Document Details

# Vertex Pharmaceuticals Incorporated - Q2 2023 Earnings Call

Tuesday, August 1, 2023 4:30 PM

# Event Participants

Executives 4 Susie Lisa, Reshma Kewalramani, Stuart Arbuckle, Charles Wagner

Analysts 11 Philip Nadeau, Liisa Bayko, Salveen Richter, Geo!rey Meacham, Robyn Karnauskas, David Risinger, Terence Flynn, Mohit Bansal, Michael Yee, Evan Seigerman, Colin Bristow

# Operator Operator

Good afternoon, and welcome to the Vertex Pharmaceuticals Second Quarter 2023 Earnings Conference Call. \[Operator Instructions\] Please note, this event is being recorded.

I would now like to turn the conference over to Susie Lisa, Senior Vice President, Investor Relations. Please go ahead.

# Susie Lisa Executive

Good evening, everyone. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our second quarter 2023 "nancial results conference call. On tonight's call making prepared remarks we have Dr. Reshma Kewalramani, Vertex's CEO...

# Vertex Pharmaceuticals Incorporated - Q2 2023 Earnings Call

Tuesday, August 1, 2023 4:30 PM

# Event Participants

Executives 4 Susie Lisa, Reshma Kewalramani, Stuart Arbuckle, Charles Wagner

Analysts 11 Philip Nadeau, Liisa Bayko, Salveen Richter, Geo!rey Meacham, Robyn Karnauskas, David Risinger, Terence Flynn, Mohit Bansal, Michael Yee, Evan Seigerman, Colin Bristow

# Operator Operator

Good afternoon, and welcome to the Vertex Pharmaceuticals Second Quarter 2023 Earnings Conference Call. \[Operator Instructions\] Please note, this event is being recorded.

I would now like to turn the conference over to Susie Lisa, Senior Vice President, Investor Relations. Please go ahead.

# Susie Lisa Executive

Good evening, everyone. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our second quarter 2023 "nancial results conference call. On tonight's call making prepared remarks we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating O#cer; and Charlie Wagner, Chief Financial O#cer. 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 forwardlooking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our "lings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed cystic "brosis medicines, our pipeline and Vertex's future "nancial performance are based on management's current assumptions. Actual outcomes and events could di!er materially.

I would also note that select "nancial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented inclusive of our foreign exchange risk management program.

I'll now turn the call over to Reshma.

# Reshma Kewalramani Executive

Thanks, Susie. Good evening all, and thank you for joining us on the call today. After a strong start to the year, we saw continued momentum into the second quarter across all aspects of the company. Our CF business continues to grow, and we are reaching more patients than ever. In the second quarter, this expanded reach drove $14 %$ global safe product revenue growth versus the prior year period.

And with this "rst half performance, we are raising our full year 2023 CF product revenue guidance to a revised range of $$ 9.7$ billion to $$ 9.8$ billion.

As we continue to deliver in CF, we're also investing for future commercial excellence, ahead of multiple potential near-term launches. In exa-cel in both severe sickle cell disease and transfusion-dependent beta thalassemia, which we expect will be the "rst in our next wave of launches. In VX-548 for acute pain, another multibillion-dollar commercial opportunity and in our Vanzacaftor triple combination therapy for cystic "brosis, which provides the opportunity to further extend our leadership in CF.

In addition to these 4 disease areas, our mid-stage clinical pipeline continues to develop rapidly and marked progress towards our 5 launches in 5 years goal. Recent achievements include: the VX-147 or Inaxaplin pivotal trial remains on track to complete the Phase IIB portion of the study by the end of this year. In our type 1 diabetes program, both VX-880, the naked cells and VX-264, the cells plus device programs are now in the clinic and dosing patients. Additionally, we announced a strategic long-term manufacturing agreement with Lonza for our type 1 diabetes cell therapy programs. And "nally, an accelerated time line for the VX-548 Phase II study in peripheral neuropathic pain, where we now expect the study to complete by the end of 2023.

In total, we're advancing programs in 8 disease areas through mid- and late-stage development, 6 of which are now past the proof-of-concept stage as detailed on Slide 5. Beyond our clinical pipeline, we're also advancing the next wave of research stage assets, re$ecting programs sourced from both internal and external innovation. This includes programs in Duchenne's muscular dystrophy, myotonic dystrophy type 1, the NaV1.7 program for pain and gentler conditioning agents for use with exa-cel. In the CF franchise, in R&D and across the business, this quarter, Vertex has continued to make meaningful advancements to bring our CFTR portfolio to more patients around the globe and bring additional "rst-in-class or best-in-class potentially transformative medicines to multiple new disease areas. With that overview, I'll turn to the details of recent R&D progress, starting with CF.

While TRIKAFTA delivers tremendous bene"t for patients. If it's possible to do better, we're committed to being the ones who do so, and that is the goal for our next-in-class vanzacaftor triple combination therapy. I am pleased to share we expect to complete all 3 Phase III studies, SKYLINE 102 and 103 in patients ages 12 years and above and the RIDGELINE study in patients ages 6 to 11 by the end of 2023 and release results from these 3 studies in early

We have high expectations from the vanzacaftor triple program to lead to further improvements in CFTR function based on the totality of the evidence generated to date. The most direct readout of higher CFTR function is chloride transport in vitro and sweat chloride in patients. In vitro, our human bronchial epithelial cell assays with the vanzacaftor triple showed greater restoration of chloride transport than with TRIKAFTA. And in Phase II in patients the vanzacaftor triple clinical studies showed correspondingly lower levels of sweat chloride than in previous studies with TRIKAFTA. We, therefore, believe the vanzacaftor triple has the potential to provide patients with enhanced clinical bene"t, the convenience of oncedaily dosing.

