Theravance Biopharma, Inc. (TBPH) Q3 2022 Earnings Report, Transcript and Summary

Ladies and gentlemen, good afternoon. I would like to welcome everyone to the Theravance Biopharma Third Quarter 2022 Conference Call. During the presentation all participants will be in a listen-only mode. A question-and-answer session will follow the Company's formal remarks. [Operator Instructions] Also today's conference call is being recorded. And now, I would like to turn the call over to Rick Winningham, Chief Executive Officer. Please go ahead.

Good afternoon and thank you for joining the Theravance Biopharma third quarter 2022 conference call to discuss our business. I remind you that this call will contain forward-looking statements that involve risks and uncertainties, including statements about our development pipeline, expected benefits of our products, anticipated timing of clinical trials, regulatory filings and expected financial results. Information concerning factors that could cause results to differ materially from our forward-looking statements is described further in our filings with the SEC. I would direct your attention to Slide 4. Joining me today Rhonda Farnum, Chief Business Officer; Rick Graham, Head of Research and Development; and Andrew Hindman, Chief Financial Officer. Now turning to Slide 5. Theravance Biopharma’s unwavering purpose is to create medicines that make a difference. The third quarter marked another major inflection point in the company's transformation. We recognized a record quarter of YUPELRI net sales and profitability and continue to build our intellectual property portfolio. Rhonda will review the details. Three opinion leaders in the field presented ampreloxetine data demonstrating clinically meaningful and durable effectiveness in MSA patients with neurogenic orthostatic hypotension in our Phase 3 Study 0170 at the opening session of the 33rd International Symposium on Autonomic Nervous System. Rick will share where we are today on ampreloxetine and where we're headed. We closed the sale of our royalty interest in TRELEGY ELLIPTA to Royalty Pharma for approximately $1.1 billion in upfront cash, $250 million in potential milestones and outer year royalties and Royalty Pharma invested in the ampreloxetine program. And as a result of the deal with Royalty Pharma, we were able to initiate a $250 million capital return program, which included purchasing GSK’s entire holdings at $9.75 cents a share and launching a Dutch auction tender offer for up to $95 million of the Theravance Biopharma ordinary shares, a tender offer that's currently open. We ended the third quarter with $487 million in cash and zero debt. Andrew will review further financial details. All of these actions drive towards our goal of maximizing shareholder value. I'll now turn the call over to Rhonda to review YUPELRI.

