Q4 2025 Arcturus Therapeutics Holdings Inc Earnings Call

March 3, 2026

Speaker #1: Thank you for your continued patience , your meeting will begin shortly . If you need assistance at any time , please press Star Zero and a member of our team will be happy to help you Hello and welcome everyone !

Operator: Thank you for your continued patience. Your meeting will begin shortly. If you need assistance at any time, please press STARR zero and a member of our team will be happy to help you. Hello and welcome everyone joining today's Arcturus Therapeutics Q4 and fiscal year 2025 Earnings Call. At this time, all participants are in a listen-only mode. Later, you will have the opportunity to ask questions during the question and answer session. To register to ask a question at any time, please press STARR one on your telephone keypad. Please note this call is being recorded. We are standing by if you should need any assistance. It is now my pleasure to turn the meeting over to Neda Safarzadeh, Vice President, Head of Investor Relations, Public Relations, and Marketing. Please go ahead.

Speaker #1: Joining today's Arcturus Therapeutics fourth quarter in Fiscal Year 2025 Earnings Call . At this time , all participants are in a listen only mode Later , you will have the opportunity to ask questions during the question and answer session .

Speaker #1: To register to ask a question at any time , please press star one on your telephone keypad . Please note this call is being recorded .

Speaker #1: We are standing by. If you should need any assistance, please let us know. And it is now my pleasure to turn the meeting over to Neda Safarzadeh, Vice President, Head of Investor Relations, Public Relations, and Marketing.

Speaker #1: Please go ahead

Speaker #2: Thank you . Operator . Good afternoon and welcome to Arcturus Therapeutics quarterly financial update . And pipeline progress . Call Today's call will be led by Joe Payne .

Neda Safarzadeh: Thank you, operator. Good afternoon, and welcome to Arcturus Therapeutics Quarterly Financial Update and Pipeline Progress Call. Today's call will be led by Joe Payne, our President and CEO, and Dr. Allan Cohen, our Chief Medical Officer. Dr. Pat Chivukula, our CSO and COO, will join them for the Q&A session. Before we begin, I would like to remind everyone that the statements made during this call regarding matters that are not historical facts are forward-looking statements within the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not guarantees of performance.

Speaker #2: Our president and CEO . And Doctor Allen Cohen , our chief medical officer Doctor Patricola , our CSO and COO will join them for the Q&A session Before we begin , I would like to remind everyone that the statements made during this call regarding matters that are not historical facts are forward looking statements within the safe harbor provisions of the private Securities Litigation Reform Act of 1995 .

Speaker #2: Forward looking statements are not guarantees of performance . They involve known and unknown risks , uncertainties and assumptions that may cause actual results , performance and achievements to differ materially from those expressed or implied by the statement Please see the forward looking statements disclaimer on the company's press release issued earlier today , as well as the risk Factors section in our most recent form 10-K and in subsequent filings with the SEC .

Neda Safarzadeh: They involve known and unknown risks, uncertainties, and assumptions that may cause actual results, performance, and achievements to differ materially from those expressed or implied by this statement. Please see the forward-looking statement disclaimer on the company's press release issued earlier today, as well as the Risk Factors section in our most recent Form 10-K and in subsequent filings with the SEC. In addition, any forward-looking statements represent our views only as of the date such statements are made. Arcturus specifically disclaims any obligation to update such statements. With that, I will now turn the call over to Joe.

Speaker #2: In addition , any forward looking statements represent our views only as of the date , such statements are made . Arcturus is disclaims any obligation to update such statements .

Speaker #2: And with that , I will now turn the call over to Joe

Speaker #3: Thank you Nedda . It's good to be with you again , everybody . I will begin today with an update on our Arctic three two and Arctic 810 programs .

Joseph Payne: Thank you, Neda. It's good to be with you again, everybody. I will begin today with an update on our ARCT-032 and ARCT-810 programs. These are the messenger RNA therapeutic candidates for cystic fibrosis and ornithine transcarbamylase deficiency, respectively. ARCT-032 phase 2 trial is progressing with higher dose testing at 15 milligrams in 4 Class I CF adults, which showed no safety concerns. The upcoming multi-month study will enroll patients in the US and internationally and is designed to evaluate safety as well as look for early signs of clinical benefit, including improvements in lung function and quality of life. We are well on track to initiate dosing for this phase 2 12-week study in the first half of this year and look forward to generating potentially meaningful clinical data for our CF program in 2026. ARCT-810 continues to advance toward pivotal development.

Speaker #3: These are the messenger RNA therapeutic candidates for cystic fibrosis and ornithine transcarbamylase deficiency , respectively Arctic 32 , phase two trial is progressing with higher dose testing at 15mg in four class one CF adults , which showed no safety concerns The upcoming multi month study will enroll patients in the US and internationally and is designed to evaluate safety as well as look for early signs of clinical benefit , including improvements in lung function and quality of life .

Speaker #3: We are well on track to initiate dosing for this Phase 2 12-week study in the first half of this year, and look forward to generating potentially meaningful clinical data for our CF program in 2026.

Speaker #3: Arctic 810 continues to advance toward pivotal development. We plan to study both adults with late-onset OTC deficiency and young children with the most severe forms. Type C regulatory meetings are scheduled during the first half of 2026, and are intended to provide clarity regarding our next steps in clinical development for our flagship rare liver disease program.

Joseph Payne: We plan to study both adults with late-onset OTC deficiency and young children with the most severe forms. Type C regulatory meetings are scheduled during the first half of 2026 and are intended to provide clarity regarding our next steps in clinical development for our flagship rare liver disease program. I will now provide regulatory updates to our partnered COVID-19 vaccine program, also known as KOSTAIVE, where in January 2026, the UK Medicines and Healthcare Products Regulatory Agency, or MHRA, granted approval for KOSTAIVE, a self-amplifying mRNA COVID-19 vaccine for use in individuals aged 18 and older. Moving to ARCT-2304. This is our next-generation STARR vaccine candidate for pandemic A/H5N1 influenza. This program is contracted with and funded by BARDA. We completed a Phase 1 study in 212 young adults and 80 older adults.

Speaker #3: I will now provide regulatory updates to our partnered Covid 19 vaccine program , also known as Costive , where in January 2026 , the UK Medicines and Healthcare Products Regulatory Agency , or My granted approval for Costive , a Self-amplifying mRNA Covid 19 vaccine for use in individuals aged 18 and older Moving to Arct 2304 .

Speaker #3: This is our next generation star vaccine candidate for pandemic , a H5n1 influenza . This program is contracted with and funded by Barda .

Speaker #3: We completed a phase one study in 212 young adults and 80 older adults Recent eight month follow up data after the initial vaccination show that all three dose levels 1.5 , five and 12 micrograms generated a durable immune response .

Joseph Payne: Recent eight-month follow-up data after the initial vaccination showed that all three dose levels, 1.5mcg, and 12mcg, generated a durable immune response. The results also reinforced the sa-mRNA platform's ability to drive meaningful cell-mediated immunity. Across all tested doses, the vaccine was well-tolerated with no safety concerns reported. The data further validates our STARR sa-mRNA platform. Also briefly, our lawsuit against AbbVie and Capstan Therapeutics, filed on 23 September 2025, remains ongoing. With that, I'll now pass the call to Allen.

Speaker #3: The results also reinforced the mRNA platform's ability to drive meaningful cell-mediated immunity across all tested doses. The vaccine was well tolerated, with no safety concerns reported.

Speaker #3: The data further validates our star mRNA platform also briefly , our lawsuit against AbbVie and Capstone Therapeutics filed on September 23rd , 2025 , remains ongoing With that , I'll now pass the call to Alan

Speaker #4: Thank you, Joe. It's certainly good to be here with all of you today. I'll begin with an update of our ARCT.

Alan H. Cohen: Thank you, Joe. It's certainly good to be here with all of you today. I'll begin with an update of our ARCT-032 program. This is our messenger RNA therapeutic candidate for cystic fibrosis or CF pulmonary disease. ARCT-032 utilizes Arcturus's LUNAR lipid-mediated aerosolized platform to deliver CFTR messenger RNA to the lungs. Expression of a functional copy of the CFTR mRNA in the lungs of people with CF has the potential to restore CFTR activity and mitigate the downstream effects responsible for the progressive lung disease and associated morbidity and mortality experienced by people with CF. We remain on track to initiate the dosing phase of our 12-week phase 2 clinical study in the first half of 2026. We recently completed once-daily dosing of 15 mg of ARCT-032 over 28 days in the third dosing cohort.

Alan Cohen: Thank you, Joe. It's certainly good to be here with all of you today. I'll begin with an update of our ARCT-032 program. This is our messenger RNA therapeutic candidate for cystic fibrosis or CF pulmonary disease. ARCT-032 utilizes Arcturus's LUNAR lipid-mediated aerosolized platform to deliver CFTR messenger RNA to the lungs. Expression of a functional copy of the CFTR mRNA in the lungs of people with CF has the potential to restore CFTR activity and mitigate the downstream effects responsible for the progressive lung disease and associated morbidity and mortality experienced by people with CF. We remain on track to initiate the dosing phase of our 12-week phase 2 clinical study in the first half of 2026. We recently completed once-daily dosing of 15 mg of ARCT-032 over 28 days in the third dosing cohort.

Speaker #4: 032 program . This is our messenger RNA therapeutic candidate for cystic fibrosis , or CF pulmonary disease or 32 utilizes Arcturus lunar lipid mediated aerosolized platform to deliver Cftr messenger RNA to the lungs .

Speaker #4: Expression of a functional copy of the Cftr mRNA in the lungs of people with CF has the potential to restore Cftr activity and mitigate the downstream effects responsible for the progressive lung disease and associated morbidity and mortality experienced by people with CF .

Speaker #4: We remain on track to initiate the dosing phase of our 12 week phase two clinical study . In the first half of 2026 .

Speaker #4: We recently completed once daily dosing of 15mg of arct . Oh 32 over 28 days . In the third dosing cohort . This cohort included four CF adults with class one null mutations and importantly , we observed no safety or tolerability concerns at this higher dose Based on these encouraging data , the independent safety Review Committee permitted us to move forward with a phase two study that will evaluate Arcto 32 over a 12 week period instead of just four weeks .

Alan H. Cohen: This cohort included four CF adults with Class I null mutations, and importantly, we observed no safety or tolerability concerns at this higher dose. Based on these encouraging data, the Independent Safety Review Committee permitted us to move forward with a phase 2 study that will evaluate ARCT-032 over a 12-week period instead of just four weeks. We will include two functional pulmonary measures, spirometry, as measured by percent predicted FEV1, as well as LCI or lung clearance index, as measured by multiple breath washout. We will also include two quality-of-life measures, the CFQ-RR and the EQ-5D-5L, as well as serial high-resolution CT testing to examine changes in airway wall thickness, air trapping, and mucus plugging scores. The 12-week study intends to enroll up to 20 participants with Class I CF mutations from clinical sites in the US and abroad.

Alan Cohen: This cohort included four CF adults with Class I null mutations, and importantly, we observed no safety or tolerability concerns at this higher dose. Based on these encouraging data, the Independent Safety Review Committee permitted us to move forward with a phase 2 study that will evaluate ARCT-032 over a 12-week period instead of just four weeks. We will include two functional pulmonary measures, spirometry, as measured by percent predicted FEV1, as well as LCI or lung clearance index, as measured by multiple breath washout. We will also include two quality-of-life measures, the CFQ-RR and the EQ-5D-5L, as well as serial high-resolution CT testing to examine changes in airway wall thickness, air trapping, and mucus plugging scores. The 12-week study intends to enroll up to 20 participants with Class I CF mutations from clinical sites in the US and abroad.

Speaker #4: We will include two functional pulmonary measures spirometry , as measured by percent predicted fev1 , as well as LCI or lung clearance index as measured by multiple breath washout .

