Vertex Pharmaceuticals Incorporated

Good day and welcome to the Vertex Pharmaceuticals second quarter 2024 earnings call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

Good evening, all. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our second quarter 2024 Financial Results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Burr, Texas CEO and President, Stuart Arbuckle, Chief Operating Officer, and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded and a replay will be available on our website. We will be making forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including without limitation those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, and beta thalassemia, our pipeline, including the potential near-term launches of the vanzecaptor triple in CF and suzetrogene in moderate to severe acute pain, and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that the select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. I will now turn the call over to Reshma.

Thanks, Susie. Good evening, all, and thank you for joining us on the call today. We've continued our momentum from Q1 with another quarter of excellent performance across the board, including outstanding commercial execution in both CF and the early launch of Kastchevy, our preparedness for the potential near-term launches of the Vanzecafter triple in CF and Sysetra gene in acute pain, as well as the rapid advancement of our broad and deep pipeline. In CF, we continue to reach more patients, delivering $2.65 billion in revenue in Q2, and based on this result and our outlook, we are increasing our full-year product revenue guidance to $10.65 to $10.85 billion, which at the midpoint represents 9% growth versus 2023. In sickle cell disease and beta thalassemia, we are pleased with the reception from patients, physicians, and payers as we continue the ongoing launch of Casgevi to bring this potentially transformative medicine to patients across multiple regions. And we are very excited about the multiple near-term opportunities to reach more patients and deliver additional revenue growth from our programs that have completed pivotal development, including the completion and acceptance of two significant regulatory submissions. The Vanzacaftor triple in patients with cystic fibrosis, six years and older, which has been given priority review designation, and VX548 or sucetragine in moderate to severe acute pain, which has also been granted priority review by the FDA. Lastly, on the mid- and late-stage pipeline, I am very pleased with our continued, rapid progress. I'll call out three specific programs. First, the SucetraGene LSR Phase II study has significantly accelerated, and we now expect Phase II results by the end of this year. Second, in the VX880 Phase 1-2 trial in type 1 diabetes, we have completed enrollment and dosing in the original 17-patient study, and we have secured regulatory endorsement to expand the study to 37 patients in total as we advance towards pivotal development. And third, in the povitacicept program, having completed successful end of phase 2 regulatory meetings, we will initiate the phase 3 pivotal trial in IgA nephropathy later this month. With those highlights, let me now turn to an R&D review, limiting my comments this quarter to the programs with the most significant recent updates, cystic fibrosis, pain, type 1 diabetes, and IgA nephropathy. Starting with CF, we are very pleased with the Phase III results from the Vanzecafter Triple program we announced in early February, as we continue to drive towards our ultimate goal of bringing all eligible patients to carrier levels, indeed to normal levels of CFTR function, as measured by sweat chloride. The Vanzacafta triple demonstrated an even greater reduction in sweat chloride than Trikafta, a very high bar to have crested, and thus sets the stage for the potential to have a new standard in the treatment of CF. The Vanzacafta triple also offers the convenience of once-daily dosing and a substantially lower royalty burden. With regard to the VANZA global regulatory submissions, in addition to the U.S. acceptance, our filings have also been validated by the EMA in the EU and the MHRA in the UK. With regard to VX522, our CFTR mRNA therapy in development with our partners at Moderna, it has completed the single ascending dose portion of the Phase 1-2 study and continues in the multiple ascending dose portion. As a reminder, VX522 seeks to provide treatment for the more than 5,000 people with CF who do not make any CFTR protein and therefore cannot benefit from CFTR modulators. Based on the pace of enrollment and study dynamics, our current expectation is to complete the study and share both efficacy and safety results from the study in the first half of 2025. Moving now to the pain program and our portfolio of novel, highly selective NAV1.8 and NAV1.7 pain signal inhibitors. In acute pain, a few points to highlight. First, we are very pleased that the Sysetrogene submission has been accepted and granted priority review by the FDA with a PDUFA target action date of January 30, 2025. Second, our next-in-class NAV1.8 pain signal inhibitor, VX993, is in the clinic in a Phase 1 trial with the IV formulation and is currently enrolling and dosing healthy volunteers. Third, VX993 will soon enter a Phase 2 study with the oral formulation in acute pain following bunionectomy surgery. This study is on track to begin later this quarter. And lastly, we continue to make strong progress preclinically with our NAV1.7 pain signal inhibitor program that may be used alone or in combination with NAV1.8 inhibitors. Just as in acute pain, we have multiple programs moving rapidly through development in peripheral neuropathic pain, or PNP, starting with painful lumbosacral radiculopathy, or LSR, a condition that impacts more than 4 million Americans. There is a high unmet need in LSR. In the US, there are no medicines approved specifically for the treatment of