Good day, and welcome to the Vertex Pharmaceuticals third quarter 2026 earnings call. All participants will be in a listen-only mode. Should you need assistance, please signal conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your touch-tone phone. To withdraw your question, please press star then two. 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 third quarter 2026 financial results conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Charlie Wagner, Chief Operating Officer and Chief Financial Officer, and Duncan McKechnie, Chief Commercial Officer. Given the January 1 transition by Charlie to the COO role solely, please note that this is his last quarterly earnings call. His successor, Jonathan Poole, our current SVP of Finance, will join us for our Q4 2026 call in February. 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 make 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, beta thalassemia, moderate to severe acute pain, and acromegaly, our pipeline, the recently completed acquisition of Crinetics Pharmaceuticals and the expected benefits of that transaction, 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 select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. I'll now turn the call over to Reshma.
Thanks, Susie. Good evening all, and thank you for joining us on the call today. I'm pleased to note that Vertex achieved another quarter of excellent commercial results and pipeline advancement. Third quarter total revenue grew 12% year-on-year. Revenue growth was nicely balanced, coming from both the U.S. and international, from CF, and from our two more recently launched medicines, CASGEVY and JOURNAVX, as well as a contribution from PALSONIFY for the month of September, post-close of the Crinetics acquisition. Rare endocrine is now our fourth commercial pillar, and with the PDUFA date later this month for povetacicept in IgA nephropathy, or IgAN, we plan to soon establish our fifth in renal. Before turning to the R&D update, I want to acknowledge Charlie's final and 31st earnings call as CFO. Charlie's leadership, integrity, judgment, and intellectual rigor are unparalleled.
He has deftly helped lead our transition from a CF-only company with $4 billion in revenue in 2019 to a company soon to be commercialized in five disease areas with more than triple the revenue, with our guidance for over $13 billion in 2026. I look forward to continuing to work with Charlie in his role as COO, driving forward the Crinetics integration and our key priorities as we grow and scale the company. I can think of no better successor to Charlie than Jonathan Poole, our Senior Vice President and current head of finance, who will take over as CFO January 1, 2027. Moving now to the R&D update for the quarter. I will cover four disease areas: CF, endocrinology, both rare endocrine disorders and type 1 diabetes, and renal in detail. First, let me start with quick highlights from four other programs.
In severe sickle cell disease and transfusion-dependent beta thalassemia, we were pleased to have recently received approval for CASGEVY in patients ages two to 11 in the U.S., U.A.E., Bahrain, as well as in patients ages five to 11 in the U.K. In pain, along with the strong growth in prescriptions, we are also seeing fast growth in the body of compelling JOURNAVX real-world data emerge, such as a recent paper detailing 80% or greater freedom from opioid use following total knee replacement when the pain management regimen included JOURNAVX. In chronic pain, both phase III studies in painful diabetic peripheral neuropathy remain on track to complete enrollment by the end of this year, and for us to be able to share results by mid-2027.
In myotonic dystrophy type 1, or DM1, we remain on track to share interim results from the GALILEO global phase I/II clinical trial of VX-670 before the end of the year. In generalized myasthenia gravis, we have completed enrollment of the ETNA phase II dose-ranging study of povetacicept and expect to share proof-of-concept data in the first half of 2027. Moving on to the more detailed R&D review, starting with cystic fibrosis. We see ALYFTREK as the most effective medicine approved for CF. With once-daily dosing, ALYFTREK can treat up to 95% of people with CF, and in our trials, more than 75% of ALY-treated patients ages 12 and older achieve sweat chloride levels in the range of CF carriers. That is to say, ALYFTREK-treated patients are achieving sweat chloride levels associated with no manifestation of CF disease nor reduced life expectancy.
On the regulatory front, we continue our work to expand to treating younger patients and have initiated global submissions for ALYFTREK approval in children ages two to five. Lastly, in CF, an update on our next-generation 3.0 correctors. We studied VX-828 as part of a triple combination in a cohort of eight people with CF and as a dual therapy in another cohort of eight. All 16 patients had F/MF mutations, which is a more challenging population to treat than patients with F/F mutations. In this F/MF population, the VX-828 dual combination did not alter sweat chloride relative to the TRIKAFTA baseline. In the triple combination versus a baseline on TRIKAFTA, VX-828 delivered a 6.6 mmol per liter reduction in sweat chloride at day 28, and a 9.4 mmol reduction through day 28. The VX-828 regimen is oral, once daily, with a good safety, tolerability, and DDI profile.
In short, these are excellent results. Given the very high bar set by ALYFTREK, we intend to wait for all the data from the NG 3.0 family of molecules before determining next steps, namely advancement into pivotal development. VX-581 and VX-272, the other NG 3.0 correctors, are currently in first-in-human studies, and the next-gen 4.0 molecules are in late preclinical development. Moving to our newest pillar, rare endocrinology. With the Crinetics acquisition now closed, PALSONIFY in acromegaly is our eighth commercialized medicine, and Duncan will provide details on the ongoing U.S. launch. On the R&D side, the most advanced molecule after PALSONIFY is atumelnant in congenital adrenal hyperplasia, or CAH, which has orphan drug designation in the U.S., E.U., and Japan, and where the phase III pivotal trial is well underway.