Speaker #4: We will also include two quality of life measures the CF and the EQ five five . As well as serial high resolution CT testing to examine changes in airway wall thickness , air trapping and mucus plugging scores The 12 week study intends to enroll up to 20 participants with class one CF mutations from clinical sites in the US and abroad .

Speaker #4: The goal of this upcoming 12 week study is to establish a clearer picture of longer term safety , 12 weeks versus four weeks , and begin to more comprehensively explore early signals of clinical efficacy , including how CF participants feel and function .

Alan H. Cohen: The goal of this upcoming 12-week study is to establish a clearer picture of longer-term safety, 12 weeks versus 4 weeks, and begin to more comprehensively explore early signals of clinical efficacy, including how the CF participants feel and function. Now moving on to the ARCT-810 program. This is our messenger RNA therapeutic candidate for ornithine transcarbamylase or OTC deficiency. We look forward to aligning with regulators on our clinical development strategy for the OTC deficiency program. We are moving to broaden our development strategy to serve both adults in late-onset disease and young children with the most severe forms of OTC deficiency. These are the patients who typically rely on liver transplantation for survival beyond early childhood. We continue active regulatory engagement to support pivotal trial designs across these two distinct populations.

Alan Cohen: The goal of this upcoming 12-week study is to establish a clearer picture of longer-term safety, 12 weeks versus 4 weeks, and begin to more comprehensively explore early signals of clinical efficacy, including how the CF participants feel and function. Now moving on to the ARCT-810 program. This is our messenger RNA therapeutic candidate for ornithine transcarbamylase or OTC deficiency. We look forward to aligning with regulators on our clinical development strategy for the OTC deficiency program. We are moving to broaden our development strategy to serve both adults in late-onset disease and young children with the most severe forms of OTC deficiency. These are the patients who typically rely on liver transplantation for survival beyond early childhood. We continue active regulatory engagement to support pivotal trial designs across these two distinct populations.

Speaker #4: Now , moving on to the Arctic , 810 program . This is our messenger RNA therapeutic candidate for ornithine transcarbamylase or OTC deficiency .

Speaker #4: We look forward to aligning with regulators on our clinical development strategy for the OTC deficiency program . We are moving to broaden our development strategy to serve both adults and late onset disease and young children with the most severe forms of OTC deficiency These are the patients who typically rely on liver transplantation for survival .

Speaker #4: Beyond early childhood . We continue active regulatory engagement to support pivotal trial designs across these two distinct populations . Our type C regulatory meetings with the health authorities , along with their feedback , remain on track for the first half of 2026 .

Alan H. Cohen: Our Type C regulatory meetings with the health authorities, along with their feedback, remain on track for the first half of 2026. We expect these interactions to help clarify our clinical development strategy for both adult and pediatric indications. Currently, we are very pleased with the momentum across both the CF and OTC deficiency programs and look forward to updating you as we progress throughout the year. I'll now pass the call back to Joe.

Alan Cohen: Our Type C regulatory meetings with the health authorities, along with their feedback, remain on track for the first half of 2026. We expect these interactions to help clarify our clinical development strategy for both adult and pediatric indications. Currently, we are very pleased with the momentum across both the CF and OTC deficiency programs and look forward to updating you as we progress throughout the year. I'll now pass the call back to Joe.

Speaker #4: And we expect these interactions to help clarify our clinical development strategy for both adult and pediatric indications. Currently, we are very pleased with the momentum across both the CF and OTC deficiency programs and look forward to updating you on our progress throughout the year. I'll now pass the call back to Joe.

Speaker #3: Thanks, Alan. We indeed look forward to initiating enrollment in our 12-week CF study and gaining clarity in alignment with regulatory agencies for the next stages of development.

Joseph Payne: Thanks, Alan. We indeed look forward to initiating enrollment in our 12-week CF study and gain clarity and alignment with regulatory agencies for the next stages of development for ARCT-810. Now, with respect to Arcturus' financial position, we issued a press release earlier today, which includes financial statements for the Q4 and fiscal year ending 31 December 2025, and provided a summary and analysis of year-over-year performance. Please also refer to our most recent Form 10-K for more details on financial performance. Year-over-year, annual, and quarterly revenue decreased $70.3 million and $15.6 million, respectively. These declines were driven by reductions in revenue from our CSL collaboration, reflecting lower supply agreement activity and a reduced number of development-based milestone achievements as KOSTAIVE was commercialized.

Speaker #3: For Arct 810 . Now , with respect to Arcturus Financial position , we issued a press release earlier today which includes financial statements for the fourth quarter and fiscal year ending December 31st , 2025 , and provided a summary and analysis of year over year performance .

Speaker #3: Please also refer to our most recent Form 10-K for more details on financial performance. Year-over-year, annual and quarterly revenue decreased by $70.3 million and $15.6 million, respectively.

Speaker #3: These declines were driven by reductions in revenue from our CSL collaboration, reflecting lower supply agreement activity and a reduced number of development-based milestone achievements.

Speaker #3: As cost was commercialized Annual and quarterly research and development expenses also decreased year over year by 83.0 million and $19.3 million , respectively , which was primarily driven by lower manufacturing and clinical costs related to the lunar Covid program .

Joseph Payne: Annual and quarterly research and development expenses also decreased year-over-year by $83.0 million and $19.3 million, respectively, which was primarily driven by lower manufacturing and clinical costs related to the Lunar COVID program, reflecting the program's transition from a development program to the commercial phase. Additional decreases relate to lower manufacturing for our LUNAR-CF and LUNAR-FLU programs, as well as lower clinical costs for our LUNAR-OTC program as we wrap up clinical activities. Clinical costs for phase two of our LUNAR-CF program partially offset these reductions as we remain focused on this clinical study. General and administrative expenses decreased annually year-over-year by $6.7 million due to reduced expenses for payroll and benefits, as well as share-based compensation.

Speaker #3: Reflecting the program's transition from a development program to the commercial phase. Additional decreases relate to lower manufacturing for our Lunar CF and Lunar Flu programs, as well as lower clinical costs for our Lunar OTC program.

Speaker #3: As we wrap up , clinical activities , clinical costs phase two of our lunar CF program partially offset these reductions as we remain focused on this clinical study General and administrative expenses decreased annually year over year by $6.7 million due to reduced expenses for payroll and benefits , as well as share based compensation Quarterly general and administrative expenses increased year over year by $1.6 million due to an acceleration of employee stock options Overall , we expect general and administrative expenses to continue to decrease during the next 12 months , driven by lower share based compensation expense , cash .

Joseph Payne: Quarterly general and administrative expenses increased year-over-year by $1.6 million due to an acceleration of employee stock options. Overall, we expect general and administrative expenses to continue to decrease during the next 12 months, driven by lower share-based compensation expense. Cash, cash equivalents and restricted cash were $232.8 million as of 31 December 2025, and $293.9 million on 31 December 2024. Through disciplined execution and a strategic refocus on existing rare disease clinical programs in fiscal year 2025, Arcturus has extended our cash runway into Q2 2028. In summary, the company remains in a strong financial position and has the cash runway needed to achieve multiple near-term value-creating milestones for both therapeutic programs. With that, let's turn the time over to the operator for questions.

Speaker #3: Cash equivalents and restricted cash were $232.8 million as of December 31st , 2025 , and $293.9 million on December 31st , 2024 , through disciplined execution and a strategic refocus on existing rare disease clinical programs in fiscal year 2025 .

Speaker #3: Arcturus has extended our cash runway into the second quarter of 2028 . In summary , the company remains in a strong financial position and has the cash runway needed to achieve multiple near-term value , creating milestones for both therapeutic programs With that , let's turn the time over to the operator for questions

Speaker #1: Thank you. If you'd like to ask a question, press star one on your keypad. To leave the queue at any time, press star two.

Operator: Thank you. If you'd like to ask a question, press star one on your keypad. To leave the queue at any time, press star two. Once again, that is star one to ask a question. Thank you. Our first question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.

Speaker #1: Once again , that is star one . To ask a question . Thank you . Our first question comes from Yasmeen Rahimi with Piper Sandler .

Speaker #1: Your line is open

Speaker #5: Good afternoon team . Thank you so much for the prepared remarks . I would love to understand , as you guys are going to be kicking off the 12 week phase two study .

Yasmeen Rahimi: Good afternoon, team. Thank you so much for the prepared remarks. Would love to understand, as you guys are gonna be kicking off the 12-week phase 2 study, I think you guys spent a lot of time thinking about optimization for the study from dose selection to baseline measurements to patient selection. Maybe help us walk us through some of the optimizations that were included versus the initial study that was conducted in the fall. That would be really helpful to go through. Then also, I know you work with the CF Foundation. Help us understand if you had a chance to work with them to warehouse a number of patients so as soon as you kick off the study, you could enroll quickly the patients for it. With that, I'll jump back into the queue.

Speaker #5: I think you guys spend a lot of time thinking about optimization for the study from dose selection to baseline measurements to patient selection .

Speaker #5: So maybe help us walk us through some of the optimizations that were included versus the initial study that was conducted in the fall.

Speaker #5: That would be really helpful to go through . And then also , I know you work with the CF Foundation . Help us understand , if you had a chance to work with them to warehouse the number of patients .

Speaker #5: So as soon as you kick off the study , you could enroll quickly . The patients for it . And with that , I'll jump back into the queue

Speaker #3: Yeah . Thanks . Yes , I appreciate the questions . As always , with respect to how the 12 week study that we're initiating here soon is , is different from the four week study we have .

Joseph Payne: Yeah. Thanks, Yas. I appreciate the questions as always. With respect to how the 12-week study that we're initiating here soon is different from the four-week study, we have Alan on the line. He'll highlight some of those differences so that the investors out there can understand.

Speaker #3: Alan on the line. He'll highlight some of those differences so that the investors out there can understand.

Speaker #4: Sure . No problem . Thanks , Joe Great question . So first things first , one of the main fundamental differences between the study that we've done with dose ranging from cohorts one through three , is that cohort four is really going to be designed somewhat differently with the intent on it being more reproducible and stable , particularly as it relates to spirometry measures .

Alan H. Cohen: Sure. No problem. Thanks, Joe. Great question. First things first, one of the main fundamental differences between the study that we've done with dose ranging from cohorts 1 through 3 is that cohort 4 is really going to be designed somewhat differently with the intent on it being more reproducible and stable, particularly as it relates to spirometric measures. We're setting parameters, we will not be enrolling a CF patient until they're stable with respect to baseline lung function measures, and this should help us allow us to observe true clinical signals by enhancing the noise-to-signal ratio. In addition, we are gonna be including lung clearance index using MBW, which does not, which is not subject to variability issues that is sometimes seen in spirometry.

Alan Cohen: Sure. No problem. Thanks, Joe. Great question. First things first, one of the main fundamental differences between the study that we've done with dose ranging from cohorts 1 through 3 is that cohort 4 is really going to be designed somewhat differently with the intent on it being more reproducible and stable, particularly as it relates to spirometric measures. We're setting parameters, we will not be enrolling a CF patient until they're stable with respect to baseline lung function measures, and this should help us allow us to observe true clinical signals by enhancing the noise-to-signal ratio. In addition, we are gonna be including lung clearance index using MBW, which does not, which is not subject to variability issues that is sometimes seen in spirometry.

Speaker #4: We're setting parameters . We will not be enrolling a CF patient until they're stable . With respect to baseline lung function measures . And this should help us allow us to observe true clinical signals by enhancing the noise to signal ratio in addition , we are going to be including lung clearance index using BW , which does not which is not subject to variability issues .

Speaker #4: That is sometimes seen in spirometry . And that's why LCI is really being used . And preferred in children because of its ability to be reproducible and not patient or performance dependent .

