Vertex Pharmaceuticals Q3 2026 Earnings Call Transcript

Vertex Pharmaceuticals (NASDAQ:VRTX) reported third-quarter financial results on Monday. The transcript from the company’s third-quarter earnings call has been provided below.

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Summary

Vertex Pharmaceuticals reported 12% year-over-year revenue growth for Q3 2026, with significant contributions from the US and international markets.

The company has successfully expanded its commercial pillars, notably with the acquisition of Kinetics Pharmaceuticals, and is on track to establish a fifth pillar in renal with the upcoming PDUFA date for povitazept.

Vertex’s pipeline continues to advance, with key updates including approvals for Casgevy in younger populations and ongoing phase 3 studies in various disease areas.

Commercially, Aliftrek and other recent launches, including Casgevy and Journavix, generated substantial revenue, contributing over $2 billion in the first nine months of the year.

The company raised its full-year revenue guidance to a range of $13.15 to $13.25 billion, reflecting strong performance across its portfolio, including new contributions from Kinetics.

Management expressed confidence in the manufacturing and regulatory processes, particularly for upcoming launches like POVI, and highlighted strategic focus areas, including expanding patient access and maintaining leadership in cystic fibrosis treatments.

Full Transcript

OPERATOR

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 the 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 touchtone phone, and 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.

Susie Lisa (Senior Vice President, Investor Relations)

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 and 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 Kinetics 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.

Reshma Kewalramani (CEO and President)

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 US and international, from CF and from our two more recently launched medicines, Casgevy and Journavix, 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 povitazept in immunoglobulin A 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 SVP 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’ll cover four disease areas: CF, endocrinology—both rare endocrine disorders and type 1 diabetes—and renal in detail. But 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 2 to 11 in the US, UAE, Bahrain, as well as patients ages 5 to 11 in the UK.

Along with the strong growth in prescriptions, we’re also seeing fast growth in a body of compelling Journavix 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 Journavix. In chronic pain, both phase 3 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 1/2 clinical trial of VX670 before the end of the year. Adding generalized myasthenia gravis, we have completed enrollment of the Aetna phase 2 dose-ranging study, POVITASTASEPT, 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 Aliftrek as the most effective medicine approved for CF. With once-daily dosing, Aliftrek can treat up to 95% of people with CF, and in our trials more than 75% of Aliftrek-treated patients ages 12 and older achieved sweat chloride levels in the range of CF carriers. That is to say, Aliftrek-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 Aliftrek approval in children ages 2 to 5. Lastly, in CF, an update on our next-generation 3.0 correctors. We studied VX828 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 VX828 dual combination did not alter sweat chloride relative to the Trikafta baseline. In the triple combination versus a baseline on Trikafta, VX828 delivered a 6.6 millimole per liter reduction in sweat chloride at day 28 and a 9.4 millimole reduction through day 28.

The VX828 regimen is oral once daily, with a good safety, tolerability, and DDI profile. In short, these are excellent results. However, given the very high bar set by Aliftrek, we intend to wait for all the data from the Next Gen 3.0 family of molecules before determining next steps, namely advancement into pivotal development. VX581 and VX272, the other Next Gen 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 US launch. On the R&D side, the most advanced molecule after Palsonify is atromelnant in congenital adrenal hyperplasia, or CAH, which has orphan drug designation in the US, EU, and Japan and where the phase 3 pivotal trial is well underway. The primary efficacy endpoint for this phase 3 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 2 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 3 study in Q1 2027. The study then calls for 32 weeks of dosing. In pediatric CAH, atumelnent is in a phase 2 dose-ranging study. Our goal is to rapidly advance the pediatric program into pivotal development following planned regulatory interactions.

In addition, the adaptive phase 2/3 global study of atumelnant in ACTH-dependent Cushing’s syndrome is already underway outside the US and was recently granted orphan drug designation in the US. 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 VX017 as our lead program. Recall, VX017 is an allogeneic, off-the-shelf, glucose-responsive, insulin-producing, fully differentiated islet cell therapy. It has a similar target product profile to Zamylacel 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 VX017, given the resource intensity, complexity, and manufacturing demands of cell therapy programs.

