Q4 2021 Prothena Corporation PLC Earnings Call

Operator: Ladies and gentlemen, thank you for standing by, and welcome to Prothena's fourth quarter full year 2021 financial results conference call. All lines have been placed on mute to prevent any background noise.

Ladies and gentlemen, thank you for standing by and welcome to Potheen as fourth quarter full year 2021 financial results Conference call.

All lines have been placed on mute to prevent any background noise.

Operator: After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press star 1. We ask that you please limit yourself to one question. Thank you. Jennifer Zabuda, you may begin your conference. Thank you, operator. Good afternoon, everyone.

After the Speakers' remarks, there will be a question and answer session.

If you would like to ask a question. During this time simply press star followed by the number one on your telephone keypad.

If you would like to withdraw your question again press Star one.

That you please limit yourself to one class.

Thank you Jennifer the Buda you may begin your conference.

Jennifer Zabuda: And welcome to Prothena's investor conference call to review our business progress, our fourth quarter and full year 2021 financial results, and our 2022 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 FCC. On today's call, Dr. Gene Kinney, our President and Chief Executive Officer, will highlight Prothena's progress across our portfolio in 2021, as well as our organizational evolution as we continue advancing towards becoming a fully integrated biotechnology company.

Thank you operator, good afternoon, everyone and welcome to Christina <unk> Investor Conference call to review, our business progress our fourth quarter and full year 2021 financial results and 2022 financial guidance. Please review the press release, we issued earlier today, which is available on our website a protein a dot com.

And it's also attached to a form 8-K filed today with the SEC.

On today's call after gene Kinney, our president and Chief Executive Officer will highlight proteins progress across our portfolio in 2020 , one as well as our organizational evolution as we continue advancing towards becoming a fully integrated biotechnology company.

Jennifer Zabuda: Following Gene's comments, Tran Nguyen, our Chief Financial Officer and Chief Strategy Officer, will review our financial results and performance for the fourth quarter and full year of 2021 and will provide our 2022 financial guidance before turning it back to Gene for closing remarks. We will then open the call for Q&A and be joined by Dr. Hideki Garren, our Chief Medical Officer, and Dr. Wagner Zago, our Chief Scientific Officer. Before we begin, I would like to remind you that during today's presentation, we will be making forward-looking statements that are subject to certain risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statement.

Following Jim's comments, Sean Nguyen, our Chief Financial Officer, and Chief Strategy Officer will review, our financial results and performance of fourth quarter and full year 2021, and we'll provide our 2022 financial guidance before turning it back to Jim for closing remarks.

We will then open the call for Q&A and be joined by a Doctor Hideki Guerin, our Chief Medical Officer, and Doctor bloggers I'll go our Chief Scientific Officer.

Jennifer Zabuda: For a discussion of the risks and uncertainties associated with our forward-looking statements, please see our press release issued today, as well as our most recent filings with the SEC. We disclaim any obligation to update our forward-looking statements.

Before we begin I would like to remind you that during today's presentation, we will be making forward looking statements that are subject to certain risks uncertainties and other factors that could cause actual results to differ materially from those referred to in any forward looking statements for a discussion of the risks and uncertainties associated with our forward looking statements. Please see our pre.

Release issued today as well as our most recent filings with the SEC, we disclaim any obligation to update our forward looking statements and with that I'd like to turn the call over to gene.

Gene Kinney: And with that, I'd like to turn the call over to Gene. Thank you, Jen, and thank you all for joining us to review our 2021 financial results and business highlights. 2021 was a productive year for Prothena, marked by meaningful progress in our R&D portfolio, which represents the culmination of multi-year efforts. We're hopeful that these efforts will soon lead to impactful treatments for the millions of patients and families that are affected by diseases caused by misfolded proteins.

Thank you Jen and thank you all for joining us to review, our 2021 financial results and business highlights.

2021 was a productive year for Athena marked by meaningful progress in our R&D portfolio, which represents the culmination of multiyear efforts.

We're hopeful that these efforts will soon lead to impactful treatments for the millions of patients and families that are affected by diseases caused by Misfolded protein.

Gene Kinney: In 2021, we also continued to attract and retain highly talented professionals with excellent track records to support our transition towards becoming a fully integrated biotechnology company. Additionally, we ended the year with a strong cash position, which included $200 million in partner payments from our collaborations with leading pharmaceutical organizations, including Bristol Myers Squibb, Novo Nordisk, and Roche. These collaborations are part of an intentional mix of wholly owned and partnered assets, which allows us to have a broad pipeline with blockbuster potential, further supporting our growth as a company.

In 2021, we also continued to attract and retain highly talented professionals with excellent track record to support our transition towards becoming a fully integrated biotechnology company.

Italy, we ended the year with a strong cash position, which included $200 million in partner payments from our collaborations with leading pharmaceutical organization, including Bristol Myers Squibb, Novo Nordisk and Roche.

These collaborations are part of an intentional mix of wholly owned and partnered assets, which allows us to have a broad pipeline with blockbuster potential further supporting our growth as a company.

Gene Kinney: Prothena is driven by our mission to make a real impact for the patients and families we serve. That mission is enabled by our deep scientific expertise in protein dysregulation, which serves as a unifying thread between our business strategy, our portfolio development, and the dedication that propels our team every day. We believe that our focus on slowing, stopping, and treating neurodegenerative and rare peripheral amyloid diseases addresses significant unmet medical needs where our biology-directed engine, our clinical expertise, and our market positioning will enable us to advance best-in-class therapies that have the potential to transform the lives of patients.

But then it was driven by our mission to make a real impact for the patients and families. We serve.

That mission is enabled by our deep scientific expertise and protein Dysregulation, which serves as a unifying thread between our business strategy, our portfolio development and the dedication that propels our team every day.

We believe that our focus on slowing stopping and treating neurodegenerative and rare peripheral amyloid diseases.

This significant unmet medical needs, where our biology directed engine, our clinical expertise and our market positioning will enable us to advance best in class therapies that have the potential to transform the lives of patients.

Gene Kinney: Our focus on neurodegenerative diseases includes Alzheimer's and Parkinson's, which are sadly growing exponentially. Combined, these two diseases affect an estimated 60 million people globally today. The significant burden is not only experienced by patients but also by caregivers and the overall healthcare system.

Our focus on Neurodegenerative diseases, including Alzheimer's and Parkinson's, which sadly are growing exponentially.

Combined these two diseases affect an estimated 60 million people globally today.

A significant burden is not only experienced by patients, but also by caregivers and the overall health care system.

Gene Kinney: In rare peripheral amyloid diseases, pirtamomab and PIRX4 are being developed in targeted patient populations at high risk for early mortality, which underscores our strategy to develop therapies for patients with an urgent need for improved survival. Since our inception, our core guiding principle has been to follow the science empirically and without bias. This rigorous approach to the advancement of medicine allows us to discover underlying pathophysiological processes and design molecules that optimally target pathogenic proteins and, consequently, have the greatest probability of slowing or preventing disease.

And rare peripheral amyloid diseases for Tim or Matt and peer explore are being developed in targeted patient populations at high risk for early mortality, which underscores our strategy to develop therapies for patients with an urgent need for improved survival.

Since our inception, our core guiding principle has been to follow the science empirically and without bias.

This rigorous approach to the advancement of medicine allows us to discover underlying pathophysiological processes and design molecules that optimally target pathogenic protein and consequently have the greatest probability to slow or prevent disease.

Gene Kinney: Over the years, we have refined our approach to include what we believe is an unparalleled knowledge of disease pathology and expertise in empirical epitope mapping, advancing only those molecules that show a robust and consistent biological effect in the reduction of disease. Using our unique biology-directed engine, which leverages our deep know-how, today we've been able to advance three programs into mid-to-late clinical stages and six discovery candidates toward the clinic, with five potential new INDs projected by 2026. Prothena's understanding of protein dysregulation is based on many decades of scientific discoveries in the field.

Over the years, we have refined our approach to include what we believe is an unparalleled knowledge of disease pathology and expertise and empirical epitope mapping advancing only those molecules that show a robust and consistent biological effect and the reduction of disease.

Using our unique biology, directed engine, which leverages our deep knowhow today, we've been able to advance three programs into mid to late clinical stages and sixth discovery candidates toward the clinic with five potential new <unk> projected by 2026.

Protein is understanding of protein Dysregulation is based on many decades of scientific discoveries in the field.

Gene Kinney: Much of our team, including Wagner, our Chief Scientific Officer, who's on the call today, has contributed key scientific and clinical discoveries in our field and has built a scientific heritage within Prothena that allows for an informed approach to the development of potentially best-in-class therapeutic candidates. Last year, we continued to add to this deep scientific heritage with the addition of key personnel such as Hideki, our Chief Medical Officer, who is also present on our call today.

Each of our team, including Wagner, our Chief Scientific officer Who's on the call today have contributed key scientific and clinical discoveries in our field and have built a scientific heritage within proteins that allows for an informed approach for the development of potentially best in class therapeutic candidates.

Okay.

Last year, we continued to add to this deep scientific heritage with the addition of key personnel such as the Dechy, Our Chief Medical Officer, who is also present on our call today.

Okay.

Gene Kinney: Before we dive into the progress we made this year, I wanted to take a moment to highlight the breakthroughs that we, as a field, have made in advancing treatments for Alzheimer's disease. 2021 was a milestone year for the Alzheimer's community. Notable developments include the FDA-accelerated approval of the first disease-modifying therapy; significant advancements in clinical study design, including optimized patient selection strategies; advancements in the use of biomarkers, including blood-based biomarkers; an increased prominence of IADRS as a clinical outcome measure; and a growing amount of evidence generated across multiple clinical data sets confirming the benefit of anti-beta therapies that interact with the immunoterminants of that target.

Before we dive into the progress we made this year I wanted to take a moment to highlight the breakthroughs that we as a field have made in advancing treatments for Alzheimer's disease.

2021 was a milestone year for the Alzheimer's community.

Notable developments included the FDA accelerated approval of the first disease modifying therapy significant advancements in clinical study design, including optimized patient selection strategy.

Advancements in the use of Biomarkers, including blood based Biomarkers and increased prominence of IAA Drs as a clinical outcome measure and a growing amount of evidence generated across multiple clinical datasets confirming the benefit of anti a beta therapies that interact with the amino terminus of that target.

