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spk07: Ladies and gentlemen, thank you for standing by. Good afternoon. I'd like to welcome everyone to the TheraFerence Biopharma second quarter 2021 conference call. During the presentation, all participants are in a listen-only mode. A question and answer session will follow the company's formal remarks. To question, please press star followed by the digit 1 on your telephone. Again, that's star 1 to ask a question. If listening via webcast, please mute the audio on your webcast device before asking a question over the phone. I will 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 Gail Cohen, Vice President, Corporate Communications. Please go ahead.
spk04: Good afternoon, and thank you for joining the Theravance Biopharma second quarter 2021 conference call to discuss our business. As always, 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. Now, I would direct your attention to slide three. Joining us are Rick Winningham, Chief Executive Officer, followed by Rick Graham, Senior Vice President Development, Frank Pascalone, Chief Business Officer, and Andrew Hyman, Chief Financial Officer.
spk10: now i will hand the call to rick winningham for opening remarks thanks gail 2021 has been about progress progress of our clinical pipeline of our commercial asset upelry and progress as we as a company adapt to the ever-changing pandemic and define what our business will look like in the future i'm grateful to the team at theravance biopharma who continue to show resilience and perseverance while continuing to ensure our advancement and commitment to developing medicines to make a difference. Starting on slide five in the second quarter, we made strong progress delivering the data of one of our four pipeline catalysts, phase two data for Nezolcetinib, our investigational inhaled lung selective PANJAC inhibitor for acute and chronic lung injury. We continue to drive forward our clinical programs, preparing for two critical data readouts, Isoncetinib phase two B data in ulcerative colitis, which will report top-line results just ahead of ampryloxetine Phase III data for symptomatic neurogenic orthostatic hypotension in the third quarter. On the respiratory front, moving to slide six, you, Pelry, and Trilogy have continued to make strides, showing signs of rebounding from the pandemic headwinds of 2020 with continued market share and net sales growth. Frank will expand on the metrics from the second quarter and trends that we are continuing to see in July of 2021. We're also planning for a future of upelry as we, along with our partner, Beatrice, are initiating phase four clinical study. This study will compare improvements in lung function in adults with severe to very severe COPD and suboptimal inspiratory flow rate following once daily treatment with either upelry delivered via standard jet nebulizer or teatropium delivered via dry powder inhaler. Findings from this study are intended to provide data to support a possible label update and help better inform physicians as they are working with their patients to design COPD treatment plans. We expect the study to kick off later this year. I'll now turn the call over to Rick Bram, who will discuss the upcoming pipeline catalyst. Rick?
spk02: Thanks, Rick. It's an exciting quarter for TheraVance Biopharma as we approach top-line data readouts for two of our key clinical programs. The Phase IIb study of Isincytinib and ulcerative colitis will read out first, followed by the first of two ongoing pivotal studies for ampryloxetine and symptomatic NOH. I'll start with isensitinib, our oral gut-selective pan-JAK inhibitor to treat inflammatory bowel diseases, which is partnered with Janssen. On slide 8, we outline details for the isensitinib base 2B study. In addition to reporting the primary endpoint, we plan to share key secondary endpoints and standard disease surrogate IBD biomarkers. We will also provide a safety analysis and systemic drug concentration. Low drug concentration in the systemic circulation is an important differentiator for Isoncitinib given the JAK class safety concerns. We will report the adverse event profile and highlight adverse events of special interest. As a reminder, the goal for Isoncitinib is to maximize therapeutic benefit to patients while minimizing side effects. We believe a gut-selective JAK inhibitor like Isoncitinib has the potential to be a game changer for the treatment of IBD and that it has a potential to become a once daily oral treatment amenable to earlier lines of therapy, as well as combination approaches. On slide 10 are the details for the ampryloxetine phase three sequoia study, which we'll read out this quarter shortly after isentitinib. Sequoia is the first of two ongoing pivotal studies. We'll share a timeline for reporting on the second study, Redwood, in the near future. As a reminder, Amproloxatine is a once-daily norepinephrine reuptake inhibitor for the treatment of symptomatic NOH. We are working to break new ground in this disease area as there is a significant unmet medical need for the treatment of patients with symptomatic NOH, a condition that profoundly impacts the quality of life and occurs in people suffering from Parkinson's disease, multiple system atrophy, and pure autonomic failure. We plan to share the primary the key secondary endpoints, and we'll also report the adverse event profile, including supine hypertension. We look forward to sharing results for both of these important pipeline catalysts soon. Next, Frank will speak to our commercial team's progress with upelry. Frank?