pain from LSR. As mentioned in my opening remarks, the pace of enrollment in this study has been rapid and significantly exceeded our projections. Study enrollment is now complete and we anticipate sharing Phase 2 LSR results by the end of this year. Also in peripheral neuropathic pain, we are excited to begin the phase three pivotal program for sucetragine in painful diabetic peripheral neuropathy or DPN later this quarter. The DPN pivotal program consists of two identical randomized control trials of approximately 1,100 patients each with sucetragine at a dose of 70 milligrams once daily and evaluating the change from baseline to week 12 in NPRS pain scores relative to placebo. The RCTs also include an active comparator arm of pregabalin. A key secondary endpoint is change from baseline at week 12 in NPRS score for sucetragine versus pregabalin assessed for non-inferiority. And if we meet non-inferiority, then we will test for superiority versus pregabalin. Lastly in PNP, I am pleased to share that we will soon initiate a Phase II study with the oral formulation of VX993 in diabetic peripheral neuropathy. Designed similarly to the SucetraGene Phase II DPN study, this trial is also on track to begin this quarter. Turning now to type 1 diabetes, VX880s are stem cell-derived, fully differentiated islet cell therapy for people with T1D and impaired hypoglycemic awareness who experience severe hypoglycemic events despite optimal medical care. At the ADA meeting in June, an oral presentation from the ongoing Phase 1-2 study included updated data with more patients and longer duration of follow-up and continued to demonstrate the potential of VX880 as a functional cure for patients with T1D. The data reflected 12 patients from Parts B and C of the study who received a full dose of VX880 as a single infusion and had at least three months of follow-up. The results are remarkable. Specifically, all patients demonstrated islet cell engraftment and glucose-responsive insulin production by day 90. All 12 patients achieved hemoglobin A1c levels less than 7% and all 12 patients also had a time in range for glucose levels of 70% or greater. 11 of the 12 patients greatly reduced or completely eliminated exogenous insulin use. And the three patients with 12 months of follow-up and therefore evaluable for the primary endpoint, each met the primary endpoint of elimination of severe hypoglycemic events with a hemoglobin A1c level below 7, as well as the secondary endpoint of insulin independence. With these results, we are planning forward towards the next phase of development for VX880. To that end, we are very pleased to have secured regulatory approval to expand the original 17-patient study, which is fully enrolled and dosed, to include an additional 20 participants. We look forward to continuing the work with regulators to finalize the requirements for pivotal development and updating you on those discussions. Beyond VX-880, our Cells Plus Device, or VX-264 program, encapsulates the same VX-880 cells in a proprietary device designed to eliminate the need for immunosuppressants. VX-264 is in a Phase I-II multi-part global study. We have completed Part A of the study at an initial dose with a stagger between patients. We are currently enrolling and dosing patients in Part B, which is at the full target dose, also with a stagger between patients. As a reminder, Part C of the trial is at the full target dose with no stagger between patients. The last major R&D update pertains to povitacicept, the lead asset from our recently closed acquisition of Alpine Immune Sciences, where our enthusiasm for both the acquisition and POVI remains high. As a reminder, POVI holds the promise of being a pipeline and a product, and has best-in-class potential for the lead indication in IgA nephropathy, given its mechanism of action with dual inhibition of both APRIL and BAF, its preclinical profile, and the clinical data through Phase II in pertinuria, hematuria, and GFR. These attributes, plus POVI's once-monthly dose frequency and small-volume subcutaneous route of administration, give us high confidence in its potential to be a transformative medicine for patients with IGAN. I am pleased to share that we are on track to initiate the global Phase III Rainier study of povitacicept in patients with IgA nephropathy this month. To recap, we had successful end-of-Phase II meetings with the FDA and global regulatory authorities and were very pleased to have reached agreement on the following important elements. The Pivotal Program is designed as a single, global, randomized, double-blind, placebo-controlled trial of approximately 480 patients with biopsy-proven IGAN and proteinuria. Patients will be randomized to receive either POVI or placebo on top of standard of care. In the U.S., the Phase III design affords us the opportunity to submit for an accelerated approval. A preplanned interim analysis will take place when a certain number of patients reaches 36 weeks of treatment to evaluate the change in pertinuria from baseline to week 36. For full approval, the study will continue through week 104 and an assessment of GFR. Beyond the Phase III study in IgA nephropathy, POVI is also being evaluated in two Phase II basket trials, one in renal diseases, termed RUBI3, and a second in B-cell-mediated cytopenias, termed RUBI4. We look forward to readouts from some cohorts in these studies later this year and into next. To close the pipeline review, a brief update on VX634 and VX668 in alpha-1 antitrypsin deficiency or AATD. Safety was demonstrated in the Phase 1 studies of both VX634 and VX668. However, based on the Phase I biomarker analyses, we have determined that neither VX634 nor VX668 would deliver transformative efficacy for people with AATD, and therefore we have decided to discontinue development of both molecules. With these learnings, our research efforts in AATD will continue. I'll now turn it over to Stuart for a commercial update.

