Q4 2023 Agios Pharmaceuticals Inc Earnings Call
Operator: Good morning, and welcome to AGIOS' fourth quarter 2023 conference call. At this time, all participants are in a listen-only mode.
Good morning, and welcome to <unk> fourth quarter 2023 conference call. At this time all participants are in a listen only mode there'll be a question and answer session. At the end. Please be advised that this call is being recorded and all Geos request I would now like to turn the call over to Chris Taylor Vice President Investor.
Operator: There will be a question and answer session at the end. Please be advised that this call is being recorded at AGIOS' request. I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations, and Corporate Communications for AGIOS. Please go ahead. Thank you, operator. Good morning, everyone.
Chris Taylor: And corporate communications.
Chris Taylor: Please go ahead.
Chris Taylor: Thank you operator, good morning, everyone and welcome to <unk> conference call and webcast to discuss fourth quarter and full year 2023 financial results and recent business highlights you can access slides for today's call by going to the investors section of our website <unk> Dot com.
Chris Taylor: And welcome to Agios' conference call and webcast to discuss fourth quarter and full year 2023 financial results and recent business highlights. You can access slides for today's call by going to the investors section of our website, agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff; Dr. Sarah Hewins, Chief Medical Officer and Head of Research and Development; Sveta Milanova, our Chief Commercial Officer; and Cecilia Jones, Chief Financial Officer. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. However, actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, I'll turn the call over to Brian.
Tom.
Chris Taylor: On today's call I'm joined by our Chief Executive Officer, Brian Goff.
Dr. Sara: Dr. Sara <unk>, Chief Medical Officer, and head of research and development.
Dr. Sara: Melanoma, our chief commercial officer, and Cecilia Jones, Chief Financial Officer.
Dr. Sara: Before we get started I would like to remind everyone that some of the statements. We make on this call will include forward looking statements actual events and results could differ materially from those expressed or implied by any forward looking statements. As a result of various risks uncertainties and other factors, including those set forth in our most recent.
Dr. Sara: Filings with the SEC and any other future filings that we may make with the SEC.
Dr. Sara: With that I'll turn the call over to Brian.
Chris Taylor: Thanks, Chris. And good morning, everyone. And thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. Driven by this goal, we continue to generate consistent and compelling data across our industry-leading PK activator franchise. And with the seamless cross-functional collaboration of the Agios team, we made remarkable progress advancing this mission in 2023.
Brian M. Goff: Thanks, Chris and good morning, everyone and thank you for joining us our mission at <unk> is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases.
Brian M. Goff: Driven by this goal, we continued to generate consistent and compelling data across our industry, leading PK activator franchise.
And with seamless cross functional collaboration of the <unk> team, we made remarkable progress advancing this mission in 2023.
Brian M. Goff: Highlighting this progress, we reported three key data readouts in the last 12 months. In June, we reported positive top-line data from the Phase 2 portion of the RISEUP study of Mitativet, our lead PK activator in sickle cell disease, followed by the full data set in December at ASH. Despite the field's recent progress in sickle cell disease, there are no novel oral therapies that both improve anemia and reduce sickle cell pain
Brian M. Goff: Highlighting this progress we reported three key data readouts in the last 12 months.
Brian M. Goff: In June we reported positive topline data from the phase II portion of the rise up study of mid tier that are lead PK activator in sickle cell disease.
Brian M. Goff: Followed by the full data set in December at Ash.
Brian M. Goff: Despite the fields recent progress in sickle cell disease. There are no novel oral therapies that that both improve anemia, and reduce sickle cell pain crises.
Brian M. Goff: And that is precisely what we aim to deliver with MediPibM. In November, we reported positive data from an Open Label Phase 2A study of our other PK activator, AG946, in lower-risk MDS, with 40% of patients achieving the transfusion independence endpoint. And just last month, we reported positive data from the Phase 3 ENERGIZE study of midipivet in nontransfusion-dependent thalassemia. As a reminder, nontransfusion-dependent, or NTD, thalassemia accounts for approximately two-thirds of thalassemia in the US and has no FDA-approved treatment option. Despite not requiring regular transfusions, NTD thalassemia patients experience significant impact on quality of life, a wide range of serious morbidities, and an elevated risk of premature death. Together, the consistency of data generated across the Mid-Pivot Development Program bolsters our conviction in the probability of success of our ongoing studies, including two additional Phase III readouts we expect by the end of this year. And this data highlights the potential of our PK activators to transform the course of multiple hematologic diseases.
Brian M. Goff: And that is precisely what we aim to deliver with mitigated that.
Brian M. Goff: In November we reported positive data from the open label Phase Iia study of our other PK activator AG 946 in lower risk Mds with 40% of patients achieving the transfusion independence endpoint.
Brian M. Goff: And just last month, we reported positive data from the phase III energized study of <unk> in non transfusion dependent thalassemia.
Brian M. Goff: As a reminder, non transfusion dependent or MTBE thalassemia accounts for approximately two thirds of thalassemia in the U S and has no FDA approved treatment option.
Brian M. Goff: Despite not requiring regular transfusions and TD thalassemia patients experienced significant impact on quality of life, a wide range of serious morbidities and an elevated risk of premature death.
Brian M. Goff: Together the consistency of data generated across the mid tier that development program bolsters, our conviction in the probability of success of our ongoing studies, including two additional phase III Readouts, we expect by the end of this year.
Brian M. Goff: This data highlights the potential of our PK activators to transform the course of multiple hematologic diseases.
Brian M. Goff: Sarah will provide more detail on our advancements and upcoming milestones across our pipeline in just a few minutes. Importantly, we believe our PK activation pipeline is well positioned, with multiple near-term catalysts, to become a multi-billion dollar franchise and deliver significant value, in parallel with advancing the late-stage mid-to-pivot development program across multiple indications. Our commercial organization is laser-focused on building the infrastructure established through our current launch in PK deficiency to prepare for potential U.S. launches of midipivet in thalassemia in 2025 and in sickle cell disease in 2026. Sveta will provide greater detail on the commercial opportunities for Midipivet and Thalassemia, as well as an update on our current launch in PK deficiency in just a bit Finally, as you'll hear from Cecilia, we ended 2023 with a strong cash position with approximately $806 million in cash and investments on the balance. In addition, we continue to track Cervier's progress toward the potential FDA approval of voracidinib, given our retained economics for both the Milestone and Royalty. This is truly an exciting time at Agios. With four additional phase three readouts and two potential launches expected on the horizon, we look forward to multiple opportunities to drive significant near-term value creation for patients, caregivers, and shareholders. With that, I'll now turn the call over to Sarah. Thanks, Brian.
Brian M. Goff: Sara will provide more detail on our advancements and upcoming milestones across our pipeline in just a few minutes.
Brian M. Goff: Importantly, we believe our PK activation pipeline is well positioned with multiple near term catalysts to become a multibillion dollar franchise and deliver significant value.
Brian M. Goff: In parallel with advancing the late stage mid pivot development program across multiple indications our commercial organization is laser focused on building the infrastructure established through our current launch in PK deficiency to prepare for potential U S launches of mid pit that in thalassemia in 2025.
Brian M. Goff: Five.
Brian M. Goff: And in sickle cell disease in 2026.
Brian M. Goff: Instead, it will provide greater detail on the commercial opportunities for <unk> in thalassemia as well as an update on our current launch in PK deficiency, and just a bit.
Brian M. Goff: Finally, as you'll hear from Cecilia, we ended 2023 with a strong cash position with approximately $806 million in cash and investments on the balance sheet.
Brian M. Goff: In addition, we continue to track <unk> progress towards a potential FDA approval of where aside nib.
Given our retained economics for both the milestone and royalties.
Brian M. Goff: This is truly an exciting time at <unk> with four additional phase III readouts.
Brian M. Goff: And to potential launches expected on the horizon, we look forward to multiple opportunities to drive significant near term value creation for patients caregivers and shareholders with that I'll now turn the call over to Sarah.
Sarah: Thanks, Brian.
Sarah Hewins: In 2023, our research and development organization made tremendous progress advancing our PK activator development program. Led by Metapiva, the industry's most advanced PK activator, now with over eight years of clinical experience, the consistent and compelling data we have generated to date in PK deficiency, thalassemia, and sickle cell disease continue to de-risk our ongoing development program and highlight the potential for this molecule to transform patients' function and quality of life. We are also enthusiastic about the potential for the rest of our growing pipeline, and we are pleased to note that we remain on track to deliver on our milestones, including enrolling the first patients in the Phase IIb trial for AG946 in lower-risk MDS and for the Phase I trial for AG181, the compound name for our PAH stabilizer for phenylketonuria, reading out top-line data for the Phase 3 Activate Kids T study in regularly transduced pediatric patients with TK deficiency, and completing enrollment of the Phase 3 Activate Kids study in pediatric patients with TK deficiency.
Sarah: In 2023, our research and development organization made tremendous progress advancing our PK activator development program.
Sarah: Led by MS Propping up the industry's most advanced ticket axeda now with over eight years of clinical experience.
Sarah: Systems and compelling data, we have generated to date in PK deficiency, thalassemia and sickle cell disease continue to Derisk, our ongoing development program and highlight the potential for this molecule to transform patient function and quality of life.
Speaker Change: We are also answers you asked about the potential for the rest of our growing pipeline and we are pleased to note that we remain on track to deliver on our milestones including <unk>.
Speaker Change: Enrolling the first patients in the phase II <unk> trial for $89 six in lower risk Mds and for the phase one trial for <unk>, one the compounds named ph stabilizer and Youll continue to be up.
Speaker Change: Reading, our topline data for the phase III activate T study in regularly transfused pediatric patients with PK deficiency, and completing enrollment of the phase III efficacy study in pediatric patients with <unk>.
Sarah Hewins: Turning to sickle cell disease, we were pleased to present detailed positive results from the Phase 2 portion of the Phase 2-3 Rise-Up Study of Mitopivac at ASH in December. The study achieved its primary endpoint of hemoglobin response, and in addition, an improvement in analyzed rates of sickle cell pain crises was achieved. And we have been delighted by the enthusiasm of the investors.
Speaker Change: Turning to sickle cell disease, we were pleased to present detailed positive results from the phase II portion of the phase III <unk> study of <unk> capital at Ash in December.
Speaker Change: The study achieved its primary endpoint of hemoglobin response and in addition, an improvement in annualized rate for sickle cell pain crisis.
Speaker Change: And we have been delighted by the answer Jeff one of the investigators.
Sarah Hewins: We continue to advance enrollment in the Phase 3 portion of this study and remain on track to complete enrollment by the end of this year. While the treatment landscape in sickle cell disease continues to evolve, there remains an urgent and unmet need for convenient, novel oral treatment options that address both anemia and sickle cell pain crises. And we believe firmly in our potential to deliver a best in class option for patients suffering from this devastating disease. And finally, on thalassemia, I'll take a moment to highlight a few key elements of our program and the positive, stunning phase 3 data we reported last month in non-transfusion-dependent thalassemia. As a reminder, the Phase 3 program of pyrokine and thalassemia, encompassing two Phase 3 randomized placebo-controlled trials, was designed to deliver data across all subpopulations of thalassemia, such as alpha and beta thalassemia and populations with different transfusions.
Speaker Change: We continued to advance enrollment in the phase three portion of this study and remain on track to complete enrollment by the end of this year.
Speaker Change: While the treatment landscape in sickle cell disease continues to evolve there remains an urgent unmet need for convenience novel oral treatment option that address both anemia in sickle cell pain crisis.
Speaker Change: And we believe firmly in the top of our potential to deliver a best in class option for patients suffering from this devastating disease.
Speaker Change: And finally on Palestine, Yes, I'll take a moment to highlight a few key elements of our program and the positive top line phase III data, we reported last month in non transfusion dependent thalassemia.
Speaker Change: As a reminder, the phase III program of <unk> senior and compacting two phase III randomized placebo controlled trial was designed to deliver data across all sub populations of policy now such as alpha and beta thalassemia in populations with different transfusion.