spk09: Thanks, Rick. Turning to slide 12, upelry is indicated for the maintenance treatment of patients with COPD. It's the first and only once daily nebulized long-acting muscarinic antagonist that provides a full 24 hours of control for patients. Last year, despite the headwinds created as a result of the global pandemic, Upelri recorded solid sales growth. Through the second quarter of 2021, the trend continues, and we remain optimistic given the significant patient opportunity for Upelri. As a reminder, TheraVans Biopharma and Beatrice co-promote in the U.S. with our combined sales infrastructure targeting healthcare professionals who treat COPD patients suitable for upelry. TheraVans Biopharma commercial and medical field teams cover the hospital segment of healthcare providers, and Beatrice covers community healthcare professionals. Also remember the Beatrice TheraVans Biopharma commercial partnership is a 65-35 profit share split. Slide 13 shows TheraVance Biopharma's implied 35% share of net sales for upelry during quarter two of 2021 of $14.6 million. Importantly, we saw upelry sales pick up momentum throughout the quarter. Quarter two of 2021, net sales were up 13% from quarter one of 2021 and up 38% compared to quarter two of last year. Turning to slide 14, you can see that our share continues to grow both in the hospital and the community setting. As we've noted previously, many patients with COPD experience an acute respiratory episode serious enough to require a trip to the hospital for immediate care. The hospital then becomes a key point to assess a person with COPD and convert or switch them from their current medicine to upelri. Data shows that many patients who receive upelri in the hospital are discharged with a prescription to continue treatment, allowing for continuity of upelry therapy post-discharge. The Vietris and Theravance biopharma teams continue to work effectively, using several tools, tactics, and coordination to convert appropriate patients from competitive products to upelry during the hospital-to-outpatient experience. As evidenced by the share gains since launch, this strategy is effectively being executed by both companies' teams. Demand doses increased 13% second quarter over first quarter 2021 and 34% over second quarter of 2020. The impact of COVID on commercial efforts may be easing somewhat as states, local governments and institutions in some parts of the country are beginning to allow in-person meetings. However, in-person access to customers as well as patient visits to HCPs remain below pre-pandemic levels. Approximately 62% of all COPD targeted hospital accounts are physically accessible to our field colleagues. However, the TVPH sales team continues to leverage customer engagement opportunities via virtual meetings and phone interactions. In the second quarter, total HCP interactions grew by 16% over quarter one of 2021, with live face-to-face interactions reaching 39% of total interactions the highest quarterly average since the pandemic began. We've also been encouraged with prescription activity through June. Both new to brand Rxs and total Rxs have continued the upward growth that was reignited in late first quarter. In addition, hospitals continue to add upelry to formularies and new accounts are being added weekly. Looking specifically at the TheraVans field sales deployment efforts in quarter two 2021, Doses sold exclusively in the hospital setting represented a 25% increase from the previous quarter. June hospital volume hit a new launch-to-date high, and we saw 127% year-over-year growth from June 2020. Quarter two of 2021 incremental volume growth was 47% from April to June, representing the highest in-quarter growth launched to date. You can see this upward growth on slide 15 progressing through the end of the second quarter. We also continue to track the key performance metrics since launch and the following are the quarter two 2021 metrics. A total of 815 hospital accounts have ordered upelri and 69% of these accounts have ordered upelri at least twice. Quarter two 2021 formulary wins totaled five, which equates to 446 formulary accounts launched to date with a formulary win rate of 91%. 85% of these formulary accounts purchased to date owing to a lag between formulary approval and ordering commencing. The medical science liaison's formulary support for presentations in quarter two 2021 was the highest since quarter one of 2019 when the brand was launched. In-person interactions by the MSL team were three times higher in quarter two versus quarter one, but remain markedly below pre-pandemic levels. At the end of quarter two, Upelri's commercial coverage was 75%. So looking ahead, it's important to understand that according to the gold guidelines, ALAMA is foundational to COPD maintenance care. The execution of our tactical plan will continue to leverage the guidelines and appropriate patient types while we continue to optimize the marketing mix through rigorous and continued measurement of tactics. As Rick Winningham mentioned, we'll be initiating a phase four PIPR clinical study, which is aimed at helping to better inform decisions when physicians are designing a personalized COPD treatment plan with patients. UPelry has demonstrated resilience to many of the external factors, And we remain committed to continuing to bring this medicine to appropriate patients in the second half of this year and beyond. So now I'll turn the call over to Andrew to review the financials.