Thanks Rick. We are very pleased to share the latest performance update on YUPELRI, which is the first and only once-daily nebulized long-acting muscarinic antagonist or LAMA that provides a full 24 hours of control for patients as is indicated for the maintenance treatment of patients with COPD. Turning to Slide 7, in Q3 net sales of YUPELRI reached another quarterly high launch to date. As a reminder, Theravance Biopharma and Viatris co-promote in the U.S. with our combined sales infrastructure targeting healthcare professionals who treat COPD patients suitable for YUPELRI. Theravance Biopharma’s commercial and medical teams cover the hospital segment and Viatris is responsible for outpatient-based community healthcare professionals. From a financial perspective, we share profits and certain expenses on YUPELRI in the U.S. with 65% going to Viatris and 35% to Theravance Biopharma. Slide 7 shows the Theravance Biopharma’s implied 35% share of net sales for YUPELRI during the third quarter of 2022 of $18.7 million. I am also pleased to highlight that YUPELRI’s year-over-year net sales has increased by 35%. Overall, Q3 2022 demand increased 4% from Q2 of 2022 and increased by 22% year-over-year. We are also very encouraged to see quarter-over-quarter growth in net sales given we saw a slight decline over the same time last year. We typically anticipate seasonality dips in the third quarter due to lower patient census, and fewer exacerbations, et cetera. And total prescriptions within the overall maintenance COPD market also decrease slightly in Q3 of 2022 versus Q2 of the prior year. Looking specifically at the Theravance Hospital segment deployment efforts on the right side of Slide 7, in Q3 of 2022 dosage sold exclusively in the hospital setting, represented a year-over-year increase of 45% and an increase of 5.2% from the previous quarter, demonstrating [indiscernible] hospital volume launch to date. As we have previously stated, the respiratory pandemic impacted the launch phase for YUPELRI's growth in 2020, particularly in the hospital setting. Since the second half of 2021 we have continued to see significant progress in YUPELRI’s hospital business growth each quarter throughout 2022. Contributing to that growth has been the team's ability to continue to achieve new key hospital system formulary placements with the total of 605 formulary placements launched to-date, which have led to now over 1200 purchasing accounts and the account number continues to increase weekly. We believe these wins and forthcoming additional system successes will yield continued growth through the remainder of 2022 and beyond, as YUPELRI will be the first LAMA of choice in many hospital systems due to the growing recognition and acceptance of YUPELRI’s once-daily value proposition and clinical benefits. Turning to Slide 8, you can see that YUPELRI’s share of the hospital setting increased to 13.4% in Q3 of 2022 up from 11.7% in the previous quarter. YUPELRI's quarterly market share in the community setting also increased to 26.3% through August of 2022, which is our latest data point up from 25.6% in Q2. As we have noted previously, many patients with COPD experience an acute respiratory episode serious enough to require a trip to the hospital and therefore the hospital becomes a key point to assess patients and convert or switch them from their current medicine to YUPELRI. Data shows that approximately 90% of patients who receive YUPELRI in the hospital setting are discharged with a prescription to continue their treatment in the community, allowing for continuity of YUPELRI maintenance therapy post-hospitalization. The Theravance Biopharma and Viatris teams continue to work collaboratively and effectively to convert appropriate patients to YUPELRI during their hospital visit, provide support through discharge and enable them to be maintained on YUPELRI after their return home. Understanding the YUPELRI opportunity in the community or outpatient setting we have also been encouraged by the growth trends seen in the retail script data where total prescriptions in Q3 have increased 21% year-over-year and new-to-brand prescriptions have increased 26.9% over Q3 of 2021, with both metrics once again reaching new quarterly highs launched to-date. As a reminder, while these script data only include the retail channel, they do serve as a useful proxy for the total community use, which includes retail plus the DME or durable medical equipment fulfillment channel, which represents the majority of YUPELRI community sales volume. We continue to see the impact of the pandemic on our business proceed, which we believe is leading to improved demand patterns and will continue growth acceleration throughout the remainder of the year as the team continues to execute against our strategy, which leverages a hybrid mix of in-person, virtual and digital education and promotional efforts that effectively communicate the core benefits of YUPELRI. Turning to Slide 9, recognizing there is a sizable niche for YUPELRI within the addressable COPD patient population, which actually represent an opportunity well beyond those patients receiving YUPELRI today, we do believe there is significant upside for the brand beyond 2022. Looking to YUPELRI's longer term, commercial potential, we are pleased to share that it has been further enhanced by another recently issued U.S. patent that covers a method of use of revefenacin in treating COPD. This new patent expires in 2039 and is now listed in the Orange Book. Lastly, turning to Slide 10, the Phase 4 PIFR-2 study comparing improvements in lung function in adults with severe to very severe COPD and suboptimal inspiratory flow rates, following once daily treatment with either revefenacin delivered via a standard jet nebulizer or tiotropium delivered via a dry powder inhaler continues to actively enroll patients. Theravance is responsible for 35% of the cost of this study and are guiding to top line results the second half of 2023. I'll now turn the call over to Rick Graham.