Thanks Reshma. I'll first discuss CF, then provide some highlights of the ongoing Casgevi launch and the outlook for Cis-Etrogen in acute pain. As Reshma noted, we once again delivered strong results in CF as we grew the number of eligible patients taking our CFTR modulators. And we continue to expect sustained growth in CF over the near, medium, and long term. In the near term, we continue to focus on reaching more eligible patients, including younger age groups, as with the ongoing CAF TRIO launches in the two to five age group in Europe, with anticipated global approvals for additional rare mutations later this year, and through additional geographies, such as Brazil, where we now have national reimbursement for Trikafta for patients ages 6 and above. We were also pleased to have announced in June an extended long-term reimbursement agreement with NHS England, which ensures access to our CFDR modulators for all existing and future eligible CF patients in England. Comparable arrangements have subsequently been entered into in Scotland, Wales, and Northern Ireland. The agreements are a result of positive recommendations for NICE and SMC for our CFTR modulators. In the medium term, we anticipate growth will be driven by the launch of our fifth CFTR modulator therapy, the vanza-kafta-triple combination. We believe many existing Trikafta patients may seek to achieve even greater levels of CFTR function and the added convenience of once-daily dosing, and there are also more than 6,000 patients who have discontinued one of our current CFTR modulators who also may be interested in a new treatment option. We continue to execute our VANSA pre-launch activities, including pre-approval information exchange with payers, and are encouraged by the outlook. And longer term, we expect continued growth in CF from developing medicines for the more than 5,000 people with CF who do not respond to CFTR modulators, which is the focus of our mRNA program, VX522. Now turning to Casgevi and our launches in sickle cell disease and beta thalassemia. We continue to make strong progress with ATC activation, as well as physician, patient, and payer engagement, as we work to bring this potentially curative therapy to patients around the globe. Kastjevi represents an enormous advancement for the estimated 35,000 people living with severe sickle cell disease and transfusion-dependent beta thalassemia in the US and Europe, as well as the estimated 23,000 eligible patients in the Kingdom of Saudi Arabia and Bahrain. To update you on the two key metrics we are sharing externally as important markers of our early launch progress. Firstly, ATC activation. We're pleased with our progress as we now have more than 35 activated centers, up from 25 last quarter and nine at launch. We continue to expect to activate approximately 75 total ATCs globally. Secondly, patient cell collections. We continue to see a growing number of patients beginning the treatment journey. Approximately 20 patients have already had cells collected. As mentioned last quarter, patients are initiating the treatment journey in every region where Casgivi is approved, the US, Europe, and the Middle East. And we are pleased to report growth in patient cell collections across all of these regions this quarter. We also continue to make strong progress with payers in all regions, who recognize the transformative clinical benefits of Casgevi and are moving quickly to provide rapid and equitable access. Outside the U.S., we are building upon our early successes, such as the Early Access Program in France for TDT, and we now have an Early Access Program approved there for sickle cell disease, as well as reimbursement in Austria, Bahrain, and KSA. In the U.S., given payer support across all market segments, commercial, Medicaid, and Medicare, I'm pleased to report that we do not see coverage as a significant obstacle to patient access. We have always known that Caschevy offers an enormous advancement for patients. We've also consistently communicated that the patient journey, that is the process to go from patient interest all the way to infusion of edited cells, is long and complex. Whilst it's still early in the launch, we have gained many learnings. Interest level is high among patients, physicians, governments, and other stakeholders. The value of Caschevy has been widely recognized, leading to broad access and reimbursement by payers. The patient opportunity in the Middle East is particularly significant given the high prevalence of these haemoglobinopathies and governments' clear focus on elevating the health of their citizens. And lastly, the treatment process does take time, but we are now even more confident in our view that Casgivi will help large numbers of patients around the world and represents a multi-billion dollar opportunity. Shifting now to cezetrogene. We believe this novel, highly selective NAV1.8 pain signal inhibitor has the potential to provide a transformative treatment option for the 90 million patients suffering from acute and peripheral neuropathic pain in the US. This quarter, I'll limit my commercial comments to the opportunity in acute pain. We have continued to make significant progress building out our commercial team. We've now completed hiring of our strategic account leads, who will primarily focus on the leadership and formulary decision makers at IDNs, as well as our pain territory account managers, who, post-approval, will call on hospitals and other large treatment sites, such as ambulatory surgical centers. Recall that approximately 80 million patients are prescribed a medicine for moderate to severe acute pain each year in the U.S., with approximately two-thirds of patients treated in the institutional setting. As a result, our field force will primarily focus on this institutional setting. We have begun engaging in pre-approval information exchanges in those institutional settings with IDN leadership and formulary decision makers who have responsibility for formularies that enable use in both the inpatient and discharge settings. we've encountered high levels of enthusiasm for a new class of treatment for pain, specifically for an effective and well-tolerated pain medication that does not possess addictive properties by way of its mechanism of action. Hospital formulary and payer processes are well-defined, and we are engaging appropriately to encourage and support swift reviews by the relevant bodies like P&T committees, including by providing key clinical and economic information. Depending on the institution or organization, It can take up to 12 months post-approval for hospital formulary and payer decisions to be finalised, but we are working to accelerate these timelines. We anticipate engaging in contracting discussions in the latter half of 2024 with the goal of building formulary and payer coverage during 2025. We also continue to be engaged with federal and state policymakers, including state governors, who have expressed strong interest in a novel, highly effective, and well-tolerated treatment for pain without the addictive potential of opioids. Federally, in December 2022, Congress passed the No Pain Act, in which non-opioid therapies are eligible for separate payment for Medicare patients in the outpatient and ACS settings, beginning in January 2025. It is promising to see CMS continuing the process of implementation as the Annual Outpatient Prospective Payment System, or OPPS, proposed rule was released for public comment last month. Because cezetrogene is still investigational, it is not currently included in the list of seven drugs in the proposed rule. But we fully expect cezetrogene will be eligible for separate payment once it is FDA approved. We view the No Pain Act as an important indication of the broad range of supportive policy initiatives, both at the federal and state level, that can provide a meaningful tailwind to sesetragene adoption. We are also encouraged by the progress of the Alternatives to Pain Act, which aims to level the playing field for access to non-opioids for Medicare Part D patients. In the discharge or outpatient pharmacy setting, it's important to understand that patients who receive a prescription must be able to access their acute pain medication immediately. Unlike patients with asymptomatic or chronic conditions, patients in acute pain cannot wait for another day or another week to have their prescription filled. We are therefore working with key pharmacy retail organizations to ensure broad availability of cezetrogene nationally. In addition, we are planning a range of initiatives for the first year of launch, including copay assistance and other financial assistance programs to enable patients at the pharmacy to access their prescribed cezetrogene prior to payer coverage decisions. We are very enthusiastic about the potential launch of cezetrogene for patients with moderate to severe acute pain, and the impact we believe it will have on society. We recognize that even in the case of significant unmet need, it can take time for some components of our healthcare system to adopt new technologies, and we are working to accelerate these processes. Ultimately, our goal is to fundamentally and forever change the way pain is treated, and we look forward to delivering on the first part of this vision for patients with moderate to severe acute pain in early 2025. In conclusion, it's an exciting time to be at Vertex. We continue to treat more CF patients around the world and are well advanced in planning for the launch of the Vanzacafta triple combination. We are entering a new era of commercial diversification with the launch of Casgevi in the U.S., Europe, and the Middle East. And our launch preparations for suzetrogene in acute pain are well underway as we seek to redefine the treatment of pain and drive further diversified revenue growth. I will now turn the call over to Charlie to review the financials.

