Theravance Biopharma, Inc.

Ladies and gentlemen, good afternoon. I'd like to welcome everyone to the Theravance Biopharma fourth quarter 2023 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. To ask a question, press the star key followed by the digit 11 on your telephone. Again, that's star 11 to ask a question. If listening via webcast, please mute audio on your webcast device before asking a question over the phone. I'll repeat these instructions after management completes their prepared remarks. Also, today's conference call is being recorded. And now I'd like to turn the call over to Rick Winningham, Chief Executive Officer. Please go ahead, sir.

Good afternoon, everyone, and thank you for joining the TheraVets Biopharma fourth quarter and full year 2023 earnings results conference call. Turning to slide two, 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 product candidates, anticipated timing of clinical trials, regulatory filings, and expected financial results, information-containing factors that can cause results to differ materially from our forward-looking statements as described further in our filings with the SEC. Today, I'm joined by Anya Miller, our Head of Development, Rhonda Farnham, TheraVance's Chief Business Officer, and Aziz Sawaf, our Chief Financial Officer. On slide four, I'll begin by hitting high points for a very productive 2023 for TheraVance. We began the year with the decision to focus on driving upelry growth and maximizing Amplilox Team's value while increasing our capital return program. I'm pleased to report that our team delivered on these objectives. For both the fourth quarter and the full year, we increased upelry's net sales 9% from $61 million and $221 million, respectively, as is recorded by Vietris. We grew hospital volumes at an outstanding 46% for the year and set the business up for continued momentum in 2024. We initiated Amproloxetine Cypress Study and immediately began evaluating and activating sites around the world. In May, we were granted orphan drug status, which confers important financial advantages such as tax credits and user fee exemptions. and Shields Amproloxatine from price negotiation associated with the Inflation Reduction Act. Cypress enrollment remains on track, and we look forward to enrolling the last patient in the open-label portion of the study in the second half of this year. Turning to our corporate progress, I'm proud we delivered on our promise of reaching non-GAAP profitability in the fourth quarter, which involves significant efforts on the part of the entire Theravance team. In addition, we completed our $325 million capital return program within the first few days of January while maintaining a strong financial profile. Now, on slide five, I'll cover plans and anticipated financial performance for the upcoming year, beginning with upelry. We expect to grow upelry net sales in partnership with Vietris and build on profit margin improvements experienced in 2023. We've set ambitious goals for our hospital business in 2024, which we believe will translate into future share gains in the long-acting nebulization market. Finally, we look forward to Vietris submitting a regulatory application for upelry in China by mid-year, which will put us on a path towards achieving meaningful economics in that territory. Turning to ampryloxetine, we're focused on completing the Cypress study. In addition, we expect to initiate regulatory, and early commercialization preparations as we progress through the year. We're very excited to host a virtual investor event during the second quarter where we will bring MSA experts and senior