And additionally, the Vanza Triple carries a substantially lower royalty burden. Another important program in our CF portfolio is VX-522, our CFTR mRNA therapy in development with our partners at Moderna for the more than 5,000 CF patients who cannot bene"t from CFTR modulators. We have enthusiasm for this approach for 3 key reasons, based on what we've achieved to date: "rst, the delivery of mRNA at high e#ciency into HBE cells in vitro; second, expression of CFTR protein leading to high levels of chloride transport; and third, successful nebulize delivery of mRNA in both small and large animals resulting an expression of CFTR protein in the desired cells.

We continue to enroll and dose CF patients in the single ascending dose or SAD study of VX-522. And we expect to complete the SAD portion and initiate the multiple ascending dose portion of the study this year.

Turning now to exa-cel, our CRISPR/Cas9-based gene editing program for sickle cell disease and transfusion-dependent beta-thalassemia, which targets the most severe patients and an estimated patient population of approximately 32,000. Exa-cel holds the promise to be a onetime functional cure for these diseases.

On the regulatory front, the FDA has accepted our "lings and granted priority review in sickle cell disease with the December 8 PDUFA date. Along with a standard review in betathalassemia with the March 30, 2024 PDUFA date. The FDA has indicated an advisory committee will be held, and we look forward to the opportunity to discuss the high unmet need, share results from the exa-cel studies and discuss the transformative potential exa-cel holds for patients.

Outside the U.S., in the EU and the U.K., reviews for our exa-cel "lings are also well underway. Our oral presentation, the most recent EHA meeting in June, provided new data that were the basis of the EMA and MHRA regulatory "lings. Both trials met the primary and key secondary endpoints with follow-up in some patients of more than 36 months.

The exa-cel EHA results continue to demonstrate transformative, consistent and durable bene"t for patients as measured by freedom from severe vaso-occlusive crises for $9 4 %$ of SCD patients, and transfusion independence in $8 9 %$ of TDT patients. The safety pro"le was generally consistent with busulfan conditioning and bone marrow transplantation.

Another signi"cant opportunity for exa-cel is in younger patients, and the pediatric trials in both sickle cell disease and beta thalassemia are underway. We have enrolled more than half the target number of patients in both pediatric studies and have dosed multiple patients. This is an important area of focus given the opportunity to intervene earlier and potentially prevent organ damage and other complications before they ever occur. As the PDUFA dates approach in the U.S. and reviews come to conclusion in the U.K.

and EU, we look forward to bringing this onetime potentially curative therapy to thousands of patients with severe sickle cell disease and transfusion-dependent beta-thalassemia. Turning next to our pain program and VX-548, our novel, highly selective NaV1.8 inhibitor that holds the promise of e!ective pain relief without the side e!ects or addictive properties of opioids. In acute pain, I am pleased to share that all 3 Phase III studies, 2 randomized controlled trials and a single-arm safety and e#cacy study will complete by the end of this year, with results available in late 2023 or early '24.

The pace of this Phase III program has been rapid which we see as indicative of the high unmet need and strong interest in an e#cacious, non-opioid acute pain therapy. We have high con"dence in the outlook for these Phase III studies given: one, the genetic and pharmacologic validation of the target; two, multiple proof-of-concept trials with the predecessor molecule and with VX-548 itself; and three, the similar methodology, design and endpoints of our Phase III studies compared to the Phase II program.

Closing on acute pain, recall that the phase III program has been designed to support a broad model-to-severe acute pain level, which would enable prescribing and usage across mule setting including in Hospital or the ambulatory surgical center post-discharge and in the home.

We are also studying VX-548 in diabetic peripheral neuropathy or DPN. A type of peripheral neuropathic pain that represents yet another signi"cant area of unmet need and another multibillion-dollar market opportunity. We have previously delivered positive proof-ofconcept data in peripheral neuropathic pain with the predecessor molecule VX-150. The current study in DPN with VX-548 is a 12-week Phase II dose-ranging proof-of-concept study. I am pleased to share the time line for this DPN study has accelerated and we have recently completed enrollment.

This study will complete by the end of this year, and we expect to share results in late 2023 or early '24.

Moving now to type 1 diabetes, where we're evaluating stem cell-derived, fully di!erentiated insulin-producing islet cells for people with type 1 diabetes. Our goal is to develop a functional cure for the millions of people living with type 1 diabetes, including the more than 2.5 million patients in North America and Europe alone.

The VX-880 program is our foundational cell therapy program for T1D in which we have already demonstrated proof of concept. In the VX-880 trial or the naked cell program, patients take standard immunosuppressants to protect the islets from the immune system. We presented updated clinical data on Parts A and B of the study at the recent American Diabetes Association Meeting. The presentation at the ADA showed that all 6 patients treated with VX-880 engrafted islet cells, produced endogenous insulin and had improved glycemic control while reducing or eliminating exogenous insulin use.