Thanks Stuart. Vertex's excellent Q2 results demonstrate once again our consistent strong performance and attractive growth profile. Second quarter 2024 revenue increased 6% year-over-year to $2.65 billion, with solid growth of 7% in the U.S. and 5% outside the U.S. The drivers of this strong quarter were in line with our expectations, including an anticipated reduction in channel inventories in select international markets. Second quarter U.S. growth was driven by continued strong patient demand for Trikafta. Outside the U.S., growth was also driven by strong demand, with continued uptake from the Caftreo launches in children's ages 2 to 5, partially offset by the reversal of the first quarter channel inventory build. On the expense front, Q2-24 combined non-GAAP R&D, acquired IP R&D, and SG&A expenses were $5.43 billion compared to $1.04 billion in the second quarter of 2023. Q2 24 operating expenses include over $4.4 billion in AIP R&D charges, primarily as a result of the Alpine acquisition, which we previously disclosed is being accounted for as an asset acquisition. This compares to just $111 million of AIP R&D charges in Q2 of 23. Q2 24 non-gap R&D expenses of $697 million were roughly flat year over year, reflecting ongoing investment in the advancement of our broad R&D portfolio, upset by reduced costs from the recently completed clinical trials, as well as the associated transition of certain costs from R&D to COGS and inventory. Q2-24 non-GAAP SG&A expenses of $280 million increased 28% versus prior year, primarily as a result of investments in the commercial organization, including launch activities for Casjevi and pre-launch activities for Suzetrogene in acute pain. We anticipate that quarterly non-GAAP R&D and SG&A expenses will increase over the remainder of 2024 within our guidance as we advance multiple studies, including suzetrogene, POVI, and enaxiplin in Phase III programs, VX993 in acute and peripheral neuropathic pain studies, and the expansion of the VX880 trial in T1D. In addition, we continue to invest in preparation for upcoming potential new launches, including the further build-out of our commercial capabilities in acute pain. Q2 24 results reflected strong revenue in underlying operating results, though due to the $4.4 billion AIP R&D charge from Alpine Transaction Accounting, we reported a second quarter 2024 non-GAAP operating loss of $3.1 billion. In the second quarter of 2023, we reported $1.15 billion in non-GAAP operating income. Our tax rate for the quarter was also impacted by the one-time non-deductible Alpine AIPR&D charge, leading to a reported non-GAAP tax rate for the second quarter of 2024 of negative 10% compared to a tax rate of 21% in Q2 of 23. Aside from the effects of the non-deductible Alpine charge, there were no material changes in Vertex's non-GAAP tax rate for the quarter, which would have been approximately 21%. The $4.4 billion AIP R&D charge for the Alpine acquisition equates to an impact of approximately $17 per share on Q2 GAAP and non-GAAP results and drove a non-GAAP loss per share of $12.83 in Q2-24 compared to non-GAAP earnings per share of $3.89 in the second quarter of 2023. We ended the quarter with $10.2 billion in cash and investments after paying approximately $5 billion to fund the acquisition of Alpine Immune Sciences. Additionally, we deployed over $300 million of cash in the second quarter to repurchase more than 700,000 shares. Now switching to guidance. We are raising our 2024 total product revenue guidance to a range of $10.65 to $10.85 billion, representing 9% revenue growth at the midpoint at current exchange rates. We continue to have high visibility into this revenue outlook as we expect continued growth in CF as we reach more patients, including younger ones, in core markets and select other countries. Guidance also continues to include a contribution in the second half of the year from the commercial launch of Casgevi. For Vertex operating expenses, our non-GAAP guidance continues to include a range of $4.2 to $4.3 billion in combined R&D and SG&A expenses, which is unchanged from the guidance provided on our last earnings call. As previously communicated, we are absorbing Alpine's projected non-GAAP operating expenses for the remainder of 2024 within our guidance range for R&D and SG&A. For acquired IPR&D, we now expect approximately $4.6 billion for the year, including the Alpine Asset Acquisition Charge recorded in the second quarter. Given that the Alpine AIP R&D charge is not deductible for tax purposes, we expect a non-GAAP full-year 2024 tax rate of approximately 100%. Note that the anticipated percentage tax rate is highly sensitive to projected pre-tax income. Aside from the impact of the non-deductible Alpine AIP R&D charge, our underlying full-year 2024 non-GAAP effective tax rate would have remained in the range of 20% to 21%. In closing, Vertex posted excellent results yet again as we delivered strong revenue growth, advanced our CastGEVI launch, and secured important regulatory approvals. We also strengthened our capabilities in preparation for additional near-term launches, progressed our pipeline, and made rapid progress closing and integrating Alpine, a compelling fit with Vertex's R&D strategy, with significant potential as a pipeline in a product. We are already leveraging Vertex's clinical, regulatory, and commercial capabilities to accelerate development in IGAN with Phase 3 set to begin this month. We are targeting U.S. accelerated approval in IGAN in late 2027 and a contribution to Vertex's revenue growth and diversification beginning in 2028. In addition, as we move through 2024, we anticipate further important achievements, including multiple milestones in our pain portfolio, such as a Phase II data readout with suzetrogene in LSR, Phase II initiation of VX993 studies in acute pain and in diabetic peripheral neuropathy, as well as progress towards pivotal development in T1D. These and other anticipated milestones of continued progress in multiple disease areas are detailed on slide 17. We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