The primary efficacy endpoint for this phase III study is the proportion of patients achieving the combination of normalization of androgens and physiologic glucocorticoid dose levels. This is the true goal in CAH therapy, and it is what was demonstrated in the phase II trial. It is also what no other CAH medicine to date has attempted to achieve. In adult CAH, we are targeting completion of enrollment in the phase III study in Q1 2027. The study then calls for 32 weeks of dosing. In pediatric CAH, atumelnant is in a phase II dose-ranging study. Our goal is to rapidly advance the pediatric program into pivotal development following planned regulatory interactions. In addition, the adaptive phase II/III global study of atumelnant in ACTH-dependent Cushing's syndrome is already underway outside the U.S. and was recently granted orphan drug designation in the U.S.
We have planned engagements with the FDA to confirm their expectations for this program and look forward to updating you in the coming months. Let me now turn to T1D. After careful analysis, we have chosen to prioritize acceleration of VX-017 as our lead program. Recall, VX-017 is an allogeneic, off-the-shelf, glucose-responsive, insulin-producing, fully differentiated islet cell therapy. It has a similar target product profile to zimislecel, but is designed for people with all blood types. This doubles the eligible patient population to about 120,000 people. The potential to bring transformative benefit to even more patients is the key reason to focus on VX-017, given the resource intensity, complexity, and manufacturing demands of cell therapy programs. We have already begun dosing patients with VX-017 in a phase I/II study.
Our near-term goals are to demonstrate proof of concept and to scale up manufacturing, with the goal of moving to pivotal development next year. Finally, we continue to progress our serial innovation work in T1D, focused on improved immunosuppression and on generating hypoimmune islets, with the goal of making this potentially curative therapy available to even more people. Turning now to renal, where we have four programs in mid and late-stage development. Starting with pove and IgAN, we are both excited and ready for our PDUFA date on November 30th, just weeks away. Duncan will address our launch readiness. We just wrapped up a sparkling ASN annual meeting with the RAINIER phase III interim analysis presentation and publication in the New England Journal of Medicine, supporting what we believe is a differentiated, potentially best-in-class profile for pove in IgAN.
Simply put, pove will offer a trifecta of excellence in efficacy, tolerability, and patient-centric administration features. I will focus tonight just on the patient-centric features. The commercial presentation of pove is clearly differentiated, with a small volume, 0.46 mils, once every four weeks, subcutaneously dosed via auto-injector at home. On this point, this advantage is reflected in the poster presented by If et al. at the recent ASN of a qualitative survey study of about 25 adults with IgAN in the U.S., that revealed 96% of patients preferred an auto-injector relative to injection via a prefilled syringe, and 80% preferred dosing every four weeks versus weekly. Our ambition is to launch pove globally. To that end, we have already completed our filing for potential accelerated approval in the Kingdom of Saudi Arabia, where it has been granted breakthrough status. We estimate KSA represents an incremental 7,000-patient opportunity.
We are planning forward for our regulatory submissions in other regions, including Europe and Asia, when the study completes and the two-year eGFR data are available. On pove in membranous nephropathy, our OLYMPUS phase II/III pivotal trial is ongoing, with phase III enrollment and dosing well underway at the selected dose of 80 mg subcutaneously every four weeks. Recall, this study has a 104-week endpoint. On inaxaplin in AMKD, we have two pieces of news since our last earnings call. First, to recap the exciting results from the AMPLIFIED study. In cohort one of patients with AMKD and modest proteinuria, treatment with inaxaplin on top of optimized standard of care led to a 42.7% reduction in urine albumin-to-creatinine ratio, or UACR, at week 13 compared to baseline, with the UPCR down 44.7%.
This is remarkably consistent with the treatment effect previously shared in the phase II data in AMKD published in the New England Journal of Medicine. In cohort two of people with AMKD and type 2 diabetes, treatment with inaxaplin led to a 17.3% reduction in UACR and a 25.4% reduction in UPCR at week 13. Of note, the majority of patients in both cohorts did not have a diagnosis of FSGS. Inaxaplin was generally safe and well-tolerated with no serious adverse events related to inaxaplin. All adverse events were mild or moderate in severity. We look forward to discussing these results with regulators in the context of the AMPLITUDE study next year. The second key milestone was that we completed full enrollment in the pivotal AMPLITUDE phase II/III trial, and we are fully on track to share the results from the interim analysis of AMPLITUDE early next year.
If positive, this interim analysis will support potential accelerated approval in the U.S. Rounding out on renal enrollment in the VX-407-AGLOW phase II study in ADPKD completed enrollment, and we are now on track for study readout next year. With that, I will turn the call over to Duncan for a commercial update.
Thanks very much, Reshma. Our commercial story continues to be one of excellence in launch execution across CF, heme, pain, and most recently, rare endocrinology. Through the first nine months of the year, our ongoing launches of ALYFTREK, CASGEVY, and JOURNAVX have generated over $2 billion in revenue, led by over $1.7 billion in ALYFTREK sales and more than $350 million in combined CASGEVY and JOURNAVX sales. To give you a brief overview and put quarter three revenue, patient, and prescription growth in context, in CF, we delivered $3.3 billion in revenue with strong switching to ALYFTREK and over 18,000 patients benefiting from ALYFTREK around the world. In heme, CASGEVY achieved $99 million in quarterly revenue with approximately 200 infusions completed since launch and a fourth consecutive quarter with more than 100 patient initiations.