spk08: Thanks, Frank. And before moving to Theravance Biopharma's quarterly financial highlights, let's start with an update on GSK's trilogy on slide 17. As a reminder, Trilogy is the first and only once-daily, single-inhaler, triple-combination therapy approved for the treatment of COPD and asthma. Theravents Biopharma is entitled to receive upward-tiering royalties on global net sales of Trilogy. At present, 75% of the income from our economic interest is pledged to service principal and interest payments on our outstanding 2035 non-recourse notes, and the remaining 25% of income is retained by us. We've received $46.3 million from TRC LLC during the first seven months of 2021. And during GSK's recent earnings call, they noted that Trilogy continued to lead the market as a single inhaler triple therapy with Q2 2021 sales growth of over 68% over Q2 2020, generating global net sales of $405 million. Moving to slide 18, here we provide our second quarter 2021 financial highlights compared to the second quarter 2020. R&D expenses for the second quarter were $51.1 million compared to $62.4 million in the second quarter of 2020. SG&A expenses for the second quarter were $25.9 million compared to $24.8 million in the second quarter of 2020. And as a reminder, all of these figures exclude share-based compensation. In addition to those end-of-quarter financial highlights, or second-quarter highlights, during June, we closed a public offering of ordinary shares at a price to the public of $15 per share, with gross proceeds of $115.6 million before deducting expenses. And we ended the second quarter with $265 million in cash and cash equivalents. Regarding financial guidance for the full year 2021, we are reiterating previously issued guidance. And that was for R&D, we expect to invest between 195 to 225 million relative to actual R&D investment of 230 million in 2020. For SG&A, we provided a range of 80 million to 90 million relative to an actual SG&A expense of 77 million in 2020. And again, all of those figures exclude share-based compensation. With that, I'll turn the call back to Rick for closing remarks.
spk10: Thanks, Andrew. On slide 19, we summarize what makes TheraVent's biopharma valuable. We're a unique entity for a company our size with value drivers that include a mix of differentiated, wholly-owned compounds coupled with strategic collaborations and partnerships. This includes our commercial partnership with Vietris to co-promote upelry in the second quarter, In the second full year since its launch, Upelry continued to experience solid net sales growth on an annual basis in 2020, which is a trend we're continuing to see in 2021. Trilogy, for which we're entitled to receive upward-tearing royalties on global net sales. A partner pipeline with Janssen on IsonCetinib and TD5202 with a potential of up to $1 billion in milestone payments to TVPH plus profit sharing in the U.S. and double-digit royalties ex-U.S., And then finally, our wholly owned assets, several in later stage development, Amproloxine in Phase 3 and Nezalcetinib in Phase 2, several other key programs to address large patient populations. When you add this to our in-house research and development capability plus U.S. commercial infrastructures that leverages analytics-driven deployment and has demonstrated success, we believe there's a strong case for value creation at TheraVance Biopharma as we deliver key clinical data, and upelry commercial performance in the future. In closing on slide 22, this quarter is critical to us as we look to deliver the data for isinsetinib and ulcerative colitis and empyroloxetine and symptomatic NOH. These programs are value drivers and have the potential not only to be transformational to Theravance Biopharma, but also to patients impacted by these diseases. Our mission to continue to develop medicines that make a difference in the progress of our clinical pipeline Along with you, power and trilogy demonstrate that we're working to make that a reality. I'll now hand the call back over to the operator for questions. Operator?
spk07: Thank you, sir. Once again, if you would like to ask a question, you may do so by pressing the star key followed by the digit 1 on your touchtone phone. 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 one if you'd like to ask a question. And we'll pause for a moment to assemble our roster. Our first question comes from the line of Jeff Porges from SVB LeRinc. Your question, please.
spk05: This is Anna Barron. I'm for Jeff Porges. Thank you for taking our questions. First, can you remind us of the hurdle for statistically and clinically significant results from the Eprilox team physical trial results coming up? And second, on cash, You ended the quarter with $265 million in cash and then put up a net loss of about $50 million, which presumably approximates cash burn. If you run those numbers out, you have less than six quarters of cash runway. Do you expect expenses to come down significantly at the end of the year? And could R&D be cut, let's say, in half once the current trials for amproloxetine and isincitinib are completed? Thank you.
spk10: Yeah, Rick, you want to take the ampryloxetine questions, and then Andrew will take the finance questions, and I'll close. Rick?
spk02: Sure. Sounds good. Thanks for the question, Anna. You mentioned the hurdle with regard to statistical and clinical significance for ampryloxetine. With regard to the Sequoia study that we'll be reading out in quarter three, the primary endpoint is a change in OHS-A1 from baselines. And what we have agreed to with regard to the endpoint with the FDA is a clinically meaningful change in OHS-A1 of one point. So it's a 10-point scale, and that's the primary endpoint for the Sequoia study.