Gene Kinney: This progress stands on the shoulders of many great scientists, including Prothena's late co-founder, Dr. Dale Shank, and multiple Prothena scientists who carefully observed and followed the iterative scientific and clinical trial design learnings to bring this new class of therapy to patients with Alzheimer's disease. At Prothena, we have celebrated these advancements, but also believe that further improvement is needed. This is why we are advancing what we believe is one of the most comprehensive therapeutic strategies to treat Alzheimer's disease. We have developed three product candidates targeting key pathological pathways of the disease cascade, which expand from next generation potentially disease-modifying treatment to potential combination and prevention strategies.

This progress stands on the shoulders of many great scientists, including Christina Lake Co founder, Dr. Dale Schenk and.

And multiple proteins scientists, who carefully observed and follow the iterative scientific and clinical trial design learnings to bring forth. This new class of therapy to patients with Alzheimer's disease.

At Christina we have celebrated these advancements but also believe that further improvement is needed.

This is why we are advancing what we believe is one of the most comprehensive therapeutic strategy is to treat Alzheimer's disease.

We have developed three product candidates targeting key pathological pathways of the disease Cascade, which expand from next generation potentially disease modifying treatment to.

So potential combination and prevention strategies.

Gene Kinney: Our portfolio takes advantage of scientific and clinical trial design advances and positions Prothena as a leader in the transformation of Alzheimer's therapeutic approach. With that in mind, let me now focus on highlighting some of the progress made across the portfolio in 2021. I'll start with PRX12, a potential best-in-class, patient-friendly, subcutaneous delivery treatment for Alzheimer's disease, targeting a key epitope at the immunoterminus of amyloid data with high binding potency. To date, preclinical data have shown that PRX12 binds to amyloid plaques with high avidity, consistent with the potential for more effective A-beta plaque clearance at substantially lower doses than approved anti-A-beta therapies.

Our portfolio. It takes advantage of the scientific and clinical trial design advances and positions per Athena as a leader in the transformation of Alzheimer's therapeutic approaches.

With that let me now focus on highlighting some of the progress made across the portfolio in 2021.

I'll start with Parex 12 potential best in class patient friendly subcutaneous delivery treatment for Alzheimer's disease targeting a key epitope at the immuno terminix of amyloid beta with high binding potency.

To date preclinical data have shown that <unk> 12 binds to amyloid plaque with high avidity consistent with the potential for more effective a beta clearance at substantially lower doses than approved anti <unk> therapy.

Gene Kinney: New preclinical data presented at the Alzheimer's Association International Conference, or AAC, this past summer demonstrated that PIR-X-12 significantly cleared both high-rebootimate modified and unmodified A-beta plaque in brain tissue at concentrations that are expected to be reached in the CNS with subcutaneous administration on a convenient treatment schedule.

New preclinical data presented at the Alzheimer's Association International Conference. Our AIC. This past summer demonstrated that peer X 12 significantly cleared both pyro glutamate modified and unmodified a beta plaque in brain tissue concentrations that are expected to be reached in the CNS with subcutaneous administration.

On a convenient treatment schedule.

Gene Kinney: We believe that PRx12 has the potential to transform the field of Alzheimer's. Our goal with PRx12 is to offer greater patient accessibility and compliance relative to the approved therapy and other immunoterminist targeted treatments currently under development. Compared to first-generation treatments, subcontaneous PIR-X12 is also expected to result in smaller fluctuations in brain antibody concentration. This feature may allow us to differentiate on both efficacy and safety endpoints. Because of its high binding potency and suitability for subcutaneous administration, PyrrHX12 has the potential to serve as a foundational anti-A-beta treatment for patients with Alzheimer's disease.

We believe that peer X 12 has the potential to transform the field of Alzheimer's disease.

Our goal with Parex 12 has to offer greater patient accessibility and compliance relative to the approved therapy and other amino terminus targeted treatments currently under development.

Compared to first generation treatments subcutaneous Purex 12 is also expected to result in smaller fluctuations in brain antibody concentration.

This feature may allow us to differentiate on both efficacy and safety endpoints.

Because of its high binding potency and suitability for subcutaneous administration <unk> 12 has the potential to serve as a foundational anti a beta treatment for patients with Alzheimer's disease.

Gene Kinney: We intend to fully leverage the learnings from other first-generation anti-aid beta therapies to maximize the probability of success for our PRX-12 program. In 2021, we also brought our tau-targeting monoclonal antibody, PRX5, into the clinic. Parix-5 is designed to be a best-in-class anti-tow antibody by specifically targeting an epitope within the microtuvial binding region, or M.T.B.R.

We intend to fully leverage the learnings from upcoming clinical regulatory and commercial milestones from other first generation anti a beta therapies to maximize the probability of success for our <unk> program.

In 2021, we also brought our tau targeting monoclonal antibody purex five into the clinic.

<unk> five is designed to be a best in class anti Tau antibody by specifically targeting an epitope within the microtubule binding region or MTV or.

Gene Kinney: How tangles, along with amyloid beta plaques, are pathological hallmarks of Alzheimer's disease, and research indicates that tal pathology is related to the clinical and cognitive decline associated with disease. By leveraging our unbiased, biology-directed engine, we found that targeting specific regions within the MTBR resulted in a more consistent and robust reduction in the pathogenic uptake of tau into neurons and the downstream neurotoxic effect. At the 15th International Conference on Alzheimer's and Parkinson's diseases, or ADPD, in March of last year, we presented new preclinical data showcasing PRX-5's ability to reduce palpathology and downstream behavioral deficits in multiple in vitro and preclinical in vivo models.

Tau tangles, along with amyloid beta plaques are pathological hallmarks of Alzheimer's disease and research indicates the Tau pathology is related to the clinical and cognitive decline associated with disease.

By leveraging our unbiased biology directed engine, we've found that targeting specific regions within the MTBE or resulted in more consistent and robust reduction in the pathogenic uptake of tau into neurons in the downstream neurotoxic effects.

At the 15th International Conference on Alzheimer's and Parkinson's diseases or ADP D. In March of last year, we presented new preclinical data showcasing purex five's ability to reduce tau pathology and downstream behavioral deficits in multiple in vitro and preclinical in vivo models.

Gene Kinney: [inaudible] PRX5 is one of three programs being developed in partnership with our colleagues at Bristol-Myers Squibb and for which we received an $80 million option payment in 2021. We also advanced a third Alzheimer's program, our dual abated tal vaccine, from discovery to pre-clinical development in 2021. For the first time, we presented data at AAIC on our dual-A-beta-Tau active vaccine. This vaccine is a multi-epitope, single-agent vaccine designed to target the two key pathologies associated with Alzheimer's disease, amyloid beta and Tau.

<unk> five is one of three programs being developed in partnership with our colleagues at Bristol Myers Squibb and for which we received an $80 million option payment in 2021.

We also advanced the third Alzheimer's program, our dual a beta tau vaccine from discovery to preclinical development in 2021.

For the first time, we presented data at AIC on our dual a beta tau active vaccine. The vaccines are multi epitope single agent vaccine designed to target. The two key pathologies associated with Alzheimer's disease, amyloid beta and Pal.

Gene Kinney: Our data showed that vaccination of mice, guinea pigs, and non-human primates generated a robust and balanced immune response to the intended epitopes on amyloid beta and tau without a cytotoxic T cell response to these endogenous proteins.

Our data showed that vaccination of mice Guinea, pigs, and nonhuman primates generated a robust and balanced immune response to the intended epitopes on amyloid beta in Tau without a cytotoxic T cell response to these endogenous proteins importantly.

Gene Kinney: Importantly, the resultant antibody response to these vaccines had the appropriate impact in functional studies, promoting both phagocytosis of A-beta plaque and blockade of tau transmission in vitro. Our vaccine offers the exciting possibility to combine amyloid data and tal targeting into a single construct, potentially aligning with a prevention strategy. Turning to Prasin Nazimab in Parkinson's disease, Roe Sharp, Partner for Prasin Nazimab, presented data at ADPD in March of last year. New analyses from Part 1 of the Phase 2 Pasadena study highlighted presinesumab's greater effect on slowing clinical decline in subgroups of patients that exhibited more rapid disease progression.

Importantly, the result of an antibody response to these vaccines have the appropriate impact and functional studies promoting both phagocytosis of a beta plaque and blockade of power transmission in vitro.

Our vaccine offers the exciting possibility to combine amyloid beta in tau targeting into a single construct potentially aligning with the prevention strategy.

Turning to <unk> in Parkinson's disease Roche, our partner for <unk> and that presented data at ADP in March of last year.

New analyses from part one of the Phase II Pasadena study highlighted <unk> greater effect on slowing clinical decline in subgroups of patients that exhibited more rapid disease progression.

Gene Kinney: These data, when combined with previously discussed datasets from the study, further add to the idea that selective targeting of alpha-synuclein at a key region within the C-terminus may provide a disease-modifying impact in patients with early Parkinson's disease.

These data when combined with previously discussed datasets from this study further add to the idea that selective targeting of Alpha nucleon at a key region within the determinant may provide a disease modifying impact in patients with early Parkinson's disease.

Gene Kinney: In May of last year, the first patient was dosed in the phase 2B Padova study, for which we received a $60 million milestone payment. And this study is currently being conducted by Rose. In addition to our progress in the nerdy generation, we also made significant advancements in our rare, peripheral amyloid disease portfolio. 2021 was an important year for our Britannia MAT program.

In may of last year. The first patient was dosed in the phase II <unk> study for which we received a $60 million milestone payment and this study is currently being conducted by Roche.

In addition to our progress in nerve regeneration. We also made significant advancements in our rare peripheral amyloid disease portfolio.

2021 was an important year for our <unk> in that program.

Gene Kinney: In February last year, we announced that we had reached an agreement with the FDA under a special protocol assessment or spot agreement, which allowed for the initiation of our confirmatory phase 3 Affirmale Study, where the pre-specified alpha for study success was defined as 0.1. [inaudible] This spa agreement followed from multiple discussions with the FDA Division of Cardiology and Neurology and ALM-ledosis expert positions on the overall safety of Britama Mab and previously observed survival benefit in patients with Mayo Stage 4 ALM-ledosis in the vital study.