In moderate to severe acute pain, JOURNAVX reported over 750,000 prescriptions and $58 million in revenue. More than 1.6 million patients have now been treated with JOURNAVX in the U.S., and JOURNAVX is now the number one prescribed branded oral analgesic in the U.S. In rare endocrinology, PALSONIFY contributed $10 million in revenue for the month of September following the close of the acquisition. For the full third quarter, PALSONIFY revenue was approximately $24 million. I will now cover these disease areas in more detail, starting with CF. The Q3 $3.3 billion in global CF revenue represents 8% year-over-year growth. Global growth overall was led by ALYFTREK, which delivered $706 million in worldwide sales in Q3. In the U.S., ALYFTREK sales year-to-date have now surpassed $1 billion.
In both the U.S. and outside the U.S., ALYFTREK sales continue to build primarily from patients switching from TRIKAFTA and new patients with rare mutations. Outside the U.S., we now have ALYFTREK reimbursement in 31 countries. Looking ahead, our CF growth drivers remain consistent and clear. Label expansions in rare mutations, penetration into younger age groups, additional geographies, and by the underlying survival benefit of patients on CFTR modulators. Turning to CASGEVY in severe sickle cell disease and transfusion-dependent beta thalassemia, where $99 million in Q3 revenue reflects 30% sequential growth. We have infused twice as many patients in the first nine months of 2026 as all of 2025. Since launch, we have initiated over 750 patients worldwide on CASGEVY, and with four consecutive quarters of initiation numbers exceeding 100 patients, we now have patients at all stages of the treatment journey.
We have also continued to enhance the patient journey, shortening the overall time from referral to infusion and decreased the number of mobilizations. We have excellent visibility into the number of infusions, which is when we recognize revenue, for the rest of this year as well as into 2027. That said, infusion timing reflects patient choice with some expected seasonality in quarter four, so I would encourage you to focus on the strong annual performance rather than any single quarter. CASGEVY will contribute meaningfully to our greater than $500 million non-CF revenue goal this year and is on its way to achieving its own blockbuster potential.
With JOURNAVX in moderate to severe acute pain, we are building a franchise for the long term and are focused on the following critical markers of success: broad payer coverage, prescription growth, breadth and depth of prescribing, the addition of JOURNAVX to hospital pathways, and revenue. These are the building blocks of a sustainable, long-term, multi-billion dollar pain business. Let me start with prescriptions because that's the best indicator of underlying physician and patient demand. In the third quarter, JOURNAVX prescriptions totaled over 750,000, up more than 40% sequentially from quarter two 2026. At the end of quarter three 2026, we are well on our way to achieving our guidance of more than three times the number of prescriptions in 2026 versus 2025. Prescriptions continue to split roughly 50/50 between hospital and retail channels.
Third quarter JOURNAVX revenue of $58 million, up 18% quarter-over-quarter, reflects continued high gross-to-net with the patient support savings program remaining on. Let me walk you through the revenue growth dynamics. A significant driver of gross-to-net is continued utilization of our patient support program. We have chosen to leave the PSP in place and extend it into 2027 so that people who are prescribed JOURNAVX, but whose plans do not yet cover it, can receive the therapy. Accordingly, when we sunset the PSP mid-next year, we continue to expect gross-to-net to stabilize at a level close to other mass market brands in the range of 50%-60%. In addition, in quarter three, gross-to-net and revenue were both affected by the one-time impact of securing broad Medicare Part D access in July.
As that access came online, previously uncontracted prescriptions shifted to contracted, rebated pricing, resulting in a one-time reset in net revenue. This is in line with our overall strategy to secure broad, sustained access across commercial and government plans so we can successfully convert physician practices to JOURNAVX for all their patients. This quarter marks our first opportunity to speak about PALSONIFY as part of Vertex following the deal close at the beginning of September, and we are pleased with the launch trajectory to date. Let me briefly describe the disease, the unmet need, and frame the key metrics at this stage in the launch. Acromegaly is a symptomatic disease that affects approximately 20,000 patients in the U.S. and a similar number in the five largest European markets, plus Japan.
Although surgery is the first line of treatment, only 40%-50% of people achieve durable remission, so the majority of patients need lifelong treatment. In the U.S., they're treated by approximately 3,000 endocrinologists. Until the launch of PALSONIFY, the main option has been monthly injections with somatostatin receptor ligands, or SRLs, delivered using large gauge needles. These treatments have three limitations. Firstly, they can cause painful injection site reactions at the beginning of the month. Secondly, their efficacy tends to taper off in the latter part of the month, leading to breakthrough symptoms such as joint pain, swelling, and fatigue. Thirdly, the recurring logistical challenges and burden of chronic depot therapy. The unmet need is therefore significant.