Importantly, the 2 patients with at least 1 year follow-up saw a complete elimination of severe hypoglycemic events, maintained hemoglobin A1Cs below $7 %$ and were insulin independent. Further, patients who were earlier on their course of therapy were on a similar trajectory as the 2 patients with long-term follow-up. Based on these results, the VX-880 trial has now advanced to Part C, where patients are treated concurrently at the full target dose. And as part of our global study plan, we've now opened clinical trial sites in Europe in addition to those already open in the U.S. and Canada.

Our second program, VX-264, the cells plus device program encapsulates these same cells, which have already demonstrated proof of concept in a proprietary immunoprotective device. And hence, there is no requirement for immunosuppressants. I am pleased to share that enrollment in the VX-264 study has initiated and we have already dosed the "rst patient.

The third program is our hyperimmune program in which we edit the same fully di!erentiated cells to cloak them from the immune system. This represents another path to obviating the need for immunosuppressants. In March, we expanded our collaboration with CRISPR Therapeutics into type 1 diabetes to use CRISPR/Cas9 to make these edits, and we continue to make progress in this research stage program.

Transitioning now to Inaxaplin or VX-147, the "rst potential medicine to target the underlying cause of APOL1-mediated kidney disease or AMKD, a genetically de"ned disease that a!ects approximately 100,000 patients in the U.S. and Europe alone. Recall the Inaxaplin pivotal program for patients with AMKD is a single adaptive Phase II/III study with a pathway to accelerate approval in the U.S. The Phase IIB dose-ranging portion of the study continues to enroll and dose and remains on track to complete this year.

We also continue to work to enhance AMKD disease awareness and genetic testing availability to support diagnosis, including through partnerships with Natera, a leader in genetic testing and Arkana, a leader in renal pathology services.

To close an update on our Alpha-1 antitrypsin de"ciency or AATD program, our small molecule approach targets both the lung and liver manifestations of this disease that a!ects an estimated 100,000 people in North America and Europe. Our program is exploring 2 hypotheses: "rst, longer treatment duration with VX-864; and second, a more potent molecule with VX-634. The Phase II program for VX-864, a 48-week study in patients with AATD that assesses both liver clearance of Z polymer and functional plasma AAT levels is ongoing and is anticipated to complete enrollment later this year. VX-634, the next-in-class molecule with multifold greater potency and better drug-like properties is projected to complete its Phase I trial by the end of this year. Overall, the AATD program remains on track, and we look forward to sharing results in 2024.

With that, I'll turn it over to Stuart to provide a commercial update, including details on our launch preparations for exa-cel.

# Stuart Arbuckle Executive

Thanks, Reshma. From a commercial perspective, we had strong second quarter results as we continue our focus on reaching all patients eligible for our CFTR modulators and maintaining high levels of adherence for patients treated with our medicines. In addition, we continue to prepare for multiple potential near-term launches, including exa-cel in severe sickle cell disease and transfusion-dependent beta-thalassemia VX-548 in moderate to severe acute pain and the vanzacaftor triple combination in CF. At the same time, we are developing new capabilities to support the commercialization of other pipeline assets. such as disease awareness for AMKD and investing in our manufacturing capabilities for type 1 diabetes.

Given our nearest term opportunity is exa-cel in hemoglobinopathies where we have completed our regulatory "lings in Europe and the U.S. and also being granted PDUFA dates in the U.S. This quarter, I will focus my comments about our pipeline on prelaunch activities for exa-cel.

But brie$y "rst on CF. At the beginning of this year, there were more than 20,000 people with CF in North America, Europe and Australia, who could bene"t, but were not yet being treated with a CFTR modulator. We continue to bring our medicines to these patients through new approvals and uptake following additional reimbursements with a focus on reaching younger patients, and this will continue to be a driver of near-term growth for our business.

Second quarter 2023 CF revenue growth of $14 %$ was consistent with this outlook and was driven primarily by expanded use of our medicines in younger age groups. Following U.S. TRIKAFTA approval in children ages 2 to 5 in late April, we've seen strong interest from the CF community with the "rst prescription written just hours after the approval and uptake across all eligible patients.

Outside the U.S., KAFTRIO growth has continued to be strong in patient ages 16 and older, following approval, reimbursement and successful launches in multiple geographies. In addition, we received EU approval for ORKAMBI in children ages 1 to 2 in early July, and we continue to expect approval for KAFTRIO in the EU in children ages 2 to 5 by the end of this year. We are also actively enrolling our KAFTRIO study in children ages 1 to 2.

Overall, we see continued growth for our portfolio of CFTR modulators, driven by approvals, reimbursement and uptake of our medicines in younger patients. In addition, approvals of future CF medicines will also drive growth. Notably, our next-generation vanzacaftor triple seeks to provide improved e#cacy for patients and a new treatment option for those who have discontinued prior CFTR modulator therapy. And longer term, VX-522, our mRNA approach could o!er a therapy for the more than 5,000 patients who cannot bene"t from CFTR modulators.

Shifting now to exa-cel, which holds curative potential for patients with severe sickle cell disease and transfusion-dependent beta thalassemia both chronic diseases that can be disabling and life-shortening and have an extremely high burden of care. On previous quarterly earnings calls, I provided details for exa-cel on the estimated eligible patient population, the geographic concentration of those patients and our proposed ATC network of 50 centers in the U.S. and 25 in Europe. The hiring and training of our "eld and medical education teams and insights from physician and patient market research.