In February last year, we announced that we had reached an agreement with the FDA under a special protocol assessment or Spa agreement, which allowed for the initiation of our confirmatory phase III <unk> study, where the pre specified Alpha study success is defined as 0.1.

The Spa agreement followed for multiple discussions with the FDA division of cardiology, and neurology and al amyloidosis excellent positions on the overall safety of <unk> and previously observed survival benefit in patients with Mayo stage for al amyloidosis in the vital study.

Gene Kinney: We initiated our global registrational AFIRM-AL study last year and are currently enrolling patients. Current treatments for AL Emily Dosis target the colonial plasma cells that overproduce light. While these therapies can reduce new protein production, they fail to directly address the amyloid that has already deposited and is causing organ toxicity. Tamomab is differentiated as it's believed to remove the amyloid most proximally associated with organ dysfunction. We have extensively published on Botanemab's well-defined epitope and depleter mechanism of action, which we believe provides for broad recognition of different types of light-chain protein that may be present in the organs of patients with this disease.

We initiated our global Registrational of firm a L study last year and are currently enrolling patients.

Current treatments for al amyloidosis target, the clonal plasma cells that overproduce light chain.

While these therapies can reduce new protein production they failed to directly address the amyloid that has already deposited in is causing organ toxicity.

<unk> is differentiated as it is believed to remove the amyloid most proximately associated with organ dysfunction.

We are extensively published on <unk>, well defined epitope and Depleter mechanism of action, which we believe provides for broad recognition of different types of light chain protein that may be present in the organs of patients with this disease.

Gene Kinney: Moving now from AL amyloidosis to ATTR amyloidosis. Following the completion of our phase one study of PRX4, we announced that Novo Nordisk acquired our ATTR business in July of 2021. This transaction is consistent with our commitment to expedite promising treatments to patients in need. We are confident that Novo will leverage its extensive expertise in developing therapies for cardiovascular diseases to advance this promising treatment to patients on an expedited timeline. As part of this agreement, Prothena is eligible to receive development and sales milestone payments of up to $1.23 billion, which included a $60 million upfront payment received last year. Current treatment approaches are focused on the reduction of new transthyretin production or the stabilization of the normal homotetrameric form of this protein.

Moving now from Al Amyloidosis <unk> amyloidosis.

Following the completion of our phase one study of peer explore we announced that Novo Nordisk acquired our <unk> business in July of 2021.

This transaction is consistent with our commitment to expedite promising treatments to patients in need.

We are confident that novo will leverage its extensive expertise in developing therapies for cardiovascular diseases to advance this promising treatment to patients on an expedited timeline.

As part of this agreement for Athena is eligible to receive development and sales milestone payments of up to 123 billion.

Which included a $60 million upfront payment received last year.

Current treatment approaches are focused on the reduction of new trends by region production for the stabilization of the normal Homo Tetra Merit form of this protein.

Gene Kinney: Sirix IV is a differentiated approach with a depleter mechanism of action that is designed to target and remove the resident protein. Moreover, Pirex IV targets a key region of transcyretin that is not available in the normal homo tetrameric structure and, as such, uniquely interacts with only non-functional forms of this protein. In addition to our portfolio accomplishments, we've also made significant organizational progress this last year as we continue to build an industry-leading, fully integrated company.

<unk> is a differentiated approach with a depleter mechanism of action that is designed to target and remove the resident protein.

Moreover, <unk> four targets a key region of Trans diary Eaton that is not available in the normal homeowner tetra merrick structure and as such uniquely interacts with only non functional forms of this protein.

In addition to our portfolio of accomplishments. We've also made significant organizational progress. This last year as we continue to build an industry leading fully integrated company.

Gene Kinney: We strengthened our management team and board of directors to best position Prothena for long-term growth and success. Starting with our board of directors, in May, we appointed Dr. Sanjeev Patel, CEO of Relay Therapeutics, and an established leader with significant industry experience. In April, we appointed Dr. Hideki Garren as its chief medical officer. Garren has extensive expertise and a successful track record of advancing neurological and rare disease programs through late stage development, registration, and law. In October, our CFO, Tran Nguyen, was appointed to the additional and newly created role of Chief Strategy Officer, and Brandon Smith was promoted from Chief Business Officer to Chief Operating Officer.

We strengthened our management team and board of directors to best position for cleaner for long term growth and success.

Starting with our board of directors in May we appointed to our board Dr. Sanjay Patel CEO of <unk> Therapeutics, and an established leader with significant industry experience and.

In April we appointed Dr. Hideki Garen as our Chief Medical Officer, Hideki has extensive expertise and a successful track record of advancing neurological and rare disease programs through late stage development registration and launch.

In October our CFO Trung Nguyen was appointed to the additional and newly created role of Chief strategy Officer, and Brian Smith was promoted from Chief business Officer to Chief operating Officer. These.

Gene Kinney: These expanded roles support our continued transition to a fully integrated biotechnology company focused on neurodegenerative and rare peripheral amyloid diseases. This is an exciting time for Prothena. We are encouraged by the significant progress we have made over the past year, and we are looking towards our future. At this time, I'd like to turn the call over to Tran for discussion of our 2021 Financial Performance and our 2022 Financial Guidance.

These expanded role support our continued transition to a fully integrated biotechnology company focused on Neurodegenerative and rare peripheral amyloid diseases.

This is an exciting time for Athena, we are encouraged by the significant progress we have made over the past year and we are looking towards our future.

At this time I'd like to turn the call over to <unk> for a discussion of our 2021 financial performance and our 2022 financial guidance John .

Tran Nguyen: Thanks, Gene, and good afternoon, everyone. Today, we reported results that were either in line with or favorably exceeded our 2021 financial guidance. Please refer to our press release for a detailed breakdown of our financial results. As Gene mentioned during his opening remarks, last year we strengthened our capital position.

Thanks, Jeanne and good afternoon, everyone.

Today, we reported results that were either in line with or favorably exceeded our 2021 financial guidance.

These refer to our press release for a detailed breakdown of our financial results.

As gene mentioned during his opening remarks last year, we strengthened our capital position first with our strong collaborations where we received $200 million in payments from our strategic partners in 2021, which includes an $80 million option payment from BMS for the U S.

Tran Nguyen: First, with our strong collaborations where we received $200 million in payments from our strategic partners in 2021, which includes an $80 million option payment from BMS for the U.S. rights to PRX5. $60 million upfront payment from Novo Nordisk for the acquisition of our ATTR Amlidosis business, and a $60 million payment from Roche for the advancement of Prasunezamab into the Phase 2B Padova Study. Additionally, during the year, we received net proceeds of $175 million raised through equity offers.

Rights for <unk> five.

$60 million upfront payment from Novo Nordisk for the acquisition of our <unk> amyloidosis business and a $60 million payment from Roche for the advancement of <unk> into the phase <unk> study.

Additionally, during the year, we received net proceeds of $175 million raised through equity offerings.

Tran Nguyen: In terms of our 2021 financial performance relative to guidance, we had net cash provided by operating and investing activities of $92 million, which was in line with our guidance of $85 to $95 million. Net income was $67 million, which exceeded our guidance of $50 to $60 million. As of December 31st, 2021, Prothena had $580 million in cash, cash equivalents, and restricted cash, which was in line and at the top of the range of our guidance of $570 to $580 million.

In terms of our 2021 financial performance relative to guidance we.

We had net cash provided by operating and investing activities of $92 million.

Which was in line with our guidance of $85 million to $95 million.

Net income was $67 million, which exceeded our guidance of $50 million to $60 million.

As of December 31, 2021, Cristina had $580 million in cash cash equivalents and restricted cash which was in line and at the top of the range of our guidance of 572 $580 million also.

Tran Nguyen: Also, we continue to have a clean capital structure with zero debt. Now, turning to our 2022 Financial Guide. We expect our full-year 2022 net cash used in operating and investing activities to be 120 to 132 million dollars, which includes an expected 40 million dollar clinical milestone payment from NOVO related to PRx4. We expect to end the year with approximately 454 million dollars in cash, cash equivalence, and restricted cash, which represents the midpoint of the race. The estimated full year 2022 net cash used in operating and investing activities is primarily driven by an estimated net loss of $154 to $170 million, which includes an estimated $32 million of non-cash, share-based compensation expenses.

So we continue to have a clean capital structure with zero debt.

Now turning to our 2022 financial guidance.

We expect our full year 2022, net cash used in operating and investing activities to be $120 million to $132 million.

Which includes an expected $40 million clinical milestone payment from novo related to <unk>.

We expect to end the year with approximately $454 million in cash cash equivalents and restricted cash which represents the midpoint of the range. The estimated full year 2022, net cash used in operating and investing activities is primarily driven by.

An estimated net loss of $154 million to $170 million, which includes an estimated $32 million of noncash share based compensation expense.

With that I'll turn the call back over to Jim to discuss our upcoming milestones Jean.

Gene Kinney: With that, I'll turn the call back over to Gene to discuss our upcoming milestones. Gene? Thanks, Tran. Before we talk about our 2022 milestones, I want to first acknowledge and thank our extraordinarily talented employees for their ongoing commitment to advancing our protein dysregulation science to make a real impact on the patients and families we serve. It's a privilege to work alongside my colleagues at Prothena, and I could not be prouder of their accomplishments.

Thanks, John before we talk about our 2022 milestones I want to first acknowledge and thank our extraordinarily talented employees their ongoing commitment to advancing our protein Dysregulation science to make a real impact for patients and families. We serve is.

It's a privilege to work alongside my colleagues at <unk> and I could not be prouder of their accomplishments.

Gene Kinney: I'd also like to thank the patients, their families, physicians, and study site staff who participate in our studies. Without their support, we could not elucidate the potential impact of these new medicines we're developing. Over the past year, our team has delivered on multiple milestones, further advancing Prothena as a leader in addressing devastating proteinopathies. As you heard today, our dedication to our mission, combined with our differentiated strategy, our diversified portfolio, and our scientific heritage and human talent, have made possible multiple meaningful achievements in 2021 and have positioned Prothena well for an exciting year ahead and beyond.

I'd also like to thank the patients their families physicians and study site staff, who participated in our studies without their support we cannot elucidate the potential impact of these new medicines, we are developing.