The ideal treatment for patients would be a highly effective, easy to take, well-tolerated oral medicine that provides sustained control of the disease, and one that has a broad indication for both naive and switch patients. This is the exact profile of PALSONIFY as the first and only once-daily oral SST2 selective agonist. As we integrate the Crinetics business, there are three areas of focus for the success of PALSONIFY, building on the excellent base of 80% reimbursed coverage. Firstly, build a broad base of repeat HCP writers for PALSONIFY. Secondly, drive growth in both the new and switch settings. Thirdly, deliver on our revenue goals. We are very pleased with the progress that the Crinetics team, and now the integrated Vertex team, are making against these goals.
Approximately 500 endocrinologists are writing PALSONIFY prescriptions, and there was a significant increase in the number of repeat writers in quarter three compared to the first half of 2026. PALSONIFY now has the leading brand share at over 40% among patients initiating or switching therapy. Lastly, we see continued strong growth in patient enrollments, leading to $10 million in revenue in September, $24 million in quarter three, and approximately $60 million for the first three quarters of 2026. Our focus is on excellence in execution to further accelerate the U.S. performance and prepare for international launches. Let me conclude with an update on our commercial readiness for pove in IgAN. Reshma 's already highlighted the trifecta of efficacy, safety, and patient-centric dosing of povetacicept.
Put simply, with the PDUFA date just days away now, we are 100% ready, and we are incredibly excited to bring pove to patients with IgAN. Our field team is fully hired, trained, and ready to go. Over 90% of the team have deep nephrology experience, and many of them have been engaging with nephrologists in IgAN disease educational activities since early this year. We also know that the patient experience is of supreme importance in biologics, and IgAN is no different. Based on years of providing comprehensive patient support to our CF patients, we have built a people-based and tech-enabled patient support program to facilitate patients to get their pove as fast and as easily as possible. In addition, our payer conversations continue to proceed very well.
Payers understand the significant unmet need, are very familiar with pove's clinical profile, and have responded positively to its differentiation and overall value proposition. We have had many engagements with nephrologists over the last few months, including at the excellent ASN Kidney Week meeting last month. They are looking for treatments that meaningfully and rapidly reduce proteinuria, have a favorable tolerability profile, and offer convenient dosing alongside a seamless treatment experience built on access and patient support. Our discussions with physicians over the last quarter have increasingly revealed the importance of dosing frequency, dose volume and viscosity, and method of administration. We continue to believe that, in addition to an excellent efficacy and safety profile, the low-dose, easy-to-use, at-home auto-injector will be an important differentiator for pove. I will now turn the call over to Charlie.
Thanks, Duncan. Vertex delivered strong third quarter results with total revenue growth of 12% year-over-year, reflecting revenue growth of 10% in the U.S. and 16% internationally. Results include an approximate 1 percentage point favorable impact from foreign exchange and $10 million of revenue from Crinetics following the close of the transaction. Globally, CF revenue grew 8% year-over-year with 5% growth in the U.S. and 12% outside the U.S., or 10% on a constant currency basis. On a non-GAAP basis, third quarter gross margin was 85.6%. On a GAAP basis, gross margin of 84.7% includes intangible asset and inventory step-up amortization resulting from the purchase accounting for the Crinetics acquisition. Turning to Q3 operating expenses, which include approximately $60 million of Crinetics operating and integration-related expenses in September. Third quarter non-GAAP R&D expense was $936 million, an increase of $74 million, or 9% year-over-year.
Approximately $30 million of the increase was attributable to Crinetics. Non-GAAP SG&A expense was $556 million, an increase of $187 million, or 51% year-over-year. Nearly 80% of the incremental spend was to enhance our commercial capabilities. Within the increase in commercial spend, the biggest drivers were pove and renal and JOURNAVX, and then PALSONIFY. Approximately $30 million of the incremental SG&A spend is related to Crinetics. We also recorded $41 million in acquired IPR&D expense in the quarter, including a $28 million upfront payment for new business development agreement with AbCellera. During Q3, we incurred approximately $50 million in non-operating costs associated with the Crinetics transaction financing, including higher interest expense due to the new bank loans and other related costs.
In addition, interest income was $15 million lower than it otherwise would have been as a result of lower cash balances after the acquisition. Our third quarter non-GAAP effective tax rate was 18%, up approximately 40 basis points compared to Q3 2025. Third quarter 2026 non-GAAP net income was $1.21 billion, and third quarter 2026 non-GAAP earnings per share were $4.76. Turning to the balance sheet. We ended the quarter with approximately $9.8 billion in cash and investments following the close of the Crinetics acquisition. Note that we raised $4.5 billion of term loans to fund a portion of the acquisition, currently bearing interest at approximately 4.8%. Even with a busy period for BD, we also deployed approximately $120 million during the quarter to repurchase roughly 250,000 shares. Year-to-date, we have repurchased approximately 2 million shares for $921 million.