leadership from Theravance together to discuss the unmet need in MSA patients with symptomatic NOH and the expected benefits of ampryloxetine. Turning to our 2024 financial outlook, we expect annual collaboration growth to remain strong and for our quarterly financial results to improve as the year progresses. During the first year, we expect to report losses on a non-GAAP basis. During the second half of the year, subject to timing of upelary growth and Cypress progress, we plan to approach break-even on a non-GAAP basis. We plan to limit cash utilization, and we believe we are in a strong position to achieve the $25 million Trilogy sales milestone in 2024, and possibly the higher $50 million milestone. If you turn to slide six, you'll see an updated summary of our compelling value proposition. In addition to upelry and ampryloxetine, we're in a strong financial position with over $100 million in cash, as well as the potential to accrue significant value through milestones and royalties on upelry and Trilogy over time. Specifically, in addition to the trilogy milestones that I referenced, we stand to receive a one-time sales milestone of $25 million when the US UPelry net sales reach $250 million in any calendar year. Additional information on our milestones and royalties may be found in our SEC filings. Moving to slide 8 to focus on Amproloxatine. We're motivated to make amproloxetine available to patients as expeditiously as possible, should the Cypress results support approval for the tens of thousands of MSA patients around the world who suffer from symptomatic NOH without effective treatment options. Data thus far support amproloxetine's potential to represent a major advance for these patients. The company retains commercial rights to amproloxetine worldwide. On slide nine, I'll start with the considerable unmet need in the United States. MSA is a neurodegenerative disease that shares features with other movement disorders, such as Parkinson's disease. It's often misdiagnosed, with many patients not confirmed to have MSA for months to years after symptoms begin. Unfortunately, most epidemiology research was conducted decades ago On Parkinsonism, more generally using survey techniques with significant limitations. For example, one off-sited study relies on a 25-year-old survey of 15 general practices in London. Using this limited sample, some have suggested that there are approximately 14,000 individuals with MSA in the United States, given the country's current population. In contrast, recent analysis rely on the use of real-world claims databases and capture important geographic variances and demographic trends which affect MSA prevalence estimates. These analyses support a much higher estimate of roughly 50,000 individuals, which is consistent with estimates from both the UCSD Department of Neurosciences and MSA Center of Excellence and the National Institutes of Health. Based on this figure, we believe that the addressable US population for amproloxetine is approximately 40,000 MSA patients suffering from symptomatic NOH. Turning to slide 10, our goal is to make amproloxetine available to MSA patients with symptomatic NOH worldwide. In Europe and Asian countries, including the EU5, Japan, and China, the number of addressable patients is several fold larger than it is in the US. And in some territories, the range of therapeutic options is even more limited than in the U.S. At this point, I'd like to turn the call over to our new head of development, Anya Miller, to characterize the value that we see in Amproloxatine and provide an update on the progress we are making with Cypress. Anya?