Over the past year, our team has delivered a multiple milestones further advancing for Athena is a leader in addressing devastating prudent apathy.

As you heard today, our dedication to our mission combined with our differentiated strategy, our diversified portfolio and our scientific heritage in human talent has made possible multiple multiple meaningful achievements in 2021 and have positioned for Athena well for an exciting year ahead and beyond as.

Gene Kinney: As new data becomes available on the clinical, regulatory, and commercial landscape in the Alzheimer's field, we believe our programs, which have been advanced through our unique and rigorous biology-directed engine and designed to be best in class, are positioned to transform the care of patients suffering from this disease.

As new data becomes available on the clinical regulatory and commercial landscape in the Alzheimer's field, we believe our programs, which have been advanced through our unique and rigorous biology directed engine and designed to be best in class are positioned to transform the care of patients suffering from this disease.

Gene Kinney: We are on track and expect to submit an IND filing for PRX12, our anti-ABETA product candidate, this quarter. For PRX5, we are expecting top-line Phase 1 data this year, further elucidating the potential of targeting MTBR, Tau, in treating Alzheimer's. We're looking forward to multiple Scientific Congress presentations throughout 2022, beginning with preclinical presentations at ADPD in March, highlighting first our new alpha-synuclein vaccine and second, additional data on our dual A-beta-tau vaccine, for which we are planning to submit an IND next year.

We are on track and expect to submit an IND filing for <unk> 12, our anti a beta product candidate this quarter.

For <unk> five we are expecting topline phase one data this year further elucidating the potential of targeting MTBE are a tau and treating Alzheimer's.

We're looking forward to multiple scientific Congress presentation throughout 2022, beginning with preclinical presentation at ADP in March highlighting first our new Alpha nucleon vaccine and second additional data on our dual a beta tau vaccine for which we are planning to submit an IND next year.

Gene Kinney: For Prasonesimab, new data will be presented at ADPD in March, and we are expecting data from the Phase 2b PDOVA study in 2024, both of which will be communicated by our partners at Roche. In our rare peripheral amyloid portfolio, we continue to enroll patients in our phase 3 AFFIRM-AL study of Britamimab and anticipate top-line data from that study in 2024. Additionally, Novo Nordisk announced plans on their year-end earnings call to initiate a phase two trial during the first half of this year for PRX4 in patients with ATTR cardiomyopathy. Prothena made excellent progress in 2021.

For <unk>, new data will be presented at ADP in March and we are expecting data from the phase <unk> study in 2024, both of which will be communicated by our partners at Roche.

And our rare peripheral amyloid portfolio, we continue to enroll patients in our phase III affirm <unk> study of <unk> and anticipate topline data from that study in 2024.

Additionally, Novo Nordisk announced plans on their year end earnings call to initiate a phase II trial. During the first half of this year for <unk> four in patients with <unk> cardiomyopathy.

<unk> made excellent progress in 2021, we have a well balanced portfolio with multiple wholly owned assets, coupled with strong partnerships and collaborations that could allow us to receive up to $365 million in partner payments over the next five years.

Operator: We have a well-balanced portfolio with multiple wholly owned assets coupled with strong partnerships and collaborations that could allow us to receive up to $365 million in partner payments over the next five years. We expect to make additional progress across our R&D pipeline this year, and we look forward to continuing to provide additional portfolio updates when appropriate. With that, we will now open the call to Q&A. Operator?

We expect to make additional progress across our R&D pipeline. This year and we look forward to continuing to provide additional portfolio updates when appropriate.

We will now open the call up to Q&A operator.

Operator: As a reminder, if you would like to ask a question at this time, please press star, then the number one on your telephone keypad. Please limit yourself to one question only. Your first question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is open. Hey, good morning, Gene and team. Congratulations on a great year of progress last year. Hard to compete with that one, but I had a quick question on PRX 012, and that is related to the upcoming IND. It sounds like you're ready for this quarter.

As a reminder, if you would like to ask a question at this time. Please press Star then the number one on your telephone keypad. Please limit yourself to one question only.

And your first question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is open.

Gene Kinney: I guess I'm wondering, when would you anticipate being able to start clinical studies with that? Could that be shortly within the first half of this year? And would that become a partnering candidate anytime soon? Or would you be able to take that through, say, clinical proof of concept? Yeah, thanks, Charles, for the question. Maybe I can start and Hideki can comment as well.

Hey, good morning, Jane and team.

That's on a great year of progress last year.

To compete with that one but I had a quick question PRA. So 012, and then it is relative to the upcoming Ied. It sounds like you are ready for this quarter I guess Im wondering when would you anticipate being able to start.

Clinical studies with that could that be shortly within the first half of this year and would that become a partnering candidate anytime soon or would you be able to take that through say clinical proof of concept.

Gene Kinney: But I mean, first, you're correct on PRX-12. We are expecting the IND filing this quarter. Obviously, you know, there's a time that occurs after that filing where we interact with the agency, and we would expect to begin phase one clinical trials thereafter. What we're envisioning right now in that phase one program is a single dose study and a multiple dose component of that study. And, you know, and I think on your other question about partnering, right now, we feel that we are in a very good position to develop that molecule.

Yes, Thanks, Charles for the question, maybe I can start.

A decade can comment as well, but first you are correct on <unk> 12.

Are expecting the IND filing this quarter, obviously, there is a time.

Occurs after that filing where we interact with the agency and we would expect to begin a phase one clinical trials thereafter, what we're envisioning right now in that Phase. One program is a single dose study and a multiple dose component of that study.

And I think on your other question around partnering right now we feel that we're in a very good position to develop that molecule. Some of the advances in the Alzheimer's field, we think have made it as.

Gene Kinney: Some of the advances in the Alzheimer's field, we think, have made it possible for us to actually think about proof of concept studies in this space for a company the size of Prothena. So we think we're uniquely positioned and well positioned given our heritage and our expertise and experience in the space to bring this molecule forward on our own. And that certainly is our current plan. But maybe, Hideki, do you want to speak further about any of the near-term clinical plans with X-12? You might be on mute, Hideki.

Such a way that we can actually think about proof of concept studies in this space for a company the size of proteinuria. So we think we're uniquely positioned well positioned given our heritage and our expertise and experience in this space to bring this molecule forward on our own and that certainly is our current plan, but maybe a decade do you want to speak further too.

Any of the near term clinical plans with exco.

You might be on mute.

Might be on mute there yet.

Gene Kinney: Might be on mute there, yeah. All right. Well, we'll take my answer. It's fullsome. Here you go. Hi, Hideki. How are you?

Alright.

I'll take my answer is fulfillment.

But is there you got a high Hideki area. So yeah, maybe maybe you want to comment further.

Gene Kinney: So yeah, maybe you want to comment further. Yep. Yeah, can you hear me okay?

Yes can you hear me okay.

Hideki Garren: Yep, we can hear it. Okay, great, thanks. Yeah, no, you stated that quite well, Gene. As a reminder, PRX-12 is our high-ponsi NTA beta compound. And because it is high-ponsi, we are given it subcutaneously. And so that's why it should have a van.

Yes, we can hear you.

Okay, great. Thanks, Yeah, No you said it quite well Jean as a reminder, <unk> 12 is our high potency and Ta beta compound and because it has high potency. We are given subcutaneously and so that's why it should have advantages both in terms of safety tolerability as well as convenience for patients.

Hideki Garren: Okay, thank you, both in terms of safety, tolerance, as well as convenience for patients. And as Gene stated, we are beginning with a single-setting dose study as well as a multiple-setting dose study very shortly after the IMG is cleared. And we will do those with healthy volunteers and patients. Thank you.

And as gene stated.

With a single ascending dose study as well as the multiple ascending dose study very shortly after the R&D is clear and we will do those in healthy volunteers and patients.

Hideki Garren: All of that will culminate in data in 2023. Great, thanks for that question, Charles. Your next question comes from the line of Michael Yee, with Jeffries. Your line is open.

Thank you that will culminate all of that will culminate in data in 2023.

Alright.

Great. Thanks for that question Charles.

Your next question comes from the line of Michael <unk> with Jefferies. Your line is open.

Okay.

Operator: Hey guys, thanks for the question and congrats on the progress. We had a question around maybe helping Wall Street think about some of the scenarios in 2022 with regard to the fact that perhaps Wall Street seems a bit mixed or skeptical about Alzheimer's, specifically PRX 012, which is just the class. And the idea that, you know, what are the scenarios and what are the thoughts around if we have negative results from the industry this year versus positive results and also how that relates to partnering or strategic pharma interest and how Thanks.

Hey, guys.

Thanks for the question and congrats on the progress.

We had a question around maybe helping wall Street think about some of the scenarios in 2022.

With regards to the fact that perhaps wall Street seems a bit mixed are skeptical around around all timers.

Is it from your <unk> just the clash.

<unk>.

The idea that what are the scenarios and what are the thoughts around if we have negative results from the industry. This year versus positive results and also how that relates to partnering or strategic pharma interest in how much that data plays a role in their thinking about the value of all timers. Thank you.

Gene Kinney: Yeah. Thanks Mike for the question. I mean, I think there are several events that we can look forward to this year in the field. Certainly, there is a lot of data coming. I'd say over the next 18 months, starting in April, we'll learn the final language around the NCD determination by CMS. We know what that draft language looks like, you know; clearly, there's been a lot of commentary that's occurred in the public comment period.

Yeah. Thanks, Mike for the question I mean, I think there are several events that we can look to this year in the field.

Certainly a lot of data coming I'd say over the next 18 months starting in April we will learn the final language around the NCD determination by CMS.

We know what that draft language looks like clearly there's been a lot of commentary that's occurred in the public.

Comment period, and we'll look forward to seeing where that lands I think here in April of course, we think.

Gene Kinney: And we'll look forward to seeing where that lands. I think here in April, of course, you know, we think, based on what we've read and what we've seen, you know, that could play into how Eli Lilly thinks about the NAMF from an accelerated approval perspective. What we understand is that there is a rolling submission there, consistent with their breakthrough status. And obviously, when they submit that final clinical section, how much is in that, you know, would probably lead one to think more about accelerated versus full approval.