Alan H. Cohen: That's why LCI has really been used and preferred in children because of its ability to be reproducible and not patient or performance dependent. In addition, we're going to be looking over a 12-week period instead of just simply four weeks, with the general thinking that the longer period of time will allow the drug that we're studying to manifest clinical benefits in the airway. Lastly, we are including not just LCI in using MBW and percent predicted FEV1 spirometry, but two additional quality of life measures, the CFQ-RR and the EQ-5D-5L. Two shots on goal for both pulmonary functions and quality of life in addition to the HRCT studies reproducibly that we have used in the past and shown early signals of success. Hopefully, that should be helpful to you.

Alan Cohen: That's why LCI has really been used and preferred in children because of its ability to be reproducible and not patient or performance dependent. In addition, we're going to be looking over a 12-week period instead of just simply four weeks, with the general thinking that the longer period of time will allow the drug that we're studying to manifest clinical benefits in the airway. Lastly, we are including not just LCI in using MBW and percent predicted FEV1 spirometry, but two additional quality of life measures, the CFQ-RR and the EQ-5D-5L. Two shots on goal for both pulmonary functions and quality of life in addition to the HRCT studies reproducibly that we have used in the past and shown early signals of success. Hopefully, that should be helpful to you.

Speaker #4: In addition , we're going to be looking over a 12 week period instead of just simply four weeks with the general thinking that the longer period of time will allow the drug that we're studying to manifest clinical benefits in the airway Lastly , we are including not just LCI and using BW and percent predicted Fev1 spirometry , but two additional quality of life measures .

Speaker #4: The Cfq-r and the L and and the EQ five d5 r . So two shots on goal for both pulmonary functions and quality of life .

Speaker #4: In addition to the Hrct studies , Reproducibly that we have used in the past and shown early signals of success Hopefully that should be helpful to you

Speaker #3: Yeah .

Speaker #5: Thank you Alan .

Joseph Payne: Yeah.

Neda Safarzadeh: Thank you, Alan.

Speaker #3: And we do continue to strengthen our relationship with the CF Foundation. They're keenly aware of the modulator non-responders in their community, both here in the U.S. and abroad.

Joseph Payne: We do continue to strengthen our relationship with the CF Foundation. They're keenly aware of the modulator non-responders in their community, both here in the US and abroad. We work closely with them. In fact, the TDN themselves permitted our study to proceed after reviewing the first three cohorts of data into this fourth cohort into this 12-week study. They're closely involved and engaged. Thank you.

Speaker #3: And so we work closely with them . In fact , the TDN themselves permitted our study to proceed after reviewing the first three cohorts of data into this fourth cohort and to this 12 week study .

Speaker #3: So they're closely involved and engaged. Thank you.

Speaker #1: We'll move next to Pete Stavropoulos with Cantor Fitzgerald. Your line is open.

Operator: We'll move next to Pete Stavropoulos with Cantor Fitzgerald. Your line is open.

Speaker #6: Yeah . Hi , Joel . Allen and team . Nice to see the progress . So , you know , you mentioned LCI for CF a Q talk a little bit about this test .

Pete Stavropoulos: Yeah. Hi, Joe, Alan, and team. Nice to see the progress. You know, you mentioned LCI for CF. Can you know, talk a little bit about this test, you know, sort of how sensitive is it? I think you mentioned it's not variable. Do you expect multiple readings at baseline? Importantly, you know, does it correlate with other endpoints you plan to use? Is it reliable at all stages of disease, say, early versus late or equally sensitive? If so, you know, how will that impact your enrollment criteria for the phase two?

Speaker #6: You know, sort of, how sensitive is it? I think you mentioned it's not variable. Do you expect multiple readings at baseline?

Speaker #6: And importantly, does it correlate with other endpoints you plan to use? And is it reliable at all stages of disease, say early versus late, or equally sensitive?

Speaker #6: And if so , how will that impact your enrollment criteria for the phase two ?

Speaker #3: Oh , it's a great question , Pete . LCI is definitely another lung function measurement that we're data that we're collecting in this 12 week study .

Joseph Payne: It's a great question, Pete. Yeah, LCI is definitely another lung function measurement that we're data that we're collecting in this 12-week study. It's definitely more sensitive. Allan, perhaps you can discuss about the multiple readings and how well it correlates and how reliable it is.

Speaker #3: It's definitely more sensitive. Allen, perhaps you can discuss about the multiple readings and how well it correlates and how reliable it is.

Speaker #4: Sure , of course . And a great question . Thank you for asking about this LCI . As I mentioned , doesn't have the subject variability issues of spirometry , although as we all know , spirometry has been a more traditional endpoint measure for most pulmonary pulmonary drugs that have been approved both in the United States and abroad .

Alan H. Cohen: Sure. Of course. A great question. Thank you for asking about this. LCI, as I mentioned, doesn't have the subject variability issues of spirometry, although, as we all know, spirometry has been a more traditional endpoint measure for most pulmonary drugs that have been approved both in the United States and abroad. That's really why LCI historically in CF has been used in children who can't always perform spirometry reproducible. It's a much more passive maneuver requiring just normal tidal breathing, so comfortable breathing in and out. As a result, it's usable measure for more importantly, the most early and more subtle changes in the smallest airways.

Alan Cohen: Sure. Of course. A great question. Thank you for asking about this. LCI, as I mentioned, doesn't have the subject variability issues of spirometry, although, as we all know, spirometry has been a more traditional endpoint measure for most pulmonary drugs that have been approved both in the United States and abroad. That's really why LCI historically in CF has been used in children who can't always perform spirometry reproducible. It's a much more passive maneuver requiring just normal tidal breathing, so comfortable breathing in and out. As a result, it's usable measure for more importantly, the most early and more subtle changes in the smallest airways.

Speaker #4: And that's really why LCI , historically and CF has been used in children who can't always perform spirometry . Reproducible . It's a much more passive maneuver requiring just normal tidal breathing .

Speaker #4: So comfortable breathing in and out and, as a result, it is a ducible measure for, more importantly, the most early and more subtle changes in the smallest airways.

Speaker #4: So, why we're focusing on LCI in addition to spirometry is not just its ability to be reproducible, but it also is measuring another component of the airway that we believe we can have more discernible benefit for earlier.

Alan H. Cohen: Why we're focusing on LCI in addition to spirometry is not just its ability to be reproducible, but it also is measuring another component of the airway that we believe we can have more discernible benefit for earlier and in a smaller number of subjects. Spirometry measures can change slightly as well in these larger airways, and these are more central airways, but it does require more active engagement to be sufficiently reproducible. That's why I was alluding earlier to the controls that we're putting into this study as to making sure that a patient has reproducibility in screening and baseline before going into drug dosing so that we have a more accurate, reproducible baseline with which to compare subsequent changes over the 12-week course of the study.

Alan Cohen: Why we're focusing on LCI in addition to spirometry is not just its ability to be reproducible, but it also is measuring another component of the airway that we believe we can have more discernible benefit for earlier and in a smaller number of subjects. Spirometry measures can change slightly as well in these larger airways, and these are more central airways, but it does require more active engagement to be sufficiently reproducible. That's why I was alluding earlier to the controls that we're putting into this study as to making sure that a patient has reproducibility in screening and baseline before going into drug dosing so that we have a more accurate, reproducible baseline with which to compare subsequent changes over the 12-week course of the study.

Speaker #4: And in a smaller number of subjects . Spirometry measures can change slightly as well . In these larger airways , and these are more central airways .

Speaker #4: But it does require more active engagement to be sufficiently reproducible. That's why I was alluding earlier to the controls that we're putting into this study.

Speaker #4: As to making sure that a patient has reproducibility in screening and baseline before going into drug dosing so that we have a more accurate , reproducible baseline with which to compare subsequent changes over the 12 week course of the study .

Speaker #6: All right . Thank you for that . And also just a question on the OTC program . You know , as you're having your discussions with regulatory authorities , you know , about a Registrational trial , how has their reception been for for certain biomarkers and assays like Ureogenesis function using the nitrogen 15 isotope or any other biomarker , they may be less familiar with .

Pete Stavropoulos: All right. Thank you for that. Also just a question on the OTC program. You know, as you're having your discussions with regulatory authorities, you know, about a registrational trial, how has their reception been for certain biomarkers and assays, you know, like ureogenesis, function using the nitrogen-15 isotope or any other biomarker they may be less familiar with? You know, what's sort of the base case outcome for a study design?

Speaker #6: And you know, what sort of the base case outcome for a study design?

Speaker #3: Well, those are all great questions. And that's currently where we are. We're actively engaged in preparing for these Type C meetings.

Joseph Payne: Well, those are all great questions. That's currently where we are. We're actively engaged in preparing for these Type C meetings in the next few months. We're gonna be in a much better position to answer those with granularity and specificity. That's exactly what we're currently engaged with the FDA on is the future study approaches, the design, the size, the scope of the study, understanding what they would like to see before we can proceed further into the clinical development. We'll have that regulatory clarity shortly. That's our intent, that's our aim. They're all good questions. We'll be in a better position to answer those in a few months.

Speaker #3: And in the next few months , we're going to be in a much better position to answer those with granularity and specificity . But that's exactly what we're currently engaged with the FDA on .

Speaker #3: Is the future study approaches . The design , the size , the scope of the study , understanding what they would like to see before we can proceed further into clinical development .

Speaker #3: So we'll have that regulatory clarity shortly . That's our intent . That's our aim . they're all good questions . But we'll be in a better position to answer those in a few months .

Speaker #6: All right. Thank you very much, and congrats on the quarter and the progress. Yeah.

Pete Stavropoulos: All right. Thank you very much, and congrats on the quarter and the progress.

Joseph Payne: Yeah. Thanks, Pete.

Speaker #3: Thanks , Pete .

Speaker #1: We'll move next to Sheamus Fernandez with Guggenheim Securities. Your line is open.

Operator: We'll move next to Seamus Fernandez with Guggenheim Securities. Your line is open.

Speaker #7: Hi , guys . This is Evan Wang on for Seamus Fernandez . Just a few from us . Looking forward to the start of the 12 weeks CF study .

[Analyst] (Guggenheim Securities): Hi, guys. This is Evan weighing on for Seamus Fernandez. Just a few from us. Looking forward to the start of the 12-week CF study. Just wanted to clarify. It sounds like dosing is proceeding at the 15 mg dose cohort. Just curious what drove the decision to proceed with the 15 mg dose over 10. Was there any evidence of dose response on any of the lung function measures, or CT scans? Second, just in current, in terms of the planned enrollment for CF, and you mentioned both US and international recruitment. Just curious how you're thinking about maybe the split between US and abroad. Thanks.

Evan Wang: Hi, guys. This is Evan weighing on for Seamus Fernandez. Just a few from us. Looking forward to the start of the 12-week CF study. Just wanted to clarify. It sounds like dosing is proceeding at the 15 mg dose cohort. Just curious what drove the decision to proceed with the 15 mg dose over 10. Was there any evidence of dose response on any of the lung function measures, or CT scans? Second, just in current, in terms of the planned enrollment for CF, and you mentioned both US and international recruitment. Just curious how you're thinking about maybe the split between US and abroad. Thanks.

Speaker #7: Just wanted to clarify . So it sounds like dosing is proceeding at the 15 mcg dose cohort . Just curious what drove the decision to proceed with the 15 mcg dose Over ten .

Speaker #7: Was there any evidence of dose response on any of the lung function measures or CT scan ? Second , just in terms of a plan , enrollment for CF , you mentioned both us and international recruitment .

Speaker #7: Just curious how you're thinking about maybe the split between us and abroad . Thanks .

Speaker #3: A couple of good questions . First of all , a point of clarification . Just so it's not misunderstood , we have achieved safety and tolerability data for the 15 milligram level , but we're actually initiating our fourth cohort at the ten milligram level .