Speaker Change: Both trials in patients with alpha or beta thalassemia, but in different populations as it relates to transfusion.
Speaker Change: We want to highlight that <unk> is the first clinical program that included patients who are not regularly transfused and alpha thalassemia patients.
Sarah Hewins: Both trials enrolled patients with alpha or beta thalassemia, but they enrolled different populations as it relates to transfusion needs. We want to highlight that ENERGIZE is the first clinical program that included patients who were not regularly transfused and who have alpha thalassemia. As Brian mentioned, there are no FDA-approved treatments for non-transfusion-dependent thalassemia, which represents approximately two-thirds of all thalassemia patients in the U.S.
As Brian mentioned, there are no FDA approved treatments for non constitution dependent thalassemia, which represents approximately two thirds of total fallacy that patients in the U S D.
Speaker Change: These patients suffer from a poor quality of life are high rates of serious morbidities, including Campbell and premature death.
Speaker Change: We were therefore very pleased to be able to announce positive results from the energized study.
Speaker Change: As a reminder, the energized study enrolled a total of 194 patients with either alpha or non transfusion.
Speaker Change: Susan dependent thalassemia randomized two to one to 100 milligrams be stuck without a placebo twice daily.
Sarah Hewins: These patients suffer from a poor quality of life, and a high rate of serious morbidities, including thrombosis and premature death. We were therefore very pleased to be able to announce positive results from the ENERGIZE study. As a reminder, the ENERGIZE study enrolled a total of 194 patients with either alpha or beta non-transfusion-dependent thalassemia, randomized 2-to-1 to 100 mg misapazot or placebo twice daily. The speed of enrollment and the actual number of patients enrolled in the study, as well as the high completion and rollover rate, support the idea that people who are not regularly transfused were motivated to take action The primary endpoint of this study was hemoglobin response rates, defined as an increase of at least one gram per deciliter in average hemoglobin concentration from week 12 to week 24 compared to baseline. The key secondary endpoints of this study were change from baseline in average traffic fatigue score and change from baseline in average hemoglobin concentration, also both assessed from week 12 to week 24.
Speaker Change: The speed of enrollment and the actual number of patients enrolled in this study as well as the high completion and rollover rate supports the idea that people who are not regularly transfused, we're motivated to take action and speaks to the unmet need for this population.
Speaker Change: The primary endpoint of this study with hemoglobin response rate defined as an increase of at least one gram per deciliter in average hemoglobin concentration from week 12 week 24 compared to baseline.
The key secondary endpoints of this study were changed from baseline in average traffic fatigue score and change from baseline in average hemoglobin concentration after both the first from week 12 to 24.
Speaker Change: On the primary endpoint treatment with Mitalipov demonstrated a highly statistically significant result, with 42, 3% of patients in the treatment arm achieving in hemoglobin response versus one 6% of patients in the placebo arm.
Speaker Change: In line with me talking about novel mechanism of action, which focuses on overall red blood cell health and the data generated with me talking about the cross additional disease areas. The beneficial effects of mix up effect in this study extended beyond hemoglobin alone.
Speaker Change: Specifically treatments with 100 milligrams with profits up resulted in statistically significant improvements in both key secondary endpoints, including a change from baseline in average faster to keep score and importantly patients report that measure of how patients feel and function.
Speaker Change: Importantly across the primary and secondary endpoints all pre specified subgroup analyses favorite he's talking about compared to placebo, suggesting that no single subgroup was responsible for driving the results, which supports our plans to file for a broad label covering all policy types.
Speaker Change: It is therefore, the first drop that not only improves hemoglobin, but actually makes people without seeing axial better consistent with what we observed in patients with PKU and what we hope to be able to deliver for patients with sickle cell disease as well.
Speaker Change: Complementing the near term benefit of thalassemia patients reported that they had less fatigue and felt better in the near term clinicians in the trial and other kols I appreciate the potential longer term benefits of reducing markers of hemolysis and the longer term potential to reduce serious morbidities.
Sarah Hewins: On the primary endpoints, treatment with Mitapivat demonstrated a highly statistically significant result, with 42.3% of patients in the treatment arm achieving hemoglobin responses versus 1.6% of patients in the placebo arm. In line with Mitapivat's novel mechanism of action, which focuses on overall red blood cell health and the data generated with Mitapivat across additional disease areas, the beneficial effects of Mitapivat in this study extended beyond hemo Specifically, treatment with 100 mg metopibop resulted in statistically significant improvements in both key secondary endpoints, including a change from baseline in average facet fatigue score, an important patient-reported measure of how patients feel and function.
Speaker Change: We are very much looking forward to presenting the full data set at a medical meeting.
Beyond the excitement we have for the enterprise data itself. The readout of the <unk> trial also gives us further confidence towards the readout of energy T cell.
Speaker Change: <unk> is the hemolytic anemia irrespective of whether a patient is the meat of transfusions or not in addition, the mechanism of action of when you're talking about is not dependent on the need for transfusions.
We have already demonstrated an improvement in hemolytic anemia in the enterprise trout with a positive change in hemoglobin.
Speaker Change: We are now waiting to see the improvement in hemolytic anemia can also be documented a reduction in transfusions in interchange.
Speaker Change: As a reminder, the primary endpoint of Energizer is transfusion reduction response defined as a 50% or greater reduction in transfused red blood cell units with a reduction of equal or more than two units of transfused red blood cell.
Any consecutive 12 week period through week 48 compared to baseline.
Speaker Change: Like the energized study in non transfusion dependent thalassemia the design of the Energizer deep trial enables us to demonstrate clinical meaningfulness in a variety of ways to see a reduction in transfusion burden, which also includes transfusion metrics in line with that other studies have used.
Sarah Hewins: Importantly, across the primary and secondary endpoints, all pre-specified subgroup analyses favored Mitopivac compared to placebo, suggesting that no single subgroup was responsible for driving the results, which supports our plan to file for a broad label covering all thalassemia subsites. This is therefore the first drug that not only improves hemoglobin but actually makes people with thalassemia feel better, consistent with what we observe in patients with PKD and what we hope to be able to deliver for patients with sickle cell disease as well. Complementing the near-term benefits of thalassemia patients reporting that they had less fatigue and felt better in the near term, clinicians in the trial and other KOLs appreciate the potential longer-term benefits of reducing markers of hemolysis and the longer-term potential to reduce serious morbidity.
Speaker Change: We designed this study incorporating learnings from prior studies and agency feedback and believe the dynamic assessments here. It is important that patients aren't static in rare disease.
Speaker Change: We look forward to the readout of this study by mid year and planet single regulatory filing to the FDA and compacting data from both energized and energized by the end of this year seeking a label that will enable people living with thalassemia access to a convenience and differentiated oral treatment option.
Speaker Change: Overall, I'm very proud of the tremendous progress made by our R&D organization in 2023 and look forward to continuing this momentum in 2024 with that I will now turn the call over to Sam.
Sam: Thanks Sarah.
Sam: <unk> remains an area of high unmet need with few treatment options.
Sam: None of these needs on the patients is significant regardless of their transfusion need.
Sam: The leukemia patients experienced increased mortality compared to the general population and can be significantly worse in non regularly transfused than those who are regularly transfused.
Sam: Patients in Europe higher rates of morbidity and increased complication as they age.
Sam: Adult patients with non transfusion dependent the leukemia may actually has similar or worse quality of life compared to as transfusion dependent patients.
Sarah Hewins: We are very much looking forward to presenting the full data set at a medical meeting. Beyond the excitement we have for the ENERGIZE data itself, the readout of the ENERGIZE trial also gives us further confidence in the readout of ENERGIZE-T. Thalassemia is a hemolytic anemia, irrespective of whether a patient is in need of transfusion or not. In addition, the mechanism of action of metaprevat is not dependent on the need for transfusions.
Sam: Of course, these burden of disease correlate to increased health care costs.
Sam: So whether that'd be some mezzanine.
Sam: And galvanized by the positive data from the phase III <unk>.
Study of <unk>, our commercial organization is actively preparing for a potential launch into Lithemia next year, beginning with the U S.
Sam: In the U S.
Sam: There are approximately 6000 diagnosed adult patients with the leukemia.
Sam: Approximately 4000 of these patients.
Sarah Hewins: We have already demonstrated an improvement in hemolytic anemia in the ENERGYSE trial with a positive change in hemoglobin. We are now waiting to see if the improvement in hemolytic anemia can also be documented via a reduction in transfusions in ENERGYSE T. As a reminder, the primary endpoint of NRGIS-T is transfusion reduction response, defined as a 50% or greater reduction in transfused red blood cell units, with a reduction of equal or more than two units of transfused red blood cells in any consecutive 12-week period through week 48 Like the ENERGIZE study in non-transfusion-dependent thalassemia, the design of the ENERGIZE-T trial enables us to demonstrate clinical meaningfulness in a variety of ways via reduction in transfusion burden, which also includes transfusion metrics in line with those that other studies have used.
Sam: Non transfusion dependent and have no available treatment options today.
Sam: The remaining 2000 patients often on fusion dependent and had no oral treatment option.
Sam: Our goal with me to feel that he stood there has been none met need us all about living with <unk>.
Sam: And become the first therapy approved for all subtypes of the disease.
Sam: In addition to the data we are generating it was done with the fever clinical development program. There are three key factors. We believe have the potential to support adoption of meetup, Veeva and monitor leukemia patients in the U S.
Sam: First.
Sam: There is strong alignment between where in the U S. These patients reside and where they receive treatment.
Sam: The map on slide 20, the fixed patient prevalence overlaid with the Idose clinical trial sites and centers of excellence represented by the Goldstar.
Sam: Second the diagnosis rate is high.
Sarah Hewins: We designed this study incorporating learnings from prior studies and agency feedback and believe a dynamic assessment period is important as patients aren't static in their disease. We look forward to the readout of this study by mid-year and plan a single regulatory filing to the FDA and contacting data from both ENERGIZE and ENERGIZE-C by the end of this year, seeking a label that will enable people living with thalassemia access to a convenient and differentiated oral treatment option. Overall, I'm very proud of the tremendous progress made by our R&D organization in 2023 and look forward to continuing this momentum in 2024. With that, I will now turn the call over to Sveta. Thanks, Sarah.
Sam: Driven by availability of newborn screening and the well established ICD 10 code.
Sam: Many patients are diagnosed before others could.
Sam: And finally as shown on slide 21, there is a concentration of patients and providers selected centers.
Sam: Approximately 50% of all diagnosed patients are treated at fewer than 150 affiliated hematology oncology practices in the U S.
Sam: Providing a clear focus for our initial launch.
Sam: Given these market dynamics and final target product profile. We believe we are well positioned to provide a potential foundational treatment option for patients with tell us EMEA regardless of subtype.
Sam: Therefore, our team is focused on four core areas of U S launch preparation.
Sveta Milanova: Thalassemia remains an area of higher medical need with few treatment options. The burden of disease on the patient is significant regardless of their transfusion needs. Thalassemia patients experience increased mortality compared to the general population and can be significantly worse in non-regularly transfused than those who are regularly transfused. Patients endure high rates of morbidity and increased complications as they age. Adult patients with non-transfusion-dependent leukemia may actually have a similar or worse quality of life compared to transfusion-dependent patients. Of course, this burden of disease correlates to increased healthcare costs.
Sam: Alright.
Sam: Building on the foundational work, we have already done we continue to deepen the sophistication of our market understanding.
Sam: We are conducting extensive market research and claims data analysis to inform ACP targeting field force sizing and deployment for launch.
Sam: Second we will be rolling out a disease education campaign for both patients and clinicians.
Sam: Highlighting the long term complication and burden of disease across auto Lithemia subtypes.
Sam: Our disease education and engagement will also work to correct. The historical misperception that non transfusion dependent patients are less likely to experience debilitating long term effects of the leukemia.