This quarter, I'd like to provide our perspective on access and reimbursement and our discussions globally with payers and policymakers. Our teams continue to make excellent progress in pre-approval discussions with both government and commercial payers in the U.S. and Europe. With more than a dozen cell and gene therapies on the market, payers across di!erent channels are increasingly experienced with these transformative types of therapies.

In the U.S., approximately $6 5 %$ of patients with sickle cell disease or beta thalassemia, have coverage through government programs with the majority via Medicaid, and the remaining $3 5 %$ of patients are covered by private insurance. Our teams have already engaged Medicaid administrators in all 50 states with a particular focus on the 24 states with the highest prevalence of sickle cell disease, accounting for an estimated $9 0 %$ of Medicaid patients with SCD. We're encouraged by the enthusiasm from state Medicaid administrators for exa-cel as well as the proactive steps they are taking to prepare for the availability of therapies like exacel including the enablement of separate payment policies for coverage of the cost of the therapy, distinct from the cost of the bone marrow transplant procedure. The Medicaidfocused CMS cell and gene therapy access model also continues to make progress towards its anticipated launch in 2026. The model is clear evidence of the federal government's recognition of the potential transformative value of gene therapies like exa-cel to treat sickle cell disease and their interest in "nding innovative payment solutions and pathways for state Medicaid programs.

Shifting to commercial payers. We have had high levels of engagement with commercial payers, including the top 4 payers that account for approximately $8 0 %$ of commercial lives. And our goal is to facilitate timely coverage decisions upon a potential exa-cel approval. Our pre-approval discussions have been encouraging and are focused on disease burden, epidemiology estimates, our clinical data and potential payment models.

In Europe, the MAA reviews are well underway and thus, we are also working on paving the way to secure reimbursed access for patients in our targeted European markets. We have been engaging with health systems to educate them on the signi"cant disease burden on patients, health care systems and society. In addition, we have been meeting with European health authorities to understand their interest in di!erent payment models and to communicate the holistic value of a onetime potential functional cure.

Given the urgent unmet need for new treatments for sickle cell disease and beta thalassemia, there is signi"cant interest from patients and physicians, particularly in geographies with high concentrations of the eligible patient population.

To conclude, it's a remarkable time to be at Vertex. We continue to make progress treating more CF patients while our excitement for the transformative promise of exa-cel for patients and the resulting multibillion-dollar market opportunity continues to grow as we approach potential approval. We are also preparing for multiple additional near-term launches, including the vanzacaftor triple in CF and VX-548 in acute pain, both of which have the potential to dramatically improve patients' lives.

I'll now turn the call over to Charlie to review the "nancials.

# Charles Wagner Executive

Thanks, Stuart. Vertex's excellent results in the second quarter of 2023 demonstrate once again our consistent strong performance and attractive growth pro"le. Second quarter 2023 revenue increased $14 %$ year-over-year to $$ 2.49$ billion. Growth was led by a $2 6 %$ year-overyear increase outside the U.S. on continued strong uptake of TRIKAFTA-KAFTRIO in markets with recently achieved reimbursement as well as label extensions in younger age groups.

Similarly, expansion in younger age groups helped drive $7 %$ U.S. revenue growth following the recent FDA approval of TRIKAFTA in patients ages 2 to 5. Second quarter and "rst half revenues also bene"ted from increases in channel inventory in certain international markets, which are expected to draw down in the second half.

Second quarter 2023 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $$ 1.04$ billion compared to $$ 750$ million in the second quarter of 2022. Q2 2023 results include $$ 120$ million of acquired IP R&D charges compared to $$ 62$ million of such charges in the second quarter of 2022. Second quarter 2023, IP R&D expense re$ects a $$ 70$ million milestone to CRISPR Therapeutics for progress made in our hypoimmune program for type 1 diabetes.

Aside from our investments in external innovation and the resulting higher acquired IP R&D charges, operating expense growth was driven as expected by continued investment in research and our advancing pipeline, which includes mid- and late-stage clinical assets across 8 di!erent disease areas. The most signi"cant areas of increased investment versus prior year included the clinical studies for the vanzacaftor Triple-NCF for $V X - 5 4 8$ in acute pain and for type 1 diabetes. In addition, we continued our pre-commercial activities for exa-cel and other anticipated near-term launches, given the potentially transformative bene"ts to patients and multibillion-dollar market opportunities for our mid- and late-stage programs, we will continue to invest appropriately.

Second quarter 2023 non-GAAP operating income was $$ 1.15$ billion compared to $$ 1.19$ billion in the second quarter of 2022. Second quarter non-GAAP earnings per share were $$ 3.89$ , representing $8 %$ growth compared to $$ 3.60$ in the second quarter of 2022. We ended the quarter with $$ 12.6$ billion in cash and investments.

Now switching to guidance. Given our strong "rst half results and our consistent execution, including the successful launch of TRIKAFTA in patients ages 2 to 5 in the U.S., we are increasing our 2023 revenue guidance as detailed on Slide #16, for the full year 2023, we now expect CF net product revenue of $$ 9.7$ billion to $$ 9.8$ billion, an increase of $$ 100$ million to $$ 150$ million compared to our prior range of $$ 9.55$ billion to $$ 9.7$ billion. Note that this revenue guidance includes an expected approximate 150 percentage point headwind to our revenue growth rate, consistent with our prior expectations.

