VERTEX PHARMACEUTICALS INC MA

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

SCHEDULE 14A

Proxy Statement Pursuant to Section 14(a) of the Securities Exchange Act of 1934

x Filed by the Registrant o Filed by a Party other than the Registrant

Vertex Pharmaceuticals Incorporated

(Name of Registrant as Specified In Its Charter)

NOTICE OF ANNUAL MEETING OF SHAREHOLDERS

Wednesday, May 14, 2025

9:00 a.m. (Eastern Time)

https://meetnow.global/MXD5MZM

Dear Shareholders:

You are invited to attend the Vertex Pharmaceuticals Incorporated 2025 Annual Meeting of Shareholders. At the annual meeting, shareholders will vote:

•to elect the eleven director nominees that are set forth in the attached proxy statement to our board of directors to serve for a one-year term until the 2026 annual meeting of shareholders and until such person’s successor has been duly elected and qualified;

•to ratify the selection of Ernst & Young LLP as our independent registered public accounting firm for 2025;

•to hold an advisory vote on our 2024 named executive officer compensation; and

•on one proposal submitted by a shareholder, if properly presented at the meeting.

Shareholders also will transact any other business that may properly come before the annual meeting or any adjournment or postponement of the annual meeting.

MEETING INFORMATION

PROXY MATERIALS:

We are using the “Notice and Access” method of providing proxy materials to you via the Internet. We are mailing to you a Notice of Internet Availability of Proxy Materials instead of paper copies of this notice, our proxy statement, and our Annual Report on Form 10-K for the year ended December 31, 2024 (“Annual Report”). Notice and Access provides a convenient way for you to access our proxy materials. The Notice of Internet Availability of Proxy Materials includes instructions on how to access this notice, our proxy statement, and our Annual Report and how to vote your shares. The Notice of Internet Availability of Proxy Materials also contains instructions on how to receive a paper copy of the proxy materials and our Annual Report, if you prefer.

MEETING ACCESS:

THE ANNUAL MEETING WILL BE HELD VIRTUALLY VIA WEBCAST. A VIRTUAL ANNUAL MEETING WILL FACILITATE SHAREHOLDER ATTENDANCE AND PARTICIPATION BY ENABLING SHAREHOLDERS TO PARTICIPATE FROM ANY LOCATION AND AT NO COST. YOU WILL BE ABLE TO PARTICIPATE IN THE MEETING ONLINE, VOTE YOUR SHARES ELECTRONICALLY, AND SUBMIT YOUR QUESTIONS DURING THE MEETING BY VISITING HTTPS://MEETNOW.GLOBAL/MXD5MZM. THERE IS NO PHYSICAL LOCATION FOR THE ANNUAL MEETING.

Shareholders will need their unique control number, which appears on the Notice of Internet Availability of Proxy Materials or proxy card (printed in the shaded bar), or within the body of the email sending the proxy statement. If you hold shares beneficially through a bank, broker or other nominee (that is, in “street name”), you must register in advance togain access to the virtual meeting and to vote shares electronically during the meeting. To register, you will need to obtain a legal proxy from your bank, broker or other nominee. Once you have received a legal proxy from them, you must submit a copy of this legal proxy, along with your name and email address to Computershare at legalproxy@computershare.com. Alternatively, you may mail your legal proxy to the following address: Computershare, Vertex Pharmaceuticals Incorporated Legal Proxy, P.O. Box 43001, Providence, RI 02940-3001. Requests for registration must be labeled as “Legal Proxy” and received no later than 5:00 p.m. (Eastern Time) on May 9, 2025. You will receive an email from Computershare confirming your registration and providing your control number. You will need your control number toaccess the virtual annual meeting, submit your questions and vote your shares electronically.

The annual meeting will begin promptly at 9:00 a.m. (Eastern Time) on May 14, 2025.

We will make a list of our shareholders of record available electronically during the annual meeting. A shareholder wishing access to the list during the annual meeting should contact our corporate secretary in advance of the meeting.

RECORD DATE:

Only Vertex shareholders of record at the close of business on March 17, 2025 are entitled to receive notice of, and vote at, the annual meeting, and, subject to applicable law, any adjournment or postponement thereof.