Based on what we've read and what we've seen that that could play into how Eli Lilly thinks about the nanometer for an accelerated approval perspective.

What we understand is that Theres, a rolling submission there consistent with their breakthrough status and obviously when they submit that final clinical section how much is in that would probably lead one to think more about accelerated versus full approval.

Gene Kinney: So that's something that we'll look to this year to kind of see how that plays out. And then we have data coming from, you know, the phase three trials in the latter part of this year from both Gantaneur Mav and McCannamap, one way Bantu 401. Those are, you know, very little bit different in terms of molecules and what they mean, how they test the biology, I think, you know, probably don't have time to get into that here. But they are a little bit different, with Gantaneur Mav being a little bit more immune to terms like that targeting.

That's something that we'll look to this year to kind of see how that plays out and then we have data coming from the phase III trials.

In the latter part of this year from both Gantner Mab in Makena formulae Vance you for one and those are very a little bit different in terms of molecules and what they mean and how they test the biology I think.

Probably don't have time to get into that here, but they are a little bit different with <unk> being a little bit more immediate term. This targeting again neuroma of having a dual epitope and the resultant biology, therefore is a little bit different.

Gene Kinney: Gantaneur Mav has a dual epitope, and the result in biology, therefore, is a little bit different. Also, you know, a little bit different in terms of clinical trial design, how they're powered, and the prior data that they're powered on. And then, of course, as we roll into next year, we'll see the banana map data set. And, you know, that'll be interesting to see, particularly coming off the phase two trailblazer. So a lot of information, I think the relevant thing for perex 12, there are a couple things to talk about. First, from an NCD perspective, we think that the language there, regardless of what it ends up being, really has the greatest impact on these newer term candidates that we just discussed.

Also a little bit different in terms of clinical trial design, how they're powered the prior data that they are powered on.

And then of course as we roll into next year, we'll see the dynamic <unk> dataset and that'll be interesting to see particularly coming off the phase II trailblazer. So a lot of information I think the relevant thing for <unk> 12.

Things to talk about first from an NCD perspective.

We think that the language there regardless of what it ends up being really has the greatest impact to these near term cannon.

Candidates that we just discussed I think for <unk> 12 at this point in time.

Gene Kinney: I think for perex 12, at this point in time, less of an impact in terms of how we think about the clinical development of that molecule, the overall program. And given what Hideki said already about the potential for subcutaneous administration, you know, we can actually even think about some of these early IV drugs being potentially in part D where a drug like Perex 12 could be considered for part D, although obviously with different implications around the final coverage determination.

<unk> have an impact in terms of how we think about the clinical development of that molecule.

Overall program and given what <unk> said already about the potential of subcutaneous administration.

Can actually even think about some of these early IV drugs being potentially in part D, where a drug like <unk> 12 could be considered for part D. Obviously with different implications there around the final coverage determination.

Gene Kinney: I think, you know, the other component here is that I would be remiss if I didn't say that there's an awfully good opportunity to learn from these trials. So, you know, we're going to have the benefit here of learning across these trials about primary outcome measures, duration of treatment, patient selection, and as we move our program forward, we fully anticipate incorporating those learnings into the perex 12 program.

The other component here is I'd be remiss if I didn't data is that there is an awfully good opportunity to learn from these trials. So we're going to have the benefit here of learning across these trials about primary outcome measures duration of treatment patient selection and as we move our program forward we fully.

Gene Kinney: So, from our perspective, just a wealth of information coming all to the benefit of the Perex 12 program. Let me pause there and ask Tron if he might have some comments on how he sees this as well, just from a strategic perspective moving forward. Yeah, no, absolutely.

We anticipate incorporating those learnings into the peer X 12 program. So so from our perspective, just a wealth of information coming all to the benefit of the peer X 12 program, let me pause there and ask Tron, if he might have some comments on how he sees this as well just from a strategic perspective moving forward.

Tran Nguyen: Thanks, Gene. I think, you know, you said it best in terms of over the next 18 months, you've got Denonimab data that looks like the middle of next year. And then, of course, you have Gansinurumab and Licanumab data later this year. And Gene has already discussed some of the differences between Gansinurumab and against both Denonimab and Licanumab.

Yes, no absolutely. Thanks, Thanks Gene I think you said it best in terms of over the next 18 months you.

<unk> got <unk> data it looks like middle of next year, and then of course, you Afghans Neuroma <unk> data later this year in January to discuss some of the differences between <unk> and against both <unk> and <unk>, but all that being said I think a lot of the data thats already been recently.

Tran Nguyen: But all that being said, I think a lot of the data that's already been recently announced, so to speak, on Licanumab and Denonimab have helped basically raise a lot of awareness in the field already in terms of, you know, the effectiveness of both of those programs, you know, the positive phase 2s. And that's why those programs only have to do one phase 3. So from that perspective, we've learned a lot already from those programs.

Sure.

<unk> so to speak on Makena Mab and <unk> have helped basically were raised a lot of awareness in the field already in terms of.

The effectiveness of both of those programs.

Positive phase II. So that's why those programs only has to do one phase III. So from that perspective, we've learned a lot already from from those programs and we're just excited to get to our data here next year in 2023, and then of course, we will account for the phase III data that come out.

Tran Nguyen: And we're just excited to get to our data here next year in 2023. And then, of course, we will account for the phase 3 data that come out. They do that before we start our registrational trials in 24. So, you know, I think everything's in front of us.

They do add before we start a registrational trials in 'twenty four so.

I think everything is in front of us and I think from a.

Operator: And from a strategic perspective, I think all, you know, as we answered Charles' question right now with the advent of iADDRESS as a potential endpoint, we think that really democratized Alzheimer's clinical development and made it affordable for companies like ourselves. So right now, we expect to wholly own this program all the way through to commercialization given the call point as a specialty call point. And it's a call point that we're clearly keenly focused on from a neurology perspective. So we're really excited for what's ahead of us and for the field. Thanks for the question. Your next question comes from the line of Neena Bitritto-Gurk with Citi. Your line is open.

The strategic perspective I think.

As we answered Charles question right now with the advent of of I address as a potential endpoint, we think that really democratized, Alzheimer's clinical development and made it affordable for companies like ourselves. So right now were real.

We expect to wholly owned this program all the way through to commercialization given the call point is a specialty call point and it's a call point that were clearly keenly focused on from a neurology perspective so.

We're really excited for what's ahead of us and for the field too. Thanks.

Thanks for the question.

Your next question comes from the line of Neena <unk> Garg with Citi. Your line is open.

Operator: Hey guys, thanks for taking my question. I apologize if somebody else already asked about this, but I was just wondering if you could give us an update on the status of enrollment in the AFIRM-AL study. And I was also just curious if you could comment on how much enthusiasm you're getting from investigators for enrolling. Yeah, thanks, Tina, for the question. So I'll ask Hideki to jump in on the recruitment and level of excitement part of the question.

Hey, guys. Thanks for taking my question. So I apologize if some Gary asked about this but I was just wondering if you could give us an update on.

The status of enrollment in the affirm al study and I was also just curious if you could comment on how much enthusiasm youre getting from investigators.

In enrolling that study.

Gene Kinney: I'll just say that, you know, we're continuing to guide to top line data there in 2024. We're obviously very excited about that program. As I mentioned in my opening remarks, that program came back following multiple discussions with both the FDA and experts in the AL amyloidosis community, where, you know, we had observed a very promising survival benefit in stage four patients in our prior vital study and also, you know, obviously, on the totality of the safety data set.

Yes, Thanks, Dana for the question. So I'll ask connect you to jump in on the recruitment and level of excitement part of the question I'll just say that we're continuing.

To guide to topline data there in 2024, we're obviously very excited about that program as I mentioned in my opening remarks that program came back following multiple discussions with both the FDA and experts in the al Amyloidosis community, where we had observed.

Very promising survival benefit in may of stage four patients in our prior vital study and also obviously on the totality of the safety data set so bringing that back under a spa with with the division of cardio renal at a predefined success value alpha value of <unk> zero, obviously, we felt.

Gene Kinney: So bringing that back under a spa with a division of cardio renal, at a predefined success value, an alpha value of point one zero, obviously, we felt, you know, was prudent to do. And we're very excited about moving that molecule forward. Maybe Hideki, do you want to speak just a bit about some of the operational components of the study? Sure, yes.

It was prudent to do and we're very excited about moving that molecule forward, maybe hideki do you want to speak just a bit too.

Some of the operational components of the study.

Gene Kinney: Thanks, Gene. Just to say, on the top line, we're expecting top line data in 2024. We're on track for that.

Sure, Yes, thanks, Jean just.

Just to stay up.

Topline, we're quoting topline data in 2024 are on track for that.

Hideki Garren: And we're seeing a lot of enthusiasm from sites. We just had an investigator meeting that was extremely well attended, and we are activating sites on a very much active upslope now, and we have randomized patients within the study. And we're doing everything and anything we can in order to maintain enthusiasm. For example, we're going back to sites we've already used in prior studies, so they know us quite well. We have a very much a hands-on, white glove type of approach to these sites so that they have direct communication with us.

And we're seeing a lot of enthusiasm from sites, we just sell a investigator meeting.

Well attended.

That we are activating sites on a very much a <unk>.

Active up slope now and we have randomized patients within the study and we're doing everything and anything we can in order to maintain that because.

For example, we're going back to sites that we've already used and parcels. So they know us quite well we have a very much a hands on white glove type of approach to these sites. So that they have direct communication with us we're engaged with patient advocacy organizations like aligns.

Hideki Garren: We're engaging with patient advocacy organizations like the Amyloid Alliance and Amyloidosis Foundation. And we're present at the conference, like Ash and Yeeha. So we're very, very active out there. We're also going to MSL Field Force, the US tights.

Im going to ask this foundation.

Tran Nguyen: And so we're very much on track for 2024. We are out. I think the other thing to add, Hideki and Gene, is that the data that continues to come out from daratumumab and ALM lidosis, although they've gotten accelerated approval, you know, the survival data is still not yet matured, and there's no survival benefit even out to around two years with that data. So, for patients at, you know, high risk of early mortality in the trial, you know, in their own trial that have already passed away, clearly, there's still a high unmet need here for a depleter mechanism like pertamumab, and of course, the data set that we showed within kind of the first nine to 12 months that we could make a potential survival benefit with a hazard ratio of.413 on We're looking forward to confirming those data in 2024.