spk08: Yeah, Andrew? Sure. With respect to the question on the financial profile there, Anna, I guess there's two components that I would focus in on. Yes, the math, if you simply straight line 265 million divided by about 50 million of cash utilization or investment during Q2, that gets you to about six months of quote unquote runway. However, that is an overly simplistic view of our business. Number one, we've been talking to investors and the sell side for quite some time about the changing financial profile of our P&L. And This relates predominantly to an increased revenue growth and cash flow from both Upelri and Trilogy that are becoming increasingly material contributors to our balance sheet. And we've mentioned previously, and it is still true today, that on a brand basis, Upelri is generating cash flow into Theravance Biopharma when we factor in our 35% profit split and all-in costs associated with commercialization of the brand, both shared costs with Beatrice and then the non-shared commercial costs that we absorb 100% at TheraVents Biopharma. So, the source of cash flow generation from both Upelri and Trilogy, even the 25% stake that is not used to pay down the 2035 notes, is becoming increasingly meaningful contributors to our balance sheet. And then secondly, and by the way, that trend is true today, it was true last year, and it will become increasingly true that upelry and Trelogy are net cash contributors to our balance sheet in 2022 and beyond. So, you know, six quarters out, five quarters out, four quarters out, that the changing financial complexion is increasingly cash flow generation from non-financing sources. The other component that's very important to keep in mind is that while Janssen is our collaboration partner on Ison Sidnib, They currently will have to make a decision once we generate the data packages, both for UC and Crohn's and deliver those data packages. After the receipt of the second data package for Crohn's, they will have approximately 90 days to decide if they want to enter into an exclusive global collaboration agreement. And if they choose to do so, they will pay us $200 million for an option payment. And that is going to be a significant source of additional capital that will extend our runway beyond 2023. So I hope that helps answer it with a bit of detail. But Rick Winningham, if I missed anything, please chime in.
spk10: Oh, I think I think you covered everything adequately. We continue to have a robust research organization and translational science group that continues to deliver research. clinical assets into the clinic. And in some of those instances, those assets will, you know, we will enter into partnerships in certain regions of the world with those assets. So I think in total, that's, you know, that's a pretty complete complexion of both the financial picture as well as our expectations for ampryloxetine from the 169 study.
spk03: Very helpful. Thank you.
spk07: Thank you. Our next question comes from the line. Mark from Cow and Ape Company. Your question, please.
spk01: Thanks for taking my questions. Maybe just on Rhea, can you remind us what you would expect on the safety analysis, just kind of on background rates of the key safety events like infections and thromboembolic events for a study population like Rhea, considering the limited follow-up that's in the Phase II portion?
spk10: Yeah, that's a great point, Mark. Rick, you want to take that?
spk02: Yeah, sure. Hey, Mark. So the RAY study, and maybe I'll step back for a minute and just remind everybody that the program here is a seamless Phase IIb-III design. So the RAY study is the IIb portion, and that's a dose-finding portion where we have three different dose levels relative to placebo. Patients that complete RAY or the Phase IIb study roll into a 44-week maintenance study. So that's the phase three portion. And then after we select a dose or more than one dose, we would initiate a second confirmatory induction study. So I think what you were alluding to with regard to some of these adverse events of special interest with a small sample size of 240 patients, you know, we're probably not going to be able to prove definitively that isancitinib is not causing any unwarranted safety effects. But what we're going to be focusing on is adverse events of special interest like multidermatome zoster, opportunistic infections, malignancy, and thrombolytic events. So these are certainly JAK class events. But again, they have a relatively low adverse event rate. We're going to be focused on those and we'll report on those as we read out the trial. Some of the things that are more sensitive, though, that we do have confidence with a sample size of 240 to really hone in on the gut-selective nature of isancitinib are lab parameters like cholesterol and CPK. So these are things that we'll also be focused on to understand whether there's a gut-selective effect or not with regard to isancitinib on safety.
spk10: And I think just to close off, Mark, obviously the The driver of the toxicity of the systemic JAKs is the concentration of the drug in the bloodstream and where that bloodstream carries the drug throughout the body. And obviously, our expectation in the Phase IIb study for isensitinib is to see extremely low concentrations of the drug in the bloodstream in contrast to the systemic JAK inhibitors.
spk01: Okay, great. That's helpful. And then maybe just follow up on the last question on cash burn. Can you just remind us kind of what the spend level is on kind of the early stage pipeline that, you know, that obviously doesn't get talked about a lot? And then, you know, kind of what the expectation would be assuming amproloxatine trial is positive, you know, in terms of needing to build out the commercial organization to kind of support that filing and hopefully approval.
spk08: Yeah, Mark, hi, this is Andrew. The quick answer is everything that is what I would characterize as early development or research is not very much of our R&D spend. You could probably use Pareto assumptions to get to what I mean by that. And with respect to the commercial build-out, I mean, I'll take a stab at it, and then Frank Pasqualin can certainly correct me if I'm wrong. But, you know, we're looking, and as we've talked about with investors for quite some time, we're looking with Amproloxatine, given that it's focused on a rare disease population, to build out our commercial infrastructure to right-size the launch. And, of course, that will be based on finalizing the development timelines with the regulators once we have the study 169 results. And, you know, we will invest in the launch appropriately, well in advance to ensure its success. but we will be leveraging existing investments that we're already making to support UPELRI in the home office and in other areas of management and medical affairs. So the incremental investment to adequately support the launch of ampyloxetine will not be a material addition to our SG&A in total. But, Frank?