Joseph Payne: A couple good questions. First of all, a point of clarification, just so it's not misunderstood. We have achieved safety and tolerability data for the 15 mg level, but we're actually initiating our 4th cohort at the 10 mg level. We were fortunate to see early efficacy, some early clinical, some early clinical signals in our smaller cohorts at 10 mg. We're gonna continue that and see if we can see improvements as we extend the study in larger numbers. With respect to the plan to enroll in the US, we are enrolling internationally, including Europe and the Middle East. Alan can maybe share some of the strategies as to why we're expanding our enrollment in other countries.

Speaker #3: We were fortunate to see early efficacy some early clinical , some early clinical signals in in our smaller cohorts at ten milligrams . So we're going to continue that and see if we can see improvements as we extend the study in larger numbers with respect to the plan to enroll in the US and we are enrolling internationally , including Europe and the Middle East .

Speaker #3: But Allen can maybe share some of the strategies as to why we're expanding our enrollment in other countries.

Speaker #4: Sure . Thank you , Joe , and a great question . So the plan right now , we've actually expanded our US sites .

Alan H. Cohen: Sure. Thank you, Joe, and a great question. The plan right now, we've actually expanded our US sites, so we have additional US sites ready to go for the cohort 4 study, which we will be initiating shortly, and have added, as Joe mentioned, European as well as Middle Eastern sites. The intent there is to really go into parts of the world where there is a higher preponderance of null or type 1 CF genetic mutants so that there is a larger percentage within those populations, and it should yield a greater likelihood of identifying, engaging, and enrolling patients in a much more timely manner over the course of the calendar year.

Alan Cohen: Sure. Thank you, Joe, and a great question. The plan right now, we've actually expanded our US sites, so we have additional US sites ready to go for the cohort 4 study, which we will be initiating shortly, and have added, as Joe mentioned, European as well as Middle Eastern sites. The intent there is to really go into parts of the world where there is a higher preponderance of null or type 1 CF genetic mutants so that there is a larger percentage within those populations, and it should yield a greater likelihood of identifying, engaging, and enrolling patients in a much more timely manner over the course of the calendar year.

Speaker #4: So we have additional US sites ready to go for the cohort four study, which we will be initiating shortly. And we have added, as Joe mentioned, European as well as Middle Eastern sites.

Speaker #4: The intent there is to really go into parts of the world where there is a higher per ponderance of null or type one cf genetic mutants , so that there is a larger percentage within those populations , and it should yield a greater likelihood of identifying , engaging , and enrolling patients in a much more timely manner over the course of the calendar year .

Speaker #7: Just one follow up from me , then , just between the 15 and ten mcg dose , because you mentioned the improvements at the ten mcg were anything you can share in terms of the responder rate at the 15 MCG relative to the ten , did we did you see a response on FEV or CT scan there ?

[Analyst] (Guggenheim Securities): Just one thought from me then. Just between the 15 and 10 mig dose, because you mentioned improvements at the 10 mig, anything you can share in terms of the responder rate at the 15 mig, relative to the 10? Did you see a response on FEV or CT scan there? I guess in terms of similar benchmarks...

Evan Wang: Just one thought from me then. Just between the 15 and 10 mig dose, because you mentioned improvements at the 10 mig, anything you can share in terms of the responder rate at the 15 mig, relative to the 10? Did you see a response on FEV or CT scan there? I guess in terms of similar benchmarks...

Speaker #7: I guess in terms of similar benchmark that you presented , the the earlier data ? Thanks .

Joseph Payne: Right.

[Analyst] (Guggenheim Securities): how you presented the earlier data. Thanks.

Evan Wang: how you presented the earlier data. Thanks.

Speaker #3: No . Yes . We we've completed the dosing phase for the third cohort at 15mg . And we've collected sufficient safety and tolerability data to share with the safety Review Committee to allow us to permit , you know , to permit us to proceed into the 12 week study with respect to the the other data that that data collection process is ongoing .

Joseph Payne: Yes, we've completed the dosing phase for the third cohort at 15 milligrams, and we've collected sufficient safety and tolerability data to share with the Independent Safety Review Committee to allow us to permit, you know, to permit us to proceed into the 12-week study. With respect to the other data, that data collection process is ongoing, and that's where we are. What was significant was to allow us to proceed into the fourth cohort.

Speaker #3: And that's where we are . But what was significant was to allow us to proceed into the fourth cohort

Speaker #7: Got it. Thank you.

[Analyst] (Guggenheim Securities): Got it. Thank you.

Evan Wang: Got it. Thank you.

Speaker #3: Thanks , Evan .

Joseph Payne: Thanks, Evan.

Speaker #1: We'll move next to Lily Songo with Leerink Partners . Your line is open .

Operator: We'll move next to Lili Nsongo with Leerink Partners. Your line is open.

Speaker #8: Hi . Good afternoon . Thank you for taking my question . So two questions for me . The first one on the CF program .

Lili Nsongo [Vice President: Hi. Good afternoon. Thank you for taking my question. Two questions for me. The first one on the CF program. Thinking about, again, moving on to the 12-week study, what was the rationale to stop at 15 mg given that you haven't seen any safety signal? And would there be enough design flexibility to potentially increase the dosing as you accumulate data? Then I have a follow-up question on the OTC program.

Aurelie Nsongo: Hi. Good afternoon. Thank you for taking my question. Two questions for me. The first one on the CF program. Thinking about, again, moving on to the 12-week study, what was the rationale to stop at 15 mg given that you haven't seen any safety signal? And would there be enough design flexibility to potentially increase the dosing as you accumulate data? Then I have a follow-up question on the OTC program.

Speaker #8: So thinking about again , moving on to the 12 week study , what was the rationale to stop at 50mg given that you haven't seen any safety signal and would would there be enough design flexibility to potentially increase the dosing as you accumulate data ?

Speaker #8: And then I have a follow-up question on the OTC program.

Speaker #3: Yes, we definitely have the flexibility to increase dosing. And we're very happy that we already have the ability to increase to 15 mg if necessary.

Joseph Payne: Yes, we definitely have the flexibility to increase dosing, and we're very happy that we already have the ability to increase to 15 milligrams if necessary. Just to maybe reiterate, the 10 milligrams showed early signs of working in the second cohort, so we're simply extending the duration of that treatment in a larger cohort. We're now pleased that we have the flexibility to increase dosing to 15 milligrams if needed. It's unlikely that we will need to increase dosing even further. We would have flexibility to do so if needed. We did dose up to 27 milligrams in our early trials in human volunteers, so there is some headroom there to expand further. We feel confident in the dose that we've selected at 10 to start this fourth cohort.

Speaker #3: But just to maybe reiterate that ten milligrams showed early signs of working in the second cohort . So we're simply extending the duration of that treatment in a larger cohort .

Speaker #3: And we're now pleased that we have the flexibility to increase dosing to 15mg if needed . It's it's unlikely that we will need to increase dosing even further , but we would have flexibility to do so if needed .

Speaker #3: We did dose up to 27 mg in our early trials in human volunteers, so there is some headroom there to expand further.

Speaker #3: But we feel confident in the dose that we've selected at ten to start the fourth cohort Okay .

Speaker #8: Thank you . Maybe just a follow up for the OTC program . Do you expect a bifurcated regulatory path for both the pediatric and then the more the more adult patient population ?

Lili Nsongo [Vice President: Great. Thank you. Maybe just a follow-up. For the OTC program, do you expect a bifurcated regulatory path for both the pediatric and then the more adult patient population?

Aurelie Nsongo: Great. Thank you. Maybe just a follow-up. For the OTC program, do you expect a bifurcated regulatory path for both the pediatric and then the more adult patient population?

Speaker #3: Yeah, I think that's safe to assume that the younger children will be treated differently than the older stable adult population, simply because the need is far more severe in younger children.

Joseph Payne: Yeah, I think that's safe to assume that the younger children will be treated differently than the older, stable adult population simply because the need is far more severe in younger children. It's a different population. Anything to add to that, Alan?

Speaker #3: And it's a different population . But anything to add to that ? Alan .

Speaker #4: Yeah , I mean , in many ways , I think where we are with the program , and important to note that since there are survivors within OTC deficiency into adulthood , even though it's vastly different in terms of the medical complexity and the ability to be functional without needing a liver transplant .

Alan H. Cohen: Yeah. I mean, in many ways, I think where we are with the program and important to note that since there are survivors with an OTC deficiency into adulthood, even though it's vastly different in terms of the medical complexity and the ability to be functional without needing a liver transplant, we were able to show up to this point safety tolerability, and we believe early signs and signals of efficacy.

Alan Cohen: Yeah. I mean, in many ways, I think where we are with the program and important to note that since there are survivors with an OTC deficiency into adulthood, even though it's vastly different in terms of the medical complexity and the ability to be functional without needing a liver transplant, we were able to show up to this point safety tolerability, and we believe early signs and signals of efficacy.

Speaker #4: We did . We were able to show up to this point , safety , tolerability , and we believe early signs and signals of efficacy .

Speaker #4: Now , in our discussions with the FDA on looking at a younger population where survival tends to be quite , quite bleak beyond preschool and school age , the intent there is to really see if we can leverage the the most recent guidances that the FDA has shared about their willingness to look into ultra rare populations with severe outcomes and their willingness to be more .

Alan H. Cohen: In our discussions with the FDA on looking at a younger population where survival tends to be quite bleak beyond preschool and school age. The intent there is to really see if we can leverage the most recent guidances that the FDA has shared about their willingness to look into ultra-rare populations with severe outcomes and their willingness to give more latitude and flexibility in terms of how one conducts those studies, as long as there's sufficient safety and tolerability and obviously, efficacy. We're encouraged by the early conversations that we're having with the agency right now. We'll continue to pursue those to the benefit of the OTC deficiency community.

Alan Cohen: In our discussions with the FDA on looking at a younger population where survival tends to be quite bleak beyond preschool and school age. The intent there is to really see if we can leverage the most recent guidances that the FDA has shared about their willingness to look into ultra-rare populations with severe outcomes and their willingness to give more latitude and flexibility in terms of how one conducts those studies, as long as there's sufficient safety and tolerability and obviously, efficacy. We're encouraged by the early conversations that we're having with the agency right now. We'll continue to pursue those to the benefit of the OTC deficiency community.

Speaker #4: Give more latitude and flexibility in terms of how one conducts those studies . As long as there's sufficient safety and tolerability and obviously efficacy .

Speaker #4: So we're encouraged by the early conversations that we're having with the agency right now and will continue to pursue those to the benefit of the OTC deficiency community

Speaker #8: Thank you for the added color.

Yanan Zhu: Great. Thank you for the update, Colin.

Aurelie Nsongo: Great. Thank you for the update, Colin.

Speaker #3: Thanks , Lily .

Joseph Payne: Thanks, Lily.

Speaker #1: We'll move next to Yanan Zhou with Wells Fargo. Your line is open.

Operator: We'll move next to Yanan Zhu with Wells Fargo. Your line is open.

Speaker #9: Thanks for taking our questions. Maybe first on the CF program—I think you mentioned, with effort in cohort four, the goal is to obtain a stable baseline.

Yanan Zhu: Thanks for taking our questions. Maybe first on the CF program. I think you mentioned one effort in cohort four is to obtain stable baseline. Remind us why, you know, that's important? How are you going to go about and do that? Also curious, during the three-month trial period, could it be possible that patient had a stable baseline, but for some reason their reading could, you know, begin to fluctuate or drift after having had that stable baseline within a three-month period? Thank you.

Speaker #9: Remind us why that's important . How are you going to go about and do that . And also curious during the three month trial period , could it be possible that patient had a stable baseline , but for some reason they're reading ?

Speaker #9: Could begin to fluctuate or drift after having had that stable baseline within a three-month period? Thank you.

