Q2 2025 United Therapeutics Corp Earnings Call

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Steve: Good morning and welcome to the United Therapeutics Corporation Second Quarter 2025 Corporate Update. My name is Steve, and I will be your conference operator today. All participants on the call portion of this webcast will be in the listener mode until the question and answer portion of this earnings call. If you would like to ask a question during this time, simply press star then the number one on your telephone keypad. If you would like to withdraw a question, simply press star then two on your telephone keypad. Please note this call is being recorded. I will now like to turn the webcast over to Dewey Steadman, Head of Investor Relations at United Therapeutics. Please go ahead.

Good morning, and welcome.

Welcome to the United Therapeutics Corporation second quarter, what do you 25 corporate update.

My name is Steve and I'll be your conference operator today.

All participants on the call portion of this cost will be in a listen only mode until the question and answer portion of this earnings call.

If you'd like to ask a question. During this time simply press. The Star then the number one on your telephone keypad.

If you would like to withdraw your question simply press Star then two on your telephone keypad.

Please note this call is being recorded.

I would now like to turn to the gosh to what to do with Steedman head of Investor Relations at United Therapeutics. Please go ahead.

Dewey Steadman: Thank you, Steve, and good morning. It is my pleasure to welcome you to the United Therapeutics Corporation Second Quarter 2025 Corporate Update webcast. Remarks today will include forward-looking statements representing our expectations or beliefs regarding future events. These statements will involve risks and uncertainties that may cause actual results to differ materially. Our latest SEC filings, including Forms 10-K and 10-Q, contain additional information on these risks and uncertainties. We assume no obligation to update these forward-looking statements. Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our products. These remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational uses. Full prescribing information for our products are available on our website.

Thank you Steve and good morning, It's my pleasure to welcome you to the United Therapeutics Corporation second quarter 2025, corporate update webcast.

Remarks today will include forward looking statements, representing our expectations or beliefs regarding future events. These statements involve risks and uncertainties that may cause actual results to differ materially.

I, just thought SEC filings, including forms 10-K, and 10-Q contain additional information on these risks and uncertainties, we assume no obligation to update these forward looking statements.

Today's remarks may discuss the progress and results of clinical trials or other developments with respect to our product and these remarks are intended solely to educate investors and are not intended to serve as the basis for medical decision, making or to suggest that any products are safe and effective for any unapproved or investigational uses.

Full prescribing information for our products are available on our website.

Dewey Steadman: Accompanying me today on today's call are Dr. Martine Rothblatt, our Chairperson and Chief Executive Officer; Michael Benkowitz, our President and Chief Operating Officer; James Edgemond, our Chief Financial Officer and Treasurer; Dr. Leigh Peterson, our Executive Vice President of Product Development and Xenotransplantation; Pat Poisson, our Executive Vice President of Technical Operations; Dr. Gill Golden, our Executive Vice President and Chief Medical Officer; and C.Q. Dean, our Senior Vice President of Biostatistics, Statistical Programming, and Data Management. Note that James Edgemond, my colleague Terry Silvers, and I will participate in a fireside chat and one-on-one meetings at the Morgan Stanley Global Healthcare Conference in New York on September 8th. Along with Martine Rothblatt, Terry and I will be at the Bernstein's Second Annual Healthcare Forum in New York on September 23rd for a fireside chat and one-on-one meetings.

Accompanying me today on today's call are Dr. Martine Rothblatt, our chairperson and Chief Executive Officer, Michael Banquets are President and Chief operating Officer, James <unk>, Our Chief Financial Officer, and Treasurer, Dr. Leigh Peterson, our executive price President of product development Encino transplantation.

It plays on our executive Vice President Technical operations. Gil Go then our Doctor Gil Golden Our executive Vice President and Chief Medical Officer, and CQ <unk>, Our senior Vice President Biostatistics Statistical programming and data management.

Note that Janssen Edmond my colleague, Harry Silvers, and I will participate in a fireside chat and one on one meetings at the Morgan Stanley Global Healthcare Conference in New York on September eight along with Martijn Rabat, Harry and I will be at the Bernstein Second annual Health Care Forum in New York on September 23rd for a fireside chat and one on one periods.

Dewey Steadman: Additionally, our Scientific, Commercial, and Medical Affairs team will present at the World Transplant Congress in San Francisco, August 2nd through 6th; the European Respiratory Society Congress in Amsterdam on September 27th through October 1st; the 18th Congress of the International Xenotransplantation Association in Geneva, September 30th to October 3rd; and the American College of Chest Physicians meetings, CHEST 2025, in Chicago, October 19th through 22nd. Now I will turn the webcast over to Martine for an overview of our development pipeline and business activities. Martine.

Definitely our scientific commercial and medical affairs team will present at the World transplant Congress in San Francisco August 2nd respect.

The European Respiratory Society Congress in Amsterdam on September 27 through October 1st the 18th Congress I think international Zeno Transplantation Association in Geneva September 30th talked over third and the American College of chest physician meeting just 2025 in Chicago October 19 through 20 seconds.

Now I'll turn the webcast over to Martina for an overview of our development pipeline and business activities our team.

Martine Rothblatt: Thank you, Dewey, and good morning, everyone. We have slides available for reference, and I encourage you to review those at your leisure. Today, we are proud to report that United Therapeutics has achieved another record quarter of earnings, marking 12 consecutive quarters of double-digit year-over-year revenue growth. Our performance is a testament to our unwavering strategic approach, which has allowed us to consistently drive sustainable growth while improving the lives of the patients we serve. Our strong foundational business is supported by our robust Tyvaso franchise, which continues to achieve record results underpinned by our first-in-class Tyvaso DPI device and enduring market fundamentals that we expect will propel future growth. Additionally, Orenitram, Remodulin, and Unituxin remain integral components of our commercial portfolio and continue to deliver strong performance.

Thank you Joey and good morning, everyone. We have slides is available for reference stand I encourage you to review those at your leisure.

Today, we're proud to absorb that United Therapeutics has achieved another record quarter of earnings marching 12 consecutive quarters of double digit year over year revenue growth.

For me this is a testament to our unwavering strategic approach.

Allowed us to consistently drive sustainable growth, while improving the lives of the patients we searched.

Strong foundational business.

Warranted by our robust Taipei, So franchise, which continues to achieve record results underpinned by our first in class IV, Some DPI device and enduring market fundamentals that we expect will propel future growth. Additionally, our Reno tram relaunch Linde and unit toxin remain.

The components of our commercial portfolio and continued to deliver strong performance.

Martine Rothblatt: Our next wave of growth, which we call our innovation wave, consists of our T-TOM studies in idiopathic pulmonary fibrosis and our advanced outcome study in pulmonary arterial hypertension, which are on the cusp of reporting results, starting with T-TOM-2 in September of this year. Each of these catalysts has the potential to fundamentally change our revenue profile and deliver growth well into the next decade. Our largest potential wave of growth, our revolution wave, continues to make progress, and we are on track to conduct the first transplant in our expanded U-kidney clinical study shortly. Concurrently with this first-ever phaseless study and as part of our multiple shots on goal approach, we are also proud to announce that we have filed an investigational new drug application for our extended study evaluating our U-thymokidney, and we expect to file for our express study evaluating our U-heart.

Next waves of growth, which we call. Our innovation waves consists of our Teton studies in idiopathic pulmonary fibrosis and our advanced outcome study in pulmonary arterial hypertension, which we're on the cusp of reporting results starting with Teton two in September of this year each of these catalysts.

<unk> has the potential to fundamentally change our revenue profile and deliver growth well into the next decade.

Our largest potential wave of gross a revolution wage continues to make progress and we are on track to conduct the first transplant in our expanded acute kidney clinical study shortly.

Currently with its first ever phase I study and as part of her multiple shots on goal approach. We're also proud to announce that we have filed an investigational new drug application for our extended study evaluating are you talking about kidney and we expect to file for our express study evaluating are you Hart.

Martine Rothblatt: Additionally, last month, we announced that we enrolled and treated the first patient in our mural liver elapsed study. Recently, our investor relations team launched a new pipeline website at pipeline.unither.com that contains detailed information and links to publications about our pipeline candidates. I encourage you to take a look. Our ability to deliver such remarkable growth and pipeline innovation is matched only by our commitment to financial prudence. The exceptional operating efficiency that we have cultivated has allowed us to generate nearly $1.5 billion in annual operating cash flow. Our disciplined approach allows us to strategically allocate capital, ensuring that United Therapeutics remains flexible, resilient, and well-positioned for sustained success in the years ahead. Given the strength of our commercial business, our robust balance sheet, and confidence in our upcoming catalysts, we believe that the recent dislocation in our share price presents a particularly compelling investment opportunity.

Additionally, last month, we announced that we enrolled and treated the first patient in our miro liver elapsed study.

Recently, our Investor Relations team launched a new pipeline website at pipeline Dod units their dotcom.

The detailed information and links to publications about our pipeline candidates I encourage you to take a look our ability to deliver such remarkable growth in pipeline innovation is matched only by our commitment to financial Prudence. The exceptional operating efficiency that we have cultivated has allowed us.