spk09: Yeah, no, thanks, Andrew. I don't know if I have much to add to that. We will take a very targeted approach. We are doing the work now to understand exactly where these patients are headed when they need help and what are those physicians that treat those patients. And we're going to focus very heavily on those as a start. And I'll just reiterate what what Andrew said, we do plan to leverage the investment that we have in the commercial organization now. Excuse me, we're, you know, in some ways we're a little bit inefficient with one product. We'll be able to leverage those investments much, much better going forward with two products in the bag.
spk10: And just to conclude, the, you know, as As other rare disease companies have done, you know, obviously the medical clinical team that is our clinical liaisons that are in the field, those clinical liaisons will move over to augment the medical group that we currently have in the field. So that really gets at some of the points that are making about incremental investment. Okay, great. Thank you.
spk07: Thank you. Our next question comes in the line. Now, Lisa Baco from Evercore ISI. Your question, please.
spk06: Hi. Thanks for taking the question. Can you maybe just elaborate a little bit more on, you kind of had mentioned in your last comment, if you're looking at various lab parameters, oh, sorry, a lipid, I think you said, parameters to see if it's, if isositinib is indeed gut selective. Can you maybe expand on a little bit more on that, what we should be looking for exactly?
spk10: Yeah, Rick.
spk02: Yeah, sure. Hi, Lisa. So what I was meaning is that for the systemic JAK inhibitors across the board, it's been reported that there are changes in a relatively short amount of time in cholesterol, whether that's HDL, LDL. And then the other one is creatinine phosphokinase. So those are those are parameters that with a gut selective JAK inhibitor like Isoncitinib, we don't expect to be targeting or modulating. So we'll take a close look at those because with a relatively small sample size, we should be able to discern whether or not there's a signal there.
spk06: Okay. So we would expect to see no changes or more modest changes or what's the goal?
spk02: Yeah, we would expect to see no changes in those parameters, again, that are relatively sensitive to systemic JAX because we're not expecting to see high levels of isincytinib in the liver where these enzymes are synthesized. Or in the case of CPK in the muscle.
spk06: Okay. Can you give us any more color on your kind of like timing in the quarter for the different studies or which one we should expect first? Should we read anything from like kind of the order in which you're discussing them? Just curious. Yes.
spk10: No, I think nothing with any more granularity. I think Isinsetinib will read out first and be shortly followed by Amproloxatine, and that's the sequence that will roll out the data. Okay. Great.
spk06: And then can you talk about next steps for your acute lung injury program?
spk10: Sure. I mean, I'll start and then Rick can chime in. We've begun to meet with regulators in Europe and we'll meet with regulators in the U.S., really focused on COVID as a part of acute lung injury and defining the sample size that we need for studies in acute lung injury, various types of acute lung injury going forward, Rick.
spk02: Yeah, the only thing I would add there, in addition to interactions with health authorities, which has been very helpful, we've been talking to a number of different groups that have platform trials, and so we're getting feedback and considering our options there as well.
spk06: Can you – is acute lung injury, how does that differ from ARDS, or is that sort of the same thing?
spk10: Yeah. No, it's not the same thing. Usually you see acute lung injury precede ARDS. That's the general clinical path that ARDS takes, and we would expect to be able to modulate acute lung injury that's related to the inflammatory cascade, like what we saw in the CRP subset with does a set in them. And I think that was a fairly important finding. And certainly, as we've shared the data with others, they've agreed with us that the biomarker that we use was a very important point to cut off in terms of rates of inflammation in the lung. Rick?
spk02: Yeah, so Lisa, if you remember, we had actually reported that we saw a meaningful reduction in 28-day all-cause mortality and time to recovery in patients with COVID who were treated with nezalcitinib and those that had a baseline C-reactive protein level of less than 150 mg per liter. So that, you know, despite the fact that we didn't hit the primary endpoint on the ordinal scale, which is a tricky one to hit, and that's been true for other molecules in the space, we do believe that this change in mortality was meaningful.
spk06: Okay. Great. And then just final question for me. For amproloxatine, can you describe any conversations that you've had with regulators that may indicate, you know, flexibility and how they're willing to consider the data? I just, you know, you look back at some of the approvals in the space and you're kind of scratching your head. So I'm just wondering kind of what the bar is for you guys in NOH. And that's my last question. Thank you.
spk10: Yeah, that's a great point. I think we've had a great relationship with the FDA on this application overall since we, you know, began the work in NOH. And it's because of the more or less paucity of data that exists for the existing agents. And in fact, the risk benefits that's there for the existing agents. And Rick, you want to provide even more color.
