

You quantified it by saying later in the year. So I guess I'm wondering if you anticipate eight out of Pasadena for a PR National Park.

Or is yeah, I misread that.

Charles Cliff Duncan: Thanks for the question, Jez. Yeah, I mean, right now with Pasadena, you know, we're saying 2020, and, you know, I think, you know, what we can do is kind of reiterate some of the timing on that. You know, clearly, that study was fully enrolled with 316 patients in late 2018. As I mentioned on the call, the last patient visit for Part 1 was towards the end of 2019. And all that said, Roche is operationally in charge of that study. So, you know, ultimately, those timelines are theirs.

Thanks for the questions as you I mean, it's the right now with Pasadena, We're saying 2020, and I think what we can do is kind of reiterate some of the timing on that.

Clearly that study.

Was fully enrolled the 316 patients in late 2018 as I mentioned on the call. The last patient visit for part of one was towards the end 2019 in all that said Roche is operationally in charge of that studies. So ultimately.

Those timelines are there and at this point in terms of granularity I think we're comfortable saying as 2020.

Gene G. Kinney: And you know, at this point, in terms of granularity, I think, you know, all we're comfortable saying is 2020. But, you know, Pasadena is, you know, again, just to remind everyone, Pasadena is a study that is 80% powered with a one-sided alpha of 0.1 to detect a 37.5% benefit at week 52 for each of the dose levels against placebo. So, it is very much a signal detection study. It's meant to be directional and informative and really guide us in terms of what it would take to design an appropriate Phase 3 if, in fact, the data indicates that we should be moving forward. So, that's where we are. And again, we can't provide any more detail than that at this point in time, but we'll be excited to see the data when it comes out. But, Chas, in regards to your question about PRX4 and PRX2, I think you're reading too much into that. I think both...

But yeah Pasadena is.

Again, just to remind everyone Pasadena is a.

Study that is.

80% power with though at a one sided alpha 0.1 to detect a 37.5% benefit at week 52 for each of the dose levels.

Against placebo. So it is very much a signal detection study I'm, it's meant to be directional informative and really guide us in terms of what it would take to.

Designed in appropriate phase three if in fact that data indicates that we should be moving forward. So that that's where we are at and again, we can't provide any more detail than that at this point in time, but but but will be excited to see the data when it comes but which adds in regards to your relative question between pure export you're actually I think you're reading too much into that I think both data.

Evan will land at the appropriate scientific or medical conference.

This year.

Gene G. Kinney: We'll land at the appropriate scientific or medical conference this year.

Okay. Okay, that's fair and that makes sense to me and then.

Charles Cliff Duncan: Okay, okay, that's fair, and that makes sense to me. And then one additional question on Crassie Newsmab and Part 1. Not that you need the cash, but can you remind us whether or not there could be a milestone payment with the completion of Part 1 or would it be, perhaps, later in the program?

One additional question on pricing is mabin and part one.

Thank you need the cash but.

Can you remind us whether or not or could be a milestone payment with the completion of part one or would that be perhaps later in the program.

Tran B. Nguyen: Actually, we haven't disclosed the size of the milestone, but I'll give a little bit of a recap. We received a milestone for the start of Phase 1, which was $15 million, and we received another milestone for the initiation of Phase 2, which was $30 million. If there is a Phase 3, and it starts, we'll receive the third clinical milestone upon the initiation of that phase 3.

Actually the we haven't disclosed the size of the milestone, but I'll give a little bit of a recap we received.

You know a milestone for phase one start which was 15 million.

Dollars and we received another milestone for initiation of phase two which was 30 million. We will if there is a phase three and initiate will receive.

The third clinical milestone upon initiation of phase three.

Your next question comes from the line.

Operator: Thank you guys. Thanks, Gene. Thanks, Tran, for the update.

From Jefferies.

Thank you guys. Thanks gene Thanks transfer the update or two questions. One is following up on.