Thanks, Rick. Let's begin on slide 11. MSA is an incurable neurodegenerative disorder associated with inappropriate deposits of alpha-synuclein in the brain. MSA patients experience a progressive loss of autonomic function, as well as challenges with standing, walking, speaking, and swallowing. Many also experience depression and anxiety. According to a 2018-19 UK survey of over 10,000 patients with neurological disorders, MSA ranks as having the second most severe impact on quality of life of any neurological disorder studied, ahead of disorders like progressive supranuclear palsy, Huntington's disease, and Parkinson's disease, among others. Neurogenic or dystatic hypotension, which causes significant and unremitting drops in blood pressure upon standing, affects about four in five patients with MSA. Patients with symptoms of NOH may feel dizzy upon sitting or standing, can become unable to stand or walk for even short periods of time, feel pain associated with a lack of profusion in their upper extremities, and face a higher risk of falls. Not surprisingly, a significant majority of patients with symptomatic NOH report that they have a reduced ability to perform daily activities, while many also expressing a loss of independence. As I'll discuss on slide 12, MSA patients with symptomatic NOH lack a safe, convenient, and durable effective treatment option. While non-pharmacological therapies are available, they are often insufficient to control symptoms. About 30 years ago, the FDA approved a product called Midodrine on the basis of its ability to increase blood pressure. However, Midodrine is not indicated to improve symptoms of NOH, must be taken three times daily and carries a black box warning for its potential to lead to a marked elevation of supine blood pressure. Nearly 20 years later, the FDA approved a second drug called Droxidopa to treat dizziness in patients with NOH. Based on the still high unmet need for these patients, the FDA granted Droxidopa a conditional or accelerated approval. after initially having rejected the sponsor's application and despite Droxidopa having failed two of the four phase three studies included in the application. As with Midodrine, Droxidopa is dosed multiple times a day and carries a black box warning for supine hypertension. It has never demonstrated a durable effect on NOH symptoms beyond two weeks of treatment in a double-blind study. And more recently, based on data reported on clinicaltrials.gov, it failed to demonstrate a benefit in the confirmatory study requested by the FDA known as Restore. Based on third-party analysis of claims and prescription data, Droxidopa is still only prescribed to a small percentage of MSA patients with NOH. Let's fast forward to the day, and it has been more than a decade since MSA patients with symptomatic NOH have been offered a novel treatment alternative. While we still have important work to do to confirm its clinical profile in the CYPR study, we anticipate that amperloxacin will represent a significant advance for these individuals, given the benefits it has demonstrated to date. Amproloxetine's durable impact on a broad range of NOH symptoms in MSA patients in study 170, coupled with its safety and tolerability profile, and convenient once daily dosing, is expected to drive high levels of adherence. Moreover, as the first novel therapy in years, we are optimistic we will be able to build a case for a broad access and significant adoption in the population for which it is indicated, should Amproloxetine be approved. Now shifting gears to the Cypress study on slide 13, I'd like to share our approach and the progress that we are making. As many of you know, Theravance is directly managing study conduct for Cypress rather than utilizing the traditional CRO models. By design, we are deeply involved in identifying sites with high standards for clinical conduct, investigators who understand the complexities of managing NOH and MSA, and patients who best fit the criteria of the Cypress study. We are informed by our experience in studies 169 and 170 and have re-enlisted many of the same sites and KOLs involved in those studies. Beyond this, we have enriched our network through AI efforts that leverage claims information, the work of data scientists, and our own expertise. This has allowed us to identify additional qualified sites in the United States. Finally, we are early adopters of telehealth and have incorporated options for patients and clinical personnel to participate in Cypress, even if factors limit patient's ability to undergo evaluations in the clinic. We are pleased with the internal metrics we are monitoring thus far, which are consistent with our expectations and Study 170. While we don't comment specifically on enrollment, we continue to make excellent progress activating sites, including many outside of the United States. Shifting now to the right-hand side of slide 13, we have aligned with the FDA and the design of Cypress, including the use of the OHSA composite score, a six-item assessment of orthostatic hypertension symptom severity as the primary endpoint. When using patient-reported outcome measures such as OHSA, the FDA recommends anchoring these data in order to determine clinical meaningful consequences. In November, at the AAS annual meeting, we presented data from our anchor-based analysis of studies 169 and 170, which support the use of the OHSA composite score for MSA patients with NOH, as well as the threshold for which is considered a clinically meaningful change. Our analysis demonstrated that threshold improvements and worsening of approximately one point on the OHSA composite were considered clinically meaningful. This is important as it supports our Cypress study design and compares favorably to the 1.6-point benefit we saw on this measure in MSA patients in Study 170. Finally, in order to minimize the time from Cypress completion to potential commercial availability, we have already completed much of the work required for our NDA submission and are in the process of ordering the application. At this point, I'll turn the call over to Rhonda to discuss Tupelary.