To generate nearly one and a half a billion dollars in annual operating cash flow. Our disciplined approach allows us to strategically allocate capital ensuring that United Therapeutics remains flexible resilient and well positioned for sustained success in the years ahead, given the strength of our.

Commercial business, a robust balance sheet and confidence in our upcoming catalysts. We believe that the recent dislocation in our share price pretense, particularly compelling investment opportunity and as such our board of directors has authorized the repurchase of up to $1 billion in our <unk>.

Martine Rothblatt: As such, our Board of Directors has authorized the repurchase of up to $1 billion in our shares through March of next year. We will continue to regularly evaluate our capital needs and deploy cash toward the highest and best uses. Even after the potential repurchase of shares, as authorized by our Board, we remain well capitalized to continue advancing our commercial and development programs. As we approach these meaningful and potentially value-creating catalysts across pulmonary fibrosis and pulmonary arterial hypertension, we could not be more confident in the future of our business. To conclude, we expect to sustain growth in our foundational business, which continues to drive significant cash flow and opportunity while also progressing our innovative small molecule pipeline and our platform of organ alternative technologies. We are excited about our current business and our growth potential, and we appreciate the feedback and support from our shareholders.

Shares through March of next year, we will continue to regularly evaluate our capital needs can deploy cash towards the highest and best uses even after the potential repurchase of shares has authorized by our board we remain well capitalized to continue advancing our commercial and development pro.

Grams, as we approach these meaningful and potentially value, creating catalysts across pulmonary fibrosis in pulmonary arterial hypertension, we could not be more confident in the future of our business to conclude we expect to sustain growth in our foundational business, which continues.

To drive significant cash flow and opportunity are also progressing our innovative small molecule pipeline and our platform is Oregon alternative technologies. We're excited about our current business and our great potential and we appreciate the feedback and support from our shareholders.

Martine Rothblatt: We have a number of different presentations this morning, with Michael Benkowitz addressing our commercial performance, Leigh Peterson outlining our TTOM-2 study, for which we expect to report data in September; C.Q. Dean, our Chief Biostatistician, to talk about the recent INSMED Phase 2 data; and Dr. Gill Golden, our Chief Medical Officer, who will outline the expected limited impact we believe TPIP will have on the market if it is approved. Mike.

We have a number of different presentations. This morning, Michael banker with addressing our commercial performance Leigh Peterson outlining our tea time to study for which we expect to report data in September <unk>, our chief by established fishing to talk about the recent ins Mad Phase two data and then Doctor Gil.

<unk>, our Chief Medical Officer, who will outline the expected limited impact we believe T. P. I P will have on the market. If it is approved Mike.

Okay.

Yeah.

Michael Benkowitz: Thank you, Martine, and good morning, everyone. Today, we are pleased to report record total revenue of $799 million, reflecting 12% growth over the second quarter of 2024. This is our 12th consecutive quarter of double-digit year-over-year total revenue growth, driven by robust results across our commercial portfolio. Underpinning this performance, Tyvaso DPI achieved a record total revenue of $315 million, representing 22% growth over the second quarter of 2024. This quarter also marked a record for patient shipments for Tyvaso DPI, as well as the total Tyvaso franchise. The underlying dynamics remain strong, with referrals and starts each reaching record levels for Tyvaso DPI during the quarter. We also saw year-over-year double-digit revenue growth for Nebulized Tyvaso, Orenitram, and Unituxin. For Orenitram, this quarter represented a record in both total revenue and patient shipments.

Thank you Martin and good morning, everyone.

Today, we are pleased to report record total revenue of $799 million, reflecting 12% growth over the second quarter of 2024. This.

This is our 12th consecutive quarter of double digit year over year total revenue growth driven by robust results across our commercial portfolio.

Underpinning this performance Cardoso DPI achieved a record total revenue of $315 million, representing 22% growth over the second quarter of 2020 for.

This quarter also marked a record for patient shipments for Kai basically D. P I as well as the total <unk> franchise the other.

Your line dynamics remained strong with referrals and starts each region, reaching record levels for today. So D. P I during the quarter.

We also saw year over year double digit revenue growth for Nebulize, Nowadays, though our rent at cram in human toxin for Iraq around this quarter represented a record in both total revenue and patient shipments.

Michael Benkowitz: Touching briefly on Remodulin performance, we are still seeing strong demand for Remodulin, which notched a top five quarter in total patient shipments, and we are confident that parenteral process cycles will continue to play a meaningful role in the marketplace. We look forward to the launch of our next-generation pump for Remunity Pump later this year. With the recent launch of a competing interprofessional dry powder inhaler, I'd like to address several areas of misinformation in the marketplace about Tyvaso DPI. The competitor is attempting to differentiate their product in the areas of dosing, tolerability, particle deposition, and ease of use. First, there is no maximum dose for Tyvaso DPI, and there's no commercially available interprofessional DPI that has published data at higher doses than Tyvaso DPI.

Touching briefly on our revived one performance we are still seeing strong demand for remodeling, which notched a cop five quarter and total patient shipments and we are confident that parental prostacyclin will continue to play a meaningful role in the marketplace. We look forward to the launch of our next generation Pompe community Pro later this year.

With the recent launch of a competing for profitable dry powder inhaler I'd like to address several areas of misinformation in the marketplace about 10 days of the API.

But what he is attempting to different different differentiate their product in the areas of dosing tolerability particle deposition and ease of use.

First there is no maximum that was for.

DPI and Theres no commercial available for possible D D.

It was higher.

Peter.

Doses than high base with Upi.

Michael Benkowitz: Recall in the BREEZE study of Tyvaso DPI, we saw patient exposure up to 33 nebulized breath equivalents, or 176 micrograms at 51 weeks. Next, tolerability. Clinical data for Tyvaso DPI showed that key tolerability factors like cough and throat irritation decreased meaningfully over time. Contrary to that, clinical data for the competitor's product shows that cough and throat irritation actually increase over time. Now, turning to deposition, it has been previously shown in peer-reviewed publications that the optimal particle size for pulmonary deposition is one to five microns, thus leading to effective delivery and absorption to more peripheral areas of the lungs. Tyvaso DPI particles at 2.6 microns are in the optimal size range to promote efficient medication delivery. This feature, coupled with our low flow and low inspiratory effort device, has been shown to allow for the deep deposition of Tyvaso DPI in the lung.

Recall in the Breeze study of Taipei. So D. P. I, we saw patient exposure up to 33 W. Life's breath equivalents or 176 micrograms at 51 weeks.

Next tolerability clinical data for <unk> D. P. I should the key tolerability factors like cough and throat irritation decreased meaningfully over time.

Contrary to that clinical data for liquidity as product shows that cough and throat irritation actually increase overtime.

Now turning to deposition.

Its been previously shown in peer reviewed publications the optimal particle size. The pulmonary deposition is one to five microns, thus leading to effective delivery and absorption to more peripheral areas of the lungs.

So DPI particles at $2 six microns or in the optimal size range could promote efficient medication delivery.

This feature a couple coupled with our low flow and low <unk> effort device has been shown to allow for the deep deposition, okay. So DPI and a lot of them.

Michael Benkowitz: Finally, there's ease of use and convenience, and we believe that Tyvaso DPI is a better all-around package for patients. Tyvaso DPI only requires one breath per cartridge four times a day. When administering Tyvaso DPI, patients can hold their head in a normal neutral position, and Tyvaso DPI requires no daily cleaning, or patients could potentially come in contact with DPI powder, causing unwanted effects. As we begin our competitive journey with Tyvaso DPI, we understand that physicians and patients may want to try new product offerings. However, we believe that over the long term, with Tyvaso DPI's product profile, along with the deep experience we've built in the pulmonary hypertension marketplace over the last three years, we are positioned for continued growth. I'll now turn the call over to Leigh Peterson to discuss the TTOM studies.

Finally, there is ease of use and convenience and we believe that high base or D. P. I is the better all around package for patients.

They said D. P. I only requires one breaths per cartridge four times a day.

When administering IV, so DPI patients can hold or had any normal neutral position and Taipei sell DPI requires no daily cleaning where patients could potentially come in contact with DPI powder, causing unwanted effects.

As we began our competitive journey with high base with Upi, we understand that physicians and patients may want to try new product offerings. However, we believe that over the long term with Televisa DPI product profile, along with a deep experience we built in the pulmonary hypertension market place over the last three years, we are positioned for continued growth.

I'll now turn the call over to Lee to discuss the two type studies.

Leigh Peterson: Thanks, Michael, and good morning, everyone. As we look ahead to the expected September data readout for our TOM-2 registration study, we wanted to spend some time today providing a brief landscape of idiopathic pulmonary fibrosis, or IPF. I will cover the biological rationale behind treprostinil as a therapeutic approach, provide details regarding our clinical trials, and set the stage for interpreting the forthcoming results. IPF is a progressive scarring disease of the lungs of unknown cause. It is most common after age 50, and it is linked to risk factors like smoking, genetics, and certain environmental exposures. It affects approximately 100,000 people in the U.S., and currently, there are only two approved therapies for IPF: Nintedanib and Pirfenidone. These drugs only slow lung function decline. They are used by about 30% of the U.S.