Unknown Attendee: Two questions. One is following up on the Parkinson's study. Could you just provide some color and thoughts around what you think is a great scenario and what you think the key data you'd like to see in these endpoints are to support an active drug? Maybe just talk about that and how you're thinking about it with your partner. And then the second question is a little more off the radar, I guess, off the rails, which is, as you mentioned in your press release, you added two new board members, one of whom is a known biotech investor. I think there are questions around whether you would be thinking about monetizing assets, thinking about various forms of monetization of things. Maybe just talk about that addition to the board and how you guys are thinking about it.

Parkinson study could you just provide some color and botch all around what you think is a great scenario and what you think is.

When you think the key data you'd like to seems endpoint charter to support an active dialogue, maybe just talk about that and how you're thinking about it with your partner.

And then the second question.

A little more.

Oh.

Off the radar I guess off the rails niches.

As you mentioned your press release, you added two new board members one of which is you should know biotech investor I think theres questions around would you be thinking about monetizing assets thinking about various forms of monetization of things maybe just talk to.

Operator: where that

Operator: Where that could create value and money. Thank you. Well, let's start with the first part of your question, and then you might have to remind us about the second part. But I think I know where you're going there.

In addition to the board and how you guys, you're thinking about where that could create value of monetization.

Thank you well, let's let's start with the first part of your question and then you might have to remind us on the second part, but I think I know youre going there, but with regards to the trx to and what we would be looking for I think I think it's good here to take a step back and think about the totality of data that that will be produced by Pasadena, I mean, the way you.

Gene G. Kinney: But in regards to PRX2 and what we would be looking for, I think it's good here to take a step back and think about the totality of data that will be produced by Pasadena. I mean, the way you can think about that, too, is that Biogen, who is about six-plus months behind us, they have a safety tolerance primary, where they'll look at secondary and exploratory endpoints, such as DAT It's the same thing here.

Can think about that too is.

Biogen, who is about six plus months behind us They haven't safety Tolerability primary we'll look at secondary and exploratory endpoints such as that aspect and other endpoints. It's the same thing here on the although we have a primary endpoint of Mds you. Peter has we'll be looking at the primary select secondary like that.

Gene G. Kinney: Although we have a primary endpoint of MDS-UPRS, we'll be looking at the primary, select secondary, like DATSPEC, and, of course, the digital biomarkers that are in the exploratory bucket. So we'll be looking at all of that comprehensive data to understand how to move forward to phase three. So I think that would be, for us, homerun data, that we have data that we can move forward with.

Pat and of course, the digital Biomarkers that are in exploratory.

Exploratory bucket. So we'll be looking at all of that comprehensive data to understand how to move forward to tumor phase threes. So I think that would be for us home run down is that we have data that we can move forward with.

Gene G. Kinney: Yeah, I agree completely. And, you know, I just want to make sure I remind everyone as well, this is not a study that was powered, you know, in the traditional way that you would power an efficacy study. This study is powered at 80%, again, with a one-sided alpha 0.1 to detect, you know, a relatively large effect size, 37.5%. We really are asking from this study is, you know, can we de-risk the approach to a Phase 3 by designing an appropriate Phase 3 trial? And, you know, across the multiple endpoints, many of which we think could be informative, that's what we need out of the trial in order to be able to continue to move the program forward. So I think that's, that's what we're looking for. And I think that's what anyone who was thinking about how you would move this through the Phase 2 to Phase 3 setting would be thinking about.

No.

Great completely and just.

I want to make make sure I remind everyone as well you know this is not a study that was powered in a traditional way that you would power and efficacy study. This study is powered at 80% again with a one sided alpha 0.1 to detect relatively large effects that 37.5%. We really are asking what we really are.

Or asking from this study is can we de risk the approach to a phase three by designing an appropriate phase three trial and across the multiple endpoints many of which we think can be informative.

Thats, what we need out of the trial in order to be able to continue to move program forward. So I think that that's what we're looking for it I think thats what anyone that was thinking about how you would move this through the phase two to phase three setting would be thinking about.

Gene G. Kinney: I think in terms of your second question regarding E-Corp One, Oleg Noliman's appointment to the board, clearly the board, was a very welcomed addition to the board, and his decade-long expertise around financial and strategic investing is clearly very additive, and it's a perspective that the board welcomes. In terms of monetization, you said something about monetization.