Thanks Rhonda. Today I'm going to focus on the norepinephrine reuptake inhibitor ampreloxetine in development for the treatment of symptomatic neurogenic orthostatic hypotension in patients with multiple system atrophy, also referred to as MSA. MSA is a rare disease affecting approximately 50,000 people in the United States. In MSA, patients with nOH, blood pressure falls when upright owing to impaired release of norepinephrine, which leads to debilitating symptoms that can have a profound impact on a patient's quality of life. Neither of the two approved therapies to treat orthostatic hypertension have demonstrated durable effectiveness in mitigating the debilitating symptoms for patients with MSA. There exists a significant unmet need and ampreloxetine has the potential to markedly differentiate from other treatment options, thereby offering hope to patients with MSA. Moving to Slide 12, with a unique mechanism of action, a single tablet administered once a day, a durable and clinically meaningful symptom effect demonstrated in MSA patients in the Phase 3 Study 0170 and no signal for supine hypertension, ampreloxetine has a potential to differentiate from other treatment options. In the Phase 3 Study 0170, ampreloxetine was effective at treating a constellation of cardinal symptoms associated with NOH. The benefit to patients with MSA was observed in multiple endpoints in the study, including a nominally, statistically significant effect on the orthostatic hypertension symptom assessment score, also referred to as the OHSA composite score. This effect on the OHSA composite score was driven by all six symptom scores favoring ampreloxetine treatment relative to placebo. These include dizziness, vision impairment, weakness, fatigue, trouble concentrating, and head and neck discomfort. The magnitude of change on the OHSA composite items was clinically meaningful and the durability of effectiveness was maintained over the length of the 22-week study. Although we've described these data previously, I'd like to underscore the importance of demonstrating benefit on a constellation of symptoms for these patients. By comparison, the basis for droxidopa approval was based on a change in only one symptom, which was dizziness over short duration. In addition to a favorable impact on symptom scores with ampreloxetine treatment, items on the daily activity composite score also favored ampreloxetine. The largest impact for the MSA patients was standing for a short-time. For someone with MSA suffering with symptomatic nOH, even standing for a short-time can have an enormous impact on their quality of life. It can mean the difference of transferring from the bed to a wheelchair. The only item that did not favor ampreloxetine was walking for a long-time, which isn't surprising considering that MSA is a disease with severely debilitating consequences. Ampreloxetine is a single 10 milligram tablet administered once per day, which is beneficial to MSA patients that may have difficulty swallowing as a result of their disease progression. This is another differentiating factor from current therapies that require multiple tablets administered several times each day. Patients with nOH are at risk for a dangerous increase in blood pressure while in the supine position. This is known as supine hypertension. The two FDA approved therapies for nOH each have boxed warnings on the label, highlighting the risk of supine hypertension. In a safety database of more than 800 patients and healthy subjects the signal for supine hypertension has not been observed with ampreloxetine treatment; offering the potential for yet another differentiating feature relative to the approved therapies. Moving to Slide 13, there's an urgency to treat MSA patients suffering within nOH due to the impact on quality of life and the extreme caregiver burden. Rare diseases and conditions pose a significant economic burden. The cost burden applies to direct medical as well as indirect and non-medical costs. Having just attended the American Autonomic Society meeting and spending time with opinion leaders, clinical investigators and patient advocacy organizations these messages were repeatedly stated throughout the meeting. For the first time, the ampreloxetine Phase 3 data were presented at a medical conference and was done so through oral presentations by three opinion leaders: Dr. Horacio Kaufmann, Dr. Italo Biaggioni and Dr. Roy Freeman. In the presentations the totality of the evidence from the Phase 3 program was highlighted, supporting clinically meaningful and durable effectiveness in MSA patients with symptomatic nOH. Moving to Slide 14, we're looking forward to starting a new registrational study in MSA patients with symptomatic nOH: Study 0197 or CYPRESS in the first quarter of 2023. Study 0197 is a 12-week open label; eight-week double-blind placebo controlled randomized withdrawal study with a primary endpoint of change in OHSA composite score. As a reminder, the primary endpoint was agreed upon with FDA during a Type C meeting or earlier this year. We expect the $25 million investment from Royalty Pharma to fund the majority of the Phase 3 study costs. I'll now turn the call over to Andrew to review the financials.