Thanks, Michael and good morning, everyone.

As we look ahead to the expected September data readout for our Teton two registration study we wanted to spend some time today, providing a brief landscape.

No pathic pulmonary fibrosis or Ips.

So I'll cover the biological rationale behind her costs now as a therapeutic approach provides detail regarding our clinical trials and that's the stage we're interpreting the forthcoming result.

So I think there is a progressive scarring of the lung unknown car.

It's not common after in 15, and it's linked to risk factors like smoking genetics and certain environmental exposure.

It affects approximately 100000 people in the U S.

Currently there's only two approved therapies for IPF and 10.

Nab and centered on and these are the only low lung function decline there they're used by about 30% of the U S patient largely due to their unpleasant side effects that together they generate over $4 billion globally.

Leigh Peterson: patients, largely due to their unpleasant side effects, yet together, they generate over $4 billion globally. As mentioned, these two therapies only showed a decrease in the rate of decline in FVC at 52 weeks in the registration study. The mean FVC change from baseline for Nintedanib was approximately 111 milliliters from placebo and 148 milliliters for Pirfenidone. However, the studies had very different placebo effects, with over 200 milliliters of FVC loss in Nintedanib study and more than 300 milliliters for Pirfenidone, demonstrating the wide variety in the placebo responses that have plagued development efforts in IPF.

As mentioned these two therapies only showed a decrease in the rate of decline in S. E. T at 52 weeks and the registration study.

The mean FCC change from baseline for Nintendo Trinidad was approximately 111 millimeters for placebo.

And 148 member leaders for Pirfenidone.

However, the studies had very different placebo effects with over 200 milliliters of SBC lie in 10 minutes study and more than 300 milliliters pressure for Pirfenidone.

Demonstrating the wide variety in the placebo responses that have plagued development efforts and Ips.

Leigh Peterson: Many investors and even physician experts in the space believe that treprostinil is just a vasodilator, and that is likely because treprostinil has become, it is much more than a vasodilator. It is likely because treprostinil has become widely used in pulmonary hypertension, but it also has activity on the IP, EP2, DP1, and PPAR receptors, collectively inhibiting fibroblast proliferation and migration, fibroblast to myofibroblast differentiation, extracellular matrix deposition, and inflammation, all of which contribute to fibrosis. These findings are supported by a post-hoc analysis from our INCREASE study, where a subset of pulmonary hypertension patients with IPF treated with Tyvaso showed an improved FVC and reduced exacerbations of underlying lung disease. This, along with interprofessional's antifibrotic properties, makes us optimistic that Tyvaso may benefit IPF patients by improving lung function through multiple pathways beyond those typically associated with pulmonary hypertension. The T.O.M. program is made up of three studies.

Many investors and even physician experts in the space believed that Coprostanol is just the nasal dilator and that's likely because coprostanol has become.

It's much more than a base dilator, it's likely because coprostanol has become widely used.

Pulmonary hypertension.

It also has activity I mean, I P E b to D. P. One N P part receptors collectively inhibiting fibroblast proliferation, and migration fibroblast to mile fibroblast differentiation extra cellular matrix deposition and inflammation all of which contribute to cypress.

Yes.

These findings are supported by a post hoc analysis from our increased study, whereas subset of pulmonary hypertension pension patients with Ikea.

Treated with Typhoon So showed an improved S. T E N reduced exacerbations of under underlying lung disease.

This along with your proximal anti fibrotic properties makes us optimistic that today, so maybe benefit IPF patients by improving lung function multiple pathways beyond those typically associated with pulmonary hypertension.

The coupon program is made up of three studies Teton. One is at 598 patient study and that'd be lifetime base, though and Ips for participants in the U S and Canada two time too.

Leigh Peterson: T.O.M.-1 is a 598-patient study of Nebulized Tyvaso and IPF for participants in the U.S. and Canada. T.O.M.-2 is a 597-patient study identical to T.O.M.-1, but evaluating participants outside the U.S. and Canada. T.O.M.-PPF is a worldwide study evaluating the use of Nebulized Tyvaso in PPF or progressive pulmonary fibrosis. As we've been saying, we expect T.O.M.-2 to report data in September, while T.O.M.-1, which was fully enrolled in January of 2025, should report data in the first half of 2026. Our focus today is on T.O.M.-2. Again, T.O.M.-2 is a 597-patient multicenter, randomized, double-blind, placebo-controlled phase III study evaluating Nebulized Tyvaso in IPF patients over 52 weeks outside the U.S. and Canada. Full enrollment was reached in July of 2024. Participants were randomized to Tyvaso or placebo, starting at three breaths four times daily or QID, titrated as tolerated, up to 12 or more breaths QID.

It was a 597 patients that he identical to Taiwan, but evaluating participants outside the U S and Canada Teatime P. P. S is a worldwide study evaluating the use of Nebulize Taipei. So in P. P S. Our progressive pulmonary fibrosis.

As we've been saying, we expect to time to report to report data in September well Teton, one which was fully enrolled in January of 2025. She report data in the first half of 2026.

And our focus today is on T content.

So again a P time too is a 597 patient multi center randomized double blind placebo controlled phase three study.

Writing Nebulize Thai base, though.

I P S patients over 52 weeks outside the U S and Canada full enrollment was reached in July of 'twenty four.

Participants were randomized to <unk> or placebo starting at three breaths four times daily Archie I D titrated as tolerated tolerated up to 12 or more breath. He leidy.

Leigh Peterson: The primary endpoint is a change in FVC at 52 weeks, and the secondary endpoints include time to clinical worsening, time to acute IPF exacerbation, overall survival, percent predicted FVC, quality of life measured by the King's Brief ILD questionnaire, and change in lung diffusing capacity. Safety is assessed via adverse events, labs, vital signs, and ECGs. Key inclusion criteria of note include subjects who are 40 or more years of age, have a predicted FVC of 45% or more, be on a stable dose of Nintenanib or Perphenadon if using one, and have a diagnosis of IPF confirmed by HRCT within the last 12 months. Key inclusion criteria of note include obstructive diseases, high supplemental oxygen use, use of drugs commonly used for PAH, recent IPF exacerbation, or pulmonary infections.

The primary endpoint is the change in F. B E. At 52 weeks and the secondary endpoints include time to clinical worsening time to acute exacerbation.

Exacerbation overall survival.

Per cent predicted SBC quality of life measured by Bruce ILD questionnaire.

Change in lung diffusing capacity.

Safety is a seth yeah adverse event lab vital signs and E C G.

He inclusion criteria of note include subjects or 40 or more years of age have a predicted SBC, a 45% or more stable.

Stable dose as an independent lab or Pirfenidone excusing one.

And have a diagnosis of IPF confirmed by HR suites within the last 12 months.

The inclusion criteria of note include.

Corrective diseases, hi, supplemental oxygen you use a drug commonly used for P. A H recent I P S exacerbation or pulmonary infections.

Leigh Peterson: Per the T.O.M.-1 and T.O.M.-2 protocols, we reviewed the blended blinded data and adjusted the sample size, considering the FVC variability, discontinuation rate, background therapy use, and regulatory feedback. In 2024, we expanded each of these studies from 396 to 576 participants to account for observed data, patient retention, and better alignment with the other major IPF trials. At ATS this year, we presented fully enrolled baseline data for TTOM-1 and TTOM-2, reflecting the full populations of both studies. The baseline demographics of TTOM-1 and 2 are largely similar and compare favorably with the recently reported FibreNIR IPF study and earlier clinical programs for Nintenanib and Perphenadon. While our statistical analysis plan is very long and detailed, we have been getting some questions in four key areas that I would like to address. First, the study is 80% powered to detect an 80 milliliter change in FVC.

Sure the two ton one and protocols.

We reviewed the blended blinded data and adjusted the sample size.

During the FCC variability discontinuation rate background therapy use and regulatory feedback.

And then 'twenty 'twenty four we expanded each of these studies from 396 to 576 participants.

To account for observed data patient retention and better alignment with the other major IPF trial.

At 18, yes. This year, we presented fully enrolled baseline data for to Taiwan, and couponing to reflecting the full populations in both studies.

The baseline demographic graphics Teton, one and two are largely similar and compares favorably with the recently reported Hibernia IPF study in earlier clinical programs for Nintendo Nab and prevent it down.

While our statistical analysis plan is very long and detailed we've been getting some questions in four key areas that I'd like to address.

Yes.

The study is 80% powered to detect an 80 milliliter change in S E C.

Leigh Peterson: This compares to a 90% power to detect a 74 milliliter change in FVC for the recent FibreNIR IPF study. Next, deaths in the study will be penalized with an FVC value at the 2.5 percentile of observed values across arms. This is based on recent feedback from the FDA. This is more conservative than the 10th percentile value used in the FibreNIR IPF study. Discontinuations for other reasons will be handled through statistical models like the mixed model repeated measures or multiple imputation. Finally, we have had five data monitoring committee reviews that evaluated safety over the course of the studies, and the last one occurred in February of this year, which covered more than 1,100 patients between the two studies.