And I think in terms of your second question regarding equal one all legs only known in appointment to the board.

Including the board. It was very welcomed addition to the board and his his decade long expertise around financial and strategic investing is clearly very additive and it's a perspective that the board welcome.

In terms, you said something about monetization I mean, I think at the end of the day.

Gene G. Kinney: I mean, I think at the end of the day, not just Oleg but other board members and also the senior management team, we're here to do what's in the best interest of both patients and, of course, our shareholders as a derivative of all that. So the point is, I think he continues to be very productive for us. I think our BD efforts have actually been turned up a little bit higher to continue to add to our neuroscience pipeline, although clearly, the major thing we'll always stick to is our expertise in neuroscience and also protein misfolding from an understanding of the biology. So we're really excited by having him on the board, and he's been clearly very helpful. And clearly, we also had another addition in Paula Cobb, who is also operational expertise, ex-Biogen, and she's been very helpful and instrumental from an operational perspective too.

Not just holding but other board or other born numbers and also the senior management team will we are here to do with in the best interest on both patients and of course, our shareholders as a derivative all that so the the point is I think he continues to.

The very productive for us I think our BD efforts have actually been.

Turned on a little bit higher to continue to add to our neuroscience pipeline. Although clearly the amazing will always take two is our expertise neuroscience and also protein is holding from an understanding of the biology. So that's why we're really excited by having him on board and he's been clearly very helpful. Include. We also had another addition.

One of Paula Poskon also operational expertise X Biogen and she's been very helpful and instrumental from an operational perspective too.

Your next question comes from the line of Kennen Mackay from RBC Your line.

Operator: Your next question comes from the line of Kenan McKay from RBC; your line is open. Hey guys, this is Bikraman from Canon. Thanks for taking our questions. Just on the early pipeline, maybe you can elaborate on what is guiding your confidence in a myeloid beta program. That would be really helpful.

Hey, guys. This is spectrum on for Ken and thanks for taking over cushions just on the early pipeline. Maybe you can elaborate on what is guiding your confidence in him come I like speed up program that would be really helpful. Thank you.

Bikraman: Yeah, well, I think we were clearly encouraged by the October announcement from Biogen around adecanumab and further by the data that they shared at CTAD in December, particularly around the eMERGE and ENGAGE trials. I think, you know, what the data appear to indicate is that an antibody like adecanumab, which would be expected to interact with both the soluble and insoluble forms of A-beta, at appropriate concentrations for appropriate lengths of time, there may be some impact on clinical endpoints. And obviously, we'll see what happens as Biogen continues to move that program through the regulatory process. There's a lot of the unknown there, a lot to occur even this year. And we'll certainly see what happens there.

Yeah, well I mean.

We are clearly encouraged by the October announcement from Biogen around added kitimat.

And further by the data that they shared at sea Ted in December, particularly around the emerging engage trials I think what the data appear to indicate is that an antibody like I can't imagine that would be expected to interact with both the cycle and inside of the forms of a beta that at appropriate concentrations for.

Appropriate lengths of time that there may be some impact on clinical endpoints and obviously, we'll see what happens as Biogen continues to move that program through now the regulatory process.

Theres lot of unknown, there are lots lots and lots to occur even this year and we'll certainly see what happens there. Nonetheless, I think this a consistency of data now across several programs.

Gene G. Kinney: Nonetheless, I think, you know, there's consistency of data now across several programs, and it encourages us that at some point, a molecule in this space will be a first entrant in the treatment of neurodegeneration and Alzheimer's disease. When we look at the slate of candidates currently undergoing clinical trials, we think for a number of reasons that there are opportunities to continue to push that science forward in the interest of patients and their families. But one angle on that is obviously patient access. We think that will be a significant issue. There are some estimates that up to 35 million individuals across the world suffer from Alzheimer's disease. And with those kinds of numbers, making sure that patients maximize patient access to potentially useful treatments will be critical.

And it encourages us that at some point.

That.

Molecule in this space.