spk02: Yeah, it's important to step back again and think about the design of this body of work. So there's two pivotal trials. One is the Sequoia study, which we'll read out very shortly. And that's a four-week efficacy study, randomized one-to-one active drug, amproloxidine to placebo. Patients that finish Sequoia can then roll into a study that's called Redwood. This is a 16-week open label study. So everybody gets active drug. And at the end of 16 weeks, they're randomized one-to-one, again, active to placebo. And we're looking then for a worsening of effect in that randomized withdrawal period over six weeks. So between the first study and the second, this is a very robust body of work to demonstrate the benefit and risk profile of amproloxetine. Again, as Rick said, Lisa, we worked closely with the FDA on the design of this body of work, and we do expect that both studies are going to be required for a full approval. However, we will have a conversation with the FDA at the end of the Sequoia study with the data in hand and have an opportunity to have a conversation about the data. In particular, we would focus on a breakthrough therapy designation request, which is an opportunity for an expedited review of an NDA based on therapies that meet an unmet medical need.
spk06: Okay, great. Thank you.
spk07: Thank you. Our next question comes from the line of Douglas from HC Wainwright. Your question, please.
spk11: Hi, good afternoon. Thanks for taking the questions. Just maybe the starting point on you, Pelri. I'm just curious. I think you indicated that you had the second quarter saw the most on formula presentations since launch, and was that just sort of improved access post-COVID, and how long should it take before we start to see those translate into wins and ultimately revenues?
spk09: Frank, go ahead. Okay. Yeah, thanks for the question. We, on the MSL, the metric that we reported related to the MSLs, they were really, had many, many requests from the field for formulary support presentations. And as I mentioned in the script, it was the highest quarterly amount since we launched the drug. We launched the drug in quarter one of 2019. So we were very pleased that that's an indicator that the level of awareness and interest that the field teams are generating is paying off for us. And we do measure the amount of time it takes from those first formulary presentations to a win, and then also ordering Now, I will tell you that the length of time has been lengthening since the pandemic began, because obviously these pulmonologists have a lot on their plate. And typically, even if you have everybody else shaking their head affirmatively for a formulary review, a pulmonologist has to weigh in very heavily in support of the drug. So the typical average time is somewhere between somewhere approaching three months. It's been as high as 90 days. It's been as low as 60 days. So I hope that answers your question, but it's just a tough metric to key in on right now because of the pandemic lengthening that cycle time for us.
spk11: No, that's very helpful. Thank you. And just on this, you know, in terms of it sounds like you're looking at sort of some of these bigger trials that are evaluating multiple products at a given time. You know, I know the mortality of benefit was quite compelling. Are you looking at that as potentially an endpoint versus one that is sort of more based on respiratory function? Thank you.
spk10: Yeah, Rick.
spk02: Yeah, thanks, Doug. The general interest, as Rick has said, not just from TheraVans BioPharma, but from the stakeholders externally that we've shared the data with has really been around the mortality benefit. So certainly, as you've said, with each of these platform trials, they have different objectives, and we're keeping our options open with regard to what makes sense for the next steps with mesocytinib.
spk07: Okay, great. Thank you. Thank you. Our next question comes from the line of Anupam Rama from J.P. Morgan. Your question, please.
spk13: Hi, guys. Thanks so much for taking the question. Can you give us an update on sort of the latest that's ongoing with the arbitration with InnoViva? I think most recently you've kind of made a response back to the courts, and I think you may be in a waiting phase for a response back. Maybe just give us an update there. Thanks so much.
spk10: Yes. Well, I think You know, we've we've concluded the obviously concluded the second arbitration period where, you know, our perspective is that there were certain guidelines relative to the usage of the royalties that became slightly, you know, slightly more clear with the with the arbitrators ruling. There are some just some points. Particular parts of that ruling, we are in the middle of seeking clarity of those particular sections. I don't have anything to update one on at this point in time with regard to that. But we continue to watch the InnoViva management of the TRC royalty company quite closely, such that the actions of InnoViva as manager are consistent with maximizing the value of the royalty stream for the partnership as well, limited partnership as well as Theravance Biopharma. So that's about it on the arbitration.
spk13: Thanks so much.
spk07: Thank you. Our next question comes from the line of Vikram Prohit from Morgan Stanley. Your question, please. Vikram, you might have your phone on mute.
spk12: Hi, can you hear me now?
spk10: Yes.
spk12: Okay, great. Great, thanks for taking my question. So I had one on the RAE program. So it seems that the highest dose you're evaluating in the Phase IIb portion here is a bit lower than the dose that was evaluated in the Phase Ib portion, so I was wondering if you could just talk us through the thinking behind dose selection for the Phase 2B study.