In addition, given our December 8 U.S. PDUFA date for exa-cel and sickle cell disease, 2023 product revenue guidance continues to re$ect revenue from cystic "brosis products only. We are also raising our 2023 guidance for combined non-GAAP R&D, acquired IP R&D and SG&A expenses to a range of $$ 4.1$ billion to $$ 4.2$ billion, an increase of $$ 200$ million from prior guidance. This increase re$ects higher IP R&D expenses from new business development, including collaborations with Entrada in DM1 and with CRISPR in type 1 diabetes. Our 2023 non-GAAP operating expense guidance now includes approximately $$ 500$ million of upfronts and milestones compared to the $$ 300$ million projected at the start of the year.

We continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid- and late-stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near-term launch potential while continuing to leverage an attractive business model a!orded by our focus in specialty markets. Our guidance for projected full year 2023 non-GAAP e!ective tax rate of $2 1 %$ to $2 2 %$ is unchanged.

In closing, Vertex delivered excellent results for the second quarter of 2023. We delivered strong revenue growth, completed important regulatory milestones, updated on signi"cant clinical trial programs and invested internally and externally. As we continue to advance our programs in 2023, we anticipate further important milestones as highlighted on Slide 17 to mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

# Operator Operator

Thanks, Charlie. Gary, can you please view the "rst question?

# Operator Operator

\[Operator Instructions\] Our "rst question is from Phil Nadeau with Cowen and Company.

# Philip Nadeau Analyst

Just a couple on exa-cel. In the prepared remarks you mentioned or at least in the press release, you mentioned that an advisory committee is likely, does Vertex have any sense of what is likely to be discussed or debated at the advisory committee?

And then second, for Stuart, thanks for all your comments on the commercial prep. We have seen gene and cell therapy launches get o! to a relatively slow starts of late with some not actually having patients dosed for 7 or so months after approval. What does Vertex learn from that? What could you do to increase the speed at which patients are adopting exa-cel post approval?

# Reshma Kewalramani Executive

Phil, this is Reshma. Let me take the "rst part of your question, and then I'll ask Stuart to comment on the commercial launch readiness. With regard to exa-cel, the FDA has informed us that there will be an advisory committee. This is not unexpected as we've discussed in the past, given the new mechanism of action.

We don't have further details. Those will be forthcoming. And I expect we'll know more as we approach the date of the AdCom, which we don't have today either. However, conventionally, the advisory committees usually take place about 1 to 2 months before the PDUFA date. So that's the general framework that we're looking at.

We are very excited to have the opportunity to share our data, to talk about the bene"t risk and to talk about the transformative potential and to have the patient's voices heard at the advisory committee.

Let me turn it over to Stuart to comment on launch readiness

# Stuart Arbuckle Executive

Yes, Phil, so thanks for the question. Obviously, the "rst most important step to provide the conditions for a successful launch are going to be to secure access and reimbursement because as you know, without access and reimbursement, there really is no opportunity for patients to get treated. And that's why I focus my comments on that, and we are doing everything we can with payers, both in the U.S. and internationally try and get access and reimbursement as close to regulatory approval as we possibly can. Obviously, that's not entirely within our control, but that's what we're working on.

In terms of the kind of uptake curve in the future, now, obviously, that's going to depend on the interest from physicians and patients. We know that, that is very high. But I would remind you that, as I've said on previous calls, we do expect the uptake with exa-cel to be slower, obviously, than we see with our CF medicines where the launches are almost vertical.

And that's largely because, as you know, this is a multi-month process that a patient has to go through to get treated with exa-cel. Obviously, they have to decide with their physician that they want to go through a gene therapy. They have to have their cells collected. The cells then have to be edited, returned to the site and then the patient has to schedule coming in for essentially the equivalent of a bone marrow transplant before they're actually dosed with the exa-cel drug product. So it is a multi-month process from start to "nish for any individual patient.

And so that's why we've always said this launch, we do expect to be slightly slower in uptake rate than in cystic "brosis, but we continue to believe there's a lot of interest. It's a big market opportunity and we see exa-cel as a multibillion-dollar opportunity in the future.

# Philip Nadeau Analyst

Great. One follow-up, if I may. On the reimbursement, we've seen warranty agreements put in place by one recent gene therapy launch. Is that something you're considering or you think would be helpful?

# Stuart Arbuckle Executive

Sorry, Phil, I didn't quite catch the question. Can you say it again?

# Philip Nadeau Analyst

Yes. In terms of reimbursement in the structure of reimbursement agreements, one recent gene therapy launch included a warranty as part of the reimbursement agreement. Is that something Vertex is considering or would think would be helpful for a launch like exa-cel?

# Stuart Arbuckle Executive

Yes. We are considering a range of di!erent options, Phil. The reason for that is kind of if you ask 1 payer, what they're looking for, you get 1 answer. If you ask another pay, you get another answer. So I think much as we've done with cystic "brosis, we're going to look to be $exible.

There are some who are going to be interested in just a straight price and just paying upfront for the bene"ts of onetime functional cures. Others are looking at more things like outcomesbased agreements on that. And so right now, we're in kind of listening mode and de"ning and designing what the nature of our payment models will be. But I think the key word is probably $exibility.

# Operator Operator

The next question is from Liisa Bayko with Evercore ISI.

# Liisa Bayko Analyst

Congratulations on the good quarter. Just wondering if you could give us a view on sort of the next data readout for your type 1 diabetes program, both the cells and the cells plus pouch?