Thanks Rick. Turning to Slide 16, as previously discussed, the TRELEGY royalty transaction with Royalty Pharma was transformational for Theravance Biopharma. The carefully structured deal that closed during the third quarter delivers three components of value, an upfront cash payment of approximately $1.1 billion in exchange for all of our units in Theravance Respiratory Company or TRC LLC, which represented our 85% economic interest in the royalty rights on worldwide sales of GSKs TRELEGY, ELLIPTA. Secondly, the medium term value is in the form of potential milestone payments up to an aggregate of $250 million. These milestones will be paid upon the achievement of various trilogy revenue thresholds throughout calendar years 2023 through 2026. In 2023 specifically, we are eligible to receive a milestone payment equal to $50 million if TRELEGY global net sales exceed $2.9 billion. As a recent point of reference, global net sales for the first nine months of 2022 have reached approximately $1.6 billion, an increase of 34% over sales in the [indiscernible] of 2021. And finally, the third component is retained long-term value in the form of the return to Theravance Biopharma of our 85% ownership of TRC [indiscernible] interest in the TRELEGY royalties. We call these the outer year royalties or OYR, and the OYR period begins in 2029 metrology sales outside of the United States and begins in 2031 for sales within the United States. As mentioned in the deal announcement in July, this creative transaction structure monetizes our economic interest in TRELEGY royalties and allows Theravance Biopharma to benefit from significant near-term cash, as well as retaining medium and long-time value of the TRELEGY royalties, which we expect will continue to benefit from GSKs global commercial execution and lead to continued strong performance of TRELEGY over time. Furthermore, this monetization also removes uncertainty with the receipt of TRELEGY royalties because the outer year royalties will be paid directly from Royalty Pharma to Theravance Biopharma and In Vivo was removed as the manager of TRC LLC. One key benefit of the TRELEGY deal was that it allowed us to pay off our indebtedness with minimal equity dilution and relatively low transaction costs. At the closing of the deal, we paid down the non-recourse TRELEGY notes for approximately $425 million, and by early August we successfully retired 100% of the company's $230 million convertible notes These two deals made Theravance Biopharma debt free during the third quarter, while also having sufficient excess cash to design outward return program outlined on Slide 17. In September, our Board of Directors authorized the $250 million capital return program with the goal of repurchasing as many shares of TBPH at attractive prices. This was an important decision by the board and before making it we took the time to source input from and speak directly with peach shareholders and our financial advisement regarding both the quantum and the components of our capital board term programs. In the end, we did [indiscernible] program. Firstly with approximately $95 million deployed to purchase GSKs equity stake in Theravance Biopharma approximately 9.6 million shares at $9.75 per share. The second component is the implementation of the ongoing $95 million Dutch auction and tender offer initiated September 28th. This is an open offer and as stated in today's press release, we are extending the length of the offer such that the offer will expire at midnight New York City time, November 17, 2022. And for more details regarding the close of the deal, please contact [indiscernible]. Finally, the third element of the authorization by the Board to repurchase up to $60 million in Theravance Biopharma share, by initiating, I think after the close of the Dutch tender offer, an open market share repurchase program. This program has the goal to complete the share repurchases by the end of 2023. At the completion of the TRELEGY royalty transaction in the subsequent debt we pay [indiscernible] program, Theravance would have strengthened its balance sheet and reduced equity share count materially. This immediately positions the company for significant future equity value creation as we focus on YUPELRI commercialization and ampreloxetine with the base of execution [indiscernible]. Moving to our third quarter financial highlights on Slide 18; R&D expenses for the third quarter of 2022 were $7.2 million compared to $36.8 million in the same period in 2021. SG&A expenses for the third quarter of 2022 were $11.1 million compared to $13.9 million in the same period in 2021. These quarterly figures exclude share based compensation, one-time restructuring and one-time transaction related expenses. We ended the third quarter of 2022 with $487 million in cash and cash equivalent. And please keep in mind that during the fourth quarter of 2022, the company will make a payment of approximately $120 million or estimated taxes due associated with the TRELEGY transaction. In addition, the ongoing Dutch tender offer could utilize an additional $95 million of cash in Q4. Moving to Slide 19, we are reiterating financial guidance for the full year of 2022. For R&D expenses, we expect to invest between $45 million to $55 million relative to actuals of $168 million in 2021. Of this expense range, approximately $10 million is non-recurring spending that was incurred in Q1 2022 to support the wind down of the izencitinib and previous ampreloxetine team clinical programs. R&D spending in Q3 and beyond has normalized and reflects the recurring measure strategic investments in our pipeline. First, SG&A expenses we expect to invest between $35 million to $45 million relative to actuals of $71 million in 2021. And again, our operating expense, share based compensation, onetime restructuring and onetime transaction related expenses. In closing on the financial section, and I'll take a moment to reflect YUPELRI's business has been properly now in two years since Q3 of 2020, and during the third quarter of 2022 the brand realized its highest quarter of sales and profitability since launch. Hence during the current quarter are even stronger, as a result of the reduced spending in 2022 and the increased cash flow generation from YUPELRI, we expect to approach breakeven cash flow on a corporate basis in 2022. With that I'll turn the call back to Rick Winningham for closing remarks.