We have already begun dosing patients with VX017 in a phase 1/2 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 POVI in IGAN. We are both excited and ready for our PDUFA date on November 30, just weeks away. Duncan will address our launch readiness. We just wrapped up a sparkling ASN annual meeting, with the Rainier phase 3 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 POVI in IGAN.

Simply put, POVI will offer a trifecta of excellence in efficacy, tolerability, and patient-centric administration features. I’ll focus tonight just on the patient-centric features. The commercial presentation of POVI is clearly differentiated, with a small volume 0.46 mL once every four weeks subcutaneously, dosed via autoinjector 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 US that revealed 96% of patients preferred an autoinjector relative to injection via a prefilled syringe and 80% preferred dosing every four weeks versus weekly. Our ambition is to launch POVI 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, and 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 POVI in membranous nephropathy, our Olympus phase 2/3 pivotal trial is ongoing, with phase 3 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 1 of patients with AMKD and modest proteinuria, treatment with inaxaplin on top of optimal 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 2 data in AMKD published in the New England Journal of Medicine. In Cohort 2 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 2/3 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 VX407AGLO phase 2 study in ADPKD completed enrollment, and we are now on track for study readout next year. With that, I’ll turn the call over to Duncan for a commercial update.

Duncan McKechnie (EVP, Chief Commercial Officer)

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 Aliftrek, Casgevy and Genavix have generated over $2 billion in revenue, led by over $1.7 billion in Aliftrek sales and more than $350 million in combined Casgevy and Genavix 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 Aliftrek and over 18,000 patients benefiting from Aliftrek 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, Genavix reported over 750,000 prescriptions and $58 million in revenue.

More than 1.6 million patients have now been treated with Genavix in the U.S., and Genavix is now the number one prescribed branded oral analgesic in the U.S. And 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’ll 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 Aliftrek, which delivered $706 million in worldwide sales in Q3. In the U.S., Aliftrek sales year to date have now surpassed $1 billion in both the U.S. and outside the U.S. Aliftrek sales continue to build primarily from patients switching from Trikafta and new patients with rare mutations.

Outside the U.S., we now have 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 the underlying survival benefit of patients on CFTR modulators. Turning to Casgevy in severe sickle cell disease and transfusion-dependent beta thalassemia, $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’ve also continued to enhance the patient journey, shortening the overall time from referral to infusion and decreasing 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’d 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 Genavix in moderate to severe acute pain, we are building a franchise for the long term and are focused on the following critical markers: broad payer coverage, prescription growth, breadth and depth of prescribing, the addition of Genavix to hospital pathways, and revenue. These are the building blocks of a sustainable, long-term, multibillion-dollar pain business. Let me start with prescriptions because that’s the best indicator of underlying physician and patient demand.

In the third quarter, Genavix 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 Genavix 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 Genavix 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% to 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 Genavix for all their patients.

This quarter marks our first opportunity to speak about Palsonify as part of Vertex Pharmaceuticals 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% to 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, the efficacy tends to taper off in the latter part of the month, leading to breakthrough symptoms such as joint pain, swelling and fatigue. And 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 naïve 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 success: 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; and 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. And 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 POVI in IgAN. Reshma has already highlighted the trifecta of efficacy, safety and patient-centric dosing of povitazept. Put simply, with the PDUFA date just days away now, we are 100% ready, and we are incredibly excited to bring POVI 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 POVI 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 POVI’s clinical profile, and have responded positively to its differentiation and overall value proposition.

We’ve had many engagements with nephrologists over the last few months, including at the excellent ASN Kidney Week meeting last month. They’re 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 autoinjector will be an important differentiator for POVI. I’ll now turn the call over to Charlie.

Charlie Wagner (Chief Financial Officer)

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 Kinetics 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 Kinetics acquisition. Turning to Q3 operating expenses, which include approximately $60 million of Kinetics 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 Kinetics. 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 POVI and renal, and Jornavix and then Palsonify. Approximately $30 million of the incremental SG&A spend is related to Kinetics. We also recorded $41 million in acquired IPR&D expense in the quarter, including a $28 million upfront payment for a new business development agreement with AbCellera.

