Good morning and welcome to the United Therapeutics Corporation Fourth Quarter and Full Year 2022 Earnings Webcast. My name is Devin, and I will be your conference operator today. [Operator Instructions] I will now turn the webcast over to Dewey Steadman, Head of Investor Relations at United Therapeutics..

Thanks, Devin, and good morning. It is my pleasure to welcome you to the United Therapeutics Corporation Fourth Quarter and Full Year 2022 Earnings Webcast. Accompanying on today's webcast 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; Pat Poisson, our Executive Vice President of Technical Operations; and Dr. Leigh Peterson, our Senior Vice President of Product Development.

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. 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 also 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 service the basis for medical decision-making or to suggest that any products are safe and effective for any unapproved or investigational use. Full prescribing information for the products are available on our website.

And United Therapeutics executives will participate in 3 investor conferences in March. First, Michael Benkowitz will participate in a fireside chat at the Cowen Healthcare Conference on Tuesday, March 7. Dr.

Martine Rothblatt will participate in a fireside chat at the Oppenheimer Healthcare Conference on Monday, March 13, and our Chief Medical Officer, Gil Golden will participate in the JPMorgan Napa Valley Biotech Forum on Tuesday, March 21. Now I will turn the call over to Dr.

Rothblatt for an overview of the fourth quarter and full year 2022 financial results and business activities of United Therapeutics. Dr.

Rothblatt?.

Thank you, Dewey, and good morning, everyone. I feel very excited to lead this call because we have so much positive news to report about 2022. In fact, reflecting back on the past few years, this is actually the best year United Therapeutics has ever had.

And it augurs even more, I think, positively to what we're going to see coming up in 2023, 2024 and 2025. Let me hit a few highlights. First, 2022 was our highest revenue year ever. Second, 2022 was our most profitable year ever. Third, 2022 was our highest operational cash flow year ever.

And fourth, we ended 2022 with more patients on our treprostinil medicines than ever before. I think you have to agree with me that these are fantastic results.

And now I'd like to give a few indications of why I think that as great as these results are, they are not laurels for us to rest upon but instead a launching pad for yet greater results in 2023, 2024 and 2025. In fact, the patient uptake of our new Tyvaso DPI medicine has been so rapid that we can project a doubling of our revenues by 2025.

This doubling of revenues is helped by the unique nature of each of our medicines including Tyvaso DPI. For example, Tyvaso DPI is the only inhaled treprostinil product that enables deep lung penetration via high-resistance low-flow device.

Another example, our Remodulin product is the only parenteral prostacyclin delivered by the small, easy, super accurate Remunity device. The differentiated aspects of Remodulin has allowed us revenues to remain steady at about $0.5 billion a year through the past 3 years running.

Our Orenitram product is also very unique because it is the only titratable oral prostacyclin product. We currently expect it's 1/3 of $1 billion a year revenue to continue growing as physicians become aware of the results of our recently released EXPEDITE study. That study showed Remodulin patients can be switched directly to Orenitram.

And Orenitram will soon be joined by new products from our pipeline. In the field of pulmonary arterial hypertension, we expect to complete our Phase III trials of ralinepag by 2025. That will enable the first once-daily dosing of a prostacyclin pill in the pulmonary hypertension field.

In the field of pulmonary fibrosis, we expect to complete our Phase III trials of Tyvaso by 2025 as well. That will, we hope, create the first disease-modifying treatment for pulmonary fibrosis, a true landmark in the field. And in the area of transplantation we hope to commence clinical trials of manufactured organs within the next few years.

That would be a major contribution to ending so many deaths on the organ transplant list and unfortunately, even more deaths from end-stage organ disease off the transplant list. In summary, our business, our patient count, our pipeline is growing longer and faster than ever before. 2022 marked the continuation of that growth factor into 2023.

We have achieved a very nice balance of growth and strength. We intend to continue building on this platform in the years to come. To provide now some additional, very median I think, extremely exciting details of how we are continuing to build on this platform, I'd like to introduce our President and Chief Operating Officer, Michael Benkowitz.

Mike?.