Thanks, Anya. Beginning on slide 15, I'm pleased to report that the TheraVance and Vietris Commercial Partnership finished the year strong, having driven upelry net sales growth of 9% for the full year of 2023. Fourth quarter net sales reached 60.6 million and full year sales reached 221 million, with upelry recording its highest level of profitability since launch. Although quarter-to-quarter results can vary depending on the timing of shipments and other seasonal factors, we remain optimistic for UPelry's continued growth based on the success we are delivering in the hospital channel as well as several key performance indicators we track across the business. While realized sales this quarter closely track with demand generation, we have traditionally experienced Seasonal dips in reported net sales as we transition from the fourth quarter to the first quarter of the following year. Moving to slide 16, I'm also very pleased to share with you the exceptional finish to the year our hospital team was able to deliver. Hospital doses shipped in the fourth quarter increased 37% year over year, with full growth reaching 46%. This was easily the highest volume quarter for the hospital channel delivered since launch. As you know, our goal continues to be to increase the number of patients exposed to upelary during hospitalization who are then discharged on upelary as maintenance patients. This is achieved by gaining formula gaining support for formulary inclusion, implementation of hospital protocols involving all nebulization strategies and therapeutic interchanges, and equally important high touch transition of care program. Our market research continues to demonstrate that the vast majority of patients who initiate upelry in the hospital setting receive a prescription for upelry maintenance care at discharge. It is with the execution of this winning strategy that our small but focused commercial organization is able to make a considerable contribution to the overall UPelry business, both directly and indirectly. Turning to slide 17, on the left side, you can see the impact our efforts have had on our hospital market share. During the quarter, our share of the long-acting NIM market in the hospital segment increased to 16.6%. While on the right side of the slide, UPelry achieved a 31% share in the community, up nearly four percentage points year over year. We attribute both segments' share growth to the increasing traction of our concomitant therapy messaging. This taps into the significant number of COPD patients who remain symptomatic on LABA therapy and could benefit from the addition of ALAMA, which is foundational in the treatment of COPD, and references the 2022 changes to the Gold Report Guidelines, which recommend dual LAMA therapy for Category B and E patients. As a basis for speaking to the trends we have achieved in the retail setting, where we have our most real-time and current demand view outside of the hospital channel, we felt it might be helpful to share another visual. If you turn to slide 18, we provide data on the fulfillment growth trends in both the total community and retail segment settings through the third quarter of the year. At the time that we share our quarterly results, we do not have a completed data capture of fulfillment in the DME channel, which accounts for approximately 60% of our total community business, because retail, which accounts for the other 40%, generally correlates With total community fulfillment over time, we have historically offered this view. You will find our most up-to-date performance in the retail channel on slide 19. Looking at the left side of slide 19, retail prescriptions grew a robust 7% sequentially during the quarter, which is consistent with recent brand performance trends. Looking to the right side of the slide, we also grew new product starts a sequential 7% in Q4. You may remember from our last update that we had experienced some quarter to quarter seasonality and new starts, which is not atypical for this metric in Q3. As anticipated, however, we were able to drive a sequential return to growth in Q4. Finishing on slide 20, we think it is important to highlight the unique and compelling value proposition we offer patients and caregivers as the only once daily nebulized llama for maintenance treatment of COPD. Upelri has demonstrated consistently meaningful lung function benefits, is typically available at low out-of-pocket costs, and requires only a few minutes to administer once per day. As such, we believe Upelri plays a key role in the COPD market where there remains a substantial opportunity to reach patients who could benefit from Upelri. Our go-to-market strategy aligns with this profile, which we believe is why upelry is only one of three branded COPD maintenance therapies in the U.S. that is delivering consistent growth. Looking ahead, we expect to achieve continued growth and value creation for upelry, driven both by continued penetration of the U.S. maintenance COPD market and the potential launch of upelry in China. Lastly, in the U.S., we are eligible to receive a one-time sales milestone of $25 million from Beatrice when upel renet sales reach $250 million in any calendar year. In China, where Beatrice is planning to file for regulatory approval by the middle of this year, we are eligible to receive a $7.5 million milestone upon approval, as well as additional sales milestones and upwardly tiered royalties of between 14% and 20%. That brings us to the end of the PEL REIT update, so I will turn things over to Aziz to cover our financials.