VOTING:

Your vote matters. Whether or not you plan to attend the annual meeting, we urge you to vote as promptly as possible by Internet, telephone or signing, dating and returning a printed proxy card. If you attend the annual meeting, you may vote your shares during the annual meeting even if you previously voted your proxy. Please vote as soon as possible to ensure that your shares will be represented and counted at the annual meeting.

April 3, 2025

By Order of the Board of Directors,

Joy LiuCorporate Secretary

IMPORTANT NOTICE REGARDING INTERNET AVAILABILITY OF PROXY MATERIALS. This notice, our proxy statement, and our Annual Report on Form 10-K for the year ended December 31, 2024 are first being made available to holders of record of our common stock on or about April 3, 2025. These materials are available to holders of record of our common stock at www.envisionreports.com/VRTX and to beneficial holders of our common stock at www.edocumentview.com/VRTX.

SUMMARY

2024 marked another year of tremendous growth for Vertex across research, development, and commercialization, along with excellent financial performance. Our strategy of investing in scientific innovation to create transformative medicines for people with serious diseases, with a focus on specialty markets, continued to deliver. We now have seven approved medicines: five that treat cystic fibrosis (“CF”), one that treats severe sickle cell disease (“SCD”) and transfusion-dependent beta thalassemia (“TDT”), and one that treats moderate-to-severe acute pain. In 2024, we extended our leadership in CF through the approval of a new product, ALYFTREK, and by continuing to reach more people than ever before with our portfolio of CF medicines. We began to diversify our revenues through the global launch of CASGEVY, our gene-edited cell therapy for the treatment of SCD and TDT. And, we recently received a landmark approval in the U.S. for JOURNAVX, a first-in-class non-opioid treatment for moderate-to-severe acute pain. In addition, our broad and diverse pipeline continued to make significant progress, with four potentially transformative medicines advancing to pivotal development. Additionally, we acquired Alpine Immune Sciences, Inc. (“Alpine”) and its Phase 3 ready lead asset, povetacicept, adding the promise of a “pipeline-in-a-product” for multiple autoimmune diseases to our robust clinical portfolio.

From a financial perspective, our outstanding performance in 2024 resulted in net product revenues of $11.02 billion, representing 12% growth versus 2023, our tenth consecutive year of double-digit growth, and the continued strength of our balance sheet, ending the year with $11.2 billion in cash and investments. In summary, we are well-positioned to continue to create long-term value for both patients and shareholders, with a marketed product portfolio of transformative medicines for CF, SCD, TDT, and acute pain, and a clinical pipeline spanning more than ten disease areas and multiple therapeutic modalities including small molecules, biologics, and genetic and cell therapies.

Financial Performance

In 2024, sales of TRIKAFTA/KAFTRIO continued to drive our financial performance. We expect that our recently approved medicines, CASGEVY, ALYFTREK and JOURNAVX, will drive both continued revenue growth and diversification in 2025 and beyond.

•Our net product revenues increased to $11.02 billion in 2024, an increase of 12% or more than $1.1 billion, from our 2023 net product revenues.

•Our total research and development (“R&D”), acquired in-process research and development (“AIPR&D”) and selling, general and administrative (“SG&A”) expenses increased to $9.7 billion compared to $4.8 billion in 2023. This increase was primarily due to higher AIPR&D, including $4.4 billion related to our acquisition of Alpine, continued investment to support additional therapies in mid-to-late stage development, and increased commercial investments to support launches of our newly-approved therapies globally.

INCREASING NET

PRODUCT REVENUES

TOTAL R&D, AIPR&D AND

SG&A EXPENSES

SUMMARY

Marketed Products

Our differentiated R&D strategy has delivered more than a decade of leadership in CF. It also delivered the historic, global approvals for CASGEVY, the first CRISPR-based gene-edited cell therapy to be approved for people with SCD or TDT. And more recently, U.S. approval of JOURNAVX, the first and only non-opioid pain signal inhibitor, representing the first new class of pain medicines approved in over 20 years.