During Q3, we incurred approximately $50 million in non-operating costs associated with the Kinetics 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 Kinetics 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 to $13.2 billion to a revised range of $13.15 to $13.25 billion. The increase reflects the addition of Kinetics, which we expect to contribute $40 to $50 million to full-year 2026 revenue. The underlying drivers of our revenue outlook are unchanged: continued CF performance, including the ongoing Aliftrek launch, together with growing contributions from heme pain and now rare endocrinology.

We continue to expect more than $500 million in revenue from Casgevian Jornavix, 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 margins slightly below 86%. On operating expenses, we are revising our prior combined non-GAAP operating expense guidance of $5.65 to $5.75 billion to a revised estimate of approximately $6 billion. The stand-alone 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 Kinetics 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 Kinetics, 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 Kinetics 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% and 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 Kinetics is well underway and, with the strong commitment of the Kinetics team, we are accelerating commercial, clinical, and valuable preclinical programs. Our continued leadership in CF, the increasing contribution of Casgevian genavics, momentum in rare endocrinology, and with POVI on the doorstep of launch, we are well positioned for continued active 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.

Susie Lisa (Senior Vice President, Investor Relations)

Thanks, Charlie. Chuck, can you please open it up to questions?

OPERATOR

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. And today’s first question will come from Corey Kasimov with Evercore. Please go ahead.

Corey Kasimov (Analyst)

Great. Good afternoon, guys. Thanks for taking the question. And, Charlie, congrats on the new role. It’s very well deserved. So, on POVI, I wanted to ask about the recent Citizen Petition that raises the question of whether Ranier’s IgG monitoring and dose-hold rules need to be carried into clinical practice. So I guess how frequently did 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.

Reshma Kewalramani (CEO and President)

Hey, Corey, it’s Reshma. Let me take that one. With regard to the Citizen 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. So 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. And on that note, there are no opportunistic infections. As you know, in the POVI program, the SAEs of infection are balanced—it’s exactly 0.5% in POVI 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.

Corey Kasimov (Analyst)

That’s very helpful, Reshma. I appreciate it.

OPERATOR

The next question will come from Jessica Fye with J.P. Morgan. Please go ahead.

Jessica Fye (Analyst)

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.

Reshma Kewalramani (CEO and President)

Yep. Just on the AMPLITUDE study. That’s the one that has 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 GFR slope. And I say that because, of course, we’re going to measure proteinuria and GFR, but our agreement with the FDA on what would be acceptable for accelerated approval is GFR—that’s where they are on the disease AMKD.

I expect the phase 3 to look a whole hell of a lot like the phase 2 in terms of proteinuria. But the key element here is GFR, and it’s a statistically significant difference between the Inaxaplin-treated group and the placebo on top of standard of care. Now, I won’t share with you the power analysis and such, but that’s what we’re looking for, because GFR is what the accelerated approval agreement with the FDA is based on.

OPERATOR

The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.

Salveen Richter (Analyst)

Thank you. Good afternoon. Just a follow-up on Corey and Jessica’s question. With regard to POVI, can you speak to your comfort and history with the manufacturer? And then with regard to inaxaplin, can you just walk through further 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 the read-through from some of the data sets that you’ve generated to date?

Reshma Kewalramani (CEO and President)

You bet. So, Salveen, let’s do POVI first and then let’s get to inaxaplin. On POVI, the specific question you had is how is it going with manufacturing? We’ve been with the same manufacturer all through Phase 3 and through to the lead-up for our PDUFA. We feel really good about where we are and, as you know, in addition to the review of safety and efficacy and 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. So 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 2a study that we published in the New England (that was the one that had the 47.6% reduction in proteinuria) and the more recent AMPLITUDE 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 homogeneous 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 cc per year, right? AMKD is a rapidly progressive disease—so more than that, 6, 7, 8 cc per milliliter per year. And the FDA themselves have said in IgAN that they are going to be comfortable accepting one-year GFR differences.