And.

And the conference like Ash.

So we're very very active out there we're also growing in our steel.

MSL feel Horst, yes sites and so we're very much on track for 2024.

I think the I think the other thing to add too Headachy in June is that the data that continues to come out from Derek <unk> doses, although they've got an accelerated approval.

Survival data is still not yet matured and there's no survival benefit even out to around two years with that data. So for patients at high risk of early mortality in the trial and their own trial that have already passed away clearly there is still a high unmet need here for a depleter mechanism like <unk> and of course, the data set that we showed with.

And then kind of the first nine to 12 months that we could make a potential that we have a potential survival benefit with a hazard ratio of <unk>.

<unk> III on a post hoc.

Alex This yes, but that's also supported by our Spa, we're looking forward to confirming those data in 2024. So we're excited by the way the field of setting up and clearly our mechanism is really relevant in the patient population. We are we are.

Tran Nguyen: So we're excited by the way the field is setting up, and clearly, our mechanism is really relevant in the patient population. We are, you know, we are, we are holding the trial in for a firm ALM. Your next question comes from the line of Jay Olson with Oppenheimer. Your line is open.

We are holding the trial and for <unk>.

And our next question comes from the line of Jay Olson with Oppenheimer. Your line is open.

Operator: Oh, hey, thanks for taking the question and congrats on all the progress. Maybe just to follow up on that last question, as you look ahead to the AFIRM AL study where you have a really favorable looking spa that you mentioned, can you just comment on the current unmet need in AL amyloidosis, including the mixed results from standard of care, chemotherapies, the anti-CD38 antibodies that you touched upon earlier, and then potential for new entrants, like I think there's a potential BCL2 inhibitor from Zentalis, and longer term, where you see Bertamomab fitting into the treatment paradigm and your plans to commercialize, whether you'll do that alone or with a partner. Thank you.

Oh, Hey, thanks for taking the question and congrats on all the progress maybe just to follow up on that last question. As you look ahead to the affirm AF study, where you have <unk>.

Really favorable looking spa that you mentioned can you just comment on the current unmet need in al amyloidosis.

<unk>.

The mixed results from standard of care Chemotherapies.

CD 38 antibodies that you touched upon earlier and then potential for new entrants like I think there is a potential bcl two inhibitor from Zen Palace.

And longer term, where you see <unk> fitting into the treatment paradigm and your plans to commercialize whether you'll do that alone or with a partner. Thank you.

Gene Kinney: Yeah, thank you, Jay. So, great questions there. Maybe I can ask Wagner to speak a little bit about this, because I think part of what you're asking, Jay, and Tran touched on this, is, you know, the relative differences between targeting protein production, which is what the majority of kind of standard of care approaches do, versus targeting for removal the resident amyloid that has already aggregated and deposited on critical organs, and, you know, what we believe is most proximal to actually leading to organ dysfunction.

Thank you Jay.

Great questions. There, maybe maybe I can ask Wagner to speak a little bit about this because I think I think part of what you are asking Jay and John touched on this is the relative differences between targeting protein production, which is what the majority of kind of standard of care approaches do versus.

Targeting for removal the resident amyloid that is already aggregated and deposited on critical organs and what we believe is most proximal to actually leading to organ dysfunction, and so maybe like where do you want to speak just a little bit about that from a mechanism perspective, and then we can jump back and talk about the commercial component.

Gene Kinney: And so maybe, Wagner, do you want to speak just a little bit about that from a mechanism perspective, and then we can jump back and talk about the commercial component? Yeah, I think these are essentially the two very important differentiators between Bertam and Maven, the other class that is attempting to slow down the disease progression by going after the source. We are talking about light-shaying that is a precursor of an amyloid that accumulates in these organs.

Yes, I can.

Essentially the two very important differentiators between near term 11, the other class that is attempting to.

Slow down the disease progression by going after the source right. We're talking about light chain that is a precursor autoimmune larger deposits and there's this oregon's when the patients are diagnosed there's a massive amount of amyloid already there. So it makes sense that you won would reduce the production of new Ami large.

Gene Kinney: When the patients are diagnosed, there is a massive amount of amyloids already there. It makes sense that one would reduce the production of new amyloids, and that is what plasma cell therapy does. There are many mechanisms that we can target here, the 38 is one of them. It makes sense that that would be one step, but also another step that would make sense. If you remove amyloids that are already causing toxicity directly to the cells in the organs, particularly in the heart, the myocytes are being directly affected by the amyloids, and an antibody like Bertam and Maven, from our perspective, is the only opportunity that we have to really reverse a process that has been built up for a long period of

And Thats, what this plasma cell therapies and there are many mechanisms that.

We can.

Yeah.

It is wonderful.

It makes sense that that would be one stop but also on other stuff.

It will make sense is to remove amyloid thats already causing.

Toxicity directly to the cells into Oregon, particularly in the heart.

Those sites are being directly affected by the army lines and an antibody like <unk>.

From our perspective is the only opportunities that we have to really reverse the process that has been built for for a long period of time.

Wagner Zago: Even in the patient populations that we classify as May stage 4, so these are newly diagnosed patients. We're not talking about different stages of the disease; we're talking about a subpopulation that somehow is at a higher risk of progression, that amyloid is already causing so much damage that you can see via biomarkers; you can identify those. And particularly in that population, it's very urgent that you have to remove that amyloid because the consequence will be death.

Even in these patient populations that we.

Cross fires may stage four so these are newly diagnosed patients we're not talking about different stages of the disease. We're talking about a sub population that somehow it's at a higher risk of progression, but the amyloid is already causing so much damage that you can see via Biomarkers identified those in particular in there.

Population is very urgent that you have to remove that annualized because the consequence will be done.

Wagner Zago: Maybe there is another population that could wait a little bit longer, and the plasma cell therapies could lead them to a point at least of extension. But the patient at the highest risk, it's urgent again, that amyloid has to be removed as quickly as possible to reverse an ongoing process of cell death. And that's a great thing, we believe it is. That's a great segue, Wagner, into the BCMA target.

Maybe there is another population that could.

Wait a little bit longer than the plasma cell therapies could lead them to a point at least of extension, but the the patients at highest risk. It's urgent again, Saddam Lloyd has to be removed as quickly as possible to reverse of an ongoing process of toxicity.

And that's a great segue we believers.

Tran Nguyen: I mean, look, you know, different ways to better control light chain production is going to be more competition on the mild side, is what we're seeing from the data sets from multiple diseases, AL and ATTR. So from that perspective, going back to what Wagner just said, for patients that are at high risk for early mortality due to the existing amyloid deposited in the heart, you're going to need a depleter mechanism in order to remove that to have any chance of benefiting that patient. And that's what's showing up in the DARA data.

That's a great segue lager into the <unk> target I mean look at different ways to better control.

<unk> light chain production is going to be more competition on the mild side is what we're seeing from from the datasets for multiple diseases al and ATR, so from that perspective going back to what.

Bognor just said four deal for patients that are at high risk for early mortality due to the existing amyloid deposited in the heart youre going to need a depleter mechanism in order to move that to have any chance at benefiting that patient and thats showing up in the Dara data and so from that perspective, we're highly.

Tran Nguyen: And so from that perspective, we're highly encouraged about our firm AL trial and our position, you know, in the disease. And then we can start thinking about the potential for combination therapies in terms of mild patients because, again, these mechanisms are complementary. So I think those are great questions, Jay, from that perspective.

Encouraged about our Afirma L trial and our position.

In the disease and then we can then start thinking about potential for combination therapies in terms of mild patients because again. These mechanisms are complementary. So I think those are those are great questions Jay from that perspective, and again from a commercial perspective, we are its our intention to wholly owned this program and commercialize it ourselves it's a very leverages bowls.

Tran Nguyen: And again, from a commercial perspective, it's our intention to wholly own this program and commercialize it ourselves. It's a very leverageable sales call point for us, calling on hematologists. We know where up to 75% of the patients are. They're at 500 centers.

Sales call point for us calling on Hematologists, we know we're up to 75% of the patients are there at 500 centers. So it's a very.

It's a very leverages will call point for us. So we're excited to commercialize it on our own and we're looking forward to data in 2024. Thanks for the question.

Tran Nguyen: So it's a very, you know, it's a very leverageable call point for us. So we're excited to commercialize it on our own, and we're looking forward to data in 2024. Thanks for the question. Your next question comes from the line of Kenan McKay with RBC Capital Markets. Your line is open.

Your next question comes from the line of Keenan Mckay with RBC capital markets. Your line is open.

Operator: Thanks for taking the question. Maybe just a housekeeping question on X12 and then one on a firm. What is your take on your conversations with the FDA? What is the status of I&D for X12 at this point? And then following up on the firm AL question, it looks like there are 117 potential clinical trial sites listed on clinical trials, but we've only 150 or so patients playing for enrollment. That doesn't quite feel right.

Hey, guys. Thanks for taking my question.

Maybe just a housekeeping question on X 12, and then one on the phone.

What is from your conversations with the FDA what is gating the IMD for X 12 at this point and then following up on the affirmed.

Question. It looks like there were 117 potential clinical trial sites listed trials, but with only 150 or so patients.

Playing for enrollment that doesn't quite feel right. So maybe as you look at the trial. How many sites are you planning on opening and I'd love to understand sort of where.

Operator: So maybe as you look at the trial, how many sites are you planning on opening? And I'd love to understand sort of where that is in terms of the number of plans being opened. Thanks. Yeah, thanks. So two good questions. So, I think the first on X-12, I think what you're kind of asking is what's gating from an ID perspective. And obviously, this is, you know, the operational pick and shovel work.

Where that is in terms of.

Number of planned sites are being opened.

Yeah.

Gene Kinney: We just need to get, you know, our work done. We need to get all the reports finalized. We need to get the ID compiled and filed. So that's, you know, we look forward to doing that. I said, the team's on track, and they're working hard. And we expect that to be done here in the first quarter. Then, on the Affirmale trial, you'd ask specifically about the number of trial sites relative to the number of patients. You know, obviously, this isn't a rare disease.