Thanks, Martine, and good morning, everyone. From a commercial standpoint, as Martine said, 2022 was a phenomenal year for us. We're extremely pleased with the progress of the Tyvaso DPI launch as referrals starts and active patients for both Tyvaso and Tyvaso DPI are among the best that we've seen to date.

We were also very excited to achieve our goal of doubling the number of Tyvaso patients following the PH-ILD approval in early 2021. This was a goal that Unitarians across the organization rallied around and supported. So we're really proud and appreciative of everyone's hard work over the last couple of years to help us reach this milestone.

Importantly, reaching this goal reinforces to us the impact that Tyvaso and Tyvaso DPI are having not only in helping patients with PH-ILD treat this serious progressive disease for which there are no other available options, but also the impact Tyvaso DPI will have in PAH.

With the simple convenience of a small inhaler that fits in the palm of the patient's hand and an elegant ease of use following the simple mantra of open, load, inhale. We believe Tyvaso DPI will meaningfully expand the use of inhaled treprostinil in both indications.

The Tyvaso DPI inhaler device developed by our partner, MannKind, is able to efficiently deliver treprostinil deep into the lung and one breadth per cartridge using less active ingredient to the nebulizer reference.

The convenience and efficacy of our DPI device, coupled with Tyvaso's known tolerability profile has us well positioned to expand our reach in PH-ILD and to move the use of treprostinil therapies like Tyvaso DPI and PAH even earlier than IP receptor agonist like selexipag.

We're seeing this play out with our prescribers as evidenced by several positive trends. Since the PH-ILD launch, we've increased the total number of Tyvaso prescribers by about 70%, an increase by almost 60%, the number of prescribers with 3 or more patients in their practice. This last point is an intra marker we look at to gauge product support.

We have found that once a physician has at least 3 patients on one of our products, they tend to become what we call supporters and start using the product much more frequently and regularly. We're also making headway with traditionally loyal selexipag prescribers.

Of the top 100 selexipag prescribers, 70% have now written Tyvaso DPI and 50% of those have written 5 or more prescriptions. From a revenue standpoint, we're very pleased with how the quarter and the year wrapped up for Tyvaso, but there are a few key points I want to highlight.

First and most relevant to the fourth quarter of 2022 is that we're still in a launch mode for Tyvaso DPI and even for the PH-ILD indication for that matter. As such, our specialty pharmacy distributors are still rightsizing product orders based on estimated underlying patient demand, both in total and between Tyvaso nebulized and Tyvaso DPI.

Therefore, our distributors are placing orders more frequently than their once or twice a month historical cadence. And these new ordering patterns did impact the timing and size of product orders and thus our product revenues during the quarter. Second, we're also building Tyvaso DPI inventory as we're launching a product.

So our distributors are not yet able to order a sufficient product to reach contractual inventory levels per their usual practice. We expect over the next several quarters, these 2 factors will normalize, and our specialty pharmacy distributors will shift back to a more historical type cadence of product orders.

For these reasons and the usual historical seasonality to our business that we have discussed on prior calls, we think annual revenue trends are a better lens through which to view and evaluate our business. The last thing I want to touch on with Tyvaso is our patient assistance program or PAP.

Patient utilization of our program -- of our PAP program for Tyvaso DPI which is covered under Medicare Part D and has high patient co-pays, has been higher than anticipated, including by many PH-ILD patients who were on the nebulizer and nPAP last year and has since transitioned to DPI.

We anticipate that this will be a short-term phenomenon and that many of these patients will be covered under their Medicare Part D plan starting in 2024 and continuing into 2025, once changes to the Part D provisions of the Inflation Reduction Act begin to go into effect. Turning to Orenitram.

We see continued momentum for Orenitram as we ended the fourth quarter with the highest number of patients on therapy since its launch.

We're also excited about the recent top line EXPEDITE data we press released in October of last year that demonstrated that prostacyclin induction with Remodulin can lead to double the average Orenitram dose when patients shift to oral therapy compared to patients who do not have a Remodulin induction.