spk02: Rick? Yeah, sure. Hi, Vikram. So the Phase 1B study that we conducted in patients with moderately to severely active ulcerative colitis, we published in the Journal of Crohn's and Colitis recently. That study used doses of 20, 80, and 270 milligrams But that study was done with a powder and capsule formulation. It was literally just the active pharmaceutical ingredient put in a capsule. When we moved on to later stages of development, we wanted to move into a tablet formulation to start getting close to a commercial formulation. And this was just a practical matter. This wasn't with regard to a difference between 270 versus 200 milligram, which is our highest dose in the 2B. It was just that that was a capsule size that we chose that could accommodate that load of 200 milligrams. So we don't consider those to be markedly different.
spk12: Okay, understood. And I had a follow-on question on amproloxetine. So I know that you've mentioned that a one-point difference is something you would consider clinically meaningful, but based on any conversations you've had with clinicians What's your sense on durability and how much duration of response would be clinically meaningful over some of the options that are currently on the market?
spk10: Yeah, well, obviously, if we saw a change of that magnitude at four weeks versus placebo, that would be a meaningful difference for clinicians. And I think that showing it at four weeks, that duration is greater than than what's been shown by droxydopa. And as Rick said, we're really shooting for two different objectives here. One of them is efficacy, both effect and duration of effect. And the second is safety with regard to supine hypertension. And that's both objectives we expect to be able to meet with the study 169 and then complement with the 170 study. Rick?
spk02: Yeah, not really much to add other than, you know, unfortunately for these patients, there isn't really anything that – is good for their durability as it stands currently. So while they have some options, I think if you look at the package insert for Droxydopa, for example, there was a one-point change approximately from placebo at one week after treatment in their pivotal study, but that went away after one week. The other point about durability, though, is in the second study, which we'll report on later after we report on the Sequoia study, But the second study really gets a bit at durability, which is the 16-week open label followed by that six-week randomized withdrawal. So in totality, the data between both of these studies is really going to get at both the four-week efficacy and then the longer-term durability. In that randomized withdrawal study, it's also a one-point change in OHS A1. coupled with an endpoint on what's called PGI, which is a patient global impression score. So those two together make up the endpoint for 170 for the Redwood study.
spk10: Yeah, I think it's important to understand that the 169 and the 170, they represent the largest data set that's been studied for symptomatic NOH in a randomized setting. So we're You know, as we've said before, we're very excited about, you know, about completing 169 and taking a look at what the 169 data says with regard to efficacy and safety.
spk12: Okay, understood. Thank you.
spk07: Thank you. Our next question comes from the line of Dazin Ahmed from Bank of America. Your question, please.
spk03: Good afternoon, and thanks for taking my questions. Most of them have already been answered, but as it relates to isincytinib, you know, you're going to have data in Q3 in ulcerative colitis and then more towards the end of the year and potentially early next year, data in Crohn's. So my question is, just based on whatever results you show for ulcerative colitis, Should we try to extrapolate, based on that result, what the data could look like for Crohn's? That's my first question. And then for you, Palri, as it relates to this phase four study, and I'm sorry if I missed this in your prepared remarks, but could it increase your adjustable patient population if run successfully, and if so, by how much? Thank you.
spk10: Sure. You know, both very good questions. I think the isincentinib data for ulcerative colitis will provide some guidance in Crohn's disease, but they're two different diseases. Crohn's being more transmural and involving from a geographic perspective more of the intestinal tract potentially than ulcerative colitis. We do believe that there's some information. Obviously, it'll be good for from the ulcerative colitis study to view Crohn's, but it is a different disease, and given that we're getting very close to the end of the Crohn's program, we'll complete that Crohn's program and see what the data are as we unblind. The second question on upelry, that's a great point to bring up because there's some estimates that as many as one in five COPD patients have low peak inspiratory flow. And I think this has been an area of significant interest for TheraVans for quite some time in addressing that particular population with nebulized therapy. Now, there are many reasons why patients use a nebulizer, dexterity issues, you know, just certain involvement of a caregiver, et cetera, the inability because of dexterity to work, of course, a metered dose inhaler or, in fact, a dry powder inhaler. But certainly what we do see is we see some patients utilizing nebulization because they do have low peak inspiratory flow. And we're hopeful that this phase four program that we're running will be able to complement an earlier phase two data set where we showed in patients with low to very low peak inspiratory flow, there was an advantage of upelry in those patients. That was a small data set, so hence the need to do the phase four confirmatory trial and look to potentially expand the overall population that is addressable by a nebulized once-a-day medicine like upelry. Frank, anything to add?