Sveta Milanova: To address this, I met me, and galvanized by the positive data from the phase 3 energized study of metapilates, our commercial organization is actively preparing for a potential launch in Thalassemia next year, beginning with the U.S. In the U.S., there are approximately 6,000 diagnosed adult patients with thalassemia. Approximately 4,000 of these patients are non-transfusion dependent and have no available treatment options today; the remaining 2,000 patients are transfusion-dependent and have no oral treatment options.
Sam: To support these initiatives, we are establishing capabilities to enable execution of our educational efforts across personnel and non personnel channel.
Sam: Third we will continue to strengthen our commercial capabilities by expanding our sales team in anticipation of the lithium year launch.
Sam: <unk> the team for a broader rare disease.
Sam: And lastly in finally, we built effort we are preparing our market access team to engage with Baird on disease State education in advance of the potential launch into Lithemia next year.
Sveta Milanova: Our goal with MetaPilot is to address the unmet needs of all adults living with thalassemia and become the first therapy approved for all subtypes of the disease. In addition to the data we are generating through the MetaPIVOT clinical development program, there are three key factors we believe have the potential to support adoption of MetaPIVOT among thalassemia patients in the U.S. for There is strong alignment between where in the U.S. these patients reside and where they receive treatment. The map on slide 20 depicts patient prevalence overlaid with the Agios clinical trial site and or centers of excellence represented by the gold stars. Beckham, The diagnosis rate is high, driven by the availability of newborn screening and well-established ITD-10 codes. Therefore, many patients are diagnosed before adulthood. And finally, as shown on slide 21, there is a concentration of patients and providers at selected centers.
Sam: Our team has the same success in market access for PK deficiency, and we look forward to watching them paved the way in the leukemia too.
Sam: In addition to the well established U S. The lithium market. There are approximately 13000 patients in the EU five and approximately 70000 cell leukemia patients in the Gulf region.
Sam: We aim to maximize the potential of these additional markets.
Sam: Coordinated regulatory filing, which we intend to pursue with partners.
Sam: Taken together, we believe the potential launch of meter pivoting into leukemia represents a significant opportunity for audio and that forward as we prepare for potential backfill back launches with sickle cell disease in 2026.
Sam: Now let me provide an update on the current launch of vital signs in PK deficiency.
Sveta Milanova: Approximately 50% of all diagnosed patients are treated at fewer than 150 affiliated hematology oncology practices in the U.S., providing a clear focus for our initial launch. Given this market dynamic and viral time target product profile, we believe we are well positioned to provide a potential foundational treatment option for patients with thalassemia regardless of subtype. Therefore, our team is focused on four core areas of U.S. launch preparation for it.
Sam: In the fourth quarter of 2023 we generated $7 1 million in net vital kind revenue compared to $7 $4 million in the prior quarter.
Sam: A total of 178 patients have completed a prescription enrollment form including 18 in the fourth quarter of 2023, and 11% increase versus the third quarter.
Sam: This translated into a net 190 patients on therapy, a 9% increase versus the third quarter.
Sveta Milanova: Building on the foundational work we have already done, we continue to deepen the sophistication of our market understanding. We are conducting extensive market research and claims data analysis to inform ATP targeting, field force sizing, and deployment for launch. Second, we'll be rolling out a disease education campaign for both patients and clinicians, highlighting the long-term complications and burden of disease across all thalassemia subtypes. Our disease education engagement will also work to correct the historical misperception that non-transfusion-dependent patients are less likely to experience the debilitating long-term effects of thalassemia. To support these initiatives, we are establishing capabilities to enable the execution of our educational efforts across personal and non-personal channels.
Sam: Just on home therapies continue to spend from a growing and diverse prescriber base of 150 for physicians and represent a broad demographic and disease manifestation range that is consistent with the adult PK deficiency population.
Sam: We continue to be encouraged by the persistence of patients on treatment and remain focused on efficiently identify and sort of either likely to treat patients with PK deficiency.
Sam: The capabilities, we continue to build and expand through the current launch, including efficient targeting analytics patient awareness and education and patient access.
Sam: Provides a firm foundation from which we can maximize the potential U S launches in the leukemia in 2025 and in sickle cell disease in 2026.
Sveta Milanova: Third, we'll continue to strengthen our commercial capabilities by expanding our sales team in anticipation of the Thalassemia launch, right-sizing the team for a broader rare disease. And lastly, in parallel with those efforts, we are preparing our micro-access team to engage with payers on disease-safe education in advance of the potential launch into leukemia next year. Our team has achieved success in market access for PGA deficiency, and we look forward to watching them pave the way for Thalassemia 2. In addition to the well-established U.S. thalassemia market, there are approximately 13,000 patients in the EU5 and approximately 70,000 thalassemia patients in the Gulf region.
Sam: As we advance through this catalyst rich period of phase III data readout for <unk>, we look forward to dramatically expanding the number of patients we serve.
Sam: With that I will turn the call over to Cecilia.
Cecilia Jones: Thanks to better our fourth quarter 2023 financial results can be found in the press release, we issued this morning and more detail will be included in our 10-K, which will be filed later today.
Cecilia Jones: Let me now take a moment to provide some context and highlight a few key points.
Cecilia Jones: Full year 2020 to be net <unk> revenue was $26 $8 million compared with $11 $7 million in Paragon revenue for 2022.
Cecilia Jones: Q4, 2023, net <unk> revenue was $7 $1 million, a 4% reduction compared to the third quarter.
Sveta Milanova: We aim to maximize the potential of these additional markets through coordinated regulatory filing, which we intend to pursue with partners. Taken together, we believe the potential launch of Mikapivat into leukemia represents a significant opportunity for Agios and a step forward as we prepare for potential back-to-back launches with sickle cell disease in 2020. Now, let me provide an update on the current launch of pyrokines in PK deficient. In the fourth quarter of 2023, we generated $7.1 million in net spiral kind revenue, compared to $7.4 million in the prior quarter. A total of 178 patients have completed a prescription enrollment form, including 18 in the fourth quarter of 2023, an 11% increase versus the third quarter. This translated into net 109 patients on therapy, a 9% increase versus the third quarter.
Cecilia Jones: The reduction was driven by lower number of weeks on hand of inventory compared to where we ended Q3, partially offset by favorability in gross to net adjustments.
Cecilia Jones: As a reminder, we anticipate lower levels of inventory at any given time, given our limited distribution network, which consists of one specialty pharmacy and one specialty distributor.
Cecilia Jones: Insistent with other rare disease launches gross to net is expected to be in the 10% to 20% range on an annual basis.
Cecilia Jones: Based on our learnings to date given the.
Cecilia Jones: The nature of the disease and the long lead times associated with initiating patients on therapy, we continue to expect slow and steady growth and quarter to quarter variability in 2024 similar to what we saw in 2023.
Cecilia Jones: Cost of sales for the fourth quarter was zero point $6 million.
Cecilia Jones: R&D expenses were $77 million for the fourth quarter and $296 million for the full year 2020 city, an increase of $16 million compared to the full year 2022.
Sveta Milanova: Patients on Therapy continue to stem from a growing and diverse prescriber base of 154 physicians and represents a broad demographic and disease manifestation range that is consistent with the adult PK deficiency population. We continue to be encouraged by the persistency of patients on treatment and remain focused on efficiently identifying providers likely to treat patients with PK deficiency. The capabilities we continue to build and expand through the current launch, including efficient targeting analytics, patient awareness and education, and patient access, will provide a firm foundation from which we can maximize the potential U.S. launches in thalassemia in 2025 and in sickle cell disease in 2026. As we advance through this catalyst-rich period of phase three data readout for MetaPivot, we look forward to dramatically expanding the number of patients we serve.
Cecilia Jones: The changes reflect an increase in development cost for me to say that and the upfront payment associated with the license agreement with a nylon.
Cecilia Jones: All set by a reduction in expenses associated with the evolution of our research organization and the sale of our oncology business to Serbia.
Cecilia Jones: SG&A expenses were $35 million for the fourth quarter and $120 million for the full year 2020 to be a decrease of $2 million compared to the full year 2022.
Cecilia Jones: As a reminder, as part of the divestiture of our oncology business to Serbia, we retain rights to a potential 200 million dollar milestone upon FDA approval of <unk> and 15% royalties on potential U S net sales.
Cecilia Jones: So have you publicly communicated plans to file for approval before the end of 2023. So we are eager to track their progress.
Cecilia Jones: We ended the year with cash cash equivalents and marketable securities of approximately $806 million.
Sveta Milanova: With that, I will turn the call over to Cecilia. Thanks, Sveta. Our fourth quarter 2023 financial results can be found in the press release we issued this morning, and more detail will be included in our 10k, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Full year 2020 to be net Pyrokan revenue was $26.8 million dollars, compared with $11.7 million in Pyrokan revenue for 2022.
Cecilia Jones: We expect that this balance together with anticipated product revenue interest income and the potential for upside and they've milestone would enable the company to fund our operating expenses and capital expenditures through several value, creating milestones and at least into 2026. This guidance does not include cash.
Cecilia Jones: Inflows that could extend our runway beyond 2026, including the potential royalties or royalty monetization from the website and at commercializing Mr. Pivot outside of the U S through one or more partnerships or other potential strategic business of financial agreements.
Cecilia Jones: Q4 2023 Net Pyracat Revenue was $7.1 million, a 4% reduction compared to the third quarter. The reduction was driven by a lower number of weeks on hand of inventory compared to where we ended Q3, partially offset by favorability and growth to net adjustment. As a reminder, we anticipate low levels of inventory at any given time, given our limited distribution network, which consists of one specialty pharmacy and one specialty distributor. Consistent with other rare disease launches, growth to net is expected to be in the 10 to 20 percent range on an annual basis. Based on our learnings to date, given the ultra-rare nature of the disease and the long lead times associated with initiating patients on therapy, we continue to expect slow and steady growth and quarter-to-quarter variability in 2024, similar to what we saw in 2023. Cost of sales for the fourth quarter was $0.6 million.
Cecilia Jones: Main focus on creating shareholder value, including by proactively managing our cost base and deploying a disciplined capital allocation approach as we prepare to support potential future launches of Paragon.
Cecilia Jones: As we move toward additional potential value, creating milestones in the near term I am confident that our strong balance sheet will enable us to execute from a position of strength as we continue to pursue ways to create shareholder value.
Cecilia Jones: I will now turn the call back over to Brian for his closing remarks.
Brian M. Goff: Thanks, Cecilia as we turned the page on a highly productive 2023, we're focused on executing across the additional four phase III readouts for <unk> that we expect over the next two years beginning with the phase III energized T study in transfusion dependent thalassemia in the middle of this year.
Brian M. Goff: As we continue to stack successes positive data readouts for mid tier that we are only growing more confident in the probability of success ahead.
Brian M. Goff: We are well positioned with a differentiated mechanism of action that improves red blood cell health beyond hemoglobin increase.
Brian M. Goff: Allows us to pursue large commercial opportunities with substantial value and the potential for two additional first in class and best in class indications for <unk> as we build a multibillion dollar franchise in PK activation.
Cecilia Jones: R&D expenses were $77 million for the fourth quarter and $296 million for the full year 2023, an increase of $16 million compared to the full year 2022. These changes reflect an increase in development costs for MetaPivot and the upfront payment associated with the license agreement with Alnylam, offset by a reduction in expenses associated with the evolution of our research organization and the sale of our oncology business to service. SG&A expenses were $35 million for the fourth quarter and $120 million for the full year 2023, a decrease of $2 million compared to the full year 2022.
Brian M. Goff: As we continue to take steps towards realizing our vision of becoming a leading rare disease company. We will continue to strive to be responsible stewards of our balance sheet and evaluate meaningful opportunities for value creation.
Brian M. Goff: Finally, I'd like to thank all of our employees for their hard work and dedication to our mission of developing and delivering transformative medicines that elevate and extend the lives of patients living with rare diseases.
And all of our partners, including the patients physicians caregivers and participants in our clinical development programs.
Speaker Change: With that we will now open the call for questions.
Thank you.
Speaker Change: To ask a question you will need to press star one on your telephone to withdraw your question. Please press star one again, please wait for your name to be announced we ask that you. Please limit your questions to one and one follow up please standby, while we compile the Q&A roster one moment for your first question. Please.