Following up on this top line data, we plan to present additional details on EXPEDITE at scientific meetings this year, along with a peer-reviewed manuscript detailing the study in the second quarter. And finally, we continue to be pleased with the performance of Remodulin in the U.S.

as the fourth quarter was one of our highest referral quarters ever. The Remunity pump for Remodulin is gaining momentum with approximately 1/3 of subcutaneous patients now on Remunity especially as Remunity is the only subcu pump widely available for any patients to treprostinil therapy.

So to wrap up, after reaching our goal of doubling the number of Tyvaso patients, we're confident in our ability to double our annual revenue run rate for approximately $2 billion today to $4 billion by the end of 2025.

We expect continued Tyvaso and Tyvaso DPI uptake in both PAH and PH-ILD to drive most of our near-term revenue growth, supplemented by Orenitram growth through the expedite protocol and other research and supported by continued Remodulin resilience. With that, I'll turn the call back over to Martine..

Michael, thank you so much for providing that wealth of detailed information supporting this great growth vector we have going here from 2022 into 2023, '24, '25. Operator, feel free to open up the lines to any questions now..

[Operator Instructions] Our first question comes from Jessica Fye with JPMorgan..

I have two, if that's okay. First, can you provide some of the assumptions, specifically around Tyvaso and Tyvaso DPI to help underpin your target to roughly double your revenue run rate for the overall company by the end of 2025.

And then second, just following up on Michael's comments in prepared remarks, I was hoping if you could elaborate a little bit more on that comment about the utilization of the PAP program for DPI being higher than anticipated among PH-ILD patients who transitioned to DPI.

Is that to say that because of the higher out-of-pocket in Part D in the short term that they're receiving free drug? And how should we reconcile that with, I think, what was anticipated to be a bit of a tailwind in 2023 from PAP patients transitioning on to reimbursed product this year?.

Yes. Thank you, Jess, and good morning. Good to hear your voice this morning. Generally, we try to like limit to one question for questioner because there are so many people in queue. But because your two questions are in a sense kind of like a tag team question, one way close into the next, Mike, I'll kind of ask if you can handle both questions..

Yes. So I think, Jess, your first question around the assumption, the underlying assumptions for our confidence in the growth of Tyvaso in both PAH and PH-ILD is, in some ways, it's a little bit of a math -- kind of a math exercise, but also just I think -- I think just the excitement and enthusiasm we're seeing around DPI.

So if you think about in the PAH or the WHO Group 1 market, there's about, I mean, roughly 50,000 patients in the U.S. diagnosed with PAH, still and shockingly and sadly, it's probably only about, I would say, about 30% to 35% of those patients are on a prostacyclin.

And there's a lot of reasons for that, and a lot of it comes down to the fact that the delivery mechanisms for prostacyclin are -- they're not terribly convenient. But I think that is changing on Tyvaso DPI.

So we feel very confident that we will be able to -- with the convenience of the DPI inhaler to be able to expand the use of prostacyclins in the PAH market meaningfully.

So I think we feel like even though it's a crowded market, even though Tyvaso has been out there, we still think that there's a lot of opportunity within the WHO Group 1 market to grow the use of prostacyclin and particularly Tyvaso.

And then a similar story, but maybe a little bit easier on the PH-ILD side because there, you have a market that's conservatively 30,000 patients with no other approved therapy. And so we've roughly tapped into about 10% of that over the last couple of years, and we think we have another other 90% available to us.

So we still feel like we have a lot of runway there to grow with Tyvaso. And again, I think just with the convenience of DPI, it's going to get easier for doctors to prescribe that drug for those patients that have PH-ILD. And then shifting to your second point on the PAP.

So yes, so the issue is that we had patients in PH-ILD, patients on Medicare and our PAP program for 2021, 2022, expected a lot of those to roll over starting in 2023. And a lot of those have started to roll over in 2023. It's not as high as -- the number that are rolled over, it's not as high as we expected for a couple of reasons.

One is I think at the end of the third quarter, I think we reported that there were about 700-ish patients in the PAP program. So some of those discontinued which we expected. Some of those even after becoming -- even with the CMS coverage, still qualified for PAP. And so they stayed in PAP.