Our strategy for capital deployment remains unchanged, with the priority on investing in innovation, including external innovation, and an additional allocation for share repurchases. Now turning to guidance. For total revenue guidance, we are raising our prior range of $13.1 billion-$13.2 billion to a revised range of $13.15 billion-$13.25 billion. The increase reflects the addition of Crinetics, which we expect to contribute $40 million-$50 million to full-year 2026 revenue. The underlying drivers of our revenue outlook are unchanged. Continued CF performance, including the ongoing ALYFTREK launch, together with growing contributions from heme, pain, and now rare endocrinology. We continue to expect more than $500 million in revenue from CASGEVY and JOURNAVX, with additional contribution from four months of PALSONIFY. Consistent with prior guidance, our outlook continues to include an expected full-year benefit from foreign exchange of roughly 150 basis points.
Given our visibility into the drivers of our business, and with just two months of the year remaining, we have a high degree of certainty in our revenue guidance range. We continue to expect full-year gross margin slightly below 86%. On operating expenses, we are revising our prior combined non-GAAP operating expense guidance of $5.65 billion-$5.75 billion to a revised estimate of approximately $6 billion. The standalone Vertex business remains at the high end of our prior range, and the increase in guidance is attributable to the inclusion of approximately $250 million of Crinetics operating expenses and integration-related costs. This updated operating expense guidance reflects continued investment in our late-stage clinical pipeline and the commercial infrastructure supporting our launches and revenue diversification.
For the full year of 2026, we expect total non-operating costs of approximately $105 million related to the financing of Crinetics, including higher interest expense and other related costs. In addition, interest income is projected to be approximately $60 million lower than it otherwise would have been as a result of lower cash balances after the acquisition. Please see slide 23 of the earnings presentation for full details on the impact of Crinetics upon Q3 results and full-year 2026 guidance. We continue to expect our full-year non-GAAP effective tax rate to be between 19.5%-20.5%. In summary, Vertex delivered strong third quarter results with 12% revenue growth and increasing revenue diversification beyond our leading CF business. The integration of Crinetics is well underway, and with the strong commitment of the Crinetics team, we are accelerating commercial, clinical, and valuable preclinical programs.
Our continued leadership in CF, the increasing contribution of CASGEVY and JOURNAVX, momentum in rare endocrinology, and with pove on the doorstep of launch, we are well-positioned for continued attractive growth and profitability for years to come. We look forward to updating you on our continued progress across multiple disease areas with key upcoming milestones detailed on slide 24. I'll now ask Susie to begin the Q&A period.
Thanks, Charlie. Chuck, can you please open it up to questions?
Will do. We will now begin the question-and-answer session. To ask a question, you may press star then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. Today's first question will come from Cory Kasimov with Evercore. Please go ahead.
Great. Good afternoon, guys. Thanks for taking the question. Charlie, congrats on the new role. It's very well deserved. On pove, I wanted to ask about the recent citizen petition that raises the question of whether RAINIER's IgG monitoring and dose hold rules need to be carried into clinical practice. I guess, how frequently do patients actually fall below the IgG threshold or require treatment interruptions, and what do those data support or potentially indicate in terms of monitoring requirements in the commercial label? Thank you.
Hey, Cory, it's Reshma. Let me take that one. With regard to the citizens petition, there are about 200 or so of these that happen every year. About 80% or so of them are from named individuals or companies, and about 20% of them are anonymous. This one, as you know, was anonymous. If the question behind your question is how do we feel about the label, where are our conversations with the agency, everything that you would expect to be happening with the FDA is happening, and we're really looking forward to our PDUFA date. On the specific of how can we think about what values IgG levels can achieve, the bottom line is before this wave of B-cell modulating therapies, the way a lot of folks thought about IgG levels were from congenital diseases of immunologic basis, and that's where a lot of these values came from.
In this day and age, what numbers could IgG levels come to? I think the best examples to look at are the clinical trials. In our example, we studied over 500 people. We measured every four weeks. If the IgG was going to go down, we certainly would have found it because we looked, and we considered a single excursion to be worth noting. I would say the most important point to think about is infections. On that note, there are no opportunistic infections, as you know, in the pove program. The SAEs of infection are balanced. It's exactly 0.5% in pove and 0.5% in the placebo group, and the rest of the infections are mild to moderate. You put this together, and you can see why we're so excited about the PDUFA date.
That's very helpful, Reshma. I appreciate it.
You bet.
The next question will come from Jessica Fye with JPMorgan. Please go ahead.
Hey, guys. Good afternoon. Thanks for taking my question. Can you help set expectations for what would represent a win coming out of the AMPLITUDE on both proteinuria and eGFR? Thank you.
Yeah. On the AMPLITUDE study, that is the one that is completed full enrollment, and it completed the interim analysis cohort enrollment last year, setting us up for the interim analysis early in 2027. A win would be a statistically significant result on the eGFR slope. I say that because, of course, we are going to measure proteinuria and eGFR, but our agreement with the FDA on what would be acceptable for accelerated approval is eGFR. That is where they are on the disease AMKD. I expect the phase III to look a whole hell of a lot like the phase II in terms of proteinuria, but the key element here is eGFR, and it is a statistically significant difference between the inaxaplin-treated group and the placebo on top of standard of care.
I will not share with you the power analysis and such, but that is what we are looking for because eGFR is what the accelerated approval agreement with the FDA is based on.
The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.