Thanks Andrew. Theravance Biopharma is in the midst of a strategic transformation and this quarter has been pivotal. As we noted the key progress and continue to demonstrate a focus on our strategy on the product and pipeline front with our partner Breztri, the team has delivered continued sales growth for YUPELRI. Recently we strengthened our intellectual property around YUPELRI, extending patent exclusivity until 2039. This quarter, we delved further into the ampreloxetine dated in a way – in a MSA patients with the world's top opinion leaders and finalized the design for the registrational Phase 3 trial. On the financial side with the closing of the sale of TRELEGY royalty interest to Royalty Pharma for over $1.5 billion in potential total value early in the quarter, we eliminated our debt and announced that we begun to make strong progress on our capital return program. We're moving forward with focus, momentum and determination. In closing, I'd like to thank the Theravance Biopharma team for their resilience and their tireless efforts to meet the needs of the patient communities we serve as we drive forward, we're well positioned to deliver medicines that make a difference in the future as well as drive shareholder value. Thank you everyone for your time and participation. I'll now hand it back to the operator for questions.

Thank you, sir. [Operator Instructions] And our first question for today comes from the line of Eva Privitera from Cowen. Your question please.

Hi. Congrats on the great quarter and thanks for taking our questions. We noticed that IQVIA scripts had incorrectly indicated a down quarter, even though previously the trends have been fairly predictive. What do you think accounts for the discrepancy and do you expect IQVIA to be less accurate going forward, or is it just going to vary?

Rhonda, do you want to take that?

Absolutely. One thing to certainly keep in mind and I try to comment to the script data that's, that's visible publicly. It is only inclusive of retail, so you have to be mindful that this is a smaller percentage, roughly 27% of our total business. So to expect that that downturn or a decrease in retail scripts is reflective of the whole business it's not depicting the entire view.

That's really helpful. Thanks. And if I can have a second question; what's your latest estimate on the timeline for reaching cash flow positivity and what some of the assumptions underlying that?

Yes. So as Andrew said on an operating basis, well our plans are to approach it in 2022. We're moving towards the cash flow positivity in 2023. We will provide more information and details on that when we give our outlook for 2023 early in the year. Andrew, anything else on that?

No. That's about it.

Thank you, and congrats again.

Thank you.

Thank you. [Operator Instructions] Our next question comes in the line of Douglas Tsao from H.C. Wainwright. Your question, please. Douglas, you might have your – your phone on mute.

Sorry about that. I had myself on mute, didn't realize it. Congrats on the progress especially with YUPELRI. Maybe just as a question, so this is I think, two quarters in a row where we've seen the recognized revenue a good deal below sort of the implied sales, and I know there are sort of different sort of moving parts in terms of what lets you recognize revenue. Should we see some normalization as we go into the fourth quarter?

Andrew, do you want – you want to take that?

Yes. Well, certainly Doug, as we've spoken about in the past, what we book is the receivable due, which nets out the collaboration expenses of the synthetic P&L behind our collaboration with Breztri. So going forward as we expect revenues of YUPELRI to continue to grow, that that booked revenue line for us should also increase commensurately. There are some fluctuations based on the GAAP accounting treatment that that we continue to try to provide a transparent disclosures on, but we're also a bit hampered by the collaboration accounting under GAAP. Hope that answers your question.

Yes.

Just one other, yes, Douglas let me add one other point. I mean, one of the aspects here was which changed sort of the recording was the restructuring the removal of our costs – reduction of our costs which cause a – as associated with the restructuring, which cause a lower level of reimbursement from Breztri to us and therefore us recording a lower level of revenue. So it does somewhat depend on a quarter-by-quarter basis of the cost that Breztri actually incurs on their site prior to the calculation of the synthetic P&L.

Okay. That's really helpful. And I guess maybe a question for Rhonda, and I apologize if it was covered in the opening remarks. I've been jumping between a couple calls, but how much seasonality you think there was in the third quarter? And should we see some seasonal strength in the fourth quarter, which historically pre-COVID typically was often the strongest period for sort of hospital based products? And I know that YUPELRI is not a hospital only product.

That's fair, Doug. And that's obviously a great question that we continue to try to understand over time with each and every year hopefully without any pandemic impact going forward. We do anticipate that that seasonality was somewhat reflected in Q3. However you may have missed this in the commentary. We were encouraged to still see the quarter-over-quarter growth in that sales. We did see an overall dip in maintenance COPD market view, which decreased a little bit in Q3 versus Q2. So I do think the seasonality was there and what we anticipate relative to that seasonality, you have correctly commented on that Q4 is typically where we anticipate that higher volume, whether that's due to increased patient census, but more importantly that is the high point of flu season and obviously all that's going on around that relative to other respiratory virus impact on COPD patients and the propensity to have an increase in exacerbations.