Speaker #3: Thanks . Yeah . Cohort four is definitely different with respect to the the three cohorts . And that we've designed it with a stronger baseline .

Joseph Payne: Thanks, Yanan. Yeah, cohort four is definitely different with respect to the first three cohorts and that we've designed it with a stronger baseline. Alan, maybe you can comment further there.

Speaker #3: Allen , maybe you can comment further there .

Speaker #4: Yeah . So so what we've done here and a great question . You know as best as we can one should realize that because of the complexity of the lung disease and the impact that it has in the various segments of the lung at any given time , what we're looking for at baseline with these adult patients , with CF is at least enough reproducibility .

Alan H. Cohen: Yeah. What we've done here, and it's a great question. You know, as best as we can, one should realize that because of the complexity of the lung disease and the impact that it has in the various segments of the lung at any given time, what we're looking for at baseline with these adult patients with CF is at least enough reproducibility and as small a possible variability within the period of time that we screen to baseline to get them enrolled, that we believe that we have an as accurate a representation of where they are at that moment in time as far as their lung disease is advancing and progressing.

Alan Cohen: Yeah. What we've done here, and it's a great question. You know, as best as we can, one should realize that because of the complexity of the lung disease and the impact that it has in the various segments of the lung at any given time, what we're looking for at baseline with these adult patients with CF is at least enough reproducibility and as small a possible variability within the period of time that we screen to baseline to get them enrolled, that we believe that we have an as accurate a representation of where they are at that moment in time as far as their lung disease is advancing and progressing.

Speaker #4: And as small as possible variability within the period of time that we screened to baseline to get them enrolled, that we believe that we have as accurate a representation of where they are at that moment in time, as far as their lung disease is advancing and progressing.

Speaker #4: It's not unexpected . In the course of a 3 or 6 month period that many of these patients may have an acute pulmonary exacerbation or an acute illness .

Alan H. Cohen: It's not unexpected in the course of a 3 or 6-month period that many of these patients may have an acute pulmonary exacerbation or an acute illness, and we're prepared to handle that. What we wanted to try to mitigate and deal with was the variability that is seen not uncommonly in patients with COPD, cystic fibrosis, asthma, et cetera, particularly those who are vulnerable and chronically infected with pathogens. We're really tightening up the enrollment criteria. We're setting parameters, and that's why we believe it. We're just looking to make sure that it's reproducible and stable at that baseline. We're not gonna be enrolling CF patients that may be in the early throes of a pulmonary exacerbation or an acute illness. Sometimes just even modest changes can be an early signal for that.

Alan Cohen: It's not unexpected in the course of a 3 or 6-month period that many of these patients may have an acute pulmonary exacerbation or an acute illness, and we're prepared to handle that. What we wanted to try to mitigate and deal with was the variability that is seen not uncommonly in patients with COPD, cystic fibrosis, asthma, et cetera, particularly those who are vulnerable and chronically infected with pathogens. We're really tightening up the enrollment criteria. We're setting parameters, and that's why we believe it. We're just looking to make sure that it's reproducible and stable at that baseline. We're not gonna be enrolling CF patients that may be in the early throes of a pulmonary exacerbation or an acute illness. Sometimes just even modest changes can be an early signal for that.

Speaker #4: And we're prepared to handle that . But what we wanted to try to mitigate and deal with was the variability that is seen , not uncommonly , in patients with COPD , cystic fibrosis , asthma , etc.

Speaker #4: , particularly those who are vulnerable and chronically infected with pathogens . So we're really tightening up the enrollment criteria . We're setting parameters and and and that's why we believe it .

Speaker #4: We're just looking to make sure that it's reproducible and stable at baseline . And we're not going to be enrolling CF patients that may be in the early throes of a of a pulmonary exacerbation or an acute illness .

Speaker #4: And sometimes just even modest changes can be an early signal for that . We want to enhance the noise to signal ratio . And once again , one more thing to think about .

Alan H. Cohen: We want to enhance the noise-to-signal ratio. Once again, one more thing to think about. Unlike lung clearance index, spirometry really does require a consistent study subject performance. It's not a passive maneuver. Anything that we can do to make sure that a patient coming into our study has a representative baseline is really what we're trying to achieve here.

Alan Cohen: We want to enhance the noise-to-signal ratio. Once again, one more thing to think about. Unlike lung clearance index, spirometry really does require a consistent study subject performance. It's not a passive maneuver. Anything that we can do to make sure that a patient coming into our study has a representative baseline is really what we're trying to achieve here.

Speaker #4: Unlike lung clearance index , spirometry really does require a consistent study subject performance . It's not a passive maneuver . So anything that we can do to make sure that a patient coming into our study has a representative baseline is really what we're trying to achieve here .

Speaker #9: Great . That's super helpful . Two more questions , if I may , on the OTC deficiency regulatory interaction front , could you lay out for us to you and to the principal investigators what would be considered a exciting outcome with regard to the alignment and and what perhaps also what might be the base case scenario for the alignment and lastly , I wanted to wondering if you have any update on the Covid 19 vaccine initiatives between you and the CSL ?

Yanan Zhu: Great. That's super helpful. Two more questions, if I may. On the OTC deficiency regulatory interaction front, could you lay out for us, to you and to the principal investigators, what would be considered a exciting outcome with regard to the alignment? What perhaps also might be the base case scenario for the alignment. Lastly, wondering if you have any update on the COVID-19 vaccine initiatives between you and CSL. Thank you.

Speaker #9: Thank you .

Speaker #3: Yeah , I can I can take those questions . So we're definitely working with the FDA to establish care clarity . Right . That's the main objective .

Joseph Payne: Yeah, I can take those questions, Yanan. We're definitely working with the FDA to establish clarity, right? That's the main objective. As investors are, you know, looking at, what are we trying to achieve with these Type C meetings, it's clarity. We want a clear path forward to helping both the children in need with high unmet medical need, more severe disease and the stable adults, right? We're presenting our case, we're presenting our data and basically looking to have clarity in the path forward. Anything to add there before I comment on CSL, Allan?

Speaker #3: So as investors are looking at what are we trying to achieve with these type C meetings ? It's clarity . We want a clear path forward to helping both the the children in need with high unmet medical need , more severe disease and the stable adults .

Speaker #3: Right . So we're we're presenting our case . We're presenting our our data and and basically looking To have clarity in the path forward .

Speaker #3: Anything to add there before I comment on CSL , Allen .

Speaker #4: No . And you know , obviously in these patients , the the goals and objectives for the children is quite different because of the severity and nature and and labil nature of the disease in children as opposed to the much more stable adults , even with current standards of care , you know , the goals and objectives of a pediatric program would would be to try to mitigate as best we can the the the damaging neurological and developmental issues that they contend and deal with on a daily basis just by having Oct deficiency Despite the fact that there are now therapies like ammonia binding agents and abilities to control diet .

Alan H. Cohen: No. You know, obviously in these patients, the goals and objectives for the children is quite different because of the severity and nature and labile nature of the disease in children as opposed to the much more stable adults. Even with current standards of care, you know, the goals and objectives of a pediatric program would be to try to mitigate as best we can the damaging neurological and developmental issues that they contend and deal with on a daily basis just by having OTC deficiency, despite the fact that there are now therapies like ammonia binding agents and abilities to control diet.

Alan Cohen: No. You know, obviously in these patients, the goals and objectives for the children is quite different because of the severity and nature and labile nature of the disease in children as opposed to the much more stable adults. Even with current standards of care, you know, the goals and objectives of a pediatric program would be to try to mitigate as best we can the damaging neurological and developmental issues that they contend and deal with on a daily basis just by having OTC deficiency, despite the fact that there are now therapies like ammonia binding agents and abilities to control diet.Success for us would be, as Joe said, a clear path forward with agreed endpoints and goals and objectives that are not only attainable, but are potable and acceptable to the families and patients as well as the caregivers and their current standards of care.

Speaker #4: So success for us would be , as Joe said , a clear path forward with agreed endpoints and goals and objectives that are not only attainable but are potable and acceptable to the families and patients , as well as the caregivers and their current standards of care

Alan H. Cohen: Success for us would be, as Joe said, a clear path forward with agreed endpoints and goals and objectives that are not only attainable, but are potable and acceptable to the families and patients as well as the caregivers and their current standards of care.

Speaker #3: And the detail . Yeah , and the details of that will be able to provide that granularity in a couple of months . But appreciate the question with respect to your CSL related question .

Joseph Payne: The details of that, we'll be able to provide that granularity in a couple of months, but appreciate the question. With respect to your CSL-related question in KOSTAIVE, yes, we definitely made some progress for the KOSTAIVE asset and for the platform in the UK. It was good to see that we advanced KOSTAIVE to the point of approval and licensure in the UK. The present administration here domestically has made it challenging to progress KOSTAIVE to licensure or approval in the near term here in the US. Because of this, and understandably, CSL and Arcturus are in active discussions regarding our collaboration, and we're gonna be able to provide more color on that in the coming months.

Speaker #3: And coast, Dave, we definitely made some progress for the coast. Dave asset, and for the platform in the United Kingdom. It was good to see that we advance coast.

Speaker #3: Dave, to the point of approval and licensure in the United Kingdom. But the present administration, the present administration here domestically, has made it challenging to progress, coast.

Speaker #3: Dave, to licensure or approval in the near term here in the US. So because of this, and understandably, CSL and Arcturus are in active discussions regarding our collaboration, and we're going to be able to provide more color on that in the coming months.

Speaker #9: Great. Thanks for all the color.

Yale Jen: Great. Thanks for all the color.

Speaker #3: Thanks .

Joseph Payne: Thanks.

Speaker #1: We'll take our next question from Miles Minter with William Blair . Your line is open .

Operator: We'll take our next question from Myles Minter with William Blair. Your line is open.

Speaker #10: Hey . Thanks , guys , for the questions . First one is just on the fact that I think you're deciding between the ten mcg and the 15 mcg dose for the 032 phase two trial , I think you're waiting on 15 mcg efficacy data .

Myles Minter: Hey, thanks guys for the questions. First one's just on the fact that I think you're deciding between the 10 mig and the 15 mig dose for the ARCT-032 phase 2 trial. I think you're waiting on 15 mig efficacy data. You've got the safety and tolerability, obviously.

Speaker #10: You've got the safety and tolerability . Obviously , I'm trying to understand what the puts and takes are for selecting dose moving forward .

Joseph Payne: Yeah.

Myles Minter: I'm trying to understand what the puts and takes are for selecting dose moving forward. Like, if you did get this efficacy data in for the 15 migs, and it looked fine, but you have more data in 10 migs, like, which dose or would you take both doses forward? I'm trying to understand your logic.

Speaker #10: Like if you did get this efficacy data in for the 15 MGS and it looked fine , but you have more data in ten mgs like which dose or would you take both doses for .

Speaker #10: I'm trying to understand your logic between .

Joseph Payne: Yeah.

Myles Minter: between picking both, doses.

Speaker #3: Sure .

Speaker #10: Sure .

Joseph Payne: Sure. Sure. It's relatively straightforward in that 10 milligrams showed early signs of working in the second cohort, so we're simply extending the duration of treatment into a larger cohort and extending that duration. We now have the flexibility to increase the dose. That's what this means. Only if needed. There's many that are suggesting that efficacy is achieved through simple duration by extending the treatment, and we're gonna prove that. At some point, because it's an open-label study, if we feel we need to increase the dose, we can. I also remind folks that it's a fairly pricey product to manufacture. If we can keep cost of goods down, that's also a good benefit by keeping the dose down at around 10 milligrams as well.

Speaker #3: So it's it's relatively straightforward in that ten milligrams showed early signs of working . In the second cohort . So we're simply extending the duration of treatment into a larger cohort and extending that duration .

Speaker #3: We now have the flexibility to increase the dose . That's what this means . And only if needed . There's many that are suggesting that that efficacy is achieved through simple duration by extending the treatment .