Thank you. Good afternoon. Just a follow-up on Cory and Jess's questions. With regard to pove, can you speak to your comfort and history with the manufacturer? With regard to inaxaplin, can you just walk through further for the reasons for confidence into the 48-week interim data early next year, specifically how we get comfortable thinking about the separation between drug and placebo at that time point, and just the read-through from some of the data sets that you have generated to date?
You bet. Salveen, let's do pove first, and then let's get to inaxaplin. On pove, the specific question you had is, how is it going with manufacturing? We've been with the same manufacturer all through phase III and through to the lead up for our PDUFA date. We feel really good about where we are. As you know, in addition to the review of safety and efficacy clin pharm, there's also review of the CMC manufacturing package, and all of the interactions that you would expect us to be having with the FDA are occurring. Overall, I feel very good about where we are.
Moving then to inaxaplin, but staying within renal, one way to think about the inaxaplin program and GFR, because to date, in both the original phase IIa study that we published in the New England, that was the one that had the 47.6% reduction in proteinuria, and the more recent AMPLIFIED results, which were from the more cohort one, the more modest proteinuria, that one was a 44.7% reduction in UPCR. I think the best way to think about that in terms of GFR, which is the endpoint we've agreed upon with FDA, is in these two ways. One, substantial reductions in proteinuria, in glomerular proteinuric kidney disease, have time and again, been linked to improvements in GFR. That's one general statement. Maybe a second way to look at this is talking about IgA nephropathy.
We used to talk about IgA nephropathy as a fairly indolent disease, but as you can see from the placebo arm of IgAN trials, those patients are losing about 5 ccs per mil per year, right? AMKD is a rapidly progressive disease, so more than that, 6 ccs, 7 ccs, 8 ccs per mil per year. The FDA themselves have said in IgAN that they are going to be comfortable accepting one-year GFR differences. When I put that all together, it adds to my confidence level of what we're going to see with AMPLITUDE. But I'd say those are two ways to think about inaxaplin in AMKD.
The next question will come from Geoff Meacham with Citi. Please go ahead.
Guys, thanks for the question. I also want to offer up some congrats to Charlie. I just have a couple of quick ones. On pove, Reshma, you mentioned data should continue to mature post-approval, including the two-year eGFR data. I guess the question is, how much of a factor do you think this will play in your competitive position ultimately? I wasn't sure if you looked at this as maybe a tipping point in terms of what the payer and physician community is going to look at. The second one, real quick on pain. I know, looks like the trials are continuing to enroll mid-year data next year. Maybe just at a high level, give us some context for kind of what you think at this point a win would look like, kind of in DPN for suzetrigine. Thank you.
Yeah. Let's do DPN first, and then I'll split the pove question with Duncan. On DPN, we are fully on track to complete enrollment in both the two phase III VX-548 or suzetrigine trials, and on track to complete the enrollment in the VX-993 DPN trial. That would put us for results somewhere mid of next year. A win would be the suzetrigine arm beating placebo treatment in the two DPN studies. In one of the studies, we have a gabapentin arm to give us context, but a win would be beating placebo. That's the regulatory enabling endpoint. On pove, I'll just give you a top-line comment. We're going to go to the two-year eGFR full completion of the trial as originally designed, because our ambition is to launch pove around the globe. The FDA has said that they're comfortable with one-year GFR, but other regulators have different expectations.
That's why we're going to full completion, and I do think the results are fully mature at that point, and that's another advantage for all of us to have fully mature two-year data. Duncan, do you want to talk a little bit about differentiation, GFR, and the pove launch in the U.S.?
Indeed. Hi, Geoff. So we've thought about this question quite a lot, as you can imagine. We've discussed it with nephrologists, and I would encourage you to think about it this way. Nephrologists already had a very strong level of conviction in the connection between proteinuria and eGFR, especially in IgAN. I would say the data that has come out from the APRIL/BAFF inhibitors over the last couple of months has only served to strengthen that conviction. So we believe, on the basis of that pove continues to have best-in-class potential through its excellent efficacy profile, impact on proteinuria, hematuria, Gd-IgA1 in just 36 weeks, as well as being well tolerated, and as Reshma alluded to in her prepared remarks, an incredible profile from a patient point of view with a low volume, low viscosity, at-home, once-a-month auto-injector.
When we've been engaging with nephrologists on this topic, which we've done a lot over the last couple of months, including, of course, at ASN Kidney Week, they're very excited in the profile of povetacicept and looking forward to trying it post-approval. We're very comfortable with where we're at.
Great. Thank you.
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. We're seeing some good traction with JOURNAVX, but you're keeping the PSP on through the rest of the year, and now pointing to gross-to-net normalization around mid-2027. Can you help us think about kind of the bridge between prescription growth and eventually reported revenue as the PSP rolls off, and whether you expect revenue growth to reflect as normalization occurs? Thank you so much.
Sure thing. Duncan, maybe you could take that one for us?
Yeah. Just to step back a little bit, Evan, just to make a couple of points, and then I will dive into the PSP program, gross-to-net, and revenue. We are very pleased with the performance of JOURNAVX. This is hard work. We are changing decades of ingrained prescribing behavior and seeking to convert practices over to the use of JOURNAVX. So, 750,000 prescriptions in one quarter, 1.6 million Americans treated, the number one oral branded analgesic, would all indicate that we are making great progress.