Yeah. Thanks, Karen so two good questions. So I think the first the next 12, I think what youre kind of asking what's gating from an R&D perspective, and obviously this is.

The operational pick and shovel work, we just need to get.

Our work done we need to get all the reports finalize we need to get the IND compiled and filed so that as we look forward to doing that as I said the team is on track to working hard.

And we expect that to be done here in the first quarter.

Gene Kinney: You know, we know these sites well. These are expert centers across the globe. The number of these sites we've worked with in the past, as Hideki had mentioned earlier, in our prior phase three vital study. And so, you know, these are sites that are, for the most part, well known to us. And, you know, our sites that we know see the patients for which we're hoping to recruit into the Affirmale trial. But maybe I'll let Hideki speak a bit more on that latter topic if you don't mind.

On the affirm a L trial.

You had asked specifically about number of trial sites relative to number of patients.

Obviously this is a rare disease.

We know these sites well these are expert centers across the globe.

A number of these sites we've worked with in the past.

<unk> you had mentioned earlier.

In our prior phase III.

The vital study and so these are sites that are for the most part well known to us and our sites that we know see the patients for which we're hoping to recruit into the affirm male trial, but maybe I'll let <unk>.

Can you speak a bit more on that latter topic, if you don't mind hideki.

Hideki Garren: Sure, sure. Yeah. So, as you mentioned, Kenan and Kuhnfert have some luck.

Sure sure, yes, so as you mentioned in Kenya, and in clinical trials, but we have 117 placements.

And that's about right.

Remember the trial has a total enrollment of 150 subjects 102.

Hideki Garren: We have 117 sites listed. And that's, that's about right. Remember, the trial has a total enrollment of 150 subjects, 102. At the time of the 50 to the fetal.

Over time at a 52 placebo. So that's about right, we don't want to spread ourselves too thin and so on.

17, approximately place we're looking at additional sites by the way.

That's about right in terms of enrolling the study on time.

So the other thing to mention too is again were when we first enrolled this trial, we are doing all comers right from Mayo stages, one through four and this time around this is mayo stage for newly diagnosed and so again.

This idiopathic disease.

As equal in regions of U S and Europe . So we just want to make sure we are.

<unk> you just said that we leave no rock unturned and we want to make sure we do enroll.

Fast as we can so hence a lot of the sites. We have already worked with and we're looking for new sites. We're working with some new sites in that number too that you quoted that's on clinical trials dot Gov, but it's just making sure we try to get as expeditiously enrolled as we can.

Hideki Garren: So, that's about right. We don't want to spread ourselves too thin. And so, 117 sites, approximately.

Hideki Garren: We're looking at additional sites, by the way. That's about right in terms of rolling out the study on time. And so the other thing to mention, too, is that when we first enrolled this trial, we were doing all comers, right, from Mayo Stages 1 through 4. And this time around, this is Mayo Stage 4, which is newly diagnosed. And so, again, this is an idiopathic disease. You know, it's equal in regions of the U.S. and Europe.

Tran Nguyen: So we just want to make sure we're, you know, as Hideki just said, that we leave no rock unturned, and we want to make sure we enroll as fast as we can. So hence, a lot of the sites we have already worked with, and we're looking for new sites, you know, we're working with some new sites in that number two that you quoted, and that's on clinicaltrials.gov. But it's just making sure we try to get you as expeditiously enrolled as we can. Your next question comes from the line of Goblin Sync with JMP Securities. Your line is up. Hey, good evening.

Your next question comes from the line of Goldman Sachs with JMP Securities. Your line is open.

Operator: Thanks for taking the questions. Just curious about a few things on the light chain amyloidosis commentary. Are you guys hearing anything for Darzalex in 2021? That's about 6 billion.

Hey, good evening, thanks for taking the questions just curious on a few things on the light chain amyloidosis commentary.

Are you guys hearing anything for <unk> in 2021 that it was about $6 billion.

Operator: How much of that is getting traction and light change since it was approved there and curious about the Elzheimer's program, on the optics, the guidance. How much of that, if there is any even for like being planned for PRS 12 and that and this, If you can comment on any specifics about that 150, I think 270, that you mentioned, Tran Nguyen, how much of that is being baked into that program? helpful. And then for the dual vaccine data that you guys presented last year, can you comment at all specifically on the pyroglutamate A-beta data that you saw in any of the models that were there? Okay, great questions, Governor. Thanks.

How much of that is.

It is getting traction in light chain since it was approved there and curious on the <unk>.

Separately on the Alzheimer's programs on the Opex.

The guidance how much of that if there is any even for like being planned for Prs 12 in that and then.

If you can comment on any specifics about that 150, I think 270 that you mentioned trends how much of that is being baked to that program would be helpful. And then for the dual vaccine data that you guys presented.

Last year can you comment at all specifically on pilot.

Beta.

Data that you saw it in any of the models that was there.

Tran Nguyen: So the kind of three questions here are just around from an AL perspective, you know, where do we, how much do we think Darzalek's getting used, kind of break out a little bit the guidance around X12, and then a little bit more around the dual vaccine and what we've presented there. So maybe I can ask, Tron, do you want to address the first two, and maybe Wagner, you could talk a little bit about the dual vaccine and what we've presented? So in terms of the AL breakout for Dera in terms of their 21 revenue, we don't have a sense of how much of that is AL at this point.

Okay, great questions Goldman. Thanks, So kind of three questions here just around from an <unk> perspective, where do we how much do we think <unk> getting usage.

To break out a little bit the guidance around X 12, and then a little bit more around the dual vaccine and what we presented there. So maybe I can ask Sean do you want to address the first two and maybe Rodney.

You can talk a little bit about the dual vaccine and what we've presented.

Tran Nguyen: Clearly, I think a lot of it is multi-myloma driven. And then, in terms of our costs, that being said, it's probably around 20% of our off-ex costs are going to be Botanomab. [inaudible] and so I think from that perspective, that gives you a sense of how that's going and, clearly, that I'll go into 23 and into 24. So with that, maybe I'll turn it over to Wagner in regards to the other questions. Yeah, so I'll repeat the question.

So in terms of the <unk> breakout for Dara in terms of their 'twenty. One revenue, we don't have a sense of how much of that is <unk> to this point clearly I think a lot of it is multiple myeloma driven.

And then in terms of our costs that being said, it's probably around 20% of our opex cost is going to be <unk>.

And so I think from that perspective that gives you a sense of.

How thats rolling and include that will go into 'twenty three in <unk> and into.

Into 'twenty four.

So with that maybe I'll turn it over to vulgar in regards to the other question.

Wagner Zago: The question was whether we have data supporting clearance of pyroglutamate with our vaccine. And you all remember last year we presented data showing that PRX12, by targeting the N-terminal portion of a protein, could also clear pyroglutamate from plaques of tissues derived from Alzheimer's patients. We think that all N-terminal antibodies will do the same thing. Whether you are acting directly, binding directly to pyroglutamate, like Dananimab or any other one of the A-beta, N-terminal antibodies, they can also, like PRX12, indirectly clear pyroglutamate because the microglia and the microflages, when they are eating the plaques and digesting the plaques, they are not selective on a molecular basis.

Yeah. So I'll repeat the question. The question was on whether we have data supporting clearance of fire blue with our vaccine and you all remember last year, we presented data showing that <unk> 12.

By targeting the N terminal portion of data could also clear quarter glutamate from blocks of tissues.

Derived from Alzheimers patients we.

We think that all of the N terminal entre bodies will do the same thing whether you are.

Acting directly binding directly in prior glue like demand them up or any other one off to a beta enter maybe antibodies.

And also like like staff can indirectly clear.

Good because the macro microglia and macrophages when they are eating the clocks and digesting the blocks. They are not selective on a molecular basis theyre going to buy the internalize the buying cycle external party, but also all the other toxic entities there are be.

Wagner Zago: They are going to internalize the binding site of the antibody but also all the other toxic entities that are part of that plaque. And that's why I believe that, like PRX12, the other N-terminal antibodies also do the same. Our vaccine was designed based on the knowledge that we built over many years, and more recently with X12. So you won't be surprised if a vaccine that's designed to generate antibodies that bind to the N-terminal portion of A-beta would also promote pyroglutamate. Your next question comes from the line of Tazine Ahmed with Bank of America. Your line is open.

Part of the block and that's why I believe that Barak slow the other intermountain bodies also do the same our vaccine was designed based on the knowledge that we've built over many years and more recently with X 12. So.

We'll stay tuned but.

Don't be surprised if a vaccine is designed to generate antibodies that bind to the N terminal portion of the data would also promote prior glutamate plants.

Your next question comes from the line of <unk> Ahmed <unk> with Bank of America. Your line is open.

Operator: I did afternoon guys, thanks for taking my questions. One for Tran and one for Genefine Mike. Tran, you did get a $50 million milestone payment from Roche for the Parkinson's program. Should we expect any other milestone payments in 2022? And then seeing, I was just curious about your thoughts on APTR. It's obviously now in Novo's hands, but just given the recent news flow on other programs that have had data, namely Bridge Bio.

Hi, Good afternoon, guys. Thanks for taking my question.

One for John and one for Gina Fine Mike.

You did get a $60 million milestone payment.

From Roche for Parkinson's program should we expect any other.

Its down payments in 2022, and then Jean.

I was just curious about your thoughts on <unk>.

It's obviously now in Davos hand, but just given the recent newsflow on other programs that have hard data, namely bridge Bayou just was curious to get your thoughts about the U S.

Six minute walk as a primary endpoint of whether or not you think ultimately mortality should be used.

Operator: I was curious to get your thoughts about the use of the 6-minute walk as a primary endpoint or whether or not you think ultimately, mortality should be used to figure out the efficacy of this class of particular drug and how you might be differentiated from not only Bridge but also the online approach. So thanks for thinking about that. Yeah, I'll take the roast question.

To figure out the efficacy of this class of particular truck and how you might be differentiate it from not only branch, but also the on island approach.

Okay.

Tran Nguyen: So yes, thank you for that. We did receive the 16 million for the phase to be put into trial last year. So that will be the remaining clinical milestones. The rest will be regulatory first commercial sale and then, of course, achieving certain tier sales milestones in the program.

So thanks for tuning in today.