# Reshma Kewalramani Executive

Sure thing. Liisa, with regard to the T1D program, on the VX-880 side, that's, let's call it the naked cells program. You should expect to have a data readout at the fall diabetes conference where there will be an oral presentation. On the 264 program, that's the cells plus device program, we've just initiated enrollment. We've just dosed, as you heard in my prepared remarks, the "rst patient.

And you should expect to hear from us with regard to results from that cells plus device program, which does not require immunosuppressants, either when we reached a milestone in terms of data readout or we have a decision to communicate. We won't be sharing results patient by patient.

# Liisa Bayko Analyst

Okay. Fair enough. And then as you think about your kind of commercial path for pain, are you going to be focusing on certain types of centers? I mean this could be obviously a very broad market and opportunity. How are you thinking about the rollout and where?

I'm curious on that kind of -- the market estimates could be -- have a very wide range depending on how you think about it.

# Reshma Kewalramani Executive

Sure. Liisa, you're right. We see this as an enormous opportunity. Let me ask Stuart to tell you how we plan to approach that opportunity. Stuart?

# Stuart Arbuckle Executive

Yes. So acute pain, obviously, which is going to be our "rst launch indication subject to the studies being positive is -- 2 things can be true at the same time, Liisa. I'd say one is acute pain therapies are prescribed by a wide range of prescribers. That is indeed true, but it's equally true that a large percentage of the prescriptions are concentrated in institutions, ambulatory surgical centers, settings like that, where patients are either prescribed and dispensed their acute pain medicine whilst they're in the institution or the facility. And then they're also prescribed and given a prescription on discharge for their ongoing pain management when they leave the facility.

That accounts for a large percentage of the prescriptions in acute pain. Those prescriptions are concentrated in somewhere around just shy of 200 sites covered by about 220 or so IDNs. And that is going to be the primary focus of our commercialization activities. We think we can cover that universe of centers with a sales force approximately in the 150 range, which "ts very nicely with our focus on specialty markets.

# Operator Operator

\[Operator Instructions\]

The next question is from Salveen Richter with Goldman Sachs.

# Salveen Richter Analyst

Just a follow-up on the acute pain program. Just can you help us understand, apart from -- upon a positive data outcome here, and given the target prescribers you mentioned, what needs to be done logistically to ensure a successful launch with regard to just the marketing aspect, the -- whether there's kind of any understanding that needs to be played out with regard to contracts and how the no pain law kind of falls into this? Just any idea of how you can ensure this plays out well.

# Reshma Kewalramani Executive

Sure. Salveen, I'll ask Stuart to comment.

# Stuart Arbuckle Executive

Yes, Salveen, thanks for the question. I think there's a couple of other things that are likely to be supportive of VX-548 in acute pain. One is, I think we are likely to see a number of the existing pain treatment guidelines, consider updates their guidelines once there is the availability of a safe and e!ective non-opioid medicine. In addition, and you mentioned one of them, I think we are increasingly going to see policies change their focus. The policies that have been put in place in states and hospitals over the last few years for understandable reasons have largely all have been about restricting prescriptions, restricting who can prescribe for which patient types for what length of time.

I think we are beginning to see the focus of those policy initiatives changed to being supportive of non-opioid pain medicines like VX-548. And I think that that's a very welcome systemic change, which will potentially support the uptake of the VX-548 subsequent to it getting approved. So in addition to our own commercialization e!orts, I think there's a number of supportive at the launch.

# Operator Operator

Question is from Geo! Meacham with Bank of America.

Geo!rey Meacham Analyst

Just had a follow-up on exa-cel. I know you guys are focused today on regulatory and commercial as well. But when you think about the improved conditioning regimen, I wanted to know kind of what we should expect from that optimization of that? What are kind of the -- what does success look like, I guess, for that? And what are the time lines, I think, that we'll see some data for?

# Reshma Kewalramani Executive

Sure. Geo!, as we think about the busulfan based conditioning regimen, which is what exa-cel will launch with, we see that as having a positive bene"t risk pro"le for the approximately 32,000 people with the most severe forms of sickle cell disease and beta thalassemia. And with the improved or gentler conditioning, we see the opportunity to serve the full 150,000 people with sickle cell disease and beta thalassemia in Europe and the U.S. What this program looks like, and we have an active set of programs internally, our partners at CRISPR are working on this problem, other academia and biotechs are working on this problem. And so I do see this as a problem that will be solved.

It's not a tomorrow solution, but I see this happening in the coming months and years.

What we see is the opportunity to have a conditioning regimen that very speci"cally targets the compartment and the cells that are limited to those hematopoietic stem cells sparing all of the other cells. And in so doing, not have the side e!ects of busulfan, including the very signi"cant cytopenias that you see with busulfan. So I do think that this is an area that we will see a solution for because we and others are working on it and because of the broad application, and I do think you'll see progress in the coming months and in our years. I don't mean decades.

# Operator Operator

Our next question is from Robyn Karnauskas with Truist Securities.

# Robyn Karnauskas Analyst

Sorry for the noise. I'm on board a plane and we're departing. So the question is, what is the bar for neurotrophic mean? I know your previous study with your previous drug kind of looks similar to Lyrica. Maybe you could step that for us in a second.

We've done some due diligence in the chemo-related peripheral neuropathy is a huge unmet need. I wanted to know whether you thought it might work in this population as well.