Speaker #3: And we're going to prove that . And at some point , because it's an open label study , if if we feel we need to increase the dose , we can also remind folks that it's it's fairly pricey product to manufacture .

Speaker #3: So if we can keep cost of goods down , that's also a good benefit by keeping the dose down at around ten milligrams as well .

Speaker #3: But it's simply based on data that at ten milligrams. We saw progress. So we think we're going to extend the duration and the size of the study to see if it works in that context and that new in the fourth cohort.

Joseph Payne: It's simply based on data that at 10 milligrams we saw progress. We think we're gonna extend the duration and the size of the study to see if it works in that context, in the fourth cohort. We now have the flexibility to increase the dose if needed.

Speaker #3: And we now have the flexibility to increase the dose if needed.

Speaker #11: Cool . Thanks

Myles Minter: Cool. Thanks.

Speaker #3: Thanks , Miles .

Joseph Payne: Thanks, Myles.

Speaker #1: We'll take our next question from Adam Walsh with Roth Capital. Your line is open.

Operator: We'll take our next question from Adam Walsh with Roth Capital. Your line is open.

Speaker #12: Hi . Good afternoon . Thanks for taking my questions . The first on 032 , the CF product you've talked about the first week in your clinical trials or two of being an onboarding phase where the drug is sort of getting through the congested airways .

Adam Walsh: Hi, good afternoon. Thanks for taking my questions. The first on ARCT-032, the cystic fibrosis product. You've talked about the first week in your clinical trials or two of being an onboarding phase where the drug is sort of getting through the congested airways. In a 12-week study, you'd have roughly 10 productive weeks versus maybe two or three in the 28-day study. How should we think about that from an extra exposure time as it relates to FEV1 and mucus clearance versus what we maybe saw at 28 days? Thank you.

Speaker #12: So in a 12 week study , you'd have roughly ten productive weeks versus maybe 2 or 3 in the 28 day study . How should we think about that from an extra exposure time as it relates to fev1 and mucus clearance versus what we maybe saw at 28 days ?

Speaker #12: Thank you .

Speaker #3: Yeah . Adam , that's a thoughtful question . And you're absolutely right . We view that in our 28 day study . We observed consistently that there was a 1 to 2 week onboarding phase .

Joseph Payne: Yeah, Adam, that's a thoughtful question, and you're absolutely right. We view that in our 28-day study, we observed consistently that there was a 1 to 2 week onboarding phase. In reality, there's really only a 2-week healing phase for that 28-day study. As we go to the 12 weeks study, assuming a similar onboarding rate of 1 to 2 weeks, you have 10 full weeks of potential healing and efficacy reads. It's a difference between 2 and 10 weeks. Under that, from that perspective, it is a significant improvement. If you look at the study as a whole, we're going from 4 weeks to 12 weeks. It's a 3-fold difference. That's also a significant bump.

Speaker #3: And so in reality , there's really only a two week healing phase for that 28 day study . So as we go to the 12 weeks study , assuming a similar onboarding rate of 1 to 2 weeks , then you have ten full weeks of of potential healing and efficacy reads .

Speaker #3: So I it's a difference between 2 and 10 weeks . So under that from that perspective , it is a significant improvement . But if you look at the study as a whole , we're going from four weeks to 12 weeks .

Speaker #3: It's a three fold difference . That's also a significant bump . And but your observation is sound . And we agree with you that it's it's not only three folding the time of the study , but increasing the duration of potential healing and efficacy with this 12 week study

Joseph Payne: Your observation is sound, and we agree with you that it's not only 3-folding the time of the study, but increasing the duration of potential healing and efficacy with this 12-week study.

Speaker #12: Thanks. And then if I could, one on 810 for OTC deficiency Phase 2 patients who stayed on standard of care. So to my knowledge, we haven't seen whether patients can actually reduce scavengers or loosen dietary restrictions on 810.

Adam Walsh: Thanks. If I could, one on ARCT-810 for OTC deficiency. Phase II patients stayed on standard of care. To my knowledge, we haven't seen whether patients can actually reduce scavengers or loosen dietary restrictions on ARCT-810. Is that something you plan to build into the pivotal? How important do you think that kind of functional clinical data will be for the approval conversations versus the biomarker package alone? Thank you.

Speaker #12: Is that something you plan to build into the pivotal ? And how important do you think that kind of functional , clinical data will be for the approval conversations versus the biomarker package alone ?

Speaker #12: Thank you .

Speaker #3: Okay , that exact question is , is in the agenda of our type C meetings this year . So for both the children , early onset and also with the the stable adult population .

Joseph Payne: Hey, that exact question is in the agenda of our Type C meetings this year. For both, the children early onset and also, with the stable adult population. It's the right question. We'll be able to provide the answer to that question in more detail in a couple of months after our Type C meetings are completed and we've received their feedback.

Speaker #3: So it's the right question . We'll be able to provide the answer to that question in more detail in a couple of months after our type C meetings are completed and we've received their feedback

Speaker #12: Thank you .

Adam Walsh: Thank you.

Speaker #3: Thanks , Adam

Joseph Payne: Thanks, Adam.

Speaker #1: We'll take our next question from Whitney Ijem with Canaccord . Your line is open .

Operator: We'll take our next question from Whitney Ijem with Canaccord. Your line is open.

Speaker #13: Hi , guys . Thank you for taking your questions . This is Angela on for Whitney . Maybe just to follow up on the program again .

[Analyst] (Canaccord Genuity): Hi, guys. Thank you for taking our questions. This is Angela on for Whitney. Maybe just to follow up on the CF program again. Understand you're progressing with the 10 milligrams for the 12-week study, but are you still looking at efficacy in the 15-milligram cohort? I guess, like what efficacy endpoints are you looking at? Will you be sharing that data at some point, either in a PR or at a medical conference? The second part is, would it be possible that you would run another 12-week study using the 15 milligrams? When you talk about the optionality to dose up, was that part of the current 10 milligram study? Thank you.

Angela Qian: Hi, guys. Thank you for taking our questions. This is Angela on for Whitney. Maybe just to follow up on the CF program again. Understand you're progressing with the 10 milligrams for the 12-week study, but are you still looking at efficacy in the 15-milligram cohort? I guess, like what efficacy endpoints are you looking at? Will you be sharing that data at some point, either in a PR or at a medical conference? The second part is, would it be possible that you would run another 12-week study using the 15 milligrams? When you talk about the optionality to dose up, was that part of the current 10 milligram study? Thank you.

Speaker #13: So understand your progressing with the ten milligrams for the 12 week study . But are you still looking at efficacy in the 15 milligram per quart ?

Speaker #13: I guess, like, what efficacy endpoints are you looking at? And will you be sharing that data at some point, either in a press release or at an analytical conference?

Speaker #13: And the second part is , would it be possible that you would run another 12 week study using the 15mg , or do you , when you talk about the optionality to dose up with that part of the current ten milligram study , because it was thank you .

Speaker #3: Yeah , it's unlikely that we'll be sharing any more data from the first three cohorts . We are focused on the fourth cohort .

Joseph Payne: Yeah. It's unlikely that we'll be sharing any more data from the first 3 cohorts. We are focused on the 4th cohort. This almost like a phase 2b type study, where we believe that our best shot on goal here is in a 12-week duration, N of 20 study. That's where we're focusing on. I think that's where the investors should also be focused on. You've asked are we collecting data for 15 mg? Absolutely. Is there a time and a place to share that data? Yeah, very likely. We remain focused on the 12-week study, is the short answer to your question.

Speaker #3: This almost like a phase two B type study where we believe that our best shot on goal here is in . In a 12 week duration end of 20 study .

Speaker #3: And that's where we're focusing on . So I think that's where the investors should also be focused on . But you've asked are we collecting data for 15mg ?

Speaker #3: Absolutely . Is there a time and a place to share that data ? Yeah . Very likely . But we remain focused on on the 12 week study as the short answer to your question

Speaker #13: Got it. And then, will you essentially be dosing up to 15 mg in this study, or would that be a separate study?

[Analyst] (Canaccord Genuity): Got it. Will you potentially be dosing up to 15mg in the 12-week study, or would that be a separate study?

Angela Qian: Got it. Will you potentially be dosing up to 15mg in the 12-week study, or would that be a separate study?

Speaker #3: Only if needed ? It's an open label study . We have the flexibility to do it based upon what's happened in the third cohort , which is great .

Joseph Payne: Only if needed. It's an open label study. We have the flexibility to do it based upon what's happened in the third cohort, which is great. We still haven't collected all the data, of course, and that additional data could sway our minds either direction. Right now, we're initiating the fourth cohort at the 10 mg dose level, and we have the flexibility now to increase it if needed.

Speaker #3: And we still have collected all the data , of course . And that additional data could sway our minds either direction . But right now we're initiating the the fourth cohort of the ten milligram dose level .

Speaker #3: And we have the flexibility now to increase it if needed

Speaker #13: Thank you .

[Analyst] (Canaccord Genuity): Great. Thank you.

Angela Qian: Great. Thank you.

Speaker #3: Thank you Angela

Joseph Payne: Thank you, Angela.

Speaker #1: And we'll take our next question from Ugo Nanocomposites with city . Your line is open .

Operator: We'll take our next question from Yigal Nochomovitz with Citi. Your line is open.

Speaker #14: Hi , guys . This is Joanne Kim on for your call . Thanks so much for taking our question . I kind of have a multi-part question , but I believe in the phase one B you had also assessed LCI , so can you remind us what you had seen previously on LCI ?

Jiwon Kim: Hey, guys. This is Jiwon Kim on for Yugal. Thanks so much for taking our question. I kind of have a multi-part question, but I believe in the phase 1B, you had also assessed LCI. Can you remind us what you had seen previously on the LCI? How should we be thinking about the level of improvement expected in the phase 2B? As you were headed into the dose ranging phase 2, did the FDA get a chance to look at the LCI data by any chance?

Joohwan Kim: Hey, guys. This is Jiwon Kim on for Yugal. Thanks so much for taking our question. I kind of have a multi-part question, but I believe in the phase 1B, you had also assessed LCI. Can you remind us what you had seen previously on the LCI? How should we be thinking about the level of improvement expected in the phase 2B? As you were headed into the dose ranging phase 2, did the FDA get a chance to look at the LCI data by any chance?

Speaker #14: And how should we be thinking about the level of improvement expected in the phase two B and as you were headed into the dose ranging , phase two , did the FDA get a chance to look at LCI data by any chance ?

Speaker #3: Yeah , you're correct that we did look at LCI in the early phase one studies and those phase one was in healthy adults , phase one B was in CF participants and we established safety and tolerability .

Joseph Payne: Yeah. You're correct that we did look at LCI in the early phase I studies. Those phase I was in healthy adults. Phase IB was in CF participants, and we established safety and tolerability that was sufficient to advance it. LCI was only after a single administration or two administrations in phase IB. I'll defer to Allen in terms of that data from phase IB. With respect to LCI as an endpoint, I think I'll also defer to Allen. He can talk about what the literature shows or the magnitudes of changes in LCI to get approval previously in children, et cetera. Go ahead, Allen.

Speaker #3: That was sufficient to advance it . So LCI was only after a single administration or two administrations in phase one B I would I'll defer to Alan in terms of that data from phase one B with respect to LCI as an endpoint , I think I'll also defer to Alan .

Speaker #3: He can talk about what the literature shows, or the magnitudes of changes in CI to get approval. Previously in children, etc.

Speaker #3: Go ahead . Alan .

Speaker #4: Sure , no problem at all . And it's a great question . I wasn't around historically when the early experience with our study drug in those first few cohorts , going from healthy to CF adults were ongoing , but I have had a chance to review the data .