We'll be at first entrant in the treatment of nerdy generation Alzheimer's disease.

When we look at the slate of candidates currently undergoing clinical trial, we think for a number of reasons that there are opportunities to continue to push that science forward and interest to patients and their families. One angle on that is obviously patient access we think that will be a significant issue. There some estimates set up to.

35 million individuals across the world suffer from Alzheimer's disease, and when those kinds of numbers, making sure that you maximize patient access to potentially useful treatments will be critical and so we obviously think about that quite a bit as we think through our programs targeting a beta including our a beta monoclonal antibodies that I discussed in the call.

Gene G. Kinney: And so we obviously think about that quite a bit as we think through our programs targeting A-beta, including our A-beta monoclonal antibodies that I discussed in the call. And as I said in the call as well, we think that tau continues to be another very important pathological driver of the cognitive decline that you see in Alzheimer's disease. I think there's a lot of literature around that that supports that statement. And from our perspective, understanding how intricately those two proteins interact with each other in the context of the disease, i.e. A-beta and tau are not separate entities per se. It's known, for example, that A-beta can actually lead to the phosphorylation of tau. There are a number of studies out there that look at that.

All and as I said the call as well, we think that towel continues to be another very important pathological driver of the cognitive decline that you see in Alzheimer's disease, I think theres a lot of literature around that that supports that statement.

And from our perspective, then understanding how how intricately those two proteins interact with each other in the context of the disease I see a beta and towel are not separate entities per se. It's known for example that a beta can can actually lead to the phosphorylation of cow. This number of studies out there that look at that.

Gene G. Kinney: And those kinds of pathways lead us to believe that approaches that target both A-beta and tau may be a potential opportunity to continue to push treatments forward. So, we see a lot of opportunity in that space. We see that opportunity around both monoclonal antibodies as well as potential vaccines, and we see opportunity both in the treatment as well as the potential prevention of.

And those kinds of pathways lead us to believe that approaches that target. Both a beta ends how maybe potential opportunity to continue to push treatments forward.

So so we see a lot of opportunity in that space, we see that opportunity around both monoclonal antibodies as well as potential vaccines and we see the opportunity both in the treatment as well as the potential prevention of the disease.

Your next question comes from the line Oh from Oppenheimer.

Operator: Your next question comes from the line of Jay Olson from Oppenheimer. Your line is open. Oh, hi.

Hi, Thanks for taking the question.

Jay Olson: Thanks for taking the question. Since President Esumab is in the lead and you'll be reading out the first clinical efficacy endpoints for an alpha-synuclein antibody in Parkinson's disease this year, could you maybe comment on the potential registrational path forward? And do you expect to conduct two pivotal phase 3 studies, or do you think that you'll only be required to conduct one, and maybe pathogenicity could count as one of your pivotal studies?

Present issue Mab is in a lead and you'll be reading out the first.

Efficacy endpoints for an alpha synuclein anti body in Parkinson's disease. This year could you maybe comment on the potential Registrational path forward and do you expect to conduct two pivotal phase III studies or do you think that you only be you're required to conduct one and.

Maybe Pasadena could count as one of your peers pivotal studies.

Gene G. Kinney: Yeah, so those are great questions and obviously we'll be the subject of much discussion, not only with Roche but obviously regulators as well. I think it's premature at this point to really speculate on what a Phase 3 clinical program would or could look like. You know, clearly, we would want to do that fully informed by the Phase 2 data in as much as we expect it to be directionally informational in terms of how we think about those things. So I think the questions you're asking are great questions. I think it's just a little bit premature on this call to really speculate as to what regulators might require or what a fulsome Phase 3 program would look like, but clearly, all of those alternatives.

Yes. So those are great questions, and obviously will be subject of much discussion not only with Roche, but obviously regulators as well I think it's premature at this 0.22 really speculate on what a phase three clinical program would or could look like clearly we would want to do that fully informed by.

The phase two data in as much as we expected to be Directionally informational in terms of how we think about those things. So I think the questions you're asking our great questions. I think it's just a little bit premature on this call to really speculate as to what regulators might require or what a fulsome phase three program look like liquidity all of those alternatives.