And then as I said in my prepared remarks, we did have a number of patients that transition to DPI between the end of the third quarter and the beginning of the first quarter. And so with the higher co-pays and Part D, they were then eligible to remain in PAP. So I think we still had about half, slightly more than half of those patients convert over.

I think they're still -- they're kind of working through the system, but it's a little bit less than we were expecting, I think, when we had the call in the third quarter..

Those are great answers. Jess, one just additional shade of color I could add on top of Mike's remarks with regard to your question as to what kind of parameters can I provide to provide greater assurance about the doubling of revenues by the end of '25 is the uptake of Tyvaso DPI has been dramatic.

And as Mike mentioned, he provided some metrics, for example, the very high number of selexipag prescribers who have not previously prescribed on Tyvaso now prescribing Tyvaso DPI. So when we achieve the doubling of our patients on Tyvaso over a period of just 18 months, I can't really overemphasize what an important metric that is.

Just to give you kind of a sense, Tyvaso was approved 10 years ago. So it took like 10 years to get up to a certain level of patient penetration for this drug and then in under two years, it doubles. I mean that's -- it's an unmistakable sign in addition to the steps that Mike shared with you that this product is going to penetrate very, very rapidly.

Now while one might think that in an area such as PH Group III, which has been penetrated by no pulmonary hypertension medicines like, oh, these are all just like people dying of thirst and just going to just slap up this new medicine right away, the reality in a disease like pulmonary hypertension is that it just doesn't happen like that.

Instead, it's a very kind of blocking and tackling exercise of physician by physician, center by center working through all of the rigorous of talking to the right payers and getting the payers to understand the right procedures and going through all the procedures and the pre-approval, diagnoses, requirements, the catheterizations and all of these things.

So while we did create like special teams focused on PH Group III before we launched into that indication, in the field of pulmonary hypertension, one year of kind of preparation is sort of like nothing compared to how much activity is needed to build a bulk of patients.

So now that one year is more than two years behind us, we've now had a year of actual practice, okay, you can actually put these patients on medicines. As Mike referred to, the payer aspects, especially with regard to Medicare, we're just very, very recently resolved favorably in our direction.

And so the -- it's just you have to like first have not just one year and not just like there wasn't like a waiting bolus of patients in Group III just waiting for a launch, you have to like develop this market and really kind of till the soil for a number of years.

We've now done that, and we're experienced in those clinics and it's this reason why we think out of those 30,000 PH Group III patients.

Fortunately, none of them have been touched by pulmonary hypertension treatment that we can rapidly grow our numbers of patients at the same rate that we've been growing them for the past year with this doubling of the number of patients on Tyvaso and thereby reach a number of total treprostinil patients, something that would be in the 20,000 that would correlate when you multiply that times the reimbursement per patient to the $4 billion per year.

And of course, it's important. In addition to this, not to be losing revenue from Remodulin or Orenitram.

But not only are we not losing revenue, we're solidifying our hold on the Remodulin revenues as Mike referred to the very rapid penetration that the Remunity pump has made and we're growing our revenues in Remodulin -- in Orenitram as a result of the EXPEDITE study that Mike described.

So we feel that doubling revenues in three years is really a very doable too.

Operator, next question, please?.

Our next question comes from Terence Flynn with Morgan Stanley..

This is Justin Phillips on for Terence. Just one question for me. I was wondering if you could provide any details today on the Tyvaso trends for January and February..

Sure.

Mike, would you like to take that?.

Sure. I'm not going to get into too much detail in terms of previewing the quarter. I mean, I think what I can tell you is and really I have got about a month of data behind us, but I can tell you that the trends in terms of referrals, that's what we call prescriptions for Tyvaso in January are very strong, had like a record level for January.

So -- and at least what I'm seeing through kind of there's a lag on the February data, but February is continuing that. So again, I think we're really pleased, just to echo what Martine said, I think we're really pleased with the uptake of generally and specifically with DPI..

Thank you, Mike. That's so nice to hear. Record January referrals after a record year, fantastic. Next question, please..

Our next question comes from Hartaj Singh with Oppenheimer & Company..