Cecilia Jones: As a reminder, as part of the divestiture of our oncology business to Serbia, we retain rights to a potential $200 million milestone upon FDA approval of voracidinib and 15% royalties on potential U.S. net sales. surveyed publicly communicated plans to file for approval before the end of 2023, so we are eager to track their progress. We ended the year with cash, cash equivalents, and marketable securities of approximately $806 million.
Speaker Change: Our first question comes from the line of Eric Smith with Cantor Fitzgerald. Your line is now open.
Eric Schmidt: Well thanks for the question and congrats on all the recent development successes I guess, maybe one for Sara Gubins.
Eric Schmidt: Next milestone next few milestone at least might be the energized T study from it appeared that the transfusion dependent patients.
Cecilia Jones: We expect that this balance, together with anticipated product revenue, interest income, and the potential for a side-enabled milestone, would enable the company to fund its operating expenses and capital expenditures through several value-creating milestones and at least into 2026. This guidance does not include cash inflows that could extend a runway beyond 2026, including the potential royalties or royalty monetization from graph side in it, commercializing MetaPivot outside of the U.S. through one or more partnerships, or other potential strategic business or financial agreements. We remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach as we prepare to support potential future launches of Pyrex. As we move toward additional potential value-creating milestones in the near term, I am confident that our strong balance sheet will enable us to execute from a position of strength as we continue to pursue ways to create shareholder value.
Eric Schmidt: Can you give us a little bit of a preview here are setup with regard to the primary endpoint I know youre looking at transfusion reductions in a slightly different way than what we've been accustomed to seeing with the list Patterson data so how might that primary endpoint definition change.
Eric Schmidt: Changed the way, we view the data and what might the hurdle big.
Speaker Change: Great. Thanks, Eric Thanks, a lot for the question just before Sarah goes I just want to welcome you back to our Geos earnings calls so Sarah do you want to get started sure. Thanks. Thanks for the question. So indeed, our endpoint primary endpoint has a different definition than the primary end point that was sputter sip to use in the sense that we have.
Sarah: We're looking at a 50% reduction in any 12 week period Rolling period basically over the 48 weeks of patients are assessed which we believe is a more.
Sarah: Appropriate measure to assess a patient in the context of the dynamic disease over a longer stretch of time, and which reflects better the real world experience of patients may have.
Cecilia Jones: I will now turn the call back over to Brian for his closing remarks. Thanks, Cecilia. As we turn the page on a highly productive 2023, we're focused on executing across the additional four phase three readouts for midipivet that we expect over the next two years, beginning with the phase three ENERGIZE-T study in transfusion-dependent thalassemia in the middle of this year. As we continue to stack SUCCESS's positive data readouts for mid-to-pivot, we We're well-positioned with a differentiated mechanism of action that improves red blood cell health beyond hemoglobin increase and allows us to pursue large commercial opportunities with substantial value and the potential for two additional first-in-class and best-in-class indications for pyrokine as we build a multibillion-dollar franchise in PK activation.
Sarah: Hmm.
Sarah: We do have a similar end points like the luxe products at the primary endpoint in our secondary endpoints in regarding to the hurdles.
Sarah: It is it is a different endpoint indeed, the hurdle is not necessarily a different in the sense that you have multiple assessments period versus a fixed period in time, the bar of 50% of course is higher than 33%, but like I said, because it's every any 12 week periods you have more shots on goal.
Sarah: To speak this wasn't endpoint that we spud our stepped also having their assessment and in their review, but as it was not a prespecified.
Sarah: Primary or secondary analysis that did not.
Sarah: Make it into the label.
Speaker Change: Thank you very much.
Speaker Change: Thank you.
Speaker Change: Thank you one moment for our next question. Please.
Speaker Change: Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open.
Speaker Change: Thanks.
Chris Raymond: Maybe just a question on the energized data that we got last months.
Chris Raymond: We've gotten a few questions around from investors around.
Cecilia Jones: As we continue to take steps toward realizing our vision of becoming a leading rare disease company, we will continue to strive to be responsible stewards of our balance sheet and evaluate meaningful opportunities for value creation. Finally, I'd like to thank all of our employees for their hard work and dedication to our mission of developing and delivering transformative medicines that improve and extend the lives of patients living with rare diseases, and all of our partners, including patients, physicians, caregivers, and participants in our clinical development program. With that, we will now open the call for questions. Thank you. To ask a question, you'll need to press star 1-1 on your telephone.
Chris Raymond: Sort of a transition from the phase two data this to the phase III data.
Chris Raymond: There was a degradation in the hemoglobin response, but you measured these effects over different time points. I know you guys had said that there was no waning of efficacy over time, but maybe just square. This difference that you saw and then I've got a follow up.
Sure. Thanks for the question so Doug.
Doug: The primary endpoint that we're using a phase two was indeed different than the endpoint that we used in the phase three.
Speaker Change: Adding depth for the phase two we just looked at Ah patients meeting the hemoglobin response at a single time point for the phase III, we incorporated the duration in that endpoint over a longer stretch of time and measure it at a later time point, because it's a chronic disease.
Operator: To withdraw your question, please press star 1-1 again. Please wait for your name to be announced. We ask that you please limit your questions to one and one follow-up. Please stand by while we compile the Q&A roster. Our first question comes from the line of Eric Schmidt with Cantor Fitzgerald. Your line is now open.
Speaker Change: From our phase II perspective, you are truly looking for maintenance over a longer duration of time. So we averaged haemoglobin over 12 weeks versus that just single time point, which is much easier to reach at the bar.
Speaker Change: In regards to.
Eric Schmidt: Thanks for the question and congratulations on all the recent development successes. I guess maybe one for Sarah, given the next milestone, the next key milestone at least, might be the ENERGIZE-T study for imidapevent and transfusion-dependent patients. Can you give us a little bit of a preview here or an idea of the setting with regard to the primary endpoint?
Speaker Change: The waning, we don't see waning of our hemoglobin response, so when you're talking about in this trial, but he is very similarly to how it behaved in TKD. So once patients show a response they tend to maintain that response over time, there's always a little bit of fluctuation on the hemoglobin over time, but overall it stays up.
Speaker Change: Positive underlying kind of stays horizontal in comparison to their baseline. So we feel very confident with the results that we have observed an energized. In addition, it's more than hemoglobin alone that we observed we really saw an improvement on the fact that fatigue, there as well, which we believe is extremely meaningful because now we are.
Eric Schmidt: I know you're looking at transfusion reductions in a slightly different way than what we're accustomed to seeing with the LISPAT or CEP data. So how might that primary endpoint definition change the way we view the data, and what might the hurdle be?
Speaker Change: Adding to the hemoglobin plus story here.
Brian M. Goff: Eric, thanks a lot for the question. And before Sarah goes, I just want to welcome you back to Agios' earnings call. So, Sarah, do you want to get started?
Things that we've observed in PK Dean I'll also have been observed in the non transfusion dependent thalassemia population and that continues to add to this consistent and compelling data story that we are continuing to generate.
Okay. Thanks, and then maybe just a follow up to Eric's question on the.
Sarah Hewins: Sure. Thanks. Thanks for the question. So, indeed, our endpoint, our primary endpoint, has a different definition than the primary endpoint that Lospater said to use, in the sense that we are looking at a 50% reduction in any 12-week period, rolling period, basically, over the 48 weeks that patients are assessed, which we believe is a more appropriate measure to assess a patient in the context of a dynamic disease over a longer stretch of time and which better We do have a similar endpoint, like Lospater said, the primary endpoint in our secondary endpoint. Regarding the hurdle...
Speaker Change: The success bogie of Energize T.
Speaker Change: And I know you're talking about different measures, it's not an apples to apples comparison that was patterson, but just.
Speaker Change: And just as you're thinking about.
Speaker Change: The obvious difference.
Speaker Change: Mid tier that is oral versus loose powder stuff, which is not just maybe talk in generalities. How you see these these two.
Speaker Change: Compound sort of co existing commercially.
Sure.
Speaker Change: So if we think about the non transfusion dependent thalassemia patient population that currently have no therapy available so that is.
Speaker Change: We talked about.
Speaker Change: If we get it through the next stages of development will be a therapy that it would be available for non transfusion dependent patient populations and his oral <unk>, which is a huge benefit specifically for that population because patients aren't going to clinic as frequently and if you have them.
Sarah Hewins: It is a different endpoint indeed, but the hurdle is not necessarily different in the sense that you have multiple assessment periods versus a fixed period in time. The bar of 50%, of course, is higher than 33%.
Speaker Change: Drugs that require three credits clinic visits that adds to the burden of disease typically for the transfusion dependent patient population there is indeed a subcutaneous.
Sarah Hewins: But like I said, because it's any 12-week period, you have more of a chanson goal, as to speak. This was an endpoint that Sputtercept also had in their assessment and in their review, but as it was not a pre-specified primary or secondary analysis, it did not make it into the label.
Speaker Change: Product available for it.
Speaker Change: Transfusion dependent beta thalassemia patients our program.
I have studied.
Speaker Change: Oh genotype <unk>. So that's one difference the oral route of administration here is very relevant because it.
Sarah Hewins: Thank you very much. Thank you. Thank you. One moment for our next question, please. Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open.
Speaker Change: Allowed for almost seamless incorporation into a transfusion schedule benefit patients may have versus requiring more visits on stop some of the transfusion as scheduled.
Christopher Joseph Raymond: Thanks. Maybe just a question on the ENERGIZE data that we got last month. We've gotten a few questions from investors around the sort of transition from the Phase 2 data to the Phase 3 data. You know, there was a degradation in the hemoglobin response, but you measured these effects over different time points. I know you guys said that there was no waning of efficacy over time, but maybe just square this difference that you saw. And I've got a follow-up. Sure, thanks for the question. So the answer is...
Speaker Change: And that says it's also important to understand there is a very different mechanism of action between those two products.
Speaker Change: Which is part of it.
Speaker Change: Stimulate red blood cell stimulator, while they talk about it.
Speaker Change: Trying to improve red blood cell health overall, and so we do think from that perspective.
Speaker Change: There they are vastly different.
Speaker Change: Yes, Chris I mean that last point is the one that I would just emphasize is that I know folks are trying to make comparisons but in so many ways theyre in comparable because of the profound difference in the mechanisms.
Sarah Hewins: The primary endpoint that we used in Phase 2 was indeed different than the endpoint that we used in Phase 3, meaning that for the Phase 2, we just looked at patients meeting a hemoglobin response at a single time point, and for the Phase 3, we incorporated duration into that endpoint over a longer stretch of time and measured it at a later time point because it's a chronic disease. So then from a Phase 2 perspective, you're truly looking for maintenance over a longer duration of time. So we averaged hemoglobin over 12 weeks versus that just single time point, which is much easier to reach as a bar.
Speaker Change: You'll hear a lot from us because we continue to be emboldened by this by the data that we see very consistently that the benefits of power of pyruvate kinase activation really do go beyond hemoglobin.
Speaker Change: So we'll await the data. Unfortunately, we don't have to wait that long energized T is coming mid year.
Speaker Change: But I think above oral and the other dimensions hemoglobin and the like that's really the big headline for this mechanism is it's ultimately about red blood cell health.
Speaker Change: Thank you.
Speaker Change: Moment for our next question.
Speaker Change: Our next question comes from the line of Danielle Brill with Raymond James Your line is now open.
Danielle Brill: Hey, guys. Good morning, Thanks, so much for the questions.
Danielle Brill: I also have a question on powering assumptions for <unk> T.
Sarah Hewins: Regarding the waning, we don't see waning of our hemoglobin response. So metapivus in this trial behaves very similarly to how it behaves in PKD. So once patients show a response, they tend to maintain that response over time. There's always a little bit of fluctuation in the hemoglobin over time, but overall, it stays positive, and the line kind of stays horizontal in comparison to their baseline.
Danielle Brill: Like Chris said, we know, it's not apples to apples, but when you look at with patterns that they're mean hemoglobin increase is about one and a half grams and they achieved I think around a 40% response rate on your primary end point with this context, what are your internal expectations for how that will perform.