Alan H. Cohen: Sure. No, no problem at all. It's a great question. I wasn't around historically when the early experience with our study drug in those first few cohorts going from healthy to CF adults were ongoing, but I have had a chance to review the data. You know, the challenge of it is, once again, it was small numbers of patients. In the way we're constructing things now, the plan is to benefit from that prior experience and perhaps do it in a more refined way. Right now, we also have the support of the CF Foundation, who is doing a natural history study.

Alan Cohen: Sure. No, no problem at all. It's a great question. I wasn't around historically when the early experience with our study drug in those first few cohorts going from healthy to CF adults were ongoing, but I have had a chance to review the data. You know, the challenge of it is, once again, it was small numbers of patients. In the way we're constructing things now, the plan is to benefit from that prior experience and perhaps do it in a more refined way. Right now, we also have the support of the CF Foundation, who is doing a natural history study.

Speaker #4: You know , the challenge of it is , once again , it was small numbers of patients in the way we're constructing things now .

Speaker #4: The plan is to benefit from that prior experience and perhaps do it in a more refined way . Right now , we also have the support of the CF Foundation , who is doing a natural history study .

Speaker #4: So being able to align with the CF Foundation and the Therapeutic development Network on their prospective study that they're doing right now , in patients with null mutations and those who are unable to tolerate current modulators allows us to align a study in a way so that when that natural history study becomes available in the coming months and year , that we can have access to that as a comparator group , which was something that was not available just a few years ago .

Alan H. Cohen: Being able to align with the CF Foundation and the Therapeutic Development Network on their prospective study that they're doing right now in patients with no mutations and those who are unable to tolerate current modulators allows us to align a study in a way so that when that natural history study becomes available in the coming months and year, that we can have access to that as a comparator group, which was something that was not available just a few years ago. The other piece about this, I think, is that there's increasingly a recognition of not only the sensitivity and the value of LCI measures in adults, but an appreciation for what may be the range and magnitude of change one needs to see in order for there to be an appreciation for a significant, meaningful change over time.

Alan Cohen: Being able to align with the CF Foundation and the Therapeutic Development Network on their prospective study that they're doing right now in patients with no mutations and those who are unable to tolerate current modulators allows us to align a study in a way so that when that natural history study becomes available in the coming months and year, that we can have access to that as a comparator group, which was something that was not available just a few years ago. The other piece about this, I think, is that there's increasingly a recognition of not only the sensitivity and the value of LCI measures in adults, but an appreciation for what may be the range and magnitude of change one needs to see in order for there to be an appreciation for a significant, meaningful change over time.

Speaker #4: The the the other piece about this , I think , is that there's increasingly a recognition of not only the sensitivity and the value of LCI measures in adults , but an appreciation for what may be the range and magnitude of change one needs to see in order for there to be an appreciation for a significant , meaningful change over time .

Speaker #4: So right now , I think we're doing the study in a manner that should optimize its utility and value . And we're also doing it in an alignment and way that should be commensurate with current standards .

Alan H. Cohen: Right now, I think we're doing the study in a manner that should optimize its utility and value, and we're also doing it in an alignment and way that should be commensurate with current standards and practices, which was certainly done before, but just not done as robustly and as long term. Really, I think in this case, just like with percent predicted FEV1 and spirometry, we will be benefiting from a cohort of upwards to 20 patients and an examination of data not just over a 4-week period, but a 12-week period. Both of those elements, in addition to having more normative data to compare to in this exact population, should make interpretation and value of this data much greater than it was previously appreciated. Hopefully, that's helpful to you.

Alan Cohen: Right now, I think we're doing the study in a manner that should optimize its utility and value, and we're also doing it in an alignment and way that should be commensurate with current standards and practices, which was certainly done before, but just not done as robustly and as long term. Really, I think in this case, just like with percent predicted FEV1 and spirometry, we will be benefiting from a cohort of upwards to 20 patients and an examination of data not just over a 4-week period, but a 12-week period. Both of those elements, in addition to having more normative data to compare to in this exact population, should make interpretation and value of this data much greater than it was previously appreciated. Hopefully, that's helpful to you.

Speaker #4: And practices , which was certainly done before , but just not done as robustly . And as long term . And really , I think in this case , just like with percent predicted Fev1 and spirometry , we will be benefiting from a cohort of upwards to 20 patients and an examination of data , not just over a four week period , but a 12 week period .

Speaker #4: So both of those elements , in addition to having more normative data to compare to in this exact population , should make interpretation and value of this data much greater than it was previously appreciated .

Speaker #4: Hopefully that's helpful to you .

Speaker #14: Yes . Thank you very much . Appreciate it

Jiwon Kim: Yes. Thank you very much. Appreciate it.

Joohwan Kim: Yes. Thank you very much. Appreciate it.

Speaker #1: We'll move next to Tom Schrader with BTIG. Your line is open.

Operator: We'll move next to Thomas Shrader with BTIG. Your line is open.

Speaker #15: Good afternoon . Thanks for all the updates . There's been a lot of questions . I assume you've been you've been looking at a lot of pictures of mucus plugs with your data .

[Analyst] (Canaccord Genuity): Good afternoon. Thanks for all the updates. There's been a lot of questions. I assume you've been looking at a lot of pictures of mucus plugs.

Angela Qian: Good afternoon. Thanks for all the updates. There's been a lot of questions. I assume you've been looking at a lot of pictures of mucus plugs.

Thomas Shrader: With your data, do you have a sense of what fraction of patients show a measurable difference? Is it very all over the place, all over the lung? Do you have any patients where it's possible to calculate that in 12 weeks the mucus plug should be gone? Did you have that level of data? I have a quick vaccine follow-up.

Speaker #15: Do you have a sense of what fraction of patients show a measurable difference ? Is it very all over the place , all over the lung ?

Speaker #15: And do you have any patients where it's possible to calculate that, in 12 weeks, the mucus plug should be gone? Do you have that level of data?

Speaker #15: I want to have a quick vaccine follow-up.

Speaker #3: Well , we we we saw four out of six subjects in the second cohort . That was the ten milligram cohort that showed a reduction of mucus plugs after just 28 days .

Joseph Payne: Well, we saw 4 out of 6 subjects in the second cohort, that was a 10 mg cohort, that showed a reduction of mucus plugs after just 28 days. So that was definitely encouraging. There was 1 subject that attributed the increase in mucus plugs to humidity and a sensitivity to humidity. Whether that's an outlier or whether that's simply a non-responder, we will learn as we collect more data, especially in this extended study that's larger. It seems that a majority of these subjects respond with a reduction in mucus plugs, and we feel that that's important to mention, and that's an early sign of, you know, some clinical activity. With respect to your other question, maybe you could restate it and we can turn that over to Alan.

Speaker #3: So that was definitely encouraging . There was one subject that attributed the increase in mucus plugs to to humidity . And the sensitivity to humidity , and whether that's an outlier or whether that's simply a non-responder .

Speaker #3: We we will learn as we collect more data , especially in this extended study . That's larger . But it seems that a majority of these subjects respond with a reduction in mucus plugs .

Speaker #3: And we feel that that's important to mention . And that's an early sign of some clinical activity . With respect to your other question , maybe you could restate it and we can turn that over .

Speaker #3: .

Speaker #15: But just a sense for—you would have had some sense of rates of clearance. Do you have confidence that 12 weeks is enough, or is that more just the next trial you're allowed to do?

Thomas Shrader: You would have had some sense of rates of clearance. Do you have confidence that 12 weeks is enough, or is that more just the next trial you're allowed to do?

Joseph Payne: That's, that's the big question. Clearly, we saw something in 28 days, so there's reason to be confident that we'll see it in an extended study, larger study. It's not just a larger extended study, but, you know, we're looking at a better study, a study that's designed more, tightly with respect to numbers and baseline, steadiness. Anything to add, Alan?

Speaker #3: That's the big question. Clearly, we saw something in 28 days, so there's reason to be confident that we'll see it in an extended study.

Speaker #3: Larger study . And it's not just a larger extended study , but , you know , we're looking at a a better study , a study that's designed more Tightly with respect to numbers and baseline steadiness .

Speaker #3: But anything to add , Alan . Yeah .

Alan H. Cohen: yeah. I was gonna say, you know, the field of using high-resolution CT scanning as a complementary way of assessing progression of disease has been used for some time. I think the technologies, particularly artificial intelligence and an ability to standardize the reads now is vastly different in many ways, much better than it was as recently as just a few years ago. I think the field is emerging. I just wanna make sure that it's understood that, you know, the time constants and the damage that occurs in the lungs of people with cystic fibrosis is really quite patchy.

Alan Cohen: yeah. I was gonna say, you know, the field of using high-resolution CT scanning as a complementary way of assessing progression of disease has been used for some time. I think the technologies, particularly artificial intelligence and an ability to standardize the reads now is vastly different in many ways, much better than it was as recently as just a few years ago. I think the field is emerging. I just wanna make sure that it's understood that, you know, the time constants and the damage that occurs in the lungs of people with cystic fibrosis is really quite patchy.

Speaker #4: Yeah . So I was I was going to say , you know , the the field of using high resolution CT scanning as a complementary way of assessing progression of disease has been used for some time .

Speaker #4: I think the technology is particularly artificial intelligence and an ability to standardize the reads . Now is vastly different in many ways much better than it was as recently as just a few years ago .

Speaker #4: So I think the field is emerging . I would be I just want to make sure that it's understood that , you know , the time constants and the damage that occurs in the lungs of people with cystic fibrosis is really quite patchy .

Speaker #4: And what's remarkable , I'm a former lung transplant physician from Washington University , and I'm one of the few people that has had the chance to actually examine the lungs of people who underwent a lung transplant and sustained significant bronchiectatic damage to the point of needing a lung transplant to survive .

Alan H. Cohen: What's remarkable, I'm a former lung transplant physician from Washington University, and I'm one of the few people that has had the chance to actually examine the lungs of people who underwent a lung transplant and sustained significant bronchiectasis damage to the point of needing a lung transplant to survive. What's impressive about the disease is the very patchy nature, both in the upper and lower lobes. You could have a completely bronchiectasis destroyed segment of lung right next to a completely normal appearing functional segment of a lung. I believe that a drug that's administered by inhalation over long periods of time will eventually have the ability, in large part, to reach many, if not all, of the segments that we need to.

Alan Cohen: What's remarkable, I'm a former lung transplant physician from Washington University, and I'm one of the few people that has had the chance to actually examine the lungs of people who underwent a lung transplant and sustained significant bronchiectasis damage to the point of needing a lung transplant to survive. What's impressive about the disease is the very patchy nature, both in the upper and lower lobes. You could have a completely bronchiectasis destroyed segment of lung right next to a completely normal appearing functional segment of a lung. I believe that a drug that's administered by inhalation over long periods of time will eventually have the ability, in large part, to reach many, if not all, of the segments that we need to.

Speaker #4: What's impressive about the disease is the very patchy nature , both in the upper and lobes , and you can have a completely bronchiectatic destroyed segment of lung right next to a completely normal appearing functional segment of a lung .

Speaker #4: So, I believe that a drug that's administered by inhalation over long periods of time will eventually have the ability, in large part, to reach many, if not all, of the segments that we need to.

Speaker #4: But I have no delusion as to whether or not there will be a consistent , almost a vacuuming of the lungs and an ability to remove and diminish mucus plugging .

Alan H. Cohen: I have no delusion as to whether or not there will be a consistent, almost a vacuuming of the lungs and an ability to remove and diminish mucus plugging. I think the time constants, the ventilation perfusion matching and just the nature of what's going on actively day to day with infections, will really always make this challenging. Even mucolytic drugs like Pulmozyme, even in patients who are using those drugs one or more times a day, will still be found to have significant mucus plugging in certain segments of the lung in any given time, and it will change from period to period, from X-ray to X-ray. The goal here is, I think, the long term.