Cystic Fibrosis

In CF, our goal for more than 20 years has been to address the underlying cause of the disease and to bring more people with the disease to normal levels of CFTR function. We have continued to serially innovate in the years since the 2012 approval of KALYDECO, which was first approved to treat a CF population of approximately 1,000 people in the U.S. Today, we have five approved CF medicines that treat nearly three-quarters of the approximately 94,000 people with CF in the U.S., Europe, Australia, and Canada. Additionally, we continue to secure formal reimbursement in multiple additional countries that collectively comprise approximately 15,000 additional people with CF. Approximately 10,000 of those additional people with CF are eligible for treatment with CFTR modulators. We previously served many of these markets through named patient sales.

•In December 2024, the U.S. Food and Drug Administration (the "FDA”) approved ALYFTREK (vanzacaftor/tezacaftor/deutivacaftor), our once-daily, “next generation 2.0” combination CFTR modulator for the treatment of people with CF 6 years of age and older who have at least one F508del mutation or another responsive mutation in the CFTR gene. In March 2025, the U.K. Medicines and Healthcare products Regulatory Agency (“MHRA”) also approved ALYFTREK.

•Regulatory submissions for ALYFTREK, which are currently under review in the European Union (“E.U.”), Canada, Switzerland, Australia, and New Zealand.

•In December 2024, the FDA approved the expanded use of TRIKAFTA for the treatment of people with CF with 94 additional non-F508del CFTR mutations. TRIKAFTA is now approved in the U.S. for a total of 272 CFTR mutations. In February 2025, the European Medicines Agency (“EMA”) adopted a positive Committee for Medicinal Products for Human Use (“CHMP”) opinion for the label expansion of KAFTRIO for the treatment of people with additional non-F508del CFTR mutations.

•We entered into an extended long-term reimbursement agreement with National Health Services (“NHS”) England providing access to KAFTRIO, SYMKEVI and ORKAMBI, and continued access to KALYDECO, for existing and future eligible CF patients in England. We have entered into similar reimbursement agreements in Wales, Northern Ireland and Scotland. These reimbursement agreements include access to any future license extensions of these medicines.

•KAFTRIO is now reimbursed in all 27 countries of the E.U.

Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia

2024 was a foundational year for the commercial launch of CASGEVY, following approvals in the U.S., the E.U., the United Kingdom (the “U.K.”), the Kingdom of Saudi Arabia (“Saudi Arabia), the Kingdom of Bahrain (“Bahrain”), the United Arab Emirates (the “UAE”), Canada, and Switzerland. We estimate approximately 60,000 people with severe SCD or TDT are or could become eligible for CASGEVY in these jurisdictions. Our global launch for CASGEVY continues to focus on countries with high unmet medical need and infrastructure to support treatment with this CRISPR/Cas9-based gene-editing therapy, including the U.S., the Middle East, and major markets in Europe. We are working with authorized treatment centers (“ATCs”) to enable patient initiation, supporting the patient journey through infusion with CASGEVY, working with payors to secure broad and equitable access for patients and expanding our manufacturing and supply chain to meet growing patient demand. Our teams are also focused on educating patients, physicians and policymakers on the treatment journey and CASGEVY clinical data, as appropriate.

•CASGEVY is now approved in the U.S., the E.U., the U.K., Saudi Arabia, Bahrain, the UAE, Canada and Switzerland for people 12 years of age and older with SCD or TDT.

•We have activated more than 50 authorized treatment centers globally, and more than 50 patients have initiated cell collection.

•In the U.S., we have broad coverage of CASGEVY with both private and public payers. In addition, we reached an agreement with the Centers for Medicare & Medicaid Services to participate in its cell and gene therapy access model, which may enable additional access mechanisms for states and authorized treatment centers.

•In the Middle East, we have reached hospital-based reimbursement for people with SCD or TDT in Saudi Arabia, and national reimbursement for eligible people in Bahrain. We are actively working to expand access to CASGEVY across Europe and the Middle East.

•We entered into a reimbursement agreement with NHS England for eligible people with SCD to access CASGEVY, consistent with the reimbursement agreement reached in August 2024 for eligible people with TDT.

•The Italian Medicines Agency has approved early access for CASGEVY, on a case-by-case basis, for the treatment of people with TDT and SCD.