Speaker Change: Also I have a follow up.
Thanks for the question. So in regards to our borrowing assumptions, we haven't spoken about piece, but we have of course studied all of the progress in front of US which includes our own internal programs in which we took a very similar development approach for thalassemia as we had for our P. J D.
Brian M. Goff: So we feel very confident with the results that we have observed in ENERGYSE. In addition, it's more than hemoglobin alone that we are looking at. We really saw an improvement in facet fatigue there as well, which we believe is extremely meaningful because now we are adding to the hemoglobin plus story here. The things that we've observed in PKD have also been observed in the non-transfusion-dependent thalassemia population, and that continues to add to this consistent and compelling data story that we are continuing to generate. Okay, thanks. And then maybe just a follow-up to Eric's question on the success bogeyman of Energize T. I know you're talking about different measures. It's not an apples-to-apples comparison to loose Patercep, but just as you're thinking about the obvious difference, you know, admitted to that is oral versus loose Patercep, which is not, just maybe talk in generalities about how you see these two compounds sort of coexisting commercially.
Speaker Change: In regards to the hemoglobin increase that you mentioned.
Speaker Change: So we don't from a transfusion dependent perspective, we don't believe you necessarily need to increase hemoglobin on top of making transfer.
Speaker Change: People reduce their transfusions this is truly.
Speaker Change: A different approach because people when they get dress shoes their hemoglobin goes down over time. So what we're trying to do here is basically avoiding that people their hemoglobin decreases back to a transfusion trigger, which then would trigger a transfusion and it comes down again to that different mechanism of action. If you were like stimulating out red blood cells.
Speaker Change: Honestly, you're going to increase hemoglobin versus where we were trying to do about keeping the red blood cells, happier and healthier, thereby reducing hemolysis, it's a completely different way of actually trying to avoid transfusions.
Brian M. Goff: Sure. But if we think about the non-transfusion dependent thalassemia patient population, they currently have no therapy available. So that which is metastasized, if we get it through the next stages of development, would be the therapy that would be available for non-transfusion dependent patient populations. And it's oral, indeed, which is a huge benefit specifically for that population because patients aren't going to the clinic as frequently. And if you have a drug that requires frequent clinic visits, that adds to the burden of. For the transfusion-dependent patient population, there is indeed a subcutaneous Lispatocept available for Transfusion Dependent Beta Thalassemia Patients. Our program has studied all genotypes of thalassemia. So that's one difference. The oral route of administration here is very relevant because it allows for almost a seamless incorporation into a transfusion schedule that a patient may have versus requiring more visits on top of the transfusion schedule. In that sense, it's also important to understand there's a very different mechanism of action between those two products, which, you know, Luciferacept is a stimulator, a red blood cell stimulator, while Metaptivap is trying to improve red blood cell health overall.
Speaker Change: Thanks, that's helpful and that actually is a perfect segue for my follow up do you have data on.
Speaker Change: <unk>.
Speaker Change: The potential of Medicare that for extending the half life of healthy red blood cells.
Speaker Change: So we.
Speaker Change: In the context of you mean.
Speaker Change: The volunteers red blood cells.
Speaker Change: Or like extending the lifespan of transfused blood.
Speaker Change: So yeah. So this is something that is extremely difficult to.
Speaker Change: To measure in the context of a transfusion setting as everything is kind of mixed.
Speaker Change: So it would require a very.
Speaker Change: Very.
Speaker Change: Unique spirit to be able to park those types of red blood cells that are available. So we're not planning on doing that right now for transfusion dependent patients.
Speaker Change: Got it thanks, Thanks again for the questions.
Speaker Change: Yes. Thank you.
Speaker Change: And our next question comes from the line of Gregory <unk> with RBC capital markets. Your line is now open.
Gregory: Hey, good morning, Brian and team Congrats on all the progress and thanks for taking my questions.
Gregory: Brian just certainly speak to the multibillion dollar opportunity available with PK activation and your portfolio. Just curious if you could maybe just elaborate a little bit on that and maybe provide some of the inputs or assumptions that youre using.
Gregory: Using too.
Gregory: To get to that characteristic whether it's worth with respect to mid a pivot in the ramp of indications or the broader portfolio and maybe I'll just layer and my second question, which.
Gregory: With respect to the landscape and PK activation, perhaps have you and Sarah can just riff a little bit about maybe the differences with <unk> versus other especially at a tap or have been certainly you've mentioned that the lead you have the body of data, but when you think about some of the nuances on Panther activation or even a selectivity maybe just help.
Brian M. Goff: And so we do think from that perspective, they're vastly different. Yeah, and Chris, I mean, that last point is the one that I would just emphasize is that I know folks are trying to make comparisons, but in so many ways, they're incomparable because of the profound difference in the mechanisms. And you'll hear a lot from us because we continue to be emboldened by the data that we see very consistently that the benefits of pyruvate kinase activation really do go beyond hemoglobin. So we'll await the data. Fortunately, we don't have to wait that long. Energize T is coming mid-year.
Gregory: US understand the differences between.
Speaker Change: A pivot in the landscape. Thanks, so much.
Speaker Change: Yes, Thanks, Greg.
Speaker Change: Get started on your first question about the multibillion dollar opportunity.
Speaker Change: Opportunities that I referenced in my prepared comments that really comes from the fact that we're rapidly progressing in our pipeline moving from clear ultra rare with PK D.
Speaker Change: Into successively larger prevalent diseases.
Speaker Change: Some of those diseases I think are.
Speaker Change: A well characterized in terms of opportunity sickle cell for sure over Theres been a lot of interest and a lot of therapeutic development focus.
Speaker Change: And here, we're talking about moving from three to 8000 patients across.
Danielle Brill: But I think above oral and the other dimensions, hemoglobin and the like, that's really the big headline for this mechanism, that it's ultimately about red blood cell health. Thank you. One moment for our next question. Our next question comes from the line of Danielle Brill with Raymond James. Your line is now open.
Speaker Change: The U S and EU five in the case of TKD jumping to just in the U S alone 100000 patients with sickle cell disease, but it's more than that I mean as we've already discussed. This morning, we have this really exciting opportunity.
Speaker Change: Relatively near term with a potential launch next year in thalassemia, which has a prevalence step up in the case of the U S from TKD sickle cell I, just mentioned and then even after that with our other PK activator AG 946, moving into low risk Mds.
Danielle Brill: Hi guys, good morning. Thanks so much for the questions. I also have a question on the powering assumptions for energized tea.
Danielle Brill: Like Chris said, we know it's not apples to apples, but when you look at Lispatercept, their mean hemoglobin increase was about 1 12 grams, and they achieved, I think, around a 40% response rate on your primary endpoint. With this in mind, what are your internal expectations for how Medipivat will perform? And then I also have a follow-up.
Speaker Change: The Great news about all this is we're moving in the right direction in terms of prevalence.
Speaker Change: And that is allowing us to enter into very compelling commercial opportunities.
Speaker Change: And it also allows us to navigate through the appropriate pricing dynamics as we go forward, but we're very excited most importantly, with the fact that as we advance our pipeline and as we've already noted we have two back to back launched potentials with thalassemia next year, followed by sickle cell disease in 2002.
Sarah Hewins: Thanks for the question. Regarding our powering assumptions, we haven't spoken about these, but we have, of course, studied all of the programs in front of us, which includes our own internal programs in which we took a very similar development approach for Thalassemia as we have for PKD, in regards to the hemoglobin increase that you mentioned. So we don't, from a transfusion-dependent perspective, we don't believe you necessarily need to increase hemoglobin on top of making people reduce their transfusions.
Speaker Change: Six.
Speaker Change: And then sorry, you want to pick up for the next question sure.
Speaker Change: So in regards to PK activation and the differences between Mitch talked about there's some other PK activator. So.
Speaker Change: We indeed.
Speaker Change: We stimulate PK different ticket ISO enzymes, amongst which the PK R, which is important for the Red blood cell. But then also became too it's important that we understand more and more of their relevance.
Sarah Hewins: This is truly a different approach because people, when they get transfused, their hemoglobin goes down over time. So what we are trying to do here is basically avoiding that people's hemoglobin decreases back to a transfusion trigger, which then would trigger a transfusion. And it comes down again to that different mechanism of action. If you stimulate red blood cells, ultimately you're going to increase hemoglobin versus what we're trying to do about keeping the red blood cells happier and healthier, thereby reducing hemolysis.
Speaker Change: The relevance of the specific isoenzyme in the context of the diseases that we are studying.
Speaker Change: As you know thalassemia sickle cell disease Mds, there is different components to these diseases in which a stimulation of became too maybe relevant.
Speaker Change: It is expressed in.
Speaker Change: Immature red blood cells. It is expressed in other tissues that are also touched by these diseases. We are planning to further study this clinically as well specifically in sickle cell disease in the kidney.
Speaker Change: No kidney is such an important organ in the context of sickle cell disease and there are many patients suffer from kidney disease and we believe that became too may have an added advantage. There in regards to how that compares to other PK activator, specifically about that is there.
Sarah Hewins: It's a completely different way of actually trying to avoid transfusion. Thanks, Sarah, that's helpful. And that actually is a perfect segue for my follow-up question. Do you have data on the potential of midipivet for extending the half-life of healthy red blood cells? So we. In the context of, you mean...
Speaker Change: This is the drug that.
Speaker Change: He used to be formats drug they always spoke about being a PK or selective HMT regards to holiday.
Speaker Change: Translate into other enzymes enzymes, they have not spoken about it that they have just highlighted that their selectivity message.
Sarah Hewins: Healthy Volunteers Red Blood Cells, or like, yeah, extending the lifespan of transfused blood. So yeah, so this is something that is extremely difficult to measure in the context of a transfusion setting as everything is kind of mixed together. So it would require a very, very unique experiment to be able to tease apart those types of red blood cells that are available. So we're not planning on doing that right now for a transfusion-dependent patient. I got it.
Speaker Change: Thank you.
Our next question comes from the line of Shelving Richter with Goldman Sachs. Your line is now open.
Salveen Richter: Hi, This is lidia on resolving thanks, so much for taking our question just one on sickle cell could you just discuss where you see power kind of fitting into the current commercial landscape just broadly.
Salveen Richter: And then can you also speak to the commercial or the enrollment progression and any physician feedback you've gotten so far thanks so much.
Danielle Brill: Thanks. Thanks again for the question. Thank you. And our next question comes from the line of Gregory Rinza with RBC Capital Markets. Your line is now open.
Speaker Change: Sure and maybe.
Speaker Change: I will just start and then quickly turn it over to Sarah and then Sarah can pick up on.
Gregory Rinza: Hey, good morning, Brian and team. Congratulations on all the progress and thanks. Brian, you certainly speak to the multi-billion dollar opportunity available with PKF. I'm just curious if you could maybe just elaborate a little bit on that, maybe provide some of the inputs or assumptions that you... The Bulletproof Executive 2013, to get to that characteristic, to submit a pivot in the Ramp of Indications or the broader portfolio, and maybe I'll just layer in my second question, with respect to the landscape and Perhaps Vivian and Sarah can just riff a little bit about maybe the differences with MetaPIVN versus others, especially TabaPIVN. Certainly, you've mentioned the lead, you have the body of data, but when you think about some of the nuances. Captivation, and others.
Sarah: The enrollment aspects I mean, the fundamental premise of what we're driving towards with sickle cell disease. As we believe that mid tier that pirate <unk> has the potential to be what we refer to as foundational therapy. This is a very different mechanism of action as we've talked about very unique.
Sarah: From currently available options we're increasingly.
Sarah: Convinced that the benefits on making the red blood cells healthier really position it as such.
Speaker Change: And then the fact that this is an oral treatment only adds to that potential, but I'll, let <unk> speak a little bit more about.
Speaker Change: Not just how we're thinking about sickle cell disease, but the bridge as we go from PK data.
Speaker Change: Dallas EMEA and then the sickle cell.