Alan Cohen: I have no delusion as to whether or not there will be a consistent, almost a vacuuming of the lungs and an ability to remove and diminish mucus plugging. I think the time constants, the ventilation perfusion matching and just the nature of what's going on actively day to day with infections, will really always make this challenging. Even mucolytic drugs like Pulmozyme, even in patients who are using those drugs one or more times a day, will still be found to have significant mucus plugging in certain segments of the lung in any given time, and it will change from period to period, from X-ray to X-ray. The goal here is, I think, the long term.

Speaker #4: I think the time constants , the the ventilation perfusion matching and just the nature of what's going on actively day to day with infections will really will really always make this challenging .

Speaker #4: Even mucolytic drugs like pulmozyme , even in patients who are using those drugs , one or more times a day , will still be found to have significant mucus .

Speaker #4: Plugging in certain segments of the lung at any given time , and it will change from period period from X-ray to X-ray . So the goal here is , I think , the long term , it's the totality of what we're able to observe .

Alan H. Cohen: It's the totality of what we're able to observe. The plan is to be able to correlate those improvements with things like lung clearance index, which clearly have. Someone was alluding to this in their question earlier. That's one of the measures that we believe, since we've already shown improvements in high-resolution CT scan mucus plug burden. It wouldn't be surprising to see and observe changes in lung clearance index commensurate with that, since those two measures actually go hand in hand. Hopefully that's helpful to you.

Alan Cohen: It's the totality of what we're able to observe. The plan is to be able to correlate those improvements with things like lung clearance index, which clearly have. Someone was alluding to this in their question earlier. That's one of the measures that we believe, since we've already shown improvements in high-resolution CT scan mucus plug burden. It wouldn't be surprising to see and observe changes in lung clearance index commensurate with that, since those two measures actually go hand in hand. Hopefully that's helpful to you.

Speaker #4: And the plan is to be able to correlate those improvements with things like lung clearance index , which clearly have . And someone was alluding to this in their question earlier .

Speaker #4: That's one of the measures that we believe , since we've already shown improvements in high resolution CT scan , mucus plug burden , it wouldn't be surprising to see and observe changes in lung clearance index commensurate with that .

Speaker #4: Since those two measures actually go hand in hand, so hopefully that's helpful to you.

Speaker #15: Yeah , that's great . Very useful . And then just a quick follow up on your pandemic flu vaccines . You haven't said a lot , but is your safety .

Thomas Shrader: No, that's great. Very useful. Just a quick follow-up. On your pandemic flu vaccines, you haven't said a lot, is your safety just qualitatively in line with a protein vaccine, or does it look more like an mRNA vaccine? Do you have any sense of-

Speaker #15: Just qualitatively in line with the protein vaccine or does it look more like an mRNA vaccine ? Do you have any sense ?

Speaker #3: Yeah , very similar .

Joseph Payne: Yeah.

Thomas Shrader: how safe these are gonna look?

Speaker #15: Things are going to look .

Speaker #3: Yeah, very similar with respect to safety and tolerability. The safety and tolerability profile was similar to other vaccine technologies. We are a lower dose technology compared to conventional mRNA.

Joseph Payne: Yeah, very similar. With respect to safety and tolerability, the safety and tolerability profile was similar to other vaccine technologies. We are a lower dose technology to conventional mRNA, so what we've seen consistently is any dose-related toxicologies will be beneficial to the self-amplifying mRNA tech from Arcturus. In general, it's simply, it's similar to other vaccine technologies from a safety and tolerability.

Speaker #3: So what we've seen consistently is any dose related toxicologies will be beneficial to the Self-amplifying mRNA tech from Arcturus . But in general , it's it's simply it's similar to other vaccine technologies from a safety and tolerability .

Speaker #3: Yeah

Thomas Shrader: Okay. Thanks.

Joseph Payne: Yeah.

Speaker #1: We'll move next to Yael Jen with Laidlaw and Company . Your line is open .

Operator: We'll move next to Yale Jen with Laidlaw & Company. Your line is open.

Speaker #16: Good afternoon, and thanks for taking the questions. In terms of the CF next 12-week study—and you mentioned you're looking for a more stable baseline—

Yale Jen: Good afternoon. Thanks for taking the questions. In terms of the CF, next 12-week study, you're looking for more stable baseline. Would that increase the time and the size for the screening for the study? Also, how long a duration to define as a more stable baseline before the patient will be eligible for the study? Then I have a follow-up.

Speaker #16: Would that increase the time and the size for the screening for the for the study . And also what sort of how long duration to to define as a stable , more stable baseline before you treat before the patient will be eligible for the study .

Speaker #16: And then I have a follow-up.

Speaker #3: Yeah . We're we're definitely not enrolling a patient until they are stable . With respect to the baseline lung function measures the duration of that stability time .

Joseph Payne: Yeah. We're definitely not enrolling a patient until they are stable with respect to the baseline lung function measures. The duration of that stability time, do you wanna comment on that, Allan?

Speaker #3: Do you want to comment on that ? Alan ?

Speaker #4: Yeah , I mean , you know , there's and this is a great question . And it's not a simple answer . So let me see if I can give as appropriate an answer as possible .

Alan H. Cohen: Yeah. I mean, you know, there's. This is a great question, and it's not a simple answer. Let me see if I can give as appropriate an answer as possible. The challenge with CF patients is that there's actively chronically something going on any given day. I think the biggest challenge in trying to identify and enroll patients into a study like ours, where, you know, you're looking for modest improvements over, in the case of our studies, first three cohorts over a four-week period to now a much larger group of patients over now a 12-week period.

Alan Cohen: Yeah. I mean, you know, there's. This is a great question, and it's not a simple answer. Let me see if I can give as appropriate an answer as possible. The challenge with CF patients is that there's actively chronically something going on any given day. I think the biggest challenge in trying to identify and enroll patients into a study like ours, where, you know, you're looking for modest improvements over, in the case of our studies, first three cohorts over a four-week period to now a much larger group of patients over now a 12-week period. We do wanna make sure that we're not just identifying the right patients, but we're also catching them at a time in the course of their disease where they're at least stable enough so that we can introduce our drug and begin the baseline assessment.

Speaker #4: The the challenge with CF patients is that there's actively , chronically something going on in any given day . And and I think the biggest challenge in trying to identify and enroll patients into a study like ours , where , you know , you're looking for modest improvements over in the case of our studies , first , three cohorts over a four week period to now a much larger group of patients over now a 12 week period , we do want to make sure that we're not just identifying the right patients , but we're also catching them at a time in the course of their disease where they're at least stable enough so that we can introduce our drug and begin the baseline assessment so that when we get to the end , we at least have a comparator that's stable , reasonable , and discernible .

Alan H. Cohen: We do wanna make sure that we're not just identifying the right patients, but we're also catching them at a time in the course of their disease where they're at least stable enough so that we can introduce our drug and begin the baseline assessment. That when we get to the end, we at least have a comparator that's stable, reasonable, and discernible.

Alan Cohen: That when we get to the end, we at least have a comparator that's stable, reasonable, and discernible. Right now, it's possible, based on the way we've constructed this study, and I've done this in other studies as well, where we may delay the enrollment of a patient by a few weeks or a month, just simply because there seems to be something acute going on, whether they're getting acutely ill, and we just happen to be catching it during the course of the baseline in the screening, or they may be in the late stages of resolving their illness, and we're seeing enough of a difference between two measures over a relatively short period of time, that it may just speak to the unstable nature of what's going on.

Speaker #4: So right now , it's possible based on the way we've constructed this study . And I've done this in other studies as well , where we may delay the enrollment of a patient by a few weeks or a Just simply because there seems to be something acute going on , whether they're getting acutely ill .

Alan H. Cohen: Right now, it's possible, based on the way we've constructed this study, and I've done this in other studies as well, where we may delay the enrollment of a patient by a few weeks or a month, just simply because there seems to be something acute going on, whether they're getting acutely ill, and we just happen to be catching it during the course of the baseline in the screening, or they may be in the late stages of resolving their illness, and we're seeing enough of a difference between two measures over a relatively short period of time, that it may just speak to the unstable nature of what's going on. We really just are looking to get the best patients at the best period of time so that we have a equivalent baseline with which to work from.

Speaker #4: And we just happen to be catching it during the course of the the baseline and the screening . Or they may be in the in the late stages of resolving their illness .

Speaker #4: And we're seeing enough of a difference between two measures over a relatively short period of time that it may just speak to the unstable nature of what's going on.

Speaker #4: We really just are looking to get the best patients at the best period of time, so that we have an equivalent baseline with which to work from.

Alan Cohen: We really just are looking to get the best patients at the best period of time so that we have a equivalent baseline with which to work from. That's really the intention. It may mean a few weeks or a month longer to enroll a given patient, but it shouldn't add much in terms of the time. I think it's really the goal here is to really find the best patient at the best time. Hopefully, that helps you.

Speaker #4: And that's really the intention . And it may mean a few weeks or a month longer to enroll a given patient , but it shouldn't add much in terms of the time it I think it's it's really a the goal here is to really find the best patient at the best time .

Alan H. Cohen: That's really the intention. It may mean a few weeks or a month longer to enroll a given patient, but it shouldn't add much in terms of the time. I think it's really the goal here is to really find the best patient at the best time. Hopefully, that helps you.

Speaker #4: Hopefully that helps you .

Speaker #16: Absolutely . That's very helpful . Maybe just a quick one on the OTC . I know it's still early , a little bit , but it was the company intended at least the desire to potentially starting both the adult and pediatric trial relatively concurrently .

Yale Jen: Absolutely. That's very helpful. Maybe just a quick one on the OTC. I know it's still early a little bit, but was the company intended at least the desire to potentially starting both the adult and the pediatric trial relatively concurrently, or there's any priority one on the before the other?

Speaker #16: Or there's any priority one before the other .

Joseph Payne: I would refer to everyone on the call to see what they've said publicly at their recent investor calls and their filings. We don't anticipate anything soon out of the UK commercially from KOSTAIVE, but I refer you to their statements that they're saying publicly. We'll see where we are with the CSL agreement and our discussions with them in the coming months.

Speaker #3: I think the intent is always to get into the children with high unmet medical need as fast as possible , but we're going to adhere to the advice and feedback from the FDA from these type C meetings .

Speaker #3: So we'll be able to answer that with more granularity in a few months .

Speaker #16: Okay , maybe the last question does CSL intended to launch the cost of it in UK , or do we know that ? And thanks

Speaker #3: I would refer to everyone on the call to to see what they've said publicly at their recent investor calls and their and their and their filings .

Speaker #3: We don't anticipate anything soon out of the United Kingdom commercially from , from cost . Dave . But I refer you to their statements that they're saying publicly , we'll see where we are with the CSL agreement and , and our discussions with them in the coming months .

Speaker #16: Okay, great. Thanks a lot. And congrats on the progress.

Yale Jen: Okay, great. Thanks a lot and congrats on the progress.

Speaker #3: Thanks . Yeah

Joseph Payne: Thanks. Yeah.

Speaker #1: And this does conclude the question-and-answer portion of today's program. I would now like to hand the call back to Joe Payne for any additional or closing remarks.

Operator: This does conclude the question and answer portion of today's program. I would now like to hand the call back to Joseph Payne for any additional or closing remarks.

Speaker #3: Thank you. Operator, I'd just like to thank everyone for attending today's call. If we see you in the main conference seasons ahead, we look forward to catching up with you there.

Joseph Payne: Thank you, operator. I'd just like to thank everyone for attending today's call. If we see you in the bank conference seasons ahead, we look forward to catching up with you there. Have a good afternoon, everybody.

Speaker #3: Have a good afternoon, everybody.

Operator: Thank you. This brings us to the end of today's meeting. We appreciate your time and participation. You may now disconnect.

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