Just a quick question on a slightly different topic with your plan to potentially double revenues by 2025, you still got the Tyvaso IPF Phase III trial reading out around then which is positive. Martine sense another nice little runway there.

Could you maybe just go over -- remind us again if Gil is on the call, the data behind that, your certainty around that project? And then just some basic sizing of the market..

Sure, Dr. Singh, so happy to hear your voice this morning, and thank you for asking a science question. We love those questions best of all. We have on our call, Dr. Leigh Peterson, and she is our Chief Scientist for the program, and she's also running the TETON clinical trials. People often wonder why they are named TETON, and it's because Dr.

Peterson is from Wyoming. So it makes perfect sense. And Leigh, if you could provide Hartaj with some of the scientific reasons why we feel very confident that the Phase III trials of Tyvaso in IPF are rightly sized and that the endpoints are rightly chosen..

Yes, sure. Thank you for the question. As you know from the results of our INCREASE study, we had an exploratory endpoint, which was forced vital capacity.

And that was really -- for the PH-ILD population, it was really a safety assessment in the study but it turned out, we actually saw an improvement of that endpoint in patients on Tyvaso and so -- relative to placebo.

And so between the results of this study, increase in PH-ILD patients as well as quite a few -- quite a bit of evidence in the literature of in vitro in nonclinical studies that Tyvaso or treprostinil does have an impact on fibrosis. It's very reasonable that we would be able to have a positive impact in an IPF population.

And so using the statistics and the treatment effect that we saw, an increase in specifically IPF patients, we were able to do sample size calculations in order to predict that we would have a successful study with a sufficient p-value to get approval. And we're actually doing 2 studies, one TETON 1 study in the U.S.

and Canada as well as TETON 2, which is outside of U.S. and Canada in order to -- in each of those studies, about 400 patients -- almost 400 patients, and enrollment is going well as expected. And as Martine -- that we expect to read out in around the 2025 time frame of both of those studies.

They both have an FVC endpoint again, same as what we saw, a positive sense in INCREASE. And we have a year-long follow-up period. We've also had some published results of the INCREASE.

You might remember that the randomized part of the study an INCREASE was 16 weeks, but we continue to follow patients -- those patients in a long-term open-label extension study.

And so we've been collecting long-term FVC data as well, which looks promising and also gives us confidence that the TETON studies will be successful, but to be determined in 2025 time frame..

Well, thank you so much, Leigh. And I just want to and toot your horn just for a moment to the hundreds of people on the call that there was similar skepticism as to whether or not Tyvaso could work in Group III patients and you proved that it could. And I believe your results were published in the New England Journal of Medicine.

So congratulations again. Next caller, please..

Thank you. Yes, they were..

Our next question comes from Ash Verma with UBS..

I have one. So for Tyvaso, was there any inventory buildup in 3Q that bind you down mostly in 4Q or do you think inventory is still at an elevated level during 4Q? I think you mentioned that specialty distributors are still rightsizing the orders..

Thank you, Ash. Thank you for that question. Fortunately, we have our Chief Financial Officer, on the phone, James Edgemond. And James, if you could perhaps help Ash with the inventory question..

Yes. Thank you, Martine. Thank you for your question. I think there's kind of 2 ways to answer. One is Michael addressed and talked about the Tyvaso and Tyvaso DPI ordering patterns in his prepared remarks.

And I think if you look at B as part of the answer, the other products there was no unusual ordering or inventory activity and our specialty pharmaceutical distributors were in line with their contractual requirements on inventory. So hopefully, that provides you insight in terms of your question this morning. So thank you, and back to you, Martine..

Thank you, James. Operator, next question please..

Our next question comes from Joseph Thome with Cowen and Company..

We're going to be seeing the full mark of sotatercept Phase III data at ACC in about 11 days. And I was just curious how you see a potential future sotatercept launch impacting the PAH market broadly and maybe how this is reflected in that 2025 revenue run rate guidance that you announced..

Yes. Thanks for the question. So it's really like super speculative to provide any kind of a meaningful answer to the question because we don't know what the regulatory time frame is going to be for sotatercept. So it's all but impossible to give you any kind of accurate sense.