Dallas: Thanks, Brian.
Speaker Change: Ill start with sickle cell disease for us, but as you said, we have a very important milestone with the Palestinian launch ahead of that which we believe will be.
Speaker Change: Unimportant from growing the commercial capabilities executing under the Lithemia launched and offered us capitalizing on obviously hotel disease.
Brian M. Goff: Thank you all. Yeah, thanks Greg. So I'll get started on your first question about the multi-billion dollar opportunity or opportunities that I referenced in my prepared comments.
Speaker Change: When we think about sickle cell disease, Brian mentioned, I mentioned that already the prevalence of the disease is a 100000 patients in the U S, which is a significant step up from where we are today with PK deficiency is a disease, where patients are diagnosed and the burden of disease is well characterized.
Brian M. Goff: You know, that really comes from the fact that we're rapidly progressing in our pipeline, moving from clear ultra-rare diseases like PKD into successively larger prevalent diseases. Some of those diseases, I think, are... are well-characterized in terms of opportunity. Sickle Cell, for sure, where there's been a lot of interest and a lot of therapeutic development focus. And here we're talking about moving from, you know, 3,000 to 8,000 patients across the U.S. and EU5 in the case of PKD, jumping to just in the U.S. alone, 100,000 patients with sickle cell disease. But it's more than that.
Speaker Change: At the moment the adult patient population with sickle cell disease has very limited treatment options available they are either improving hemoglobin levels, which is the case.
Speaker Change: Or improving do you see is based on the phase two data and the target product profile, we have clarified our recon for launch we believe that we will be very well positioned with viral kind to provide that treatment option, which will bring benefits to physicians patients and payers as.
Brian M. Goff: I mean, as we've already discussed this morning, we had this really exciting opportunity. Relatively near term, with a potential launch next year in thalassemia, which is a step up in the case of the U.S. from PKD, sickle cell, as I just mentioned, and then even after that with our other PK activator, AG946, moving into low-risk MDS. The great news about all this is we're moving in the right direction in terms of prevalence. And that is allowing us to enter into very compelling commercial opportunities, and it also allows us to navigate through the appropriate pricing dynamics as we go forward. But we are very excited, most importantly, about the fact that as we advance our pipeline, and as we've already noted, we have two back-to-back launch potentials for thalassemia next year, followed by sickle cell disease in 2026.
Speaker Change: Well by improving hemoglobin <unk> C and ultimately improving the patients feel and function and that's going to be a unique value proposition. If we were to deliver on that profile. So we're very excited about that opportunity to.
Speaker Change: To come but before when we get to sickle cell disease.
Speaker Change: And we are very excited to progress with our launch preparation or lithemia as well.
Speaker Change: After we saw the results from the NR giant data in the year, we have definitely pressed the button.
As it relates to bearing fruit the lithemia launch to come in 2025 senior to sickle cell disease, I think that the lithemia launch will be meaningfully differentiated in terms of market characteristics compared to <unk> and then it will position us well for adoption of cytokine assuming approval in 2025.
Brian M. Goff: And then, Sarah, you want to pick up with the next question? Sure. So, in regards to PK activation and the differences between Miltapivas and some other PK activators, so... We indeed, while we stimulate PK, different PK isoenzymes amongst which the PKR, which is important for the red blood cell, but then also PKM2 is important, and we understand more and more the relevance of this specific isoenzyme in the context of the diseases that we are studying. As you know, thalassemia, sickle cell disease, MDS, there is different components to these diseases in which stimulation of PKM2 may be relevant, as it is expressed in. Immature Red Blood Cells.
Speaker Change: Including again these patients are diagnosed at 6000 diagnosed patients in the U S with the leukemia, and a well established ICD 10 codes.
Speaker Change: A stronger concentration of the prescriber base and all of its elements gives us confidence on our ability to commercialize.
Speaker Change: The product and drive adoption at launch.
Speaker Change: And similar to sickle cell disease, there is a better understanding of the lithemia unmet needs.
Speaker Change: The transfusion dependent.
Transfusion dependent patients as well so we are gearing up and getting ready for commercial organizations to go launch into lithium in 2025 actually followed by backfill that launches in sickle cell disease.
Sarah Hewins: It is expressed in other tissues that are also touched by these diseases. We are planning to further study this clinically as well, specifically in sickle cell disease in the kidney. As we know, the kidney is such an important organ in the context of sickle cell disease and that many patients suffer from kidney disease, and we believe that PKM2 may have an added advantage there. In regards to how that compares to other PK activators, specifically ethargopifa, this is the drug that used to be Phorma's drug. They have always spoken about being a PKR-selective agent in regards to how they translate into other isoenzymes. But they have not spoken about that.
Speaker Change: Okay.
Speaker Change: I was just going to say, that's great set and I think everybody can sense, our excitement about what.
Speaker Change: What we have in front of us and I was just going to ask Sarah to make a comment about the progress with the rise up phase III for sickle cell exactly because we are equally excited to move towards those launches. So we are heavily focused on our phase III.
Speaker Change: Enrollment of course right now.
Speaker Change: Sure.
Sarah: The trial is progressing and we are anticipating theres a lot of office you have both within our teams and of course on the by the investigators as well and so everything is on track to deliver it to the milestone that we have set out for this year.
Sarah Hewins: They have just highlighted their selectivity. Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Thank you so much.
Speaker Change: Thanks, Steve.
Speaker Change: Our next question comes from the line of Tessa Romero with Jpmorgan. Your line is now open.
Tessa Romero: Great Good morning, Brian and team. Thank you for taking our question So sure thing Gary.
Salveen Richter: Hi, this is Lydia on behalf of Salveen. Thanks so much for taking our question. Just one on sickle cell. Could you just discuss where you see pyrokine fitting into the current commercial landscape, just broadly? And then can you also speak to the enrollment progression and any physician feedback you've gotten so far?
Tessa Romero: Debt to commercial TKD.
Tessa Romero: Do you still think that PK D could be at 200 $250 million peak opportunity here in the U S.
Tessa Romero: And if so how long do you think it could take you to get there and then my second question is.
We know that you're moving <unk> forward in lower risk Mds, well, we were curious.
Have you formulary deprioritize the program in sickle cell disease is we haven't heard anything on this in a while.
Brian M. Goff: Sure, and maybe I will just start and then quickly turn it over to Sveta, and then Sarah can pick up on the enrollment aspects. I mean, the fundamental premise of what we're driving towards with sickle cell disease is that we believe that midipivate pyrokine has the potential to be what we refer to as foundational therapy. This is a very different mechanism of action, as we've talked about, very unique from currently available options. We're increasingly convinced that the benefits of making the red blood cells healthier really position it as such. And then the fact that this is an oral treatment only adds to that potential.
Tessa Romero: Can you confirm if that's the case or not.
Speaker Change: Thanks, so much for taking our questions.
Speaker Change: Thanks, a lot test actually the second question, we can handle that very quickly, which is no and we have not de prioritized.
Speaker Change: Anything with $89 six I think we are inspired by the potential and at the right time, we will provide updates about the progress not just.
Speaker Change: In our pursuits of low risk Mds, but also where we stand with respect to sickle cell disease. So it's really if you want to comment on the first one yes sure. Thanks, that's all the questions. So we definitely remain excited about the opportunity in P. J D and we continue to expect those peak sales at 200 to 225 million for the U S. We continued to make progress each quarter.
Brian M. Goff: But I'll let Sveta speak a little bit more about not just how we're thinking about sickle cell disease but the bridge as we go from PKD to thalassemia and then to sickle cell anemia. Thanks, Brian.
Speaker Change: And we're learning in a furniture that is helping also baked those capabilities for that launch and we think it's going to be slow and steady continuing to see the trends we've seen in 2023 for the next few years, but we just stick.
Sveta Milanova: I'll start with sickle cell disease first, but as you said, we have a very important milestone with the thalassemia launch ahead of that, which we believe will be an important point from growing the commercial capabilities, executing on the thalassemia launch, and after that, capitalizing on sickle cell disease. When we think about sickle cell disease, Brian mentioned that, and Sarah mentioned that already, the prevalence of the disease is 100,000 patients in the US, which is a significant step up from where we are today with TK deficiency. It's a disease where patients are diagnosed, and the burden of disease is well characterized. At the moment, the adult patient population with sickle cell disease has very limited treatment options available. They are either improving hemoglobin levels, which is the case with Brita, or improving VOCs.
Speaker Change: Maintain our peak of 225, yes.
Speaker Change: PK D and we've talked about this previously but.
Speaker Change: In the deep commercial experience that looks better than I have across multiple rare disease launches. This one stop it's a challenge it is ultra rare.
Speaker Change: Diagnostics intensive.
Speaker Change: There's long lead times for patients so slow and steady is the right phrase what we're continue to be inspired by each quarter is that persistency, which is something we saw relatively early with the launch of <unk> in PK D.
Speaker Change: That is a really important feature as we think about chronic rare disease launches to come that are in our sights.
Speaker Change: So we will we'll take the slow and steady path and we're going to continue to expect that going forward, but the way pirate China's performing is what we believe really puts us in a position of strength as we approach energize, sorry, I keep seeing energized as we approach that with <unk>.
Sveta Milanova: Based on the phase two data and the target product profile we have for pyrokines for launch, we believe that we'll be very well positioned with pyrokines to provide a treatment option that will bring benefits to physicians, patients, and ultimately payers as well by improving hemoglobin, reducing VOCs, and ultimately improving the way patients feel and function. And that's gonna be a unique value proposition if we were to deliver on that So we are very excited about that opportunity to come. But before we get to sickle cell disease, we are actually very excited to progress with our launch preparation for thalassemia as well. After we saw the results from the ENERGIZE data this year, we have definitely pressed the button and are actively preparing for the thalassemia launch in 2025.
Speaker Change: As well as sickle cell beyond that.
Speaker Change: Okay. Thanks, so much for taking my questions you bet. Thanks, a lot. Thank you.
Speaker Change: Our next question comes from the line of Greg Harrison with Bank of America. Your line is now open.
Greg Harrison: Hey, good morning, Thanks for taking the question.
Greg Harrison: Also just wanted to follow up on AG 946.
Greg Harrison: How are you thinking just generally and development.
Development and potentially overlapping indications.
Greg Harrison: With <unk> there could be improvements.
Greg Harrison: For example, in sickle cell I can discuss store or even a female.
Greg Harrison: And what would you need to see from 94 six in order to make that decision.
Speaker Change: Yeah, I'll start and then Sarah can jump in.
Sarah: First of all Greg I hope, we're in that position, where we have multiple indications just as we have right now with <unk>.
Sarah: <unk> one of the key advantages of <unk>, having really a leading PK activation franchises, we have not one but.
Sveta Milanova: Similar to sickle cell disease, I think the thalassemia launch will be meaningfully differentiated in terms of market characteristics compared to PKD, and that will position us well for adoption of pyrokines, assuming approval in 2025, including, again, these patients are diagnosed. It has 6,000 diagnosed patients in the US with thalassemia, a well-established ICD-10 cause, a stronger concentration of the prescriber base, and all of these elements give us confidence in our ability to commercialize the product and drive adoption at launch. And similar to sickle cell disease, there is a better understanding of the thalassemia and medical needs across both the transfusion-dependent and non-transfusion-dependent patients as well.
Sarah: Two products that we're developing.
Sarah: And that allows us to have different economics different pricing dynamics across the indications in between the products.
Sarah: There is a wide enough space for US right now given where we are in the development program with AG 946 that we can tailor the appropriate target product profiles, whether it's for sickle cell disease or for low risk Mds.
Sarah: And in the case of low risk Mds.
Sarah: I think folks know.
Sarah: We just reported out last year are very encouraging.
Sarah: Proof of concept from our Phase Iia study and we're in the process right now of making enhancements in the design. So we can pursue phase two b I feel very good about the work the team has done and that'll be the next step and as I mentioned before at the right time, We'll also report out the progress on sickle cell disease anything you want to answer.