Gene G. Kinney: are on the table.

Our on the table.

Gene G. Kinney: And Jay, they'll be data-dependent.

And then Jay there'll be data dependent so.

Gene G. Kinney: And Jay, they'll be data dependent, so that's a great question, but we need to have more data in order to answer that.

Great question, but we need to have more data in order to answer that.

Well.

Your next question comes from.

Gerd Heslitz: Your next question comes from the line of Gerd Heslitz. Thanks. Thank you for taking the question. Just with regard to the BMY-Cellgene collaboration, could you remind us of the structure of that collaboration and the decision-making process that you'll need to go through to advance Tau and TDP-43 into IND studies? And then, are the same people at the table now that that collaboration is closed just interested to find out a little bit more about the design, and the dynamics now that Cellgene is part of the MS? Thanks.

Great Hazlett from <unk>.

Thanks, Thank you for taking the questions just with regard to the.

I am why Celgene collaboration can you remind us of the structure of that collaboration and the decision mentioned making process that.

You will need to go through to advance talent PDP 43 to R&D.

Hi, Andy studies.

And then are.

Are the same people at the table now that that collaboration is closed just interesting.

Gene G. Kinney: Yeah, maybe I'll answer the last part of that question a little bit first, then get to the first part last, which is the team that's on the ground in terms of the joint steering committees are the same, and they've moved on over to Bristol, which has been a welcomed fact, and so we're still working on a collaborative basis every day, and we continue to move all the programs forward. From an economic and decision-making perspective, as you can recall, or as you do recall, we had it up front of $100 million across three different targets, and of course, an equity investment of $50, which allowed us to take control over decision-making on how to move those three programs forward.

Interested to find out a little bit more about the design the dynamic nowadays so.

Thanks.

Yeah ill answer the last part of the question all the first and then get to the first part last which is the team that's on the ground in terms of the joint steering committees are the same and they moved on over to Bristol, which has been a welcome.

Welcomed a fat so we're still working on a collaborative.

Basis every day and so we continue to move all the programs for from an economic and decision making perspective as you can recall, whereas you do recall, we had an upfront of $100 million across three different targets and of course in equity investment, a 50, which allowed us to take.

Control over this decision making.

Of how to move those three programs forward in terms of how BMS Celgene Slash now BMS would participate is at I envy of each of the programs. They don't have the ability to off.

Gene G. Kinney: In terms of how BMS, Celgene slash now BMS, would participate in IND for each of the programs, they would have the ability to opt in or exercise their option right for U.S. rights at IND and then for ex-U.S. rights after Phase 1. And then from there, you know, they can choose one way or the other, but they can choose to basically operate the program from there in terms of executing the phase twos and the phase threes, depending on the clinical plan going forward. So, and then, of course, there's downstream clinical regulatory approval, first commercial sale, and then we have royalties after that. So that's kind of how it all is both governance and economically spread between the three programs.

And our exercised their option right for US right at R&D, and then for ex US right after phase one.

And then from there.

They can choose one way the other but they can choose to.

Basically operate the program from there in terms of execute the phase twos in the phase threes, depending on the clinical plan going forward. So and then of course, there's downstream clinical regulatory first commercial sale and then we have royalties after that so that's kind of how it all is both governance and X.

Formigli spread between the three programs.

I'm showing no further questions at this time I know like to turn the country senior mystery shops.

Operator: I am showing no further questions at this time, and I would like to turn the conference back to you, Mr. Gene Kinney, CEO.

Gene G. Kinney: Thanks, Joan. I appreciate it, and thank you all for joining us this afternoon. We appreciate your interest in Prothena, and we look forward to sharing future updates on our program.

Thanks, John I appreciate it and thank you all for joining US. This afternoon. We appreciate your interest in Pristina and we look forward to sharing future updates on our programs.

Thank you.

Ladies and gentlemen. This concludes today's conference. Thank you for participation and have a wonderful thing you may all disconnect.

Operator: Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for your participation and have a wonderful day. You may all disconnect. BF-WATCH TV 2021

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