Aziz? Thanks, Rhonda. Starting off with the results for the quarter, slides 22 and 23 cover the detailed financials. I'll cover the highlights on slide 24. Starting with collaboration revenue, we reported an all-time high of $17.4 million, representing year-over-year growth of 19%. Operating expenses were in line with expectations for the quarter, resulting in full-year operating expenses, excluding share-based comp, to be under the low end of R&D guidance and within the range for SG&A and total OPEX. The combination of judicious expense management and increased supelary net sales led to a non-GAAP profit of $1.4 million in the quarter. Please note that our GAAP loss of $8.5 million was affected by a larger-than-expected income tax expense in the quarter. primarily due to better than expected results and other non-cash charges from one of our operating entities. However, this is a non-cash item and we expect to have immaterial if any cash tax is payable for 2023. In Q4, we repurchased approximately $30 million worth of shares, leaving 400,000 on the return of capital program at quarter end, which was completed in early January. This reduced our share count by 3 million shares in the quarter and by 31 million shares from the program's inception, a 37% reduction in share count. We closed the period with 102 million in cash and approximately 48 million shares outstanding. On slide 25, I'll provide an update on our potential to earn milestones from Trilogy, noting that GSK delivered another excellent quarter of growth. Quarterly and year-to-date sales reached 737 million and 2.7 billion, respectively. up 35% and 28% year over year. As a result, we are well positioned to achieve milestones in 2024 and beyond. Compared with 2023 actuals, we need only 5% growth in annual net sales to achieve the first 25 million milestone and 17% to achieve the second $50 million milestone. As a reminder, these milestones are not cumulative. If both milestones were to be achieved, we would receive a total of 50 million, not 75 million. Lastly, turning to financial guidance on slide 26, we will continue to provide R&D and SG&A operating expense guidance, excluding share-based comp in 2024. In addition, to enhance our financial disclosure, we will be adding non-cash share-based compensation to our guidance metrics. For R&D OPEX excluding share-based comp, we are expecting between 30 and 36 million, which will be exclusively allocated to APRLOX A significant majority of this will be for the CIPRS study execution. In addition, guidance includes gated spend towards NDA preparation, primarily during the second half of the year. The ungating of this spend will depend on being on track with CIPRS enrollment in line with industry best practices. For SG&A OPEX, excluding share-based comp, we are expecting between 45 and 55 million. While our upelary-related spend will be largely flat year over year, Guidance includes incremental spend for Amprolox team prelaunch commercial activity, primarily in market research, medical affairs, and market access, which will occur mostly in the second half of the year. Given our focus on expected return on invested capital, any incremental spending for prelaunch activities will be gated based on CIPRS enrollment and will be subject to board approval. Partially offsetting these increases is a reduction of G&A spend by approximately 20% driven by ongoing cost-cutting initiatives. Starting in Q1, we will break out G&A separately from SG&A within our MD&A commentary in our 10Qs and 10Ks. For share-based comp, we are expecting between 18 and 22 million, the midpoint reflecting a year-over-year reduction of approximately 20%. In terms of our non-GAAP metric, we expect we will turn from a non-GAAP profit in Q4 2023 to a non-GAAP loss in early 2024. This is due to an expected decrease in collaboration revenue in Q1 from Q4 of 2023, driven by typical seasonality for upel renet sales, as mentioned by Rhonda, combined with a temporary increase in R&D spend due to the expected ramp in patient enrollment and site initiation for the CYPR study. Turning to the second half of 2024, we expect our non-GAAP metric to approach breakeven, which will be dependent on continued net sales growth for upelary, as well as the amount of spend on Amperlox team prelaunch commercialization. As discussed on prior earnings calls, this non-GAAP metric is a proxy for cash flow, and we therefore expect limited cash burn in 2024, most of which will be incurred early in the year. Given multiple potential milestones in 2024 and beyond, such as 25 or $50 million milestone for Trilogy, we expect to generate net cash prior to the Cypress top line data readout in 2025. Lastly, we may continue to incur non-cash income tax expense of several million each quarter. However, we continue to expect to have immaterial, if any, cash taxes in 2024 from ongoing operations. With that, I'll pass it back to Rick to conclude. Rick?