As far as the gross-to-net is concerned, I would make the comment that obviously negotiated agreements to secure access for the full population with payers are important to the long-term sustainable growth of the product. And so, it is important that we are able to get those plans in place. For example, the two Medicare Part D plans that came in place in July this year.
At this point, we have about 82% managed lives covered, but that does mean that there are patients who are yet to be covered, and we want to make sure that those patients have a great experience. So, we are taking the strategic decision to keep the PSP program switched on. We will sunset it by the middle of 2027, and at that point, you can expect, as we have said before, I think, gross-to-net to stabilize at the sort of normal oral branded level of 50%-60%, and revenue growth to grow commensurately.
Great. Thank you.
The next question will come from Brian Abrahams with RBC Capital Markets. Please go ahead.
Hey, good afternoon. Thanks for taking our question, and congrats to Charlie from us as well. Just on the pove launch, I am just wondering, what is the right way to think about how initial uptake might balance both the growing awareness and enthusiasm versus the potential that a lot of nephrotic patients may have already come onto therapy with a drug in the class? Then just secondarily, ALYFTREK conversion looks like it has been picking up steam the last few quarters. I am just wondering the right way to think about the continued trajectory there. Thanks.
You bet. Brian, I am going to ask Duncan to comment on both. Let us do your second question first, and then we will go back to pove.
Yeah, Brian. ALYFTREK is being driven predominantly by new reimbursement agreements, obviously outside the U.S. We have had another slew of those agreements in quarter three. It is also being driven by the new rare mutation indications, which obviously offer a de novo patient population to the CFTR modulator class writ large in some cases, and certainly ALY specifically. Those are essentially the two main drivers of ALY growth over the last couple of months, which we are particularly happy with. In terms of pove and uptake, a couple of comments there. Firstly, as with say, CASGEVY and JOURNAVX, we will be providing you with the metrics that we think are most useful to look at in our earnings call at the beginning of 2027. I would say you make a great point.
The physician enthusiasm for the new BAFF inhibitor or BAFF/APRIL inhibitors has been incredible, and that is certainly driving success in the market. The numbers are a little bit unclear at this point, but let's say, sorry, not pove, Voyxact and Trutakna close the year with about 3,000 patients on medicine, which is probably roughly where they're going to end up. That leaves us with 163,000 yet to go. So, with the level of nephrology enthusiasm for advanced therapy and treating early in the disease, for the nephrologist enthusiasm for povetacicept specifically, both its clinical profile and the patient experience, and that vast number of patients who still need treatment, remember, 75% of patients with IgAN have a proteinuria above 1 gram, we think there's a huge opportunity here.
Thanks.
The next question will come from Michael Yee with UBS. Please go ahead.
Hey, guys. Mike Yee at UBS. Two questions on inaxaplin. Reshma, you made some great comments about some of the previous data we already know in phase II. I guess one new thing that has come out is obviously some of the IgAN data that shows significant eGFR benefits even at nine months on just a couple mil per minute deltas and similar proteinuria reductions you're seeing with the inaxaplin. So my question is, given the significant benefits you're seeing and given a 12-month time point, our math suggests that a 2 mil per minute benefit should be stat sig. Just wanted to understand your view about the IgAN data and how that translates here given the deltas you see. The second question is PARASOL, I think the working group has been trying to push proteinuria as an endpoint.
Was there any color that you got out of their working group and how that may be an accelerated endpoint? Thank you.
Yeah. Mike, first let's do PARASOL. PARASOL is a very important and influential group. They've come together multiple times over time and worked with the FDA to evolve endpoints. In FSGS and their work with the agency, I do think helped to move the agency to a protein-based endpoint. We are members of the broader PARASOL community. The thing that I'm paying most attention to is the community clearly seem interested in moving to a proteinuria endpoint for AMKD. At the same time, the FDA and our agreement is indeed with GFR. Given that, we're focused on GFR. On your math for GFR, I won't argue with your math. Seems reasonable enough.
The thing to say, Mike, is I think what we're learning from the example of IgA nephropathy, because there's so many different classes now that have been used in IgAN, it matters not only that you get the proteinuria down, it matters how you get the proteinuria down. Decreasing proteinuria by way of APRIL/BAFF inhibition has more beneficial impact on GFR than perhaps other methods of reducing proteinuria. The thing that I take away from it is targeting the underlying cause of disease is always a better move than going upstream or downstream. It's actually another reason I have confidence in AMPLITUDE, because it's another example of a proteinuric kidney disease where we're targeting the underlying biology.
I think both in the dimension of quantity of protein reduction, but also the how, the quality of protein reduction in IgAN APRIL/BAFF upstream in the four-hit hypothesis has beneficial effect. I think that's what we're going to see with AMPLITUDE, because inaxaplin is equally targeting that underlying cause.
Perfect. Thank you.
The next question will come from Tazeen Ahmad with Bank of America. Please go ahead.