This compares to a 90% power to detect a 74 milliliter change and SBC for the recent fiber near IPF study.

No.

And the study will be Penalised with an S. T E value at the 2.5 percentile of observed values across arms.

This is based on recent feedback from the FDA.

This is more conservative than the 10th percentile values used in the fiber near IPF study.

Discontinuing discontinuation for other reasons will be handled through statistical models like the mixed model repeated measures or multiple imputation.

Finally, we've had five data monitoring committee reviews that evaluated safety over the course of the study.

Last one occurred in February of this year, which covered more than.

1100 patients between the two studies.

Leigh Peterson: To close, our expectation is that our TTOM-2 study will report top-line data in September of this year, as said, and TTOM-1 will report top-line data in the first half of 2026. If both trials are successful, we intend to use the data from the study to support a regulatory filing with the FDA to add IPF to the labeled indications for Nebulized Tyvaso and setting up a commercial launch by 2027. With that, I will now turn the call over to C.Q. to discuss TPIP.

To close our expectation is that our two times. He study will report topline data in September of this year, I said and to Taiwan will report topline data in the first half of 2026 and it's both trials are successful we intend to use the data from this study to support our.

Regulatory filing with the FDA to add I P. S. Two the labeled indications for Nebulize Taipei, So in setting up a commercial launch by 2027.

And with that I'll now turn the call over to <unk> to discuss C. P. I P.

C.Q. Dean: Thank you, Lee. It's a pleasure to speak with you today about the questions we have concerning the TPIF phase 2b PAH data that was recently presented. Of course, our discussions are based on publicly available information. First, we believe the patient population in the recently announced phase 2b PAH study was imbalanced between the active and the placebo group. That may have favored the treatment effect in the active group. Second, we believe inappropriate statistical analysis was conducted in the PAH study, again favoring the active arm of the study and potentially overestimating the treatment effect. Finally, we did not see compelling data in the phase 2a PAH ILD study that gives us confidence that TPIF can be successful in a phase 3 PAH ILD study.

Thank you Avi.

Hmm.

About the platforms that we have.

Uh huh.

Okay. That's good I wonder what the refund.

Of course, I wasn't talking about Mike.

Poverty coming on that are buying from us.

Uh huh.

You deal with that patient population.

The company.

Hum.

Yeah actually we're buying them.

Hum.

Cool.

Robert My how hormones.

Hi.

The acting group.

Uh huh.

Uh huh.

I think if I'm honest I want to come back to you Mark.

Uh-huh.

Hum.

Uh huh.

Uh huh.

Finally, we did not do that.

Oh yeah.

Yes, I am.

What do you want to probably keep them.

Hum.

That's right yes.

C.Q. Dean: We think the study population in the phase 2b PAH study was imbalanced and not reflective of PAH patients who present today that are more heavily pretreated and less symptomatic than when we first developed Nebulized Tyvaso. The combined baseline 6-minute walk distance in the phase 2b study was meaningfully lower, at least 45 meters lower relative to the recent clinical studies in PAH, potentially favoring a treatment effect. Most, if not all, recent PAH studies conducted this decade have had the baseline 6-minute walk distance of 400 meters or more, reflecting improvement in the standard of care of this patient population globally. Further, there was an imbalance between the two arms of the study with baseline 6-minute walk distance. The 23-meter difference in baseline 6-minute walk distance between the active and placebo arms is more than three times that of previous well-controlled studies in PAH.

We think the study population.

Yeah actually starting with inbound.

Hum.

Okay.

More than.

And some of them back.

Well, we have one o'clock burden at all.

The combined pipeline.

Oh.

Garden wasn't meaningful NOL.

Although these funds will be about similar molecules.

Oh pardon me.

Oh.

I'm trying to confirm Uh huh.

Well not at all.

And you're starting to come back to you as I can.

How has the pipeline you know Joaquin and Paul.

Uh huh.

Oh hang on for me that's all.

All right.

Hmm.

That spun out of a hotel pattern a good support from our partner.

Taking all morning.

How's that.

What are you embedding for being part of a pool, often a pattern with a baseline.

Good thing.

With plenty of time either.

Hmm.

It would be kind of acting on the placebo arm.

In the morning, So many times that all about premium.

We're controlling pardon.

C.Q. Dean: Of course, this favored the treatment arm of the study, potentially leading to great treatment effect. Moving to study discontinuation, we also saw a large imbalance that could favor the active arm, with 10% of active participants discontinued the study versus no discontinuation in the control group. The high discontinuation level imbalance, especially relative to the control group, could influence how missing values should be imputed. Moving to statistical analysis, the change from baseline to week 16 data is not symmetric, and it's skewed to opposite directions. In the TPIF group, the mean value was approximately 20% higher than the median, suggesting that the data was right skewed or positively skewed. In the placebo group, the mean was 40% lower than the median, suggesting that the data was less skewed or negatively skewed.

Uh huh.

Uh huh.

Hum.

Well, thank you like Google glass to treat them in fact.

Moving to slide 19.

Awesome.

No problem.

I called a prevalence of active.

So 10% off Ecmo.

Hum.

Although difficult to reconcile.

Cool.

Hi.

What about them, especially relative to the control group.

Just wondering how do you think about them.

Yeah.

Oh man I didn't find out what changed my mind so.

Uh huh.

Hi, Matthew.

You know the two opposite directions.

Well keep up a group.

The move out with approximately 20% of the hunger games unbeatable.

Hum.

Like most of my background.

Right.

Hum.

The placebo group one being.

On the Dog Man, Oh, just one block.

That's a skewed negatively.

Thank you Tony.

C.Q. Dean: The non-parametric method used to report this data, in this case, Zenk and Kovar and the Hodges-Lehman estimate, relied on the data to be symmetric or at least skewed toward the same direction. However, the right skewed data in the active arm and the left skewed data in the control arm is likely causing the overestimation of the treatment effect by Hodges-Lehman estimate or making Hodges-Lehman estimate of the location shift in medians not interpretable. Finally, there were eight subjects or 12% with missing data at week 16 in the active group and zero in the control group. A severe imbalance in dropout rate suggests that the data is not missing at random. The multiple imputation method relies on the data actually being missing at random, which is not the case here. As such, we think this analysis may have overestimated the treatment effects of Tyvaso DPI in PAH.

Uh huh.

I told him quantity yeah.

Okay.

Uh huh.

Uh huh.

Uh huh.

It relies on but they're not.

It would be so much.

Oh I believe you have to.

Towards the direction.

However, the rate of skill to do that.

Hum and to the left the skew the data that control arm.

And with cotton.

It's been amazing.

In fact, I apologize for that and my estimate on Beckman Hodges Amendment actually not at all.

Okay.

We're meeting both of them possible.

Right.

Well Oh.

Okay.

Do you think they're not all the weakness we've seen.

Yeah that actually will go under you know.

I can tell Google.

Awesome, yeah, even violent drop out of the room.

Yes.

You cannot do you think there's a lot of them.

Somebody pointed with your passion marathon relies on well what about actually being do you think it is in London.

We can it's not yeah.

As such we think we've found out of my Oh man estimate the treat them any impact at all.

Well, yes.

Yes.

C.Q. Dean: Beyond the concerns with the recent phase 2b PAH data, we continue to question the earlier phase 2a PAH ILD data, and it may not be an indicator of potential phase 3 success in this indication. First, the study was extremely small in sample size with a 3:1 randomization ratio. There were only 10 patients in the placebo arm, so it is difficult to draw any efficacy conclusion from the study. In addition, no baseline 6-minute walk distance was given, and the 6-minute walk distance result was not statistically significant. Further, the ILD subtypes observed in the PAH ILD study were not balanced between arms. For example, only two CPSE patients were randomized into the study, but were all randomized to placebo group on a 3:1 Tyvaso DPI to placebo randomization ratio. CPSE is known to be a category in which inhaled treprostinil is less effective.

Yeah on the timeframe.

That's to be interesting about what kind of questions Oh, yeah. That's two O P H IHOP eating it up.

Well not a handicap all potential that's one.

Okay.

Well I think it wasn't really a small yourself on time.

321 randomization ratio.

There were only four patients were classy malls hum, it's difficult to draw any conclusions.

I'm, calling from the problem with that.

Yeah.

The person I think walking people through what's going on but we're thinking of Watson.

But we're not I can't think of it.

Well you saw the pipeline without P&C Iot, it's pretty well now the violent that'd be come on.

Apple only impulse C T R E.

Well randomized.

But what all randomized.

All my friends, who want to partner with antibodies.

Hmm.

It's a known to be a part of your body, which it will happen.

I'll start off it's less impacted.