Thanks, Aziz. On slide 27, we summarize TheraVance's compelling vision and value we offer shareholders. Having focused our organization's efforts behind UPelri and Amproloxa team, the TheraVance team is now unified in pursuit of three objectives. First, we'll work to drive US UPelri net sales growth in the hospital. while collaborating closely with our partners at Beatrice to maximize the brand's overall potential in the hospital and community settings. Second, we'll continue to work diligently in pursuit of the Cypher study's successful completion, while making appropriate regulatory preparations and laying the groundwork for its broad access, if approved. Third, we'll maintain a strong capital structure as we work to deliver value for shareholders. Based on the choices we made regarding upelry, ampryloxidine, and trelogy, we believe we're at the crossroads of Theravance's evolution, where we stand poised to deliver significant incremental value through our operational assets, as well as near-term milestones and royalties, while making limited incremental investments in managing risk. We thank you for your time and attention this afternoon, and we're ready to take your questions. Operator?

Thank you, sir. Once again, if you'd like to ask a question, you may do so by pressing the star key followed by the digits 1-1 on your telephone. If listening via webcast, please mute audio on your webcast device before asking a question over the phone. If you're using a speakerphone for today's call, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, that's star 1-1 if you'd like to ask a question. and we'll pause for a moment to assemble our roster. And our first question comes from the line of Douglas Tsao from HC Wainwright. Your question, please.

Hi. Can you hear me? Yes, we can hear you. Okay. Good afternoon, and congrats on the progress. Just a couple questions. First, maybe starting with you, Pelri, Rhonda, I'm just curious, when we think about the share gains that you're seeing, especially those in the hospital, to what extent are those coming from adding new accounts versus gaining share within the existing account base? Thank you. And then I've got a follow-up.

Thanks, Doug. Great question. Actually, thinking about that share gain up to 16.6% for the quarter, that is drawn both from the new accounts, but I would say the predominant growth there is from those accounts that continue to build upon their base business where we are converting them to therapeutic interchange. And for those accounts where we do have that all-NEB strategy implementation as well as therapeutic interchange, we see that the market share is even higher in those accounts.

Typically, maybe just as a follow-up to that, Rhonda, what's the process or how long does it take to get a hospital to sort of move to that therapeutic interchange and all-neb approach?

If we are moving from their initial formulary to therapeutic interchange, that can range anywhere from six months to a year. If we're converting prior existing formulary review approvals, it's usually six to nine months.

That's on average. And within your account, what percent would you say are at you know, sort of doing that have achieved therapeutic interchange in an all-neb approach?

That varies. It's based on the growing base, but roughly two-thirds of our volume already have a therapeutic interchange, or I should say two-thirds of our volume is driven from those therapeutic interchange accounts, if that makes sense.

Well, but I guess as a follow-up to that, though, what percentage of your accounts are therapeutic interchange? Because obviously, given that two-thirds, it would seem that there's significant growth by getting accounts to that. Yes.

Yes. You've got it, Doug. If we move them to therapeutic interchange, that automatic substitution is what converts every existing LAMA, whether handheld or from the past experience over. So that is the ultimate of what we are trying to achieve here with these new gains.

No, no, I get it. But what percentage of your overall accounts are there? Have you achieved that? Is it 10%, 20%, 30%? Just to sort of help understand the magnitude of the opportunity still in front of you.

Roughly 35% of our COPD focus accounts have a therapeutic interchange. Is that helpful?

Thank you. Yes, that's really helpful. And then just, Rick, as a follow-up, obviously, you have now brought yourself and the company to expense management and some difficult choices to a point where your cash burn is pretty minimal. you are also, you know, on the cusp of, you know, seemingly we're starting to bring in some milestones, via Petrology as well as it seems like DuPelry, which could begin to enhance your cash balance. When you think about DuPelry and the success you're achieving in a hospital, does it ever, you know, how close are you to the point where it would make sense strategically to gain some leverage with that sales organization and bring in another product and not necessarily one even of the same, you know, magnitude of opportunity as you tell Reed, but just something that, you know, could give you some efficiency or sort of some additional leverage because in theory, even a small product could drive some pretty nice incremental margins on that sales force. Thank you.