I will say that our revenue forecast is agnostic with regard to whether or not sotatercept is approved or not. In other words, we will remain confident about achieving the doubling of our revenues by 2025 without regard to its launch. There -- it's a very large and diversely treated patient population.

Changes in treatment patterns are relatively slow and cautious especially other than frontline treatments such as like ETRAs or PD5s. So I'd be very, very skeptical that you would see an impact of sotatercept on United Therapeutics revenue profile or product uptake across the board, whether it's Remodulin, Tyvaso, Tyvaso DPI or Orenitram.

More broadly, the experience has been that when new agents have been introduced into the market, it has grown the market for all of the existing patients. It's kind of like a market growth thing.

You saw this with, for example, back in the day when we launched Remodulin and J&J's precursor Actelion launched bosentan, the treprostinil revenues did not shrink. In fact, they grew and then later on, when PD5s were introduced, the market for ETRAs, and treprostinil did not shrink. In fact, it grew, it grew quite a bit.

And this has been just a continuous process, and it harkens back to the landmark number that you should keep in your mind that Michael Benkowitz mentioned in his remarks was 50,000, that's 5-0 thousand. That's the number of patients diagnosed with pulmonary hypertension.

And all of these drugs have just like scratched the surface of being able to really treat the patients and get them back to a New York Heart Association Functional Class I or even Functional Class II level. So there is so much robust room for growth and improvement in pulmonary hypertension.

We at United Therapeutics, welcome any new agent that can help the health of the pulmonary hypertension patient population. And by the way, all that is with respect to WHO Group I pulmonary hypertension. So everything I just said, then you've got this other huge pool that Dr.

Peterson opened up with her New England Journal article, WHO Group III, 30,000 patients, that's 3-0 thousand, of which the only approved treatment right now is our Tyvaso drug. And I think sotatercept, I would love to see another good drug to help people with pulmonary hypertension. I don't think it's going to have any effect on our revenue growth.

Next question, operator, and we'll have to cut it after that due to coming to the end of time..

Our final question comes from Andreas Argyrides with Wedbush Securities..

Congrats on a great year. Just a quick one here on Tyvaso DPI.

Are you still seeing more rapid up taking new patients versus transition? And what is the split between new and transition patients?.

A very good question.

Mike, can you give us our final answer on the call?.

Sure. Yes. So it's -- I think it's -- I have to go back to look, I haven't look at it in a couple of weeks, but I think it's still weighted towards new patients in terms of DPI. I mean the transitions are coming.

It's just as I think I said on the last call, I think what physicians are doing is they're waiting until patients come in for the regular checkup. So they're kind of coming -- they are coming in at a healthy clip, healthier than what we were seeing and I think that will continue through the course of the year.

And so I fully expect at the end of the year, those patients that want to transition to DPI will transition to DPI. So it's certainly a kind of a point of emphasis for our sales team.

And certainly, as I said -- certainly, I think the physicians are aware of it and as those patients come in and they decide that the patient is eligible to transition, they'll move them over..

Thank you, Mike. Well, to wrap up the call, we are tremendously excited about 2022. This is the year that we hit our $2 billion revenue run rate that has been our goal for really much of the past several years.

And we are even more jazzed and more pumped by the fact that the $2 billion level, makes it very clear to us that $4 billion is achievable with all of the products that we are currently marketing and explaining to physicians, the scientific and medical benefits of.

And then beyond that, as Hartaj indicated in his question, we have a whole another slew of type -- of products coming out of our Phase III pipeline, particularly a whole new disease indication, pulmonary fibrosis and then on top of that, a best-in-class treatment for pulmonary hypertension, which would be Ralinepag.

So 2022 was amazing, a huge kudos to everybody on the team for achieving it. 2023 is looking even better. And with that, operator, you can close out the call..

Thank you for participating in today's United Therapeutics Corporation Earnings Webcast. A rebroadcast of this webcast will be available for one week by visiting the Events and Presentations section of the United Therapeutics Investor Relations website at ir.unither.com. Have a good day..