C.Q. Dean: Finally, the safety data in the PAH ILD uncovers additional imbalance between arms, as the five subjects or 17% of active subjects had dyspnea compared to only one subject or 10% of subjects in the control group. Dyspnea is not across the sizing class of the event, and we saw more dyspnea in the control group than the active group in INCREASE study. As you can tell, we think investors have overreacted to the Tyvaso DPI phase 2b PAH data. The baseline imbalance skewed data in opposite directions, and aggressive statistical analysis based on the missing at random assumption may all contribute to the potential overestimation of the treatment effect. We still have no convincing data in PAH ILD. I will now hand the call to Gill Golden, our Chief Medical Officer, to outline the expected immediate impact we believe TPIF will have on the market if it is approved.

Necessity, there that is not uncommon.

Thomas I think something like Mcdonald's would be put on file.

Oh, I don't think I can probably.

Yeah.

Patents have only 110% or something.

Awesome.

If it happens or not.

Across the hiking cost on the walk in van.

We saw Martin.

Oh cool brings the active group and the increase in spending.

As you can tell we think that that's Oh my left here to keep our place to be.

Yeah actually data.

And I am battle.

Yeah.

Rocky.

A question on so that did have a modest one for Beth Baum.

We think the random assumption.

Assumption by all contribute to the partnership.

All.

But.

Yeah, well I'm ranking data.

I went all kinds of carton no Gordon, our Chief Medical Officer, who outlines exactly.

And we do not have or will have on the market.

Approved.

Gill Golden: Thank you, C.Q.

Thank you C Q.

Michael Benkowitz: We believe that investors have overreacted to the TPIP data and misunderstand the opportunity or lack thereof in the marketplace. Specifically, we do not see a near-term path to market in IPF. Long-term safety has not been proven. A potential launch, even if it happens, is many years away, and our business profile will look very different if and when TPIP reaches the market. First, TPIP lacks a clear path to approval in IPF before 2034 if Tyvaso gains approval in 2027 due to orphan drug exclusivity. Further, as an estro-pro drug, TPIP would need to show clear clinical superiority over Tyvaso or a meaningful improvement in patient care, and less frequent dosing may not qualify. The slide lists an example for Lumirise from Avidel that was the only recent declaration of meaningful improvement in patient care by FDA that was of the same dosage form.

We believe that investors have overreacted to the T. P IP data and Miss understand the opportunity or lack thereof in the marketplace. Specifically, we do not see a near term path to market in IPO long term safety has not been proven a potential launch even if it happens is many years away and our business profile looks very.

Different if and when it reaches the market.

So first <unk>.

He likes a clear path to approval in Ibs before 2034 visa gains approval in 2027 due to orphan drug exclusivity.

Further as an extra prodrug TPI P would need to show clear clinical superiority overtime, so or a meaningful improvement in patient care and less frequent dosing may not qualify.

Slide listen example for loom rise from Avondale and that was the only recent declaration of meaningful improvement in patient care by FDA that wasn't the same dosage form.

Michael Benkowitz: Next, long-term safety data for a liposomal pro-drug in pulmonary hypertension is lacking, with the longest studies covering only 16 weeks. For progressive diseases like PAH, PAH ILD, and IPF, robust long-term data is essential. Recent experience with sotatarcept, for example, shows that even after FDA approval, unexpected safety issues can arise over time, highlighting the need for caution. If TPIP were to pass through all these remaining hurdles, it is still the end of the decade or even the next decade before the product will reach the market. Recent phase 3 studies in PAH have taken an average of three years to complete, with clinical outcome studies taking even longer to complete. If everything works perfectly, we could see a product on the market in late 2029 or 2030. Looking ahead to 2030, the market landscape will likely shift significantly.

Next long term safety data for a lysosomal prodrug in pulmonary hypertension is lacking with the longest studies covering only 16 weeks for progressive diseases like P. H ph ILD and Ips robust long term data as a central recent experience with some 10 or so for example shows that even after FDA.

Approval unexpected safety issues can arise over time, highlighting the need for caution.

So TPI pure to pass through all these remaining hurdles and still be under the decade or even the next decade before the product will reach the market recent phase III studies in ph have taken an average of three years to complete with clinical outcome studies thinking even longer to complete.

If everything works perfectly we could see a product on the market in late 2029 from 2030.

Looking ahead to 'twenty 30, then the market landscape will likely ship significantly if the true.

Michael Benkowitz: If the advanced outcome study succeeds next year, Ralinepag may become the first true once-daily oral prostacyclin for PAH, potentially reducing the need for inhaled therapies like TPIP. We are also working on our own once-daily inhaled prostacyclin, which is on a similar development timeline as TPIP and could serve both PAH and PAH ILD. Additionally, in line with our approved then improved strategy, we are developing new Tyvaso devices and combinations to enhance convenience for patients. Lastly, by 2030, our organ development programs could begin generating revenue, making competition from small molecule drugs relatively minor compared to our broader long-term opportunities. To close, with no near-term path to market in IPF, unproven safety, and many, many years before reaching the market, we have little reason to be concerned about our prospects in the face of TPIP.

If the advanced outcome study succeeds next year when Winnipeg may become the first true once daily oral prostacyclin for PVH potentially reducing the need for inhaled therapies like G. P. I P.

We're also working on our own once daily inhaled prostacyclin, which is on a similar development timeline is G. P IP and could serve both P. A H a handful beach ILD.

Additionally in line with our approved then improve strategy, we're developing new tiny so devices in combinations to enhance convenience for patients.

And lastly by 2030, or Oregon development programs could begin generating revenue, making competition from small molecule drugs relatively minor compared to our broader long term opportunities.

So to close with no near term path market and Ips unproven safety and many many years before reaching the market. We have little reason to be concerned about our prospects in the face of T. P. I P and with that I'd like to turn the call back to Marty to start our Q&A session for team.

Michael Benkowitz: With that, I would like to turn the call back to Martine to start our Q&A session. Martine.

Martine Rothblatt: Thank you, Gill. Operator, you can open up the phones for Q&A.

Thank you Gil operator, you can open up the phones for Q&A.

Steve: Thank you. We will now begin the question and answer session. To ask a question, you may press star, then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been answered and you would like to withdraw your question, please press star, then two. At this time, we will pause momentarily to assemble a roster. The first question comes from Olivia Braver from Canton Fitzgerald. Please go ahead.

Thank you.

We will now begin the question.

A question and answer session.

To ask a question you May press Star then one on your telephone keypad.

If youre using a speakerphone please pick up your handset before pressing the keys.

If at any time your questions has been answered.

And you would like to withdraw your question. Please press Star then two at this time, we will pause momentarily to assemble our roster.

The first question comes from Olivia Bravo.

Canton Fitzgerald. Please go ahead.

Speaker 8: Olivia, are you on mute?

Olivia are you on mute.

Martine Rothblatt: Operator, maybe you should proceed to the next question.

Operator, maybe you should proceed to the next question.

Oh, yes, Olivia kidney euros.

Steve: Oh, yes. Miss Olivia, can you hear us?

Jessica Fye: Yep. Can you guys hear me?

Yeah can you guys hear me.

Steve: Yeah, please go ahead.

Yeah. Please go ahead, we can okay.

Speaker 8: Yep, we can.

Jessica Fye: Okay, perfect. Sorry about that. Hi, good morning. Thank you for the question. Any comments on what you're seeing in terms of Tyvaso uptake in both PAH and ILD so far? It looks like you're not really seeing any impact on Tyvaso DPI, but I appreciate anything you can tell us. Any color on why XUS Nebulized Tyvaso was down sequentially, whether that had more to do with ordering patterns or any sort of demand trend that you're seeing? I have one follow-up question on Orenitram, if you do not mind.

Perfect sorry about that hi, good morning. Thank you for the question any comments on what you're seeing in terms of your trip you uptake in those page and I'll do so far I mean, it looks like you're not really seeing any impact on D. P. I, but I. Appreciate anything you can tell us any color on why X U S. Nebulize titration was with Televisa was down sequentially.

Whether that had more to do with.

Ordering patterns or any sort of demand trends that you're seeing and then I've got one follow up question on <unk>, If you don't mind.

Martine Rothblatt: Olivia, there's no more. There's so many people in the queue. There's not going to be time for a follow-up question. Sorry. The marketing question, Michael will handle.

Olivia if there's no more there's so many people in the queue, but it's not going to be time for a follow up question sorry.

The marketing question, Michael Balsamic sure. Thanks for the question Olivia.

Michael Benkowitz: Sure. Thanks for the question, Olivia. Yeah, based on the visibility we have into what is going on, which admittedly is not perfect, things are going about as we expected in terms of the launch. I mean, we finished Q2 really strong in terms of shipments and orders in June. July, based on what we are seeing so far, looks really good. So, really, from our standpoint, no surprises in terms of what we are seeing in terms of the launch. As I said in my opening remarks, we know that docs are curious people. There is a new kid on the block, a new product, and some of them are going to want to try it out and see what it could potentially do for patients. I think particularly in light of some of the claims that Liquidia is making about their product.

Hum.

That's right.

Based on the visibility we have into what's going on which admittedly is not perfect.

Yeah.

Sure.

Things are going about as we expected in terms of watch them and we said that we finished Q2 are really strong in terms of.