We will now begin a question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. And to withdraw your question, please press star, then two. And at this time, we'll pause momentarily to assemble our roster. And the first question will come from Salveen Richter with Goldman Sachs. Please go ahead.

Good afternoon. Thanks for taking my question. Noting that around 6,000 patients have discontinued CFTR modulators, as we think about uptake for vanzecaptor triple, can you help us understand what the early launch dynamics could look like and whether they could be a significant bolus of early adopters? And then just a second question, if I may, what is the relative contribution of Kes-GEVI to the updated product revenue guidance? Thank you.

Hey, thanks, Alvin. We won't be breaking down the revenue for the CF franchise versus Kastchevy, and I'll turn it over to Stuart to tell you a little bit more about the Vanzecafter launch dynamics.

Yes, Alvin, thanks for the question. I don't think there's going to be a single bolus of patients based on our research with physicians that they are considering for the Vanzecafter triple combination. I'd say that they are excited about the prospects for Banzacaptor, both for their existing patients who are on a CFTR modulator, many of whom I think are going to be very interested in a treatment option which promises the potential for increased CFTR function, and also being the fact that it's once a day. And then, as you say, there are also patients who are not currently on a CFTR modulator who I think are going to welcome the opportunity for a new treatment option. So I don't think it's going to be one or the other. I think there's going to be a broad interest in the vanzecaf to triple across both patients who are persistent today and those who've discontinued previously.

The next question will come from David Rissinger with Larynx Partners. Please go ahead.

And congrats on the strong execution. I have two questions. First, could you just discuss the potential to develop VX548-XUS for neuropathic pain? And second, could you provide the latest on your preclinical development efforts for NAV1.7 inhibitors? Thanks very much.

Sure thing. Hey, Dave, this is Reshma. Let me break that into two parts and let me take... the preclinical NAV1.7 first, and then I'll turn it over to Stuart to talk about our goals XUS. So we are making really strong progress on the NAV1.7 inhibitors. They are still in preclinical development, but I would characterize it, Dave, as it's in late preclinical development. And to contextualize this a little bit more for everybody else, We expect that the NAV1.7s could be used alone in acute pain or neuropathic pain, or they could be used in combination with our NAV1.8 inhibitors, be it 548 or 993 or any in our portfolio. With that, I'll turn it over to Stuart for a little bit on XUS ambitions.

Yeah. Hi, Dave. Thanks for the question. So I would say that the clinical landscape, and by that I mean the kind of the treatment options and the way that they're used is very similar outside the U.S. as it is here in the U.S. with things like NSAIDs, acetaminophen in neuropathic pain, things like pregabalin, gabapentin, and then obviously opioids. And that's true in both acute pain and neuropathic pain. And I know you were asking specifically about neuropathic. There are differences. I think it's fair to say that the level of abuse and misuse of opioids is less. It's not zero, but it's less outside of the U.S. But in addition, the pricing dynamics and the value recognition of healthcare and innovation by healthcare systems outside the U.S. is very different. And as such, our focus at this time is very much on the unmet need and opportunity to serve patients here in the U.S. first. And ex-U.S. is something that we will consider later on.

Thank you.

The next question will come from Jessica Phi with JP Morgan. Please go ahead.