Brian M. Goff: So we are gearing up and getting ready for the commercial organization to go, launching thalassemia in 2025, potentially, followed by back-to-back launches in sickle cell disease in 2026. I was just going to say, that's great, Sveta, and I think everybody can sense our excitement about what we have in front of us, and I was just going to ask Sarah to make a comment about the progress with Rise Up Phase 3 for Sickle Cell. Exactly, because we're equally excited to move towards those launches, so we are heavily focused on our Phase 3 enrollment, of course, right now. The trial is progressing as we are anticipating. There's a lot of enthusiasm both within our teams and, of course, by the investigators as well. And so everything is on track to deliver on the milestone that we have set out for this year. Thank you so much.
Sarah: Just high level I think what you can expect from development is that we always strive to design our trials to meet multiple stakeholders their needs, meaning we take our target product profile very seriously. So that is something that for a 96 is the same figure out very seriously.
Sarah: We incorporate.
Sarah: Will it be incorporating patient voice into regular regulatory feedback obviously as well.
Sarah: Great example of that is in the case of sickle cell disease, a point that we're very proud of at <unk>.
Sarah: We have deeply involved the community and in fact, Sara and I attended the conference last year, where we won an award from the community about how carefully and thoughtfully, we involved sickle cell disease Warriors.
Tess Romero: Thank you. Our next question comes from the line of Tess Romero with J.P. Morgan. Your line is now open.
Sarah: And caregivers in how we think about designing the trials recruiting for the trials and ultimately what the commercial profile should look like.
Tess Romero: Great. Good morning, Brian and team. Thank you for taking our question. So a little bit about commercializing PKD. Do you still think that PKD could be a 200 to 250 million peak opportunity here in the US? And if so, how long do you think it could take you to get there?
Sarah: And we'll do the same thing with AG 946.
Speaker Change: Great. Thanks for taking the question.
Speaker Change: You bet. Thanks, Thank you.
Speaker Change: And our last question will come from the line of Devin Ryan with TD Cowen. Your line is now open.
Devin Ryan: Hi, guys. This is David on for Mark. Thanks for taking my questions I have two kind of follow up questions. One on Eric's question earlier.
Tess Romero: And then my second question is: We know that you're moving AG946 forward in lower-risk MDS, but we were curious, have you formally deprioritized the program in sickle cell disease as we hadn't heard anything on this in a while? Can you confirm if that's the case or not?
David: Was there a difference in the primary endpoint between Mad men and put that in.
David: Ruth Cotter sets for that transfusion dependent patients something that was recommended to you by regulatory authorities or was it more of an internal choice and then my second question is turning to their desire for things to be in Mds.
Brian M. Goff: Thanks so much for taking our question. Thanks a lot, Tess. Actually, the second question, we can handle that very quickly, which is no, and we have not deprioritized. Anything with AG946, I think we're inspired by the potential, and at the right time, you know, we'll provide updates about the progress, not just in our pursuits of low-risk MDS but also where we stand with respect to sickle cell disease. Cecilia, do you want to comment on the first one? Yeah, sure. Thanks, that's a good question.
David: Do you plan to test multiple dose levels of <unk>, six and any color on the enrollment criteria versus what Rob was so hot in the commands trial would be would be great. Thank you.
Speaker Change: Awesome. Thank you. Thanks, Steve Yeah. So in regards to the first question primary endpoints, yes, Indeed, we do.
Speaker Change: Mentioned on the previous question as well we do.
Speaker Change: Our development in collaboration with regular regulator. So we take feedback from the regulators are very seriously and try to.
Cecilia Jones: So we definitely remain excited about the opportunity in peak AD, and we continue to expect those peak sales at 200 to 225 million for the U.S. We continue to make progress each quarter, and we're learning, and as Fela said, this is helping us also build those capabilities for cell launch. We think it's going to be slow and steady, continuing to see the trends we've seen in 2023 for the next few years, but we do still maintain our peak of 200 to 225. Yeah, I mean, I've been with PKD, and we've talked about this previously, but in the deep commercial experience that both Sveta and I have across multiple rare disease launches, this one's tough. It's It's a challenge. It is ultra rare.
Speaker Change: Really incorporate the feedback as best as we can and.
Speaker Change: And so that's how we ended up settling for the 50% endpoints in and our Rolling 12 week period interval, which we indeed truly believe is a more dynamic endpoint and really reflect the real world experience of our patients. So this is where it's always.
Speaker Change: Very good.
Speaker Change: And we're always very grateful to be able to have those conversations because I do think.
Speaker Change: Incorporating feedback from multiple stakeholders.
Speaker Change: Always leads to better design choices so.
Speaker Change: So that's that on the primary endpoint and then in regards to your question for Mds Phase two b, yes, the phase II B is indeed.
Brian M. Goff: It's diagnostically intensive, and there are long lead times for patients. So slow and steady is the right phrase.
Speaker Change: <unk>.
Speaker Change: Multiple doses that we are testing, we are going to test higher doses than we originally anticipated just because we have learned from our phase Iia that Mds patients overall have lower exposure to same amount of drug that other other patient populations in healthy volunteer.
Brian M. Goff: What will continue to be inspired by each quarter is that persistency, which is something we saw relatively early with the launch of pyrokine and PKD, that is a really important feature as we think about chronic rare disease launches to come that are in our site. And so we'll, you know, we'll take the slow and steady path, and we're going to continue to expect that going forward. But the way pyrokine is performing is what we believe really puts us in a position of strength as we approach energized. Sorry, I keep saying energized as we approach thalassemia, as well as sickle cell beyond that. Okay, thanks so much for taking our questions. You bet. Thanks a lot.
Speaker Change: So we are incorporating those learnings into our phase two b and in regards to our inclusion criteria we have not.
Speaker Change: Yeah.
Speaker Change: You know as we Havent presented a trial in progress poster or anything like that yet, but you can expect that population to be relatively similar to how our population was in the phase Iia. However, we will be focusing on transfusion patients with transfusion burden.
Greg Harrison: Thank you. Our next question comes from the line of Greg Harrison with Bank of America. Hey, good morning.
Speaker Change: It will also be abroad are brought into this population just like we allowed into two way and we're not.
Greg Harrison: Thanks for taking the question. Also, just wanted to follow up on AG946. How are you thinking, just generally, about development and potentially overlapping indications with mid-epithetics, there could be improvement. And, you know, for example, in sickle cell, like you've discussed, or, or even thalassemia. And what would you need to see from 946 in order to make that decision?
Speaker Change: Excluding for say a population like specific mutations.
Speaker Change: Like that.
Speaker Change: Okay.
Speaker Change: Thank you.
Speaker Change: Thank you.
Speaker Change: Now I'd like to hand, the conference back over to Mr. Brian Goff for closing remarks.
Brian M. Goff: Alright, Thanks, a lot normal and thank you very much everyone for participating in today's call very good questions, which we very much appreciate as you heard today, our team has great conviction in our potential to deliver transformative new therapies to patients.
Brian M. Goff: Yeah, I'll start, and then Sarah can jump in. First of all, Greg, I hope we're in that position where we have multiple indications, just as we have right now with Pyrokine. One of the key advantages of having, at Agios, a really leading PK activation franchise is that we have not one but 2 products that we're developing, and that allows us to have different economics, different pricing dynamics across the indications and between the products. I think there's a wide enough space for us right now, given where we are in the development program for AG946, that we can tailor the appropriate target product profiles, whether it's As I think folks know, we just reported out last year, very encouraging proof of concept from our Phase 2a study, and we're in the process right now of making enhancements in the design so we can pursue Phase 2b. I feel very good about the work the team has done.
Brian M. Goff: And significant long term value to shareholders and we really look forward to speaking with all of you again soon so thanks a lot.
Speaker Change: This concludes today's conference call. Thank you for your participation you may now disconnect everyone have a wonderful day.
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Brian M. Goff: And that'll be the next step. And as I mentioned before, at the right time, we'll also report out the progress on sickle cell disease. Anything you want to add, Sarah? Just high level, I think what you can expect from development is that we always try to design our trials to meet multiple stakeholders, their needs, meaning we take our target product profile very seriously. So that is something that for 946 is the same. We take that very seriously and we incorporate, we will be incorporating patient voice and the regulatory feedback, obviously, as well. Yeah.
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Sarah Hewins: I think a great example of that is in the case of sickle cell disease, a point that we're very proud of at Agios, is that we have deeply involved the community, and, in fact, Sarah and I attended a conference last year where we won an award from the community for how carefully and thoughtfully we involved sickle cell disease warriors and caregivers in how we think about designing the trials, recruiting for the trials, and ultimately what the commercial And we'll do the same thing with AG946. Great, thanks for taking the time to answer the question. You bet, Greg.
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Brian M. Goff: And our last question will come from the line of Divya Rao with PDKelvin. Your line is now open. Hi, guys. This is Vivian with Mark.
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Divya Rao: Thanks for taking my questions. I have two kinds of follow-up questions. One, on Eric's question earlier, was the difference in the primary endpoint between MediPivot and loose powder sets for the transfusion-dependent patient something that was recommended to you by regulatory authorities? Or was it more of an internal choice?
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Sarah Hewins: And then my second question is turning to the design of the phase 2B in MDS. Do you plan to test multiple dose levels of 18946, and any color on the enrollment criteria versus what Repozol had in the commands trial would be great. Thank you. Thank you. Thanks, Divya.
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Sarah Hewins: So, in regards to the first question, primary endpoints, yes, indeed, we do, as I just mentioned in the previous question as well, we do our development in collaboration with regulators, so we take feedback from the regulators very seriously and try to.., you know, really incorporate the feedback as best as we can. And so that's how we ended up settling for the 50 percent endpoint in a rolling 12 week period interval, which we indeed truly believe is a more dynamic endpoint and really reflects the real world experience of a patient. So this is where it's always very good. And we're always very grateful to be able to have those conversations because I do think incorporating feedback from multiple stakeholders always leads to better design choices. So that's that on the primary endpoint.
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Sarah Hewins: And then in regards to your question about MDF Phase 2b, yes, the Phase 2b is indeed, you know, multiple doses that we are testing. We are going to test higher doses than we originally anticipated just because we have learned from our phase 2A that MDS patients overall have lower exposure to the same amount of drug than other patient populations and healthy volunteers. So we are incorporating those learnings into phase 2B. And in regards to our inclusion criteria, we have not.
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Sarah Hewins: You know, as we haven't presented a trial in progress post or anything like that yet, but you can expect the population to be relatively similar to how our population was in phase 2a. However, we will be focusing on transfusion patients with transfusion burden. It will also be a broad MDS population, just like we allowed in phase 2A. We're not excluding, per se, a population like specific mutations, things like that.
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Sarah Hewins: Thank you. I would now like to hand the conference back over to Mr. Brian Goff for closing remarks. All right.
Brian M. Goff: Thanks a lot, Norma. And thank you very much, everyone, for participating in today's call. Very good questions, which we very much appreciate. As you heard today, our team has great conviction in our potential to deliver transformative new therapies to patients and significant long-term value to shareholders, and we really look forward to speaking with all of you again soon. So thanks a lot.
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Operator: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone have a wonderful day. ?? ?? ?? ?? ?? ?? ?? ?? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? Title Microsoft Office Word Document MSWordDoc Word.
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Chris Taylor: Document.8 Good morning, and welcome to AGIOS' fourth quarter 2023 conference call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at AGIOS' request. I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations, and Corporate Communications for AGIOS. Please go ahead.
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Speaker Change: Good morning, and welcome to <unk> fourth quarter 2023 conference call. At this time all participants are in a listen only mode there'll be a question and answer session. At the end. Please be advised that this call is being recorded.
Chris Taylor: MS. Thank you, operator. Good morning, everyone.
Speaker Change: GFS request I would now like to turn the call over to Chris Taylor, Vice President Investor Relations and corporate Communications for <unk>. Please go ahead.