Shipments and orders in June.

July based on what we're seeing so far looks looks really good.

So really from our standpoint, no surprises in terms of what we're seeing.

In terms of the launch as I said in my opening remarks, I mean, we know that docs are curious people.

There's a new kid on the block in new product and some other kind of wanted to want to try it out and.

See you know what a competitor to potentially do for patients I think particularly in light of some of the claims that liquidity is making about their product and so we're seeing it a little bit of that but as I said and do you have to really cut our to wrap up my opening remarks, I think we're really confident that with today's shows Televisa DPI product profile plus the associated support.

Michael Benkowitz: So we are seeing a little bit of that. As I said, to really kind of wrap up my opening remarks, I think we are really confident that with Tyvaso DPI's product profile plus the associated support that we provide to physician offices and patients, along with the really deep experience, I mean, more than 10,000 patients have used Tyvaso DPI. You have got almost 3,000 prescribers for Tyvaso DPI. So we think, over the long term, that is going to support continued growth of Tyvaso DPI well into the future.

We provide to our physician.

Physician offices and patients.

Along with the really deep experience I mean really you know.

More than 10000 patients.

Have used <unk> to almost 3000 prescribers for.

For Chinese or <unk>. So we think over long term, that's going to support ticket growth of traditional DTI well into the future.

Martine Rothblatt: Thank you, Michael. Operator, next question.

Thank you Michael Operator next question.

Steve: Question comes from the line of Joseph Thome with TD Cowen. Please go ahead.

Operator, English shouldn't from comes from the line of Joseph <unk> with.

T D talk Kelvin. Please go ahead.

Joseph Thome: Hi there. Good morning. Congrats on the progress, and thank you for taking my question. Leigh Peterson called out the variability seen in FVC decline in placebo arms of IPF studies. Is there a way in the TTOM trials that you attempted to standardize this, or is there a way to make this predictable? When we think about any considerations in clinical practice between your U.S. and XUS experience, what should we think about when we see the first data in September and translatability into the U.S. trial in the first half of next year? Thank you.

Hi, there good morning, Congrats on the progress and thank you for taking my question.

We called out the variability seen in FCC decline in placebo arms of IPF studies.

Is there a way in the Teton trials that you attempted to standardize this or is there a way to make this predictable and when we think about any considerations in clinical practice between the U S. Ex U S experience.

Should we think about when we see the first data in September and translate ability into the U S trial in the first half of next year. Thank you.

Martine Rothblatt: Thank you, Joe. Questions relating to Tyvaso will be answered by Dr. Peterson.

Thank you Joe.

Questions relating to key Tom will be answered by Dr. Liquidation.

Leigh Peterson: Thanks, Martine. Yeah, so that, again, as you noticed, there is very, very wide variability in FVC measures, and this really shows in the placebo arms, especially of the two approved drugs. What we have done to really narrow that is we have a central reader of our FVC results, and we have also made very, very huge attempts at each at the site level in order for training and for, you know, on the procedures and to make sure that people are doing everything consistently with regard to the pulmonary function testing. That is really been at the top of our list as far as management of these studies. Hopefully, we will see that we have less variability, which will show better a true result.

Thanks, Marci, yeah, so that that again as you noted and they're there.

Why.

Very very wide variability in an FCC measures.

And this is this really shows in the in the placebo arm, especially of the the two approved drugs and what we've done to really narrow that is.

And we we have a central readers of of our SBC results and and we've also.

Made yeah, there they should attempt at each at the site level in order for training and for you know on the procedures and to make sure that that people are doing everything consistently with regard to that the pulmonary function test testing and so you know that.

That's really been at the top of our list as far as management of these.

The study.

And so hopefully we will we will see that we have less variability, which will show better results.

Martine Rothblatt: Thank you very much, Dr. Peterson. Operator, next question, please.

Thank you very much Dr. Peterson operator next question. Please.

Steve: The next question is from the line of Jessica Fye from JPMorgan. Please go ahead.

The next question is from the line of Jesse Coffey from J P. Morgan. Please go ahead.

Jessica Fye: Hey, guys. Good morning. Thanks for taking my question. Another one for Dr. Peterson, which is really a question that we hear from investors, and that is how to read across from the compelling increased IPF subgroup where the patients saw improvement in FVC, but they also all had pulmonary hypertension. So the question is, how do we read that across to an IPF population where presumably, you know, the majority of folks are not going to have pulmonary hypertension? Can you address that kind of question on the read across? If I can ask one more, it would be just whether you can touch on the circumstances under which you would deploy the share repo authorization. Thank you.

Hey, guys. Good morning, Thanks for taking my question another one for Dr. Peterson.

It really a question that we hear from investors and that is how to read across from the compelling increase IPF subgroup.

Where the patient improvement in S. E C. But they also all had pulmonary hypertension and so the question is how do we read that across to an IPF population, where presumably you know something.

Alrighty folks are not gonna have pulmonary hypertension can you can you address that that's kind of question on the read across them and if I can ask one more it would be just whether you can touch on the circumstances under which you would deploy the share repo authorization. Thank you.

Martine Rothblatt: Thank you, Jeff. Dr. Peterson, it's another Tyvaso question for you.

Thank you Jeff.

Dr. Peterson, that's another T. Tom question for you.

Leigh Peterson: Yeah, sure. So for, as I discussed in my script earlier, treprostinil has multiple mechanisms of action. It works through multiple receptors. In INCREASE, of course, Tyvaso had already been approved for PAH. We believe, and some non-clinical studies support that that really is, for PAH, the main mechanism, as I also discussed, is through maybe a vasodilation function. That tends, at least the non-clinical studies have shown that really is working through the IP receptor to do that. But on top of it, there are other receptors, EP2 receptor, DP1, PPAR receptors that they have additional functions. They basically, as I went through, they can inhibit fibroblast activity and extracellular matrix deposition and really work on the fibrosis end of the disease.

Yeah sure yeah, so so far I mean as I.

Discussed in in the in my script.

Script.

Earlier he.

Two processing all has.

Barry you know multiple mechanisms of action that works through multiple receptors and so an increase of course, we we'd already seen one in Taipei still had already been approved for P. A H and and we believe and some non clinical studies support but that re.

Really and you know for P. A H the main mechanism as I also discussed it through maybe a basal dilation function and all that.

The non clinical studies have shown that really work working through the I T receptor to do that but on top of that.

There's other receptors.

P. T was softer duty one P par receptors.

They have additional function.

Okay.

They basically.

As I went through they can inhibit fibroblast activity.

Extracellular matrix acquisition and on really work on the fibrosis and of the disease and so well you know two possible. It does work on IP working through these other receptors.

Leigh Peterson: So while treprostinil does work on IP, working through these other receptors, we believe that it can work on fibrosis, which means it would be effective in IPF and PPF. Again, multiple mechanisms of action would lead to efficacy in multiple indications.

We believe that it can work on on fibrosis with me it would be effective and Ips M. P. P. A M. So again.

Multiple mechanisms.

Multiple mechanisms of action would lead to a efficacy in multiple indications.

Martine Rothblatt: Superb answer, Dr. Peterson. James Edgemond, could you kindly address Jess's question regarding the buyback?

Perfect cancer Doctor Peterson.

James Edwin could you kindly address <unk> question regarding the buyback.

James Edgemond: Yeah, thanks, Martine. Jess, thanks for the question. Good to hear your voice this morning. We did announce this morning that our board of directors authorized a share repurchase of up to $1 billion of our shares, and we plan to implement this board of director authorization expeditiously. As a little bit of background as to why now, it really is given the continued strength of our commercial business, our robust balance sheet, our confidence in our upcoming catalysts, and our belief in our share price potential. We, and the board of directors, concluded that now was the right time to authorize this share repurchase. Like many shareholders we've met with, we believe the return of capital represents confidence in our near term as well as long-term business prospects. We share the view of many shareholders that our stock is an excellent investment opportunity.

Yes, Thanks, Martijn and Jeff. Thanks for the question good to hear your voice this morning.

We did announce this morning that our board of directors authorized a share repurchase of up to $1 billion of our shares.

And we plan to implement this board of director authorization expeditiously.

It's a little bit of background, maybe as to why now.

It really is given the continued strength of our commercial business, our robust balance sheet, our confidence in our upcoming catalysts and our belief in our share price potential we and the board of directors concluded that now was the right time to authorize the share repurchase.

And like many shareholders. We've met with we believe the return of capital represents confidence in our near term as well as long term business prospects and.

And we shared the view of many shareholders that our stock is an excellent investment opportunity. So Jeff. Thanks for the question Martijn back to you.

James Edgemond: So Jess, thanks for the question, and Martine, back to you.

Martine Rothblatt: Thank you so much for that great response, James. Operator, you may take the next question.

Thank you so much for that sake response, James Operator, you may take the next question.

Steve: The next question is in the line of Roger Song from Jefferies. Please go ahead.

The next question is from the line of Roger song from Jefferies. Please go ahead.