Hi. Thanks for taking my question. Let's go back to the CF franchise for a second. Can you just give us your thoughts, Reshma, on how the data for 828 compare to your expectations, just based on the preclinical data that you looked at? Then, if you think about the other CFTR modulators that you have, where do you think is the biggest unmet need at this point, and where is the most room for improvement over what you have with ALYFTREK? Thanks.
You ask such a good question, Tazeen, around what is the unmet need? Let me just take a step back and tell you about 828 and then where we're going. The 828, if you look, and I think we provided it on the slide, if you look at the range of outcomes, the decrease in sweat chloride, certainly the range of outcomes covers our expectations, on sweat chloride reduction, that is. But it is obviously a small study. It's N equals eight. The reason we are not advancing 828 in and of itself, although the results are excellent, if you were at a different company, you would just be over the moon with results like this, right? At 28 days, we're more than 6 points of sweat chloride improvement, and through 28 days, we're touching 10 points of sweat chloride.
Those are good numbers, especially when you take into account it's versus TRIKAFTA. This is not versus a placebo baseline. So, those are excellent results. It's once a day, good DDI, it's favorable safety. The thing for us is we have three medicines in this NG 3.0 family, and we want to pick the best one. We're going to have the results from the other two medicines, [581] and 272, next year. When we have all of those results, we'll pick the one that's best suited to move forward. If you say, "What is the residual unmet need?" I think, Tazeen, that's a very, very hard question to answer, because when we look at the data with ALYFTREK, we are almost superimposable onto the Gaussian distribution of sweat chloride of normal people.
So, really, it is a matter of now not almost being superimposable, but being fully superimposable. So, a little bit more sweat chloride, more patients getting to less than 30. That is what we are looking for.
The next question will come from Akash Tewari with Jefferies. Please go ahead.
Hey, thanks so much. Can you talk a bit more about your decision to file on two-year eGFR data? I know you were going to make a decision, I was anticipating sometime next year. It sounds like you are making the call now. Just from a statistical perspective, if a patient on placebo starts another APRIL/BAFF drug during that one- to two-year window, how are they actually accounted for statistically? Are they included in the eGFR final analysis? Thank you.
Yeah. I just want to make sure I understood your question about the decision for two years. I think you were saying, why continue two-year GFR? Did I understand correctly?
Right. Why make the call now? I know you had previously talked about regulators in a global setting wanting two-year data, but we already knew that. So, what led to the decision to go forward with two-year today?
Yeah. Obviously, we can decide if we wish to cut the data and do a one-year cut. We could do that at any time. Our decision to indicate that we are going to continue to two years is because people have asked us the question, including our clinical trial sites, about what our goal is and how we see this. So, to allow preparation for everyone, we've let folks know that our intention is, and our ambition is global filings, and that's going to require two-year GFR because ex-U.S., not all the regulators have agreed to one-year GFR. So, that's the rationale for that. With regard to how our patients manage, there are clear rules in the statistical analysis plan that not only the FDA, but global regulators have set forward for management of dropouts, missing data, and how to handle if patients are no longer in the study.
So, we're simply going to follow the rules that are very clearly laid out. I won't go through all of them in excruciating detail, but they are in excruciating detail.
The next question will come from Terence Flynn with Morgan Stanley. Please go ahead.
Great. Thanks so much for taking the question. I guess one more on inaxaplin. I was just wondering, on the AMPLIFIED data, I know there has been some questions about the breadth of response in the moderate proteinuria cohort. So, just maybe, Reshma, you could provide a little bit more detail. I just want to ensure that there wasn't a small subset of FSGS patients that was driving that proteinuria reduction that was broader based. Maybe you could talk about the response rate across the population in that cohort one. Thank you.
Yeah. So, Terence, on AMPLIFIED and cohort one, that, let's call it the modest proteinuria group, because this was the 0.3 to 0.7 UPCR proteinuria cohort, the majority of patients did not have FSGS. So, they didn't have a biopsy and they didn't have FSGS, which you would expect because their proteinuria is modest. You are correct. The response, therefore, was not driven by an FSGS cohort because there weren't many of them. Most people in the study were non-FSGS patients.
One more question, please, Chuck.
The next question will come from Mohit Bansal with Wells Fargo. Please go ahead.
Great. Thank you very much for taking my question and congrats on all the progress. My question is kind of circling back to pove manufacturing, and one concern is around the potential use of continuous manufacturing in this process, which is relatively new for biologics at this point. Should we worry about it at all, or do you think FDA has been involved enough from the beginning here for us to feel comfortable about this? Thank you.
Hi, Mohit. On whether the agency has been involved, yes, the agency has been involved, and we're now coming towards the end of the process, right? We're at the point where all data has been submitted. There's an entire module on CMC and manufacturing, and you know we filed towards the end of March of this year, so they've had all that data now for a long time. All of the discussions that you expect us to be having, we're having. If you asked me if I was feeling good about the filing, all included, including manufacturing, I'd say yes, I feel good about the filing.
Thank you.
You bet.
Chuck, could you please wrap us up?
Will do. This will conclude our question and answer session, as well as our conference call for today. A replay will be available shortly after the call concludes by dialing 1-855-669-9658 or 1-412-317-0088 using replay access code 10208189. Thank you for your attendance today. You may now disconnect.