Hey there. Thanks for taking my question. I wanted to ask about your type 1 diabetes effort. How do you envision the regulatory path for VX880 and for VX264, the encapsulated cells product? I believe you've completed Part A with the low-dose patients. Is there anything you can share with respect to kind of what you're seeing so far with that one? Thank you.

Yeah. Hi, Jess. It's Reshma. Let me take those two questions. Maybe we'll go with 264 first, and then we'll go to VX880. So on VX264, this is the selfless device program. You're exactly right about the stage of the program. We're in Part B, which is the full dose. It's a full dose with a stagger period between patients. I would say that results are a 2025 timeframe. We're making progress and I'm really happy to be in the clinic with both 264 and 880. On Vx880, this is the naked cell program, so cells alone. This is the one that has now completed, which is obviously a big milestone, enrollment and dosing in the original 17 patient study. We are in the phase of development where we're in full dose with patients who don't have a stagger. I'm really happy with the regulatory discussions to date and their endorsement for us to expand the study to a total of 37 patients, so an additional 20 patients. And with regard to your direct question on how should we think about the path forward with regard to regulatory expectations, I don't have an answer for you today because that's exactly the conversations that we're going to complete in the coming months. But I would think about the type 1 diabetes program more like a Caschevy program than a small molecule program. You'll remember that the Caschevy program in either TDT or in sickle cell disease was a very efficient sample size. And what we did in the case of Kastchevy is convert it from a phase 1-2 to a phase 1-2-3 trial. Exactly what it will look like for VX880. I'll look forward to keeping you updated as we complete the discussions with regulators.

The next question will come from Evan Seigerman with BMO Capital Markets. Please go ahead.

Hi, guys. Thank you so much for taking my question. I think, Stuart, in your prepared remarks, you suggested that the launch of cesetrogene might be more gradual than some other launches. Maybe once approved, can you walk me through some of the gating factors to really get this into the hands of patients to have a maximal impact on the healthcare system, kind of what you have to do once approved to really get it to these patients? Thank you.

Sure, Evan. Thanks for the question. And just to be, you know, absolutely crystal clear, our enthusiasm for Suzette's gene is growing as we get closer to launch, not diminishing. And that's due to the benefit we've got from, you know, market research and also our interactions and discussions with physicians post the phase three data and the filing. But there are, you know, practical realities that we are going to have to face. they are things like. Obviously, the majority of patients with acute pain are treated in the institutional setting. That means we're going to have to go through formulary and P&T processes with those institutions. We're going to have to work with payers and work through their formulary and other policy adoption processes. And so whilst those policies are very well defined, they do take time. And obviously, we're going to do everything we can to accelerate those timelines, and that's why we're already engaging, for instance, with GPOs and IDN leadership to support institutional use. We're talking with payers and PBMs to support rapid policy adoption. In addition, you know, we are going to want cesetrogene to be broadly available at retail pharmacies across America, and so we're also engaging with the major retail pharmacy organizations as well. And lastly, because we know that these processes can take time, despite the fact we're going to do everything we can to accelerate them, we are also looking at deploying a range of initiatives, including things like copay assistance and financial assistance programs so that if a physician and patient decide that cezette gene is right for them, that patient can access the product without delay and isn't forced to kind of abandon the prescription because their particular plan or payer has not finalized their medical policy yet. So those are some of the challenges we're going to be facing. They're not unique to Vertex. They are, you know, relatively well-defined, and we're going to do everything we can to accelerate them so that suzettegine can become the multibillion-dollar drug we know it's going to become. Great. Thank you.

The next question will come from Chris Raymond with Piper Sandler. Please go ahead.

Hey, thanks. Just maybe two questions. First, maybe on POVI, just a competitive question as IGAN seems to be getting a little bit more crowded. Biogen just got access to falzardamab, which I think had pretty interesting Phase II data. Just maybe talk a little bit about, you know, how you view the sort of match-up to that, and maybe how does anti-CD38 compare to BAF, April inhibition? And then maybe a CasGevi commercial question. Just on the HHS suit around fertility treatments for patients getting CasGevi, can you maybe talk about the overall timelines there with that case, and maybe also talk about how much of an impact it is to to not have this reimbursement for fertility in place during the early stage of the launch. Thank you.

Sure. Hey, this is Rachel. Let me take the first question first, and then I'll turn it over to Stuart to talk about Caschevy and how that's going. So important things to know about IgA nephropathy. It is a rare disease, but it is one of the more common rare diseases. There's more than 130,000 with IgA nephropathy in the U.S. alone. And it's actually the most common primary glomerulonephritis. So there are lots of patients that are waiting to be served. To date, there is no specific therapy that treats the underlying cause of this disease. And the reason for our enthusiasm and after a IgA nephropathy has been in our sandbox, as it were, a disease area of interest for a long time, and after there has been some activity in this space and a full analysis by us of everything available out there, Our enthusiasm for Alpine and their povitacicet, which is a dual April bath inhibitor, comes from the fact that it is the agent that works directly on the underlying cause of the disease. To put it in a short way, the disease is caused by B cells. It is the activation of these B cells. It is about autoantibodies. And this drug, Aprilbaf, directly inhibits B-cell proliferation, maturation, and proliferation. And what we have seen by way of mechanism of action, this dual Aprilbaf inhibition, all of the preclinical data, potency, affinity, as well as the clinical data, it is through its Phase II development, So we're talking about proteinuria, hematuria, GFR, and also the biomarker of what's called GDA, IgA. That's the aberrantly glycosylated IgA, which is the underlying problem. Not to mention two monthly dosing, it's subcutaneous and small volume. You put that all together, POVI has the most transformational profile and holds the potential to be best in class for IGAM, but also holds the potential to have effect, transformative effect, in a whole host of other B-cell mediated kidney diseases like lupus nephritis, membranous, ANCA associated, and a host of B-cell mediated heme diseases like ITP, cold agglutinin disease, warm hemolytic anemia. So I couldn't be more excited about this molecule getting to its first phase three program, which is IgA nephropathy.