spk09: I think you hit most of the key points. There are a lot of patients that are on handheld agents that have dexterity issues. Separate from dexterity, they have coordination issues where you have to manipulate the handheld device. You have to breathe in deeply at just the right time, as well as cognitive issues. Excuse me. The other thing is we're testing, pardon me, We're testing a bit of a hypothesis because previous nebulized agents maybe were not optimal in this patient population. Upelri is the first once-a-day agent that provides a full 24 hours of control, and it takes about eight minutes in the morning, and then you're good for the rest of the day until the following morning. And with a nebulized agent, you only have to execute tidal breathing as opposed to deep inhalations with a handheld device. So we look at this as an opportunity well worth investing in, not only for the brand, but particularly for the patients that potentially will be treated with upelri with low PIPR.
spk03: Okay. Thanks for that, Kohler. And I know it's probably difficult to answer numerical questions, but, you know, just
spk10: you know i don't know could it increase the patient population by 50 percent more than that less than that well there's about you know nine to ten percent of patients that use nebulizers for maintenance uh therapy and and again it's been some indication that one in five patients have have low peak inspiratory flow uh so you're looking at you know a fairly significant increase i think 900 000 patients or something that use nebulizers for maintenance therapy with COPD. So this is a significant additional segment of the market. However, I think what's exciting for us with UPelri is the progress that UPelri is making with our existing marketing strategy with Beatrice in really targeting those patients who are underserved by either existing handheld therapy or, in fact, using short-acting agents and just not getting the benefit of the short-acting agents for an entire 24-hour period, like what is possible with Upelri. So, again, I do think the way you're looking at it is right. This is really targeting to expand the size of the pie with Upelri, but we have a significant amount of work And I think we can do that work successfully in positioning UPelry and increasing its share, continuing to increase its share in the existing market segment. Frank, anything there?
spk09: No, no, I think that's it. I don't have anything to add, Rick.
spk03: Okay, great. Thank you, Rick.
spk07: Thank you. Our final question for today comes from the line of Joseph Stringer from Needham and Company. Your question, please.
spk14: Hi, everyone. Thanks for taking our questions. Two from us. One sort of on amperloxacin and NOH, kind of related to the questions that have been asked earlier. Just curious, you know, in your discussions with clinicians, with the available options and therapies out there, what's really the main sort of concern or main drawback that you can point to, I know there are several, but is it really efficacy-based sort of durability of effect, or is it safety-related in terms of supine hypertension? And I guess where I'm going is that if you had an efficacy result with amproloxacin that's clinically relevant but similar to other therapies, but you have better safety, such as lower supply and hypertension. Do you think that would still translate into the ability to catch the majority of market share in sort of the current competitive dynamics? And then the second question is just beyond NOH and UC Crohn's, what's a top program that we can look for in terms of, you know, advancing in the clinic or we could see clinical data from? Thanks for taking our questions.
spk10: Sure. Well, I'll just start with ampriloxetine. I think, you know, when you look at the market research is that physicians are, you know, are looking for a therapy where they can be – there can be a level of confidence with their patient that they're going to achieve durability of response. And durability of response without titration – you know, potential titration – with unknown consequences and certainly in some instances with that titration increasing the risk of supine hypertension. This is, and you look at the program of 169 and 170, this is the most significant body of evidence that's been developed for symptomatic NOH. There is not another compound that's used either on-label or off-label that will have a data set like ampryloxetine. So I think overall it's simply the ability to deliver on the promise of a product and delivering efficacy without significantly increasing the risk of supine hypertension. I'll just tie it back to another product where we're seeing success, and that's in upelre. And if you look at the success of upelre with clinicians, and the feedback loop that they get from patients. The root of UPelry's success is it delivers on its promise as a product, and that's what we're seeking to achieve with ampryloxetine. So, you know, on the next significant clinical program, well, I think the significance, obviously, of the the Amproloxacin 169 and 170 study, ulcerative colitis, and Crohn's for isensitinib. These are very, very significant programs for us. And now we've just announced another program, a phase four study in upelry with low PIFR patients versus teatropium. So that's likely to be the next, but we remain quite excited about the InhaleJack program, both the inhaled from a dry powder inhaler, as well as for a certain segment of the population, as well as the acute use of a JAK inhibitor for acute lung injury caused by viral illnesses, as well as promise that we might have in both acute and chronic lung allograft dysfunction, i.e. transplant. So all these programs are moving forward, but obviously our focus is on right now in the near term, which is the data on ampryloxetine and the data in ulcerative colitis.
spk14: Great. Thank you.
spk07: Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Mr. Whittingham for any further remarks.
spk10: Thank you, Operator, and I'd like to thank everyone for joining us today. Obviously, we're on the eve of some very important data readouts for us in ulcerative colitis as well as symptomatic neurogenic orthostatic hypotension, and we're very excited by the continued strength that UPelry is showing even in the face of a continuing pandemic, and we look forward to updating you on these programs as the remainder of the year unfolds. So thank you very much for your time.
spk07: Thank you, ladies and gentlemen, for your participation at today's conference. This does conclude the program. You may now disconnect. Good day.
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