Joseph Thome: Great. Congrats for the progress, and thank you for taking our question. Also, a question related to Tyvaso. Given the INCREASE subgroup data and the powering assumption 80% to detect the 80 milliliter difference, what will be considered clinically meaningful FVC results from that trial? What will be the homerun scenario from that trial? Also, a follow-up on Jessica Fye's question earlier. Do you have a sense or any corp level comment on how many patients from the Tyvaso is actually having the pulmonary hypertension with the IPF versus the pure IPF? Thank you.

Great Congrats for the the progress and thank you for taking my question also question are related at your Chi Tom So given the increased subgroup subgroup data and then Oh powering assumption, 80% to detect the 80 minute ETA difference, so what will be considered cleaning coating or.

You bet.

So on that trial, and then what will be the homerun scenario.

Strong dot com.

Then also follow up on that just cause question earlier, so do you have a sense or any any copper metal.

A comment on how many patients are Sonic Chi Tung is actually having the pulmonary hypertension.

The tension with Ikea versus a pure Ips. Thank you.

Martine Rothblatt: Thank you, Roger, for that concatenated question. It is all basically in the domain of biostatistics. I will ask Dr. Dung to kindly answer that question.

Thank you Roger for that Concatenated question, it's all basically in the domain the bio statistics, so I'll ask Dr.

Dr. Dunne declines the answer that question.

C.Q. Dean: Since the TTOM study was testing the antifibrotic effect, not the vasodilator effect, we designed our study to enroll the patients similar to other IPF studies, not try to design the study similar to previous PAH ILD studies. We actually did not perform the hemodynamic measure to actually determine if the subject had pulmonary hypertension or not.

Since the chemo study with testing.

The anti fibrotic effect not.

That's our dialogue.

<unk>, let's say.

We designed our studies.

So enjoy the pension just similar to other IPF studies or not.

Ah trial.

Try to design a study similar to the previous ph ILD studies.

So we actually did not.

The.

Hmm, a dying that camera dynamic on vaccines can actually determine if the subject that had that.

Pulmonary hypertension or not.

Martine Rothblatt: Thank you, C.Q., for responding to Roger's question. Operator, you could open the line to the next question.

Thank you CQ4 responding to Roger's question, operator U K.

Open the lines for the next question.

Steve: The next question is from the line of Andreas Argyrides from Oppenheimer. Please go ahead.

The next question is from the line of Andreas <unk> from Oppenheimer. Please go ahead.

Andreas Argyrides: Yeah, good morning. Thanks for taking our question. Congrats on the quarter, all the positive updates. Appreciate the additional color here. I wanted to ask about Ralinepag. With the PAH space, with the space moving towards more convenient dosing, can you share your thoughts more on the Ralinepag opportunity with once-daily oral dosing and the powering assumptions from the advanced outcome study? Then just a quick question for Dr. Peterson. You mentioned the refined imputation for TOM-2. Can you expand on how that method aligns with the FDA expectations on whether to add topping from the strength of the upcoming readout? Thank you.

Hey, good morning, Thanks for taking our question congrats on the corner of all the positive updates I appreciate the additional color here I wanted to ask about relented peg.

With the ph space or the page space moving towards more convenient dosing can.

Can you share your thoughts.

More on the relented peg opportunity with once daily oral dosing and the powering assumptions from the events outcomes study.

Then just a quick question for Dr. Peterson.

You mentioned.

The refined.

Finishing for tea time, too can you expand on how that aligns with the expectations are there.

And the strength of the upcoming readout. Thank you.

Martine Rothblatt: All righty, Andreas Argyrides, thanks for the kudos on the quarter. Both of those questions are really within Dr. Leigh Peterson's domain, so Dr. Leigh Peterson, could you address them?

Alrighty Andreas Thanks for the kudos on the quarter and both of those questions are really within Dr. Peterson.

Uh huh.

Domains, so Dr. Peterson could you address them.

Yeah, So I guess.

Leigh Peterson: Yeah. So I guess for the powering, I am not sure that I got all of the questions, but the powering for Ralinepag, it is powered at 80% to detect a treatment difference, the 0.65 hazard ratio. So that is for clinical worsening events. We are on target to achieve the number of clinical worsening events to be able to see a difference and to detect a treatment difference by the end of the year. I think that was your question about the powering. You had a TTOM question, and I did not quite get all of that. I am sorry.

Powering.

And I'm not sure that I got all of the questions.

The powering for relented pegged it is powered at 80% to detect the treatment different eclipsing five hazard ratio.

So that for a clinical worsening event and and we're on target to achieve the number of clinical worsening event.

To to be able to see a difference and to detect the treatment difference by the end of the year.

And and so I think that was your question about the powering and then you had a teton question and I didn't quite get all of that I'm, sorry can you repeat your T com question.

Martine Rothblatt: Argyrides, can you repeat your TTOM question?

Yeah.

Andreas Argyrides: He's out of the queue, man.

Is that on the queue now.

Martine Rothblatt: Okay. I am sure IR can follow up with him. Operator, can you answer the next question?

Okay, well I'm sure I can follow up with him operator can you answer the next question.

Steve: Yes. The next question is from the line of Ash Verma from UBS. Please go ahead.

Oh, Yes. The next question is from the line of Ashwin <unk> from UBS. Please go ahead.

Joseph Thome: Thanks for taking my question. I wanted to ask about the design of Tyvaso studies, specifically about the potential amputation of measurement for discontinuation per the protocol. In this case, based on your protocol, would these be reported as a missing or a zero or excluded from the analysis? That is one. Secondly, to the extent there is Tyvaso-induced cough in the study, would not that mean functional unblinding if patients are only seeing that in the Tyvaso arm? Thanks.

Yeah. Thanks, Thanks for taking my question. So I wanted to ask about the design of Teton study, specifically about the potential application of measurement for discontinuation.

But the protocols in this case based on your protocol.

Would these be reported as a missing or zito on exchange from the analysis. So that's one and then secondly to the extent like that is <unk> to induce cough. In this study wouldn't that mean functional unwinding if patients are only seen that in the ib's alarm.

Thanks.

Martine Rothblatt: Okay. Thank you, Ash, for that question. I would like to ask C.Q. if he could answer the first part of the question, C.Q., if you got it all, and then Dr. Peterson to answer the second part of the question on the unblinding.

Okay. Thank you asked for that question I'd like to ask CQ, if he could answer the first part of the question.

<unk>, if you've got it all and then Dr. Peterson to answer the second part of your question on the UN blinding.

C.Q. Dean: I'll address that potential unblinding due to the cough event. Actually, based on the previous study, even the patients who are randomized to the placebo group, they will also experience some cough event. It's not just once you see the cough event, you can guess that the subject will be in the active arm. You probably see a little more cough in the active group than placebo group, but placebo patients also experience the cough event. We don't think that potential unblinding is an issue there.

Oh just the.

Potential on blinding due to the cost of event.

I'm actually going to them.

Based on the preclinical study, even the patients who are randomized to the placebo group.

There will also experience some coffee brand.

There's a lot there.

Just the one thing you'll see is a coffee vanda.

You can you can test the subject will be in the active arm.

So.

You'll probably see neither mall cough in the active group have been plenty of bulk of about let's say about pension, but also expanding our coffee brands. So we don't think of that on blinding.

And blindness is the issue there.

Martine Rothblatt: Thank you, C.Q. Dr. Peterson, since C.Q. answered kind of the second question, do you want to comment on the first question?

Thank you C G. Dr. Peter Simpson since you answered kind of the second question do you want to comment on the first question.

Leigh Peterson: Yeah. So we talked quite a bit about the deaths, how they will be penalized with the FVC value at 2.5 percentile of observed values. Discontinuations for other reasons will be handled through statistical models like the mixed model repeated measures or multiple amputation. I agree with what C.Q. said. It is just like any study where there is a known AE that can be associated with the treatment, but very often, there is a similar AE that is seen with the placebo. We generally are, we definitely are surprised at the end of the day. Sometimes we see things, we think, "Oh, yeah, maybe that is on active because of cough." It is definitely not. So I would say there is no risk, especially in this study of cough because people cough a lot just by inhaling placebo. So no worries there.

Yeah, So we talked quite a bit about the death, how that'll be kind of lies with the F. B C value at 2.5 percentile of the observed values and then discontinuation for other reasons will be handled through statistical models like the mixed model repeated measures or multiple amputation.

Yeah, and I agree with what <unk> said I mean, we are at it just like any study where there's unknown a E. That's a that can be associated with with the treatment, but very often.

There, there's a similar AE that seen with the placebo and and we I mean, we generally are.

We definitely are surprised at the end of the day, sometimes where we see things we think Oh, yeah, maybe that's an active because of course, it's definitely not so I would say, there's there's no risks and especially in the study of costs because people cost a lot just by inhaling placebo. So no worries there.

Martine Rothblatt: Perfect, Dr. Peterson. Thank you so much. Operator, can you take the next question, please?

Perfect. Dr. Peterson. Thank you so much operator can you take the next question. Please.

Steve: The next question is from the line of Jason Gerberry from Bank of America. Please go ahead.