Yeah, Doug, that's a good question. A couple of points. One, you know, we see such a significant opportunity in ampryloxetine and the execution of the Cypress study and the preparatory work over the next year, both on the regulatory side as well as some very early commercial preparation work that, you know, any distraction from anything else I think would be net harmful from where we are uh right now i'd say the second point is as ronda mentioned you know the we have a we have a small sales force and they're doing an outstanding job executing a particular strategy and we are early we are in the early days uh of the execution of the strategy uh both at theravance and i'd say in particular in combination with the the efforts of viatras so You know, we've got a significant amount of opportunity, I think, within the hospital with you, Pelry, and we would pay some opportunity costs by shifting our focus to anything else, given sort of where we sat with those accounts where we're on formulary and we need to move and take the next step towards therapeutic interchange. And those steps, those institutions, largely, which are multidisciplinary, hospital sort of groups of going from not being on formulary to being on formulary with therapeutic interchange. So, you know, we really view as there's just such significant opportunity behind both Upowery and Amproloxatine that we need to keep our focus, you know, on those two assets. Okay, great. Thank you so much.

Thank you. One moment for our next question. And our next question comes from the line of David Reisinger from Lee Ring Partners. Your question, please.

Yes, thanks very much, and thank you for the update. So my first question is, can you talk a little bit about how you're thinking about the introduction of encephentrine from Verona and what implications that might have for upelry? And then second, if you could just provide a little bit more detail on the execution of the ampryloxetine trial from here, the event path, and then the likely timing of the press release with the results.

Thank you. Okay. Ron, do you want to take encephentrin?

Absolutely. Thanks, David, for the question. We're very excited about the opportunity for Insufentrin. Having additional share of voice focused on a nebulized asset in the COPD maintenance space would be tremendous. And thinking about as well how that particular product would enter the market and most likely still needing the backbone or the foundation of therapy. Thinking about that as an add-on therapy is a great opportunity for us to both ensure that the patients that could benefit from both products have that chance.

So, you know, on the ampryloxetine, obviously, you know, we're, you know, we've initiated a lot of sites, as Anya hit on her comments, high quality, you know, high quality sites with physicians who understand MSA patients, understand the care of MSA patients, and and understand the execution of the clinical trial. We'll continue to activate sites, and there is some work that's necessary there, but more and more work, obviously, is focused on just getting patients into and through the sites for the study. We're making very good progress there, and I think You know, if you split that, we've got this year is really about, is a little bit tilted towards patients as opposed to sites. And that's where our focus will be. In terms of the, you know, where the, you know, where the study is, I think, you know, we'll enroll our target. And right now that's what we believe we can do is enroll the last patient into the open label portion in the second half of the year. You know, this would sort of mean data probably sometime in the first half of next year. And, you know, that's what we'd be looking forward to. But, you know, stay tuned as we progress throughout the year. I think, at least from the science and the medicine part of ampryloxetine and the value that it can provide for patients with MSA and NOH, I think hopefully our investor event that we have in the second quarter will be able to provide good information to investors about the opportunity that we see there. Great.

Thank you very much.

Thanks, David. Thank you. One moment for our next question. And our next question comes from the line of Eva Prevotira from Cowan.

Your question, please.

Hi, guys. Congrats on the great quarter, and thanks for taking our questions. I have a question about the Q2 investor event for Amproloxatine. Will there be any additional analyses that we haven't seen before?

Yeah, thanks, Eva.

I think relative to Amproloxatine, I think the additional analysis will be relatively limited. I think with as We mentioned we will have opinion leaders there that present other analyses, obviously, of both NOH and MSA patients as part of their presentations that outline the medical need and the opportunity that ampryloxetine has to meet that medical need through the data that they provide. that they have and that is currently published, but certainly consolidating it into one particular event.

Got it. That's helpful. And another one from me. How should we think about Amproloxatine's market opportunity relative to NorthEra, which I believe achieved $400 million in peak sales, given all of NorthEra's shortcomings and Amproloxatine's differentiation? How much bigger could Amproloxatine be?