Yeah, let me just take a step back before I talk specifically about fertility preservation. Because of the treatment journey to get Casgivy, which requires multiple trips to the activated and authorized treatment centers, and because there's only a certain number of sites in the United States, and in addition, because of the Bucel fan conditioning regimen, which is where the fertility risk comes in, we have sought to try and provide support to patients in two particular areas. One is travel and lodging. And the other one is in fertility preservation. And we want to provide those support services to patients equitably, no matter what their payer is. We are able to provide both of those services to commercially insured patients. And we are able to provide travel and lodging support to government insured patients because that has previously been ruled on by the OIG. What they have not given us an affirmative decision on is on fertility preservation. And that's why we've launched our suit to try and get fertility preservation approved for government-insured patients as well. It's impossible to speculate exactly on the timing of when that suit will be heard and resolved. In the short term, I don't see it as being rate-limiting to a successful launch of CasGevi, and I think we're already seeing that in the number of patients who are beginning the treatment journey and in the number of cell collections. Having said that, we are completely committed to the sickle cell and TET communities, and we are going to fight for their rights to get equitable access, whatever their payer.

And the next question will come from Terrence Flynn with Morgan Stanley. Please go ahead.

Hi. Thanks for taking the question. Maybe two for me. Stuart, you discussed at a high level your confidence in, you know, VanZaKafter pricing. Maybe just, I know you're not going to comment directly on the price, but just what are some of the inputs you're considering as you think about making that decision next year? And then any update on where we might see the full phase three data for VX548 this fall? Thank you.

Terrence, let me take the second question first. I think it's now been released, the VX548 success regime data have been accepted at the ASA Fall Conference, and it has been accepted in the Best Abstract category, so you can expect to see it there. I'm sure the teams are also going to be working on full manuscripts probably in the fall-winter timeframe, but the Congress acceptance of Soussette Regine as Best in Class Abstracts has already been announced. Stuart, over to you.

Yeah, Terence, on Vanzacafta, we're going to approach the pricing of Vanzacafta as we have with all of our medicines, which is we're going to base it on the clinical benefits and the value it provides to patients. And as you know, we're very positive about the Vanzacafta profile. It performed brilliantly in the phase three program, non-inferior as anticipated to Trikafta on FEV1, but demonstrated superior Restoration of CFTR function is measured by sweat chloride and, of course, it has the convenience of being once daily. So we're going to take all of those factors into consideration when thinking of the pricing, which is obviously a decision we'll make much closer to the launch.

The next question will come from Mohit Bansal with Wells Fargo. Please go ahead.

Thank you very much for taking my question. Maybe one question on LSAR trial. If you could help set some expectations there. It's a placebo-controlled trial, so did we think a two-point improvement just like a DPN trial would be good enough here? And then the other one is that are you expecting any outcome for the acute pain program at this point? Thank you.

Sure. Mohit, let me take the second question first. As I said in my prepared remarks, we are thrilled that, to Cetra Jean, the submission was not only accepted but granted priority review. The agency has let us know that they do not plan to hold an ADCOM as it stands today, but also, as you know, the agency can let us know that they wish to have one at any time between the acceptance of the filing and the actual approval. On the LSR, so that's also a VX548 trial. That's the trial that has significantly, honestly, far significantly exceeded our projections in terms of enrollment and study completion. We're now expecting that study to finish this year and for us to be able to share results this year. So with regard to this study and how you can think about it, it uses the high dose, so the 69 milligrams from the phase two study of DPN. The big difference between DPN and LSR is that LSR has no specific therapy approved for the treatment of this kind of radiculopathy pain. And so our phase two trial in LSR is a within group, so it's within arm change of the NPRS score for the LFR, sorry, for the VX548 group, and equally we'll have the placebo group within group change. And the goal for the LSR study, which frankly was the same goal as the DPN study, is to get a magnitude of the treatment effect so that we can appropriately power the phase three study. And the reason the DPN study had a pregabalin arm was because pregabalin is an available therapy for the treatment of DPN. This study, LSR, has a placebo arm because there is no specifically approved therapy for the treatment of LSR. I hope that helps.

Thank you.

Chuck, we'll take two more questions, please.

Yes, ma'am. The next question will come from Lisa Baco with Evercore ISI. Please go ahead.