The next question is from the line of Jason Goldberg from Bank of America. Please go ahead.

Terrence Flynn: Hey, guys. Thanks for taking my question. Mine's also just on IPF. I guess the physician KOLs seem to think that the neurin-domalast data at ATS were pretty underwhelming, just the neutral benefit on exacerbation as a secondary endpoint and the lack of a p-value in the monotherapy subgroup. So I'm just kind of curious, how important is it in your view to show a meaningful improvement on the exacerbation as well as sort of establish with stats a benefit maybe in a pooled manner in the monotherapy subgroup?

Hey, guys. Thanks for taking my question mine is also just on IPF and I guess, the physician kols seem to think that the Marin Domo as data at Ats, where we're pretty underwhelming just the neutral benefit on exacerbation as a secondary endpoint and the lack of a P value in the mono therapy subgroup. So I'm just.

Kind of curious.

How important is it in your view to show a meaningful improvement.

Movement on the exacerbation as well as sort of established with stats a benefit maybe in a pooled manner and the mono therapy subgroup.

Martine Rothblatt: Thank you so much for the question. Dr. Leigh Peterson, I think you'd be the best person to answer it.

Thank you so much for the question and Dr. Peter is saying I think you'd see the best person to answer it.

Leigh Peterson: Okay. Yeah. So, I mean, there was definitely a positive study for the Fibrinir IPF and PPF, but they met their endpoints. They had 90% power to detect a 74 milliliter change in FVC. We are 80% powered to detect 80 milliliter change. We look forward to seeing events or seeing a result where, ideally, we would see that our Tyvaso is disease-modifying and that patients don't decline. However, we may see a slight decline or more decline, but we fully anticipate having a clinically meaningful effect, which would be greater than an 80 milliliter change in FVC. Again, but blinded, we will know in September.

Yeah. So.

So I mean, yeah. They they there was definitely a there was.

A positive study for the fiber and here I P. S N P. P S.

But and and they they met their endpoint.

They had 90% power to detect a 74 milliliter change and as we see them, where 80% powered to detect 80 milliliter change them, but we you know obviously, we look forward to seeing events are seen a result, where you know.

<unk>.

Ideally we would see that are high they sell is a disease modifying in that.

Patients don't decline however, we may see a slight decline or more decline.

But.

We we fully anticipate having clinical and clinically meaningful effect, which would be greater than an 80 milliliter change and SBC, so again, but blinded.

We will know in September.

Martine Rothblatt: Thank you so much, Dr. Peterson. That's an excellent answer. Operator, you can take the next question.

Well. Thank you so much Dr Peterson.

Excellent answer and operator, you can take the next question.

Steve: The next question is from the line of Terrence Flynn from Morgan Stanley. Please go ahead.

The next question is from the line of Terence Flynn from Morgan Stanley. Please go ahead.

Terrence Flynn: Great. Thanks so much for taking the question. I will stick to one. Just on Tyvaso, when you look at background therapy from the INCREASE study, it looked like there was maybe a difference in terms of patients that were on background TKI versus those that were on no background TKI. Maybe you could just talk through that dynamic. Then as we think about the phase 3, the mix there and how that might impact the overall treatment effect that you are expecting to see. Thank you so much.

Great.

Thanks, so much for taking the question I'll stick to one.

Just on Teton.

When you look at background therapy from the increased study it looked like there was maybe a difference in terms of patients that were on background Teekay I versus those that were on.

No background T Cai and so maybe you could just talk through that dynamic and then as we think about the phase three the mix there and how that might impact the overall treatment effect that youre expecting to see thank you so much.

Martine Rothblatt: Thank you, Terrence. Good to hear your voice this morning. Dr. Leigh Peterson, you'd be the best person.

Thank you Karen and good to hear your voice. This morning, Dr. Peter said you'd be the best person.

Leigh Peterson: Yep. So we, I mean, we definitely versus INCREASE, we see more background therapy use in both TTOM-1 and TTOM-2 as shown on one of the slides that I went through today. TTOM-1 and TTOM-2 have 77% background therapy use and 75%. So it is more. I mean, it can, just like any, again, any study, when you have effective background therapy, then it can mute your efficacy of your investigational drug. But again, we are right in there. Fibrinir IPF also had, you know, 78% use of background therapy. There is a lot of room for improvement. I mean, I also showed the slide that the patients even on the active background therapies have, you know, have a significant decline in FVC. So there is a lot of room for improvement, and this is exactly what we expected as far as the use of background therapy.

Yeah, So we I mean.

Definitely versus increase.

We see more a background therapy and both to kind of wanting to talk to as shown in one of the sites that I went through today.

And two times, one antitank to have 77% background therapy use and 75%. So it's more I mean, it can just like any again in study when you have effective background therapy, then it can mute your efficacy of up here.

Of your investigational drugs, but again, we're right in there fiber near Ics also had you know 78% use of background therapy, and there's a lot of room for improvement I mean, I also showed the slide that that the patients even on the accurate active background therapies have you now.

Have have a significant significant decline in.

In S E T. So theres a lot of room for improvement and this is exactly what we expected as far as the use of background therapies. So again.

Leigh Peterson: Again, stay tuned in September, but that is not a concern.

Tuned in September but that doesn't it.

Not a concern.

Martine Rothblatt: Dr. Peterson, thank you so much. Just because you've been on the phone so much answering these questions, I do want to toot your horn for a moment to make sure these questioners understand your expertise, that you are the lead author on the New England Journal of Medicine publication on our INCREASE study, in addition to being the lead author of our Physiological Reviews publication on xenotransplantation. Folks on the phone, you're privileged really to hear from such an expert source as Dr. Peterson. Operator, I think we're ready to take the second questions from people. Next question.

Dr. Peter saying, thank you so much and just because you've been on the phone. So much answering these questions I do want to toot your horn for a moment to make sure. These questioners understand your expertise.

You were the lead author on the New England Journal of Medicine publication on our increased study.

In addition to being the lead author of our physiological reviews, a publication on female transplantation. So.

Folks on the phone you have privilege really to hear from such an expert sources Dr. Peterson operator.

I think we're ready to take the second question is from people. So next question.

Terrence Flynn: Martine, there are no more questions in the queue, but I do have Andreas Argyrides's follow-up question. He was asking, can you expand on how the FVC imputation method in TTOM aligns with FDA expectations and whether this adds confidence in the strength of the upcoming readout? So it relates to the recent change in how we handle deaths in that study.

Oh Martini Theres no more questions in the queue, but I do have Andreas it's a follow up question and he was asking can you expand on how the FTC imputation method and Teton aligns with FDA expectations and whether that's had the confidence in the strength of the upcoming readout. So it relates to the.

The recent change in how we handle deaths in that study.

Martine Rothblatt: Well, since we have the New England Journal of Medicine lead author in this field on the line, we will ask Dr. Peterson to answer.

Sure well since we have been a new England Journal Medicine lead author and in this field on the line, we'll have Dr. Peterson dancer.

Leigh Peterson: Yeah. I must correct, I am not lead, but I am one of them.

Yeah, and I must I must correct I'm, not lean, but I'm one of them Hum.

Steve: for that one. But thank you, Martine. Very, very cool.

I've heard that one but thank you my team very well because I think you are the boxes you are the boss of the week.

Dewey Steadman: Because I think you are the boss. You are the boss of a lead.

[laughter], Okay, what was the question.

Steve: What was the question? I'm just.

Dewey Steadman: Okay.

Yeah. So we have or our statistical analysis plan is you know very lengthy and very long and all of that is submitted to F. D. A for their feedback and so and often they and they have and I'm, giving us feedback.

Steve: Yeah. So we have our statistical analysis plan. It is very lengthy and very long, and all of that is submitted to FDA for their feedback. Often they have given us feedback. Again, we have talked extensively about the death penalty with them. This is the current feedback as of just a few weeks ago. So that is already set. Then CQ and his group have been in conversations with FDA, as was true for increase, the same for these studies, where what specific statistical models should be used and how to impute the measures. Again, the mixed model repeated measures or multiple imputation.

Then we've talked extensively about that.

Death penalty with them. This is but this is the current feedback is just you know just a few weeks ago. So that's already set and then C. Two and his group have been in conversations with FDA about as was true for increase the same for the B studies.

Where you know what specific statistical models should be used and and how to implement the measures again, the mixed model repeated measures or multiple amputation.

Dewey Steadman: Perfect. Thank you so much, Dr. Peterson. Thank you, folks on the call. Operator, you can wrap up the call now.

Perfect. Thank you so much Dr Peterson.

You folks on the call operator, you can wrap up the call now.

Martine Rothblatt: Thank you for participating in today's United Therapeutics Corporation earnings webcast. A rebroadcast of this webcast will be available for replay for one week by visiting the events and presentation section of the United Therapeutics Investor Relations website at ir.unither.com. Thank you.

Thank you for participating in today's United Therapeutics Corporation earnings webcast.

Broadcast of this webcast will be available for replay for one week by visiting the events and presentation section of the United Therapeutics Investor Relations website.

I adored U N I T O T O dot com.

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