# Reshma Kewalramani Executive

Yes. So Robyn, the bar for neuropathic pain is to have a better overall pro"le bene"t risk taken together than existing therapies. As you know, the existing therapy has limitations in terms of e#cacy, but there are also limitations on the safety/AE side. And the reason for that is what we use for neuropathic pain is frankly, a recycled medicine that comes from fundamentally central nervous system depression that we are reusing for neuropathic pain because that's the best we have.

So what we're going to be looking for is improvement in diabetic peripheral neuropathic pain scores, change from baseline and our Phase II dose-ranging proof-of-concept study also has a Lyrica arm for context. So we'll be able to see the magnitude of the treatment e!ect as well as a Lyrica arm for context.

# Operator Operator

The next question is from David Risinger with Leerink Partners.

# David Risinger Analyst

Yes. I wanted to change gears, please, to your 2 AAT candidates. Could you frame the e#cacy results to watch in 2024? And potential time line for those readouts next year?

# Reshma Kewalramani Executive

Sure. David, I think you're asking about the AATD program. And just to ground everyone on that one, this is our program where we have 2 molecules, VX-864, which is in a Phase II study and VX-634, which is making its way through a Phase I study. Our excitement for this particular program and disease comes from the fact that it "ts the Vertex strategy like a glove. We are seeking to target both the liver and lung manifestations of this disease.

And our small molecule approach is the only one that holds the potential to treat both liver and lung manifestations. And I do believe you need to treat both in order to have a transformative medicine.

Our VX-864 study, which is in Phase II is a long-term study. It's a 48-week study. And there, we are looking at the impact of long-term dosing on both functional AAT levels in the blood and clearance of liver polymer. You might recall that on a post-hoc analysis of our VX-864 Phase II data from a few years ago, we saw a 90-plus percent reduction in serum Z polymer levels, which is why we're so interested in the liver polymer. And in the 634 study, we are going through our "rst in-human studies.

So I expect that we'll have all the results from both of these trials by sometime next year, so 2024, and I expect that we'll be able to share the results at that time. Exact timing, we're going to need to get a few more months under our belt to look at the enrollment dynamics, but I do expect we'll be sharing results by sometime next year. So it's a '24 milestone.

# Operator Operator

The next question is from Terence Flynn with Morgan Stanley.

# Terence Flynn Analyst

Stuart, you mentioned there were about 20,000 patients not on drug at the start of the year that could potentially be eligible. Just wondering where that "gure will end, assuming you achieve your new 2023 guidance?

# Stuart Arbuckle Executive

Yes, Terence. So we've kind of gone away over the last few years of kind of giving detail to the forensic accounting of all the di!erent patient numbers. And so I'm not going to kind of give you an updated estimate at this time. But as Charlie said in his remarks and I set in mine, we've continued to make good progress in treating more patients, including in younger age groups and including in other countries where we've secured reimbursements and launches. But other than that, we're not going into more detail at this time.

We may -- if there's a substantial change, we may update those numbers as we've done in the last couple of years or so at the beginning of next year when we talk about our guidance for the following year.

# Operator Operator

Next question is from Mohit Bansal with Wells Fargo.

# Mohit Bansal Analyst

Just wanted to get some color on how do you -- talked about sweat chloride improvement with the vanzacaftor trial. Is there a correlation between the amount of sweat chloride you reduced versus the \[ SCD \] improvement. If I'm not mistaken, the improved -- the sweat chloride improvement was about $30 %$ more than the dry cast combo, this combo. So just trying to understand how should we think about the bar for SEB that this new combined?

# Reshma Kewalramani Executive

Mohit, I think you're talking about the vanzacaftor triple, that's our next-in-class regimen for CF. This is the program that's in Phase III, and we expect to complete both studies in the 12- plus-year-old age group and the 6 plus year age group this year with results from that pivotal program early next year.

With regard to your question on sweat chloride and ppFEV1, yes. There is a very strong association between improvements in sweat chloride and improvements in lung function. And you can see that across all of our previous CFTR modulators, all the way from KALYDECO through ORKAMBI SIM and TRIKAFTA. So that relationship is strong. In terms of what you should expect from the vanzacaftor triple.

Or let me put it another way, the reason we have such high enthusiasm for the vanzacaftor triple, in the preclinical experiments, including the very important HBE assays, which have been not only qualitatively predictive, but quantitatively so, the vanzacaftor triple, I know this is hard to believe in a tall order, but the vanzacaftor triple preclinically is even better than TRIKAFTA in our HPE cells.

And when we look across the Phase II studies that have been done, the vanzacaftor triple have better sweat chloride than even TRIKAFTA. It's hard to call -- make a call on ppFEV1 because in the Phase II studies, the sample sizes are obviously smaller and ppFEV1 is a more variable endpoint. So I think the right measure to look at is indeed sweat chloride. And from all of the data we've collected, vanza is even better than TRIKAFTA on that measurement of sweat chloride.

# Operator Operator

The next question is from Michael Yee with Je!eries.

# Michael Yee Analyst

You announced that the chronic pain neuropenic pain study, Phase II was complete enrollment. So that's super exciting and the data, I guess is end of '23, early '24. Can you talk a little bit about, I guess, on one side, you feel con"dent because of the biology and the acute data was also quite strong, there's also some early chronic data as well as the last gen. But also, I guess, historically, chronic pain studies can be challenging with placebos, even with vicoden and opioids, you can get mixed results. So I just wanted to ask about your con"dence around this probability success versus the acute study, and how we should take this study into consideration from an expectation standpoint, give it just a Phase II?