Chris Taylor: And welcome to Agios' conference call and webcast to discuss fourth quarter and full year 2023 financial results and recent business highlights. You can access slides for today's call by going to the investors section of our website, agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff; Dr. Sarah Hewins, Chief Medical Officer and Head of Research and Development; Sveta Milanova, our Chief Commercial Officer; and Cecilia Jones, Chief Financial Officer. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. However, actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, I'll turn the call over to Brian.
Chris Taylor: Thank you operator, good morning, everyone and welcome to <unk> conference call and webcast to discuss fourth quarter and full year 2023 financial results and recent business highlights.
Chris Taylor: Can access slides for today's call by going to the investors section of our website.
Chris Taylor: <unk> Dot com.
Chris Taylor: On today's call I'm joined by our Chief Executive Officer, Brian Goff.
Doctor Sara: Doctor, Sara <unk>, Chief Medical Officer, and head of research and development <unk> melanoma, our chief commercial officer.
Doctor Sara: And Cecilia Jones, Chief Financial Officer.
Doctor Sara: Before we get started I would like to remind everyone that some of the statements. We make on this call will include forward looking statements actual events and results could differ materially from those expressed or implied by any forward looking statements. As a result of various risks uncertainties and other factors, including those set forth in our most recent.
Doctor Sara: Filings with the SEC.
Doctor Sara: Any other future filings that we may make with the SEC.
Doctor Sara: With that I'll turn the call over to Brian.
Brian M. Goff: Thanks, Chris, and good morning, everyone, and thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. Driven by this goal, we continue to generate consistent and compelling data across our industry-leading PK activator franchise. And with the seamless cross-functional collaboration of the Agios team, we made remarkable progress advancing this mission in 2023.
Brian M. Goff: Thanks, Chris and good morning, everyone and thank you for joining us our mission at <unk> is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases.
Brian M. Goff: Driven by this goal, we continued to generate consistent and compelling data across our industry, leading PK activator franchise and.
Brian M. Goff: And with seamless cross functional collaboration of the <unk> team, we made remarkable progress advancing this mission in 2023.
Brian M. Goff: Highlighting this progress, we reported three key data readouts in the last 12 months. In June, we reported positive top-line data from the phase two portion of the RISE UP study of midipibet, our lead PK activator in sickle cell disease, followed by the full data set in December at ASH. Despite the field's recent progress in sickle cell disease, there are no novel oral therapies that both improve anemia and reduce sickle cell pain. And that is precisely what we aim to deliver with MediPivX.
Brian M. Goff: Highlighting this progress we reported three key data readouts in the last 12 months.
Brian M. Goff: In June we reported positive topline data from the phase two portion of the rise up study of mid tier that are lead PK activator in sickle cell disease.
Brian M. Goff: I would buy the full dataset in December at Ash.
Brian M. Goff: Despite the fields recent progress in sickle cell disease, there are no novel oral therapies that.
Brian M. Goff: Both improve anemia in reduced sickle cell pain crises.
Brian M. Goff: And that is precisely what we aim to deliver with mitigated that.
Brian M. Goff: In November, we reported positive data from the Open Label Phase 2A study of our other PK activator, AG946, in lower-risk MDS, with 40% of patients achieving the transfusion independence endpoint. And just last month, we reported positive data from the Phase 3 ENERGIZE study of midipibet in non-transfusion-dependent thalassemia. As a reminder, nontransfusion-dependent, or NTD, thalassemia accounts for approximately two-thirds of thalassemia in the US and has no FDA-approved treatment options. However, despite not requiring regular transfusions, NTD thalassemia patients experience significant impact on quality of life, a wide range of serious morbidities, and an elevated risk of premature death. Together, the consistency of data generated across the Mid-Pivot Development Program bolsters our conviction in the probability of success of our ongoing studies, including two additional Phase III readouts we expect by the end of this year. And this data highlights the potential of our PK activators to transform the course of multiple hematologic diseases. Sarah will provide more detail on our progress and upcoming milestones across our pipeline in just a few minutes.
Brian M. Goff: In November we reported positive data from the open label Phase <unk> study of our other PK activator AG 946 in lower risk Mds with 40% of patients achieving the transfusion independence endpoint.
Brian M. Goff: And just last month, we reported positive data from the phase III energized study of <unk> in non transfusion dependent thalassemia.
Brian M. Goff: As a reminder, non transfusion dependent or MTV thalassemia accounts for approximately two thirds of thalassemia in the U S and has no FDA approved treatment option.
Brian M. Goff: Despite not requiring regular transfusions MTV thalassemia patients experienced significant impact on quality of life, a wide range of serious morbidities and an elevated risk of premature death.
Brian M. Goff: Together the consistency of data generated across the mid tier that development program bolsters, our conviction in the probability of success of our ongoing studies, including two additional phase III Readouts, we expect by the end of this year.
Brian M. Goff: This data highlights the potential of our PK activators to transform the course of multiple hematologic diseases.
Brian M. Goff: Sara will provide more detail on our advancements and upcoming milestones across our pipeline in just a few minutes.
Brian M. Goff: Importantly, we believe our PK activation pipeline is well-positioned with multiple near-term catalysts to become a multi-billion dollar franchise and deliver significant value, in parallel with advancing the late-stage mid-PIVOT development program across multiple indications. Our commercial organization is laser focused on building the infrastructure established through our current launch in PK deficiency to prepare for potential U.S. launches of midipivet in thalass Sveta will provide greater detail on the commercial opportunities for Mitopibat in thalassemia, as well as an update on our current launch in PK deficiency in just a bit. Finally, as you'll hear from Cecilia, we ended 2023 with a strong cash position with approximately $806 million in cash and investments on the balance. In addition, we continue to track Cervier's progress toward the potential FDA approval of voraci This is truly an exciting time at Agios. With four additional phase three readouts and two potential launches expected on the horizon, we look forward to multiple opportunities to drive significant near-term value creation for patients, caregivers, and shareholders. With that, I'll now turn the call over to Sarah. Thanks, Brian.
Brian M. Goff: Importantly, we believe our PK activation pipeline is well positioned with multiple near term catalysts to become a multibillion dollar franchise and deliver significant value.
Brian M. Goff: In parallel with advancing the late stage mid of Tibet development program across multiple indications our commercial organization is laser focused on building the infrastructure established through our current launch in PK deficiency.
Brian M. Goff: Pair for potential U S launches of mid pit that imbalance EMEA in 2025 and in sickle cell disease in 2026.
Brian M. Goff: So that it will provide greater detail on the commercial opportunities for <unk> in thalassemia as well as an update on our current launch in PK deficiency, and just a bit.
Brian M. Goff: Finally, as you'll hear from Cecilia, we ended 2023 with a strong cash position with approximately $806 million in cash and investments on the balance sheet.
Brian M. Goff: In addition, we continue to track <unk> progress towards a potential FDA approval of where aside nib.
Brian M. Goff: Given our retained economics for both the milestone and royalties.
Brian M. Goff: This is truly an exciting time at <unk> with four additional phase III readouts.
Brian M. Goff: Two potential launches expected on the horizon, we look forward to multiple opportunities to drive significant near term value creation for patients caregivers and shareholders with that I'll now turn the call over to Sarah.
Sarah: Thanks, Brian in.
Sarah Hewins: In 2023, our research and development organization made tremendous progress advancing our PK activator development program. Led by Metapiva, the industry's most advanced PK activator, now with over eight years of clinical experience, the consistent and compelling data we have generated to date in PK deficiency, thalassemia, and sickle cell disease continue to de-risk our ongoing development program and highlight the potential for this molecule to transform patient function and quality of life. We are also enthusiastic about the potential for the rest of our growing pipeline, and we are pleased to note that we remain on track to deliver on our milestones, including enrolling the first patients in the Phase IIb trial for AG946 in lower-risk MDS, and for the Phase I trial for AG181, the compound name for our PAH stabilizer for phenylketonuria, reading out top-line data for the Phase 3 Activate Kits T study in regularly transduced pediatric patients with TK deficiency, and completing enrollment of the Phase 3 Activate Kits study in pediatric patients with TK deficiency.
Sarah: In 2023, our research and development organization made tremendous progress advancing our PK activator development program.
Sarah: Led by MS Propping up the industry's most advanced PK activator now with over eight years of clinical experience the consistent and compelling data we have generated to date in PK deficiency thalassemia and sickle cell disease continue to de risk our ongoing development program and highlights the potential for this.
Sarah: Molecule to transform patient function and quality of life.
Sarah: We are also often asked about the potential for the rest of our growing pipeline and we are pleased to note that we remain on track to deliver on our milestones including and.
Sarah: Enrolling the first patients in the phase II trial for $89 six in lower risk Mds and for the phase one trial for <unk>, one the compounds named for our ph stabilizer Fazzino kitchen will be up.
Sarah: Reading, our topline data for the phase III activate T study in regularly transfused pediatric patients with PK deficiency, and completing enrollment of the phase III efficacy study in pediatric patients with <unk>.
Sarah Hewins: Turning to sickle cell disease, we were pleased to present detailed positive results from the Phase 2 portion of the Phase 2-3 Rise-Up Study of Mitapiva at ASH in December. The study achieved its primary endpoint of hemoglobin response and, in addition, an improvement in analyzed rates of sickle cell pain crises for the. And we have been delighted by the enthusiasm of the investors. We continue to advance enrollment in the Phase 3 portion of this study and remain on track to complete enrollment by the end of this year. While the treatment landscape in sickle cell disease continues to evolve, there remains an urgent and unmet need for convenient, novel oral treatment options that address both anemia and sickle cell pain crises. And we believe firmly in Metapodoc's potential to deliver a best-in-class option for patients suffering from this devastating disease.
Sarah: Turning to sickle cell disease, we were pleased to present detailed positive results from the phase two portion of the phase III <unk> study of <unk> capital at Ash in December.
Sarah: The study achieved its primary endpoint of hemoglobin response and in addition, an improvement in annualized rate of sickle cell pain crisis.
Sarah: And we have been delighted by the answer that one of the investigators.
Sarah: We continued to advance enrollment in the phase three portion of this study and remain on track to complete enrollment by the end of this year.
Sarah: While the treatment landscape in sickle cell disease continues to evolve there remains an urgent unmet need for convenience novel oral treatment option that address both anemia in sickle cell pain crisis.
Sarah: And we believe firmly in the top of our potential to deliver a best in class option for patients suffering from this devastating disease.
Sarah Hewins: And finally, on thalassemia, I'll take a moment to highlight a few key elements of our program and the positive topline phase 3 data we reported last month in non-transfusion-dependent thalassemia. As a reminder, the Phase 3 program of pyrokine and thalassemia, encompassing two Phase 3 randomized placebo-controlled trials, was designed to deliver data across all subpopulations of tha Both trials enrolled patients with alpha or beta thalassemia, but they enrolled different populations as it relates to transfusion needs. We want to highlight that ENERGIZE is the first clinical program that included patients who were not regularly transfused and who have alpha thalassemia. As Brian mentioned, there are no FDA-approved treatments for non-transfusion-dependent thalassemia, which represents approximately two-thirds of total thalassemia patients in the U.S. These patients suffer from a poor quality of life, and a high rate of serious morbidities, including thrombosis and premature death. We were therefore very pleased to be able to announce positive results from the
Sarah: And finally on thalassemia I'll take a moment to highlight a few key elements of our program and the positive top line phase III data, we reported last month in non transfusion dependent thalassemia.
Sarah: As a reminder, the phase three program of <unk> senior and compassion to phase III randomized placebo controlled trial was designed to deliver data across all sub populations of policy now such as alpha and beta thalassemia in populations with different transfusion.
Sarah: Both trials enrolled patients with alpha or beta thalassemia, but enrolled different populations as it relates to transfusion.
Sarah: We want to highlight that <unk> is the first clinical program that included patients who are not regularly transfused and alpha thalassemia patients.
Sarah: As Brian mentioned, there are no FDA approved treatments for Nokia institution dependent thalassemia, which represents approximately two thirds of total policy net patients in the U S D.
Sarah: These patients suffer from a poor quality of life are high rates of serious morbidities, including Campbell and premature death.
Sarah: We were therefore very pleased to be able to announce positive results.