Okay, great. Thank you so much.

Thank you. [Operator Instructions] And our next question comes from the line of Joseph Stringer from Needham. Your question please.

Hi, thanks for taking our questions. First one is on the operating cash flow breakeven. Just curious how much of the potential label expansion of YUPELRI from the PIFR-2 trial factored into your previous guidance on breakeven operating cash flow and if the delay in the results sort of affects how you can get guidance on that? And then secondly given the cash balance a current cash balance understand that you have a capital return program in place, but what are your updated thoughts on any plans for bringing additional, say preclinical or early stage programs into the clinic or any potential BD activity? Thank you.

Yes. So yes, the previous comments that we – that we'd made on both 2022 and 2023 outlook really didn't include any significant effect from the PIFR study. So the fact that we've increased the size of that study and pushed the data out until the end of 2023 has no effect on our other – on the – our previous estimates. I think the fact is that the YUPELRI is in fact the driver of the cash flow profile of the company. And we do expect, as we're on the highlighted obviously growth in the fourth quarter and continued growth into 2023 as both the pandemic recedes and we have greater and greater success with the positioning of YUPELRI in the institutions, but also in the outpatient – also in the outpatient setting. I'm sorry, Joe, your second question?

Yes. In terms of given the current I understand that you have a capital return program in place, but just curious if you could provide your updated thoughts the rest of the pipeline in terms of any potential BD activity or advancing internal programs into the clinic.

Well, we're extraordinarily focused clinically on the completion of the PIFR study and the launch and the rapid accrual of the ampreloxetine program that's really going to take a vast majority of our resources, and we really don't see any other programs right now circuit adding to what our cash consumption profile is. But I do think all of our focus here when we turn into 2023 is going to be on the rapid execution of ampreloxetine, and Rick can make some comments on that if you'd like.

Yes, that's the focus of the team right now. Like I said in the prepared remarks, just coming off of the American Autonomic Society meeting where we, I think, through the presentations by the KOLs created quite a bit of energy around where we're headed with this program. So a lot of energy and effort going into that in the first quarter and the rest of 2023.

Great. Thank you.

Thank you. One moment for our next question. And our next question comes from the line of David Risinger from SVB Securities. Your question, please?

Yes, thanks very much. And let me add my congrats as well on all the progress. So I guess first could you comment on the potential timeline for the ampreloxetine CYPRESS trial? So, obviously Side 14 is quite help that it's essentially five months for each patient, but you're launching it in the first quarter of 2023, when should we expect a top line readout? I'm guessing that would be in 2024, but I just don't know, how you're thinking about that. So, that is the first question. And then second, with respect to the TRELEGY target of $2.9 billion for next year, I believe that consensus GSK expectations are below $2.9 billion for 2023. So just wanted to get any additional color from you on the potential to realize that $50 million milestone. Thank you.

Yes, thanks for the questions. Well on ampreloxetine, I think, once we roll into 2023, we've got probably 90% of the – 90%, 95% of the design discussions finished with FDA on ampreloxetine. We've got a little bit of just ticking and trying to do with them. And I think once we get that done, we'll be able to provide a better outlook as to the size of the study and then the size of the study translated into the timing for finishing the study and then filing the MDA. So I don't, Rick you want to make any other comments on that?

No, that's it, that's exactly right.

Then on TRELEGY, I think, TRELEGY, variety of people forecast TRELEGY. There are obviously some tailwinds behind TRELEGY as we come out of the pandemic. I think in particular related to the kind of the COPD business for TRELEGY getting back on track. I would say that's certainly something to watch as is the continued asthma progress. And then the potential for the biologics that are built on top of controller medicines that as they continue to execute their promotional strategy, they in fact drive more patients through TRELEGY on the way to biologic. But I think those are sort of the factors in the market that can affect TRELEGY whether it gets to 2.9 and we get the $50 million, we'll just have to see. I think importantly for us is that the number that gets us $50 million in 2023 is also the number that gets us 2025 and 2024. So, if we were to come up short in 2023 – TRELEGY were to come up short, then I think, it dramatically probably increases the probability of that lower end of the of the 2024 milestone. I don’t know, Andrew, anything else on that?

The only other comment I would make is that given the outperformance versus consensus on a quarterly basis, we've seen the consensus continually increase after GSK reports their quarterly earnings. So, I think you're right, David, that the current consensus for next year is just over $2.4 billion. And we expect that to continue to have upward revisions based on the performance that GSK is producing.