# Reshma Kewalramani Executive

Sure. My con"dence level in the VX-548 program is equal for the acute pain studies in that Phase III program as it is for the diabetic peripheral neuropathy Phase II program. And you're right, that con"dence comes from the pharmacologic validation of the target, which we ourselves conducted with our predecessor molecule, VX-150, and also the genetic validation of the 1 8 target.

With regard to a double-click on what you could expect from both acute and the neuropathic pain studies, the acute pain program is 2 randomized clinical trials in the same bunionectomy, abdominoplasty. Those are 2 of the RCTs. And the third is a single-arm safety and e#cacy study to allow a broad, moderate-to-severe acute pain label in the various settings that Stuart described in terms of use. And I expect that those results will be available late this year, early next.

And the goal there is, gosh, if we see what we saw in Phase II for VX-548 acute pain, that would be a home run. So the diabetic peripheral neuropathy program, this is a multiple-doseranging proof-of-concept study where we also have a gabapentin arm for context. So what you should be looking for there is improvement in the pain score from baseline to the 12- week time point when we have the pain endpoint and you'll be able to make assessments versus the gabapentin arm that's in their fourth context. That study is fully enrolled and should also be available in terms of results late this year, early next.

# Operator Operator

The next question is from Evan Seigerman with BMO Capital Markets.

# Evan Seigerman Analyst

Kind of a follow-up to Mohit's question on the Vanza Triple, Talk about what the added bene"t of the vanza triple needs to be versus TRIKAFTA to get patients to switch. You also mentioned getting patients to levels of carrier levels of sweat chloride. Could you ever get to a wild-type level of sweat chloride?

# Reshma Kewalramani Executive

Yes. Let me take the second half of your question, Evan, and then I'll turn it over to Stuart to talk through how we're seeing the commercial opportunity for the vanza triple. So when you look at parents, so carriers of the CF mutation, for those who don't have disease. When you

are at those carrier levels of sweat chloride, you have virtually no manifestation of disease.

That's why we're targeting carrier levels of sweat chloride.

You're fundamentally -- just like you and me, I don't -- I'm not a carrier and I'm not a patient with CF. But if you are a carrier of CF, you are fundamentally una!ected. That's why that's the highest bar to achieve. And that's why that's the bar we continue to chase. The TRIKAFTA triple gets some patients there, the vanzacaftor triple will get more patients there.

But our research continues, and we've already identi"ed additional potentiators and correctors that will get us to that ultimate goal of carrier levels of sweat chloride. Stuart?

# Stuart Arbuckle Executive

Yes. So -- and in terms of the sort of uptake and what's attractive of the pro"le, we know from speaking with CF clinicians if vanzacaftor has the sort of pro"le that Reshma described earlier, where it's delivering increased levels of bene"t in terms of CFTR function as measured through sweat chloride that, that in and of itself will be an attractive proposition because as Reshma said, the link between increases in CFTR function and improvements in outcomes has been demonstrated through our own work.

In addition, you were talking about patients potentially transitioning. I do think there's an important group we should also consider, which is -- there have been a number of patients who over the years have discontinued their CFTR modulators. It's probably somewhere north of 6,000 patients who we know want to be on a CFTR modulator, but have had to discontinue over the years. And I do think that's another population who will welcome an additional treatment option being available.

# Operator Operator

The next question is from Colin Bristow with UBS.

# Colin Bristow Analyst

Congrats on the quarter. Maybe one of the CRISPR-based DMD program. Are you still on track to "le the IND in the second half? And then assuming all goes to plan, would it be reasonable to expect some clinical data in 2024? And then maybe if I could just have a quick follow-on to the vanzacaftor triple question.

Just what do you think you need to see for this to be a launch that is as a major component of switches versus just a new patient acquisition launch?

# Reshma Kewalramani Executive

Colin, I think there are 2 separate questions in there. One about the vanza triple and what do we need to see and then one on DMD. Let me tackle the DMD, DM1 question, I'll come back to vanza. On the DMD question, I'm going to broaden it out to muscular dystrophies as a whole, and I'll talk about DMD. and DM1.

We have programs in DMD that are going through IND-enabling studies now as well as in DM1. We actually have multiple programs in DM1. The lead program is the one that we inlicensed from Entrada. And that program also is already in IND-enabling studies and both of them should have those results in the second half of '23. And our timing remains to "le the IND for both DMD and for DM1 for the lead program in DM1 in the second half of this year.

With regard to the vanza, I think Stuart just covered that. What we're looking to see in the way the study is designed is vanzacaftor in the Phase III program head-to-head versus TRIKAFTA and the primary endpoint is sweat chloride. And the reason for that is, again, with patients who -- with carriers, those with who have 1 CF gene, they have virtually no manifestations of disease. And that is measured assessed by the sweat chloride carrier level is a description of sweat chloride levels. So that's what we're measuring.

We are, of course, going to have PPFEV1 in there. And as Stuart said, if the pro"le is, as I described it to be, improvement on sweat chloride levels, we expect it to have real value to patients. I'll also add that the vanzacaftor triple has a lower royalty burden than the TRIKAFTA combination.

# Susie Lisa Executive

Thanks, Reshma. Thanks, Colin. Gary. That brings us to time. Could you close it out, please?

# Operator Operator

This concludes the question-and-answer session, and the conference is also now concluded.

Thank you for attending today's presentation. You may now disconnect.