Hi. Thanks for taking the question. Just to follow up on amfanzacaptor, maybe you can talk about how you're expecting the rollout there in terms of patient uptake, You know, it's not quite as much of a leap as some of your other therapies are, but nevertheless, like, you know, the value there is obvious. You know, do you expect, like, quite quick conversion? Will it happen slowly over time? Do you think the vast majority of patients will switch over? Just curious about what the feedback's been there. Thanks.

Are there any additional comments to make?

Yeah, just that we are, we're as excited about the VanzaCap, the launches of any of our other CFTR modulators for the reasons I think you were referring to, Lisa. It's got a great benefit-risk profile, and I think it is going to, as I said earlier, I think it's going to be equally of interest to patients who are on a CFTR modulator today but would like increased CFTR function as demonstrated by sweat chloride because These patients know that that is important for their health and well-being, but I think it's also going to be of value to those who've discontinued. As I said earlier on, I really don't think there's one group or another who are going to be more interested than others. I do think it's something that's going to be broadly of appeal to people. And as I also mentioned, not to forget the fact that it has the benefit of being once daily, which again is an attractive part of a chronic medication. So as I said, we're as excited about the launch of BANZA as we have been about any of our other CFTR modulators.

I was just trying to get a sense of how quickly people might convert over to your thinking. Do you think it would be kind of slow and steady or pretty rapid?

Yeah, I mean, certainly the reaction we've had from physicians and patients to profile has been very enthusiastic. I'm not going to speculate exactly on how rapidly we're going to get transitions and people restarted, Lisa.

Lisa, maybe I'll just add one thing if you want to think through it. Patients with CF usually visit their doctors once a quarter. As Stuart said, the patients are very aware of drug development and Vanzecaptor in particular, as are their physicians. And patients have consistently expressed interest in thinking about medicines that may bring them the potential for higher efficacy. I think that that's as far as we can go with regard to timing, but maybe those are pieces of information that are helpful to you.

Thanks. The next question will come from Michael Yee with Jefferies. Please go ahead.

Hey, guys. Thank you. Great. Two questions for us. On the Alpine product, can you just remind me, I know you guys think it's best in class, but how to think about greater reduction in proteinuria?

versus say a program that will have data in first half 25, and is it your idea that you have greater reductions and therefore better stabilization of EGFR, or that it also will just be shining through in lupus and other autoimmune diseases for which we'll have to wait for Ruby 3 data? So just maybe talk about and remind us how you think the benefits will be seen on that product. And then really quickly on the acute pain launch, can you just remind me, On the comments on the No Pain Act, you believe you will eventually get reimbursement there, but that's more of a CMS exposure population to take that in consideration. And for commercial, that's more about blocking and tackling on formularies and commercial plans. Thank you.

Yeah. Mike, I'm going to ask Stuart to comment on No Pain first. I think it was a little hard to hear you, Mike, but I think, Stuart, Mike's question is, Does the No Pain Act pertain to government-paid patients, and how are you thinking about commercial? And then I'll come back for Povey.

Yes, so No Pain, Mike, is looking at the add-on payment to patients who are treated in the outpatient ambulatory surgical center setting. As you said, we were not listed as one of the products, but that is because we're not approved. And so, yes, we do anticipate being added to that list once Suzette Jardine is approved. In terms of in the Medicare area, maybe you're also thinking of the Alternatives to Pain Act, which is looking to level the playing field in terms of things like step therapy and not allowing things like that, and utilization management in Part D, and also making sure that there is parity in terms of the copay for patients between opioids and non-opioids. In terms of commercial, as you said, these are less relevant to that. This is really sort of, as you said, blocking and tackling is what we'll be doing in talking to commercial plans.

And Mike, on the question on POVI, I think the question was how should we think about POVI in IgA nephropathy and then how should we think about it in the other studies? Is it all about proteinuria? So the way I would think about it is underlying cause of disease, and B-cell mediated diseases. We have two phase two studies going on. It was a very clever design by Alpine scientists. There's a Ruby 3, which is a basket of B-cell mediated renal diseases, IgA nephropathy, which is now going to phase three this month. It has lupus nephritis in there, ANCA-associated nephritis, as well as membranous. All of these diseases are B-cell mediated diseases. In many of these diseases, proteinuria is important. But I'll tell you, for example, in membranous, PLA2R is a very important biomarker. And in some of the nephritides, as you may know, hematuria is very, very important. So I think proteinuria is clearly very important in IgA nephropathy. And its prominence is elevated because of the FDA's acceptance of proteinuria in IgA nephropathy as an accelerated approval endpoint. But hematuria is important in some, looking at biomarkers like PLA2R is important in others. And in the Ruby 4 basket, these are B-cell mediated heme diseases It's really not about proteinuria. It's about other markers of interest, like it could be something like hemoglobin or in the case of ITP, it would be platelets. But the way I would look at it and my enthusiasm for povitacicept is because it is such a good B cell. It's such a good medicine to tamp down the B cells because it's dual inhibition. and impacts maturation, proliferation, and differentiation of B cells. And that's where my optimism for B cell-mediated diseases comes from.

Thank you. Yep. Thanks, Mike. Chuck, we'll wrap it there, please.

Thank you. This concludes our question and answer session, as well as our conference call for today. Thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 1-877 344-7529 or 1-412-317-0088 using replay access code 10186971. Thank you for your participation and you may now disconnect.