Well, I think we're very, you know, we're optimistic on ampryloxetine. That's one of the reasons why we focused on both in my comments as well as Anya's comments on, you know, patient populations and the fact that there really is no solution that's adequate out there for patients that have MSA and NOH. but in a population of 40,000 patients with MSA and NOH, and given that, as Anya presented, this is, in fact, a debilitating condition that keeps many of them really unable to interact with their environment, I think that being able to show among multiple different parameters as measured by the OHSA composite score that we improve the well-being of these patients, I think should open up a significant, you know, opportunity for us. And, you know, as a reminder, we were granted orphan drug designation. This is an orphan drug for a rare disease. So we're, you know, quite excited about, you know, obviously continuing to progress with the study. the investor event that we have in quarter two, which I think will fill in some more information, and then continue to provide additional information as we work towards closing the study and data.

Perfect. Thank you. Congrats again.

Thank you. One moment for our next question. And our next question. comes from the line of Julian Harrison from BTIG. Your question, please.

Hi, congrats on the quarter, and thank you for taking my questions. It was great to see a positive outcome from your Phase 3 trial of upelry in China back in November. I'm wondering if you could remind us about how you're thinking about the China market opportunity there and what are the gating steps to filing later this year. And then on Cyprus, do you have a good sense now for what the U.S.-ex-U.S. enrollment split will likely look like Any big differences there relative to the 170 study? Thank you.

Ron, do you want to comment on China? And then, Anya, maybe give just a high-level comment on U.S. and on U.S. on Cyprus. Rhonda, first.

Yes. Thanks, Julian, for the question and recognizing the positive outcome of that phase three that Beatrice completed. So they will be continuing to prepare. And as they've indicated, we'll be striving to make that filing for the application by the midpoint of this year. And in thinking about the market for UPowery, we haven't made an outwardly communication around an absolute market projection and just thinking about, you know, certainly it's a very significant financial burden on that healthcare system, not too dissimilar from the U.S. We can ensure that we continue to evaluate what that opportunity can be for you, Corey.

Yeah, and I think, yeah, just to add to that, Julianne, Beatrice will be commercializing the medicine in China. They have a substantial organization in China, which is one of the reasons that we licensed UPelry to them in China. I think that they've, since it is sort of their commercial responsibility, they have, I think their call is coming up and you may you may get some uh ask a question of them on on opportunity but obviously the china market and copd is is very very large and it's about capturing you know as much of that opportunity as as uh it really makes economic sense julian just to give you some fact bases for the china market itself um copd affects about 100 million patients in that marketplace and a significant

Roughly 40% of those patients are moderate to very severe patients suffering with COPD. So as you can think about that relative to that being the focus for us here in the U.S., I think that can give you some estimates.

Julian, hey, it's Aziz. Thanks for the question. One additional point, in our 10-K, which we'll file in a couple days now, we're going to be actually disclosing the eukaryote economics for both the U.S. sales milestones and the China milestones and royalty rates in more detail. So we'll actually break out the sales milestones. And you can see for the first time we broke out the actual percentage of the royalties, 14 to 20%. So a pretty significant royalty in a huge market, obviously.

So we're really excited about the opportunity and the economics there. Ania, do you want to talk about ample oxygen?

Julian, thanks for the question on the cipher study. As I alluded to earlier, we've already made a lot of great progress activating sites in Europe and the US. And we have reengaged a lot of the sites in the US and Europe that we had previously engaged in the prior studies. I would expect that the majority of patients will still come from Europe, as it did in the previous program, although we are making efforts to expand our footprint in the U.S. and identify additional qualified sites, and I spoke about how we're going about that in terms of using an AI tool. So overall, I think the more patients will come from Europe, but the actual percentage of the split may differ for a Cypress study. Hopefully that's helpful.

Very helpful.

Thank you again. Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Mr. Winningham for any further remarks.

Thank you. I'd like to just thank everyone for joining us today. We're pleased with the accomplishments of 2023 and look forward to what we can accomplish in 2024. both through effective financial management of the business as well as the growth of UPelry and the execution on the Cypher study in order to bring what we believe will be an important medicine to patients with MSA and NOH. Thank you very much.

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