Thank you.

Thank you.

Yes, thank you.

One moment while we have our next question. And our next question comes from the line Vikram Purohit from Morgan Stanley. Your question please.

Hi, this is Will on for Vikram. And congrats on the progress this quarter. We have two questions on ampreloxetine. The first is around the CYPRESS study, any additional color you guys could provide on the profile of MSA patients you intend to enroll and what the expected pace of that enrolment might be would be terrific. And secondly, if you could just remind us about what the IP estate on that molecule currently is and what the duration of protection that is provided by that would be very helpful. Thank you,

Rick.

Yes, so I'll take the first part Rick if you want to take the second part around IP. So with regard to the profile Will what we're purposely doing is designing the CYPRESS study to be as close to the prior 170 study as possible. And as a reminder, with just 38 patients in the 170 study we saw that there was a nominally statistically significant effect on OHSA composite, which will be the primary endpoint for the new study. The changes that we're making to the study are relatively minor, but they are data-driven. So for example, when you look at Slide 14 of what we presented today, our open label period is 12 weeks, and our randomized withdrawal period is eight weeks. In the prior study that was 16 weeks and six. So we've just made those sorts of adjustments, but for the most part, we're targeting the same patients and with a relatively similar study design. With regard to enrolment rate, too early to comment on that. At this point, we're in the process of doing detailed feasibility. Now, I think one advantage for us is we have some significant experience here. We had a relatively large Phase 3 program previously, and that allowed us to identify really top performing and top tier sites, and we've established and built relationships with those sites. So we will be going back to those sites. We've got those relationships established, we have data that seem to be compelling and interesting, so more to come on the enrolment rate as we get the feasibility.

And then on IP for ampreloxetine, I think, with composition of matter and patent term extension associated with it, that's probably looking at 2035 and then a used patent for ampreloxetine in the treatment of MSA patients, I think, is 2037.

Okay, that's very helpful. Thanks.

And we're also likely, obviously, because it is MSA to pick up an orphan drug designation.

Thank you. One moment for our next question. And our next question comes in the line of Brian Skorney from Baird. Your question, please?

Yes, thank you for taking the question guys. Just one question on the new updated Orange Book IP for YUPELRI, it's a pretty big extension opportunity, I think, the latest patent after the one that's just been issued expires in 2031. So I was hoping you could talk about that 531 patent that's the basis of this extension versus the other method of use patents you have for COPD and [indiscernible] over the other one.

Yes, absolutely. Sorry, that's a great question, Brian. The information for the patent comes from the PIFR-1 study obviously that we did, without getting just into that number of details obviously addresses PIFR FEV1 and FVC which the observations that that we made in the PIFR-1 study were novel and in fact form the basis for the use patent. And those patients are in fact COPD patients. And they are sort of in our Phase 3 program such that the patent really covers an integral group that is resident in the indication section of the label.

Great. And then if we could just ask second one on the PIFR-2 study, can you just read the sample size increase, sort of changes those assumptions?

Yes, Rick you want to just review the sample size?

Yes, sure. So sample size assumptions are on Slide 10 and what we say is the potential to increase the sample size from 3660 to 488. Now that was based on a protocol, pre-specified, blinded sample size re-estimation. And the reason we did that, which by the way is very common to do in terms of the blinded sample size re-estimation. The reason we did that is because we had relevant information from the prior PIFR study, but it was relatively limited information. For example, the primary endpoint of that study was day 30 for FEV1 and the second study PIFR-2 the primary endpoint is change from baseline FEV1 at day 85. So, where the gap was, was does the variability, which we used to estimate the sample size translate from day 30 to day 85. Well, it turns out in a blinded fashion, the variability was a little bit higher at day 85, then we could have predicted based on the day 30 data that we have for PIFR-1. So that was the basis for the increase. Again, there is no read into the outcome of the study here. This is just simply based on factors that determine sample size.

Great. Thank you.

Thank you. There appears to be no further questions at this time. I'd like to turn the program back to Mr. Winningham for any further remarks

So we thank everyone for participating. We're very aware this is an incredibly busy time for everybody with quarterly calls. So we appreciate you joining us for our update. And if you have any questions, please reach out, contact us, and we'll answer the questions that that we can. So thank you very much for your time and have a good day.

Thank you ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.