So 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.

OPERATOR

The next question will come from Jeff Meacham with Citi. Please go ahead.

Jeff Meacham (Analyst at Citi)

Guys, thanks for the question. I also want to offer up some congrats to Charlie. I just have a couple of quick ones on POVI. 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.

And the second one—real quick—on pain. It looks like the trials are continuing to enroll, mid-year data next year. Maybe just at a high level, give us some context for what you think at this point a win would look like—kind of in DPN for VX-548 versus etrogin. Thank you.

Reshma Kewalramani (CEO and President)

Yeah, let’s do DPN first and then I’ll split the POVI question with Duncan. On DPN, we are fully on track to complete enrollment in both the two Phase 3 VX-548 (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. And a win would be the suzetrigine arm beating placebo treatment in the two DPN studies. You know, 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 POVI, 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 POVI around the globe. The FDA has said that they’re comfortable with one-year GFR, but other regulators have different expectations. So 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 matured two-year data.

Duncan, do you want to talk a little bit about differentiation, GFR, and POVI launch in the U.S.?

Duncan McKechnie (EVP, Chief Commercial Officer)

Indeed. Hi Jeff. 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 strong level of conviction in the connection between proteinuria and eGFR, especially in IgAN. And I would say the data that has come out from the BAFF/APRIL inhibitors over the last couple of months has only served to strengthen that conviction.

So we believe on the basis of that that POVI 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. So 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 ASN week, they’re very excited in the profile of POVI and looking forward to trying it post-approval.

So we’re very comfortable with where we’re at. Great, thank you.

OPERATOR

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

Evan Seigerman (Analyst)

Hi, guys. Thank you so much for taking my question. So, you know, we’re seeing some good traction with Jornavix, 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 the bridge between prescription growth and eventually reported revenue as the PSP rolls off, and whether you expect revenue growth to inflect as normalization occurs? Thank you so much.

Reshma Kewalramani (CEO and President)

Sure. Duncan, maybe you could take that one for us.

Duncan McKechnie (EVP, Chief Commercial Officer)

Yeah. So just to step back a little bit, Evan, just to make a couple of points and then I’ll dive into the PSP program, gross-to-net, and revenue. We are very pleased with the performance of Genavics. You know, this is hard work—we’re changing decades of ingrained prescribing behavior and seeking to convert practices over to the use of Genavics. So 750,000 prescriptions per quarter, 1.6 million Americans treated, the number one oral branded analgesic, would all indicate that we’re 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’s important that we’re 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 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’ve said before, gross-to-net to stabilize at the sort of normal oral branded level of 50% to 60% and revenue to grow commensurately.

OPERATOR

Thank you. The next question will come from Brian Abrams with RBC Capital Markets. Please go ahead.

Brian Abrams (Analyst at RBC Capital Markets)

Hey, good afternoon. Thanks for taking our question, and congrats to Charlie from us as well. Just on the POVI launch, it sounds like you guys have had great engagement with physicians and payers. I’m just wondering what’s 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. And then just secondarily, ALYFTREK conversion looks like it’s been picking up steam the last few quarters. Just wondering the right way to think about the continued trajectory there. Thanks.

Reshma Kewalramani (CEO and President)

You bet. Brian, I’m going to ask Duncan to comment on both. Let’s do the second question first and then we’ll go back to POVI.

Duncan McKechnie (EVP, Chief Commercial Officer)

Yeah, Brian. So ALYFTREK has been driven predominantly by new reimbursement agreements—obviously outside the U.S. we’ve had another slew of those agreements in quarter three. And it’s also been 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 ALYFTREK specifically. So those are essentially the two main drivers of ALYFTREK growth over the last couple of months, which we’re particularly happy with.