Yes, I'll, just say I'll take the Roche questions. So yes. Thank you for that we did receive the $60 million for the phase <unk> trial last year. So that will that will be the remaining clinical milestones. The rest will be regulatory first commercial sale and then of course, achieving certain tier sales milestones in the program.

So.

We look forward to of course, those milestones too, but that's that would be the update on the press. It doesn't map program and then I'll, let Jean answer your second question.

Tran Nguyen: So we look forward to, of course, those milestones too, but that would be the update on the person as a map program. And then I'll let Gene answer your second question. Yeah, so it's a good question about ATTR.

Gene Kinney: And, you know, it's related to what we were discussing around AL amyloidosis and bortamomab, in as much as, you know, much of the current focus in the field is targeting the production of proteins. And, you know, it's a little bit different in ATTR because the normal form of the ATTR protein that underserves or underlies its normal function is this homotetrameric state, so four units. And, and so you've got kind of two ways to turn off the source of protein coming into this pathological pathway, if you will, right? One way is to just silence the production of protein.

Yes, so it's a good question <unk> and it's related to what we were discussing around al amyloidosis and <unk> in as much as much of the current focus in the field is targeting the production of protein and it's a little bit different in ATR, because the normal form of the ATR protein.

And that underserved or under is its normal function is this homo <unk> states of four units and.

And so you've got kind of two ways to turn off the source of protein coming into this pathological pathway. If you will right. One way is to just silenced the production of proteins. So these are the <unk> RNA approaches.

Gene Kinney: So these are your siRNA approaches, you know, and, and, and, you know, your antisense approaches and what have you. The other is to stabilize the normal form, right? So these are your stabilizers, like the IDOS molecule that you're referring to, as well as famitis, Pfizer's compound in this space. And so, what have we learned in the field about that approach, i.e. reducing new proteins coming into the pathway?

And Youre antisense approaches and what have you.

The other is to stabilize the normal form writes an easier stabilizers like like the Idose molecule that you are referring to as well as to famine as pfizer's compound in this space and so what have we learned in the field about that approach I E, reducing new protein coming into the pathway and what we've learned is that you know and it's.

Gene Kinney: And what we've learned is that, you know, and it's best exemplified, I think, in Pfizer's data set with the famitis, is that you can see a survival benefit. In fact, they saw, I believe, a hazard ratio over a 30-month period of about 0.7, so about a 30 percent, or a 30 percent relative risk benefit on mortality, which is obviously meaningful When you dig into the data that Pfizer disclosed, what you see is that the majority of that effect is in New York Heart Association class 1-2 patients, very, very little effect. I think the p-value is 0.78, if I remember correctly, in New York Heart Association class 3 patients.

Best exemplified I think advisers dataset with the families.

You can see a survival benefit in fact, they saw I believe a hazard ratio over a 30 month period of about <unk> seven so about a 30% 30% relative risk benefit on mortality, which is obviously meaningful when you dig into the data that Pfizer disclosed what you see is that the majority of.

That effect is in New York Heart Association class one two patients very very little effect I think the P value was <unk> seven to eight if I remember correctly.

In New York Heart Association class III patients. So this would argue I think what <unk> was referring to earlier that when you target. The front end of this biological pathway the production side.

Gene Kinney: So this would argue, I think, what Tron was referring to earlier, that when you target the front end of this biological pathway, the production side, that, you know, you need to survive long enough, if you will, to actually achieve the benefit of reducing new proteins coming into these pathways. That seems to speak to me and to us. And therefore, you know, a little bit more of a mild patient population might be a place that's appropriate for those types of approaches.

You need to survive long enough, if you will to actually achieve the benefit of reducing new protein coming into these pathway. That's what it seems to speak to me and to us and therefore.

A little bit more of a mild patient population might be a place that's appropriate for those types of approaches of course, when you move to a more mild patient population than the progression of functional endpoints like six minute walk.

Gene Kinney: Of course, when you move to a more mild patient population, then, you know, the progression of functional endpoints, like the six-minute walk, which you mentioned, might be a little bit harder to measure change over time because it may just change more slowly. So I'm speculating a bit, but I think it's a reasonable conclusion. Where PIRX4 differentiates is in its mechanism of action.

You mentioned might be a little bit harder to measure change over time, because it may just change more slowly so I'm I'm speculating a bit but I think it's a reasonable.

A reasonable conclusion, where peer explore.

Gene Kinney: It's not designed to reduce new protein coming into the pathway. It's designed to address the resident protein that's already aggregated and causing dysfunction at the organ level and to remove that protein. The way PIRX4 was designed was to interact with a region or an epitope that is not available in the homotetrameric form, the normal form, but is available when that form is in a non-normal state.

<unk> is in its mechanism of action, it's not designed to reduce new protein coming into the pathway is designed to address the resident protein, that's already aggregated and causing dysfunction at the Oregon level and to remove that protein in the way peer explore was designed was to interact with it a region.

Or an epitope.

That is not available in the home of Tetra Merit from the normal form but is available when that form is in a non normal state and therefore, we can target that we believe in target that material for removal.

Gene Kinney: And therefore, we can target that, we believe, and target that material for removal. So we, you know, refer to that as a depleter mechanism of action. It's leveraging information that we can see is somewhat similar from a biology perspective between AL amyloidosis and ATTR, even though they're different diseases, with AL being a little more of an aggressive disease in terms of function, or functional decline, I should say. And so, you know, we think that the field may very well move in the same direction, which is for patients with an appreciable amount of resident amyloids causing And ultimately, you may think about combination approaches since those mechanisms of action are complementary.

Refer to that as a depleter mechanism of action. It's leveraged information that we can see is somewhat similar from a biology perspective between al amyloidosis, and ATR, even though they're different diseases with <unk> being a little more of an aggressive disease.

In terms of function.

Our functional decline I should say and so we think that the field may very well move in the same direction, which is for patients with impressionable amounts of resident amyloid, causing dysfunction or <unk>.

Peter mechanism of action like pier explore may be uniquely suited for those patient patient then ultimately.

You May you may think about combination approaches since those mechanisms of action are complementary. So as you as you mentioned in your question <unk> we did.

Gene Kinney: So, you know, as you mentioned in your question, Tazine, we did have an agreement with Nova Nordisk in this space. We're very happy with that agreement, and they're now taking that forward. You know, they announced in their earnings call here this month that they expect to start a clinical trial for ATTR cardiomyopathy here in the first half of this year. So, we're real excited to see that move forward. And, obviously, we think working with Novo, particularly on this program, gives us an opportunity to bring that type of medicine to patients on an expedited timeline. And so, we're very happy with that collaboration. I think maybe Tron, did you want to also mention this?

We have an agreement with Novo Nordisk in this space, we're very happy with that with that agreement and they're now taking that forward.

They've announced in their earnings call here. This month that they expect to start a clinical trial in <unk> cardiomyopathy here in the first half of this year.

So we're real excited to see that move forward and obviously, we think working with Novo, particularly on this program gives us an opportunity to bring that type of medicine to patients on a on an expedited timeline and so we're we're very happy with that collaboration I think.

Tran Nguyen: Did you have any additional points? Yeah, absolutely. So, I mean, I think the tefaminus data is the Bible that everyone's been working from, and clearly, I think BridgeBio and Alnylam have seen that data set. And it corroborates basically what Gene was just discussing, which is that the stabilizer really worked much better in milder patients, right? The New York Heart Association class 1 and class 2 patients, and wasn't very efficacious in the class 3 patients.

Maybe <unk> did you want to also mentioned on this did you have additional point yeah, absolutely. So I mean, I think that to family. This data as the Bible that everyone's been been working from and clearly I think bridge buyout bio and <unk> seen that data set and it corroborates basically what gene was just discussing which is the.

A stabilizer.

Really worked much better in milder patients right, the New York Heart.

Association class, one and class two patients and wasn't.

Tran Nguyen: So, then I think those mechanisms, both silencers and stabilizers, went to the more milder population to actually better their survival readout, although they might want to extend it past 30 months. But that being said, that's what they were trying to do.

Very efficacious in the class III patients. So then I think.

Those mechanisms, both silencers and stabilizers went to the more milder population to actually better their survival readout.

Although they might want to extend past 30 months, but that being said that's what they were trying to do so then when you go to milder patients and then you say, okay, let's have them.

Tran Nguyen: So, then when you go to milder patients and then you say, okay, let's have them progress in a one-year time period, I think the first look at that was that that was a pretty tall task based on the BridgeBio data. So, from that perspective, we'll see here shortly on Alnylam, and maybe that was just an artifact of BridgeBio's trial, but that is something you have to think about in terms of, again, enrolling a milder patient to advantage you in your mechanism of survival.

Let's have them progressed in a one year time period I think the first look at that was that that's a pretty tall task from the bridge biodata. So from that perspective, we will see here shortly on Elba Island, and maybe that was just an artifact of bridge <unk> trial, but that is something you have to think about in terms of again enroll enrolling.

A more milder patients to advantage you in your mechanism on survival.

Tran Nguyen: So, that's really what we learned from that, and I would say, again, from what Gene was saying, from a depleted perspective, we are thinking about a more advanced patient population, and so we're looking forward to the cardiomyopathy phase 2 trial that Novo is going to run here and initiate here in the first half of this year, and we're looking forward to basically further clinical studies as needed, all right? So, thank you for the question. That is all the time we have for questions. I'd like to turn the call back to Gene Kinney.

So so that's really what we learned from that and I would say again from what gene was saying from a depleter perspective, we are thinking about.

But more advanced patient population and so we're looking forward to the cardiomyopathy phase II trial that Novo has is going to run here initiate here in the first half of this year and we're looking forward to.

Basically further clinical studies as needed alright, so that so thank you for the question.

That is all the time, we have for questions I'd like to turn the call back to gene Kinney for closing remarks.

Gene Kinney: Closing remarks. Well, thank you, Josh. And thank you all for joining us. We appreciate your interest in Prothena. And over the coming months, we look forward to sharing further updates on our programs. Thank you. This concludes today's conference call. Thank you for your participation. You may now disconnect.

Well, thank you Josh and thank you all for joining US we appreciate your interest and Christina and over the coming months, we look forward to sharing further updates on our progress. Thank you.

This concludes today's conference call. Thank you for your participation you may now disconnect.

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Yes.

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