In terms of POVI and uptake, a couple of comments there. Firstly, as with, say, CASGEVY and Genavics, 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. And I would say you make a great point: the physician enthusiasm for the new BAFF/APRIL inhibitors has been incredible, and that is certainly driving success in the market. And the numbers are a little bit unclear at this point, but let’s say—not POVI—Voisakt and Drew Tachner close the year with about 3,000 patients on medicine, which is probably roughly where they’re gonna 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, the nephrologists’ enthusiasm for POVI 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.

OPERATOR

The next question will come from Michael Wee with UBS. Please go ahead.

Mike Yee (Analyst at UBS)

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 2. I guess one new thing that has come out is obviously some of the IgAN data that shows significant eGFR benefits even at 9 months on just a couple mL per minute deltas, and similar protein reductions you’re seeing with inaxaplin. So my question is, given the significant benefits you’re seeing and given a 12-month time point, our math suggests that a mL 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. And 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.

Reshma Kewalramani (CEO and President)

Yeah, Mike, first let’s do Parasol. Parasol is a very important and influential group. You know, they’ve come together multiple times over time and worked with the FDA to evolve endpoints and 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 and, at the same time, the FDA and our agreement is indeed with GFR.

So 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 are 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. And decreasing proteinuria by way of APRIL/BAFF inhibition has more beneficial impact on GFR than perhaps other methods of reducing proteinuria. And 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 underlying biology. So 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.

Mike Yee (Analyst at UBS)

Perfect. Thank you.

OPERATOR

The next question will come from Tazeen Ahmed with Bank of America. Please go ahead.

Tazeen Ahmed (Analyst)

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 preclinical data that you looked at? And 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 Trikafta? Thanks.

Reshma Kewalramani (CEO and President)

You asked such a good question, Tazeen, around what is the unmet need. So 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 8. 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 are more than 6 points of sweat chloride improvement. And through 28 days we’re touching 10 points of sweat chloride. Those are the numbers, especially when you take into account it’s versus Trikafta. This is not versus a placebo baseline. So those are excellent results and it’s once a day, good DDIs, 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, 571 and 272, next year. When we have all of those results, we’ll pick the one that’s best suited to move forward. And 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 Trikafta, we are almost superimposable onto the Gaussian distribution of sweat chloride of normal people.

So really it’s 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’s what we’re looking for.

OPERATOR

The next question will come from Akash Tewari with Jefferies. Please go ahead.

Akash Tewari (Analyst)

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’re making the call now. And just from a statistical perspective, if a patient on placebo starts another APOL1 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.

Reshma Kewalramani (CEO and President)

Yeah, I just want to make sure I understood your question about the decision for two years. I think you were saying why continue to two-year GFR? Did I understand correctly?

Akash Tewari (Analyst)

Right? Why make the call now. I know you had previously talked about regulators in a global setting wanted two-year data, but we already knew that. So what led to the decision to go forward two-year today?

Reshma Kewalramani (CEO and President)

Yeah, obviously we can decide if we wish to cut the data and do a one-year cut. We can do that at any time. But 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 patients who 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.

OPERATOR

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

Terrence Flynn (Analyst)

Great. Thanks so much for taking the question. I guess one more on inaxaplin. I was just wondering on the AMPLITUDE data—I know there’s 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 it was broader based. Maybe you’d talk about kind of the response rate across the population in that Cohort 1.

Thank you.

Reshma Kewalramani (CEO and President)

Yeah. So, Terrence, on AMPLITUDE and Cohort 1—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 proteinuria is modest. And 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.

Susie Lisa (Senior Vice President, Investor Relations)

One more question, please, Chuck.

OPERATOR

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

Mohit Bansal (Analyst)

Great. Thank you very much for taking my question. Congrats on all the progress. My question is circling back to PV manufacturing, and one concern is around the potential use of continuous manufacturing in this process, which is relatively new for biologics at this point. So the question is, 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.

Reshma Kewalramani (CEO and President)

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? So 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. And 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.

Mohit Bansal (Analyst)

Thank you.

Susie Lisa (Senior Vice President, Investor Relations)

You bet. Jacob, please wrap us up.

OPERATOR

Will do. And 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 1-412-317-1066 using replay access code 10208189. Thank you for your attendance today. You may now disconnect.

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