SUMMARY

Acute Pain

In January 2025, the FDA approved JOURNAVX for the treatment of moderate-to-severe acute pain in adults. JOURNAVX is a first-in-class, oral pain signal inhibitor that is highly selective for NaV1.8 voltage-gated sodium channels. Through this mechanism, JOURNAVX provides effective relief of pain without evidence of the limitations of other currently available therapies, including the addictive potential of opioids. Our launch strategy for JOURNAVX in the U.S. focuses on securing broad access for people with acute pain, educating patients and physicians on the clinical profile of JOURNAVX, and making investments to provide seamless treatment experiences for physicians and people with acute pain. We are engaging with payors and formulary decision-makers to secure reimbursement and access to JOURNAVX. We have secured broad stocking agreements at various national retail pharmacies as well as regional chains to facilitate broad availability of JOURNAVX. We have also established financial and co-pay assistance programs for patients that will support access to JOURNAVX.

Research and Development

We invest in research and development to discover and develop transformative medicines for people with serious diseases, with a focus on specialty markets. Our research and development strategy combines advances in the understanding of human disease and the science of therapeutics to dramatically advance human health. This strategy was designed to deliver transformative medicines for serious diseases at high rates of speed and success, and it has delivered just that. Our research and development approach also includes pursuing multiple modalities tailored to the specific disease area target under investigation, using biomarkers that translate from the bench to the bedside, and advancing multiple candidates into clinical trials with the goal of bringing first-in-class and/or best-in-class, therapies to patients. In addition to expanding our small molecule programs, we have also advanced an industry-leading portfolio of biologics, cell therapies and genetic therapy programs.

The advancement of novel candidates from the bench into clinical trials and successfully completing pivotal development and obtaining regulatory approvals reflects our strategy in action. It has yielded multiple commercial products including ALYFTREK, TRIKAFTA/KAFTRIO, SYMDEKO/SYMKEVI, ORKAMBI, and KALYDECO for CF, CASGEVY for SCD and TDT, and JOURNAVX for the treatment of moderate-to-severe acute pain. Our approach to drug discovery has also yielded therapies that have demonstrated clinical proof-of-concept in additional disease areas, including diabetic peripheral neuropathy with suzetrigine, AMKD with inaxaplin, and T1D with zimislecel. Furthermore, in 2024, we acquired Alpine and its lead asset, povetacicept, which has the potential to be a “pipeline-in-a-product” and a best-in-class approach to treat multiple B cell-mediated autoimmune diseases including IgA nephropathy (“IgAN”), where it has demonstrated positive proof-of-concept.

Our advancements across multiple disease areas and modalities since the beginning of 2024 include:

•Cystic Fibrosis. We are enrolling and dosing a Phase 3 clinical trial evaluating ALYFTREK in children with CF 2 to 5 years of age who have at least one F508del mutation or a mutation responsive to triple combination CFTR modulators. We continue to serially innovate in CF, raising the bar each time we do so, as we continue our mission to bring all patients with CF to normal levels of CFTR function. Our first “next-generation” triple combination of TRIKAFTA (NG 1.0) set a high bar for improvements in CFTR function, and ALYFTREK (NG 2.0) has improved upon TRIKAFTA. Our next triple combination regimen, NG 3.0, will consist of tezacaftor, VX-828 (a new CFTR corrector), and either VX-118 (a new CFTR potentiator) or deutivacaftor. We have completed Phase 1 clinical trials evaluating VX-118 and we are in the process of completing Phase 1 clinical trials with VX-828. We expect to enter clinical trials evaluating NG 3.0 in people with CF this year. We are also pursuing genetic therapies for people with CF who do not make full-length CFTR protein and, as a result, cannot benefit from our current CF medicines. For these more than 5,000 people, in collaboration with Moderna, we are developing VX-522, a CFTR mRNA therapeutic designed to treat the underlying cause of CF in these people by enabling cells in the lungs to produce functional CFTR protein. The multiple ascending dose portion of the clinical trial for VX-522 in people with CF is ongoing and we expect to share data in the first half of 2025.

•Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Two global Phase 3 clinical trials evaluating CASGEVY in children 5 to 11 years of age with severe SCD and TDT are ongoing. We have completed enrollment in these two clinical trials, and we expect to complete dosing in 2025. We are advancing preclinical assets for myeloablative conditioning agents with improved tolerability profiles, which could be used in connection with treatment with CASGEVY and significantly broaden the eligible SCD and TDT patient population. We are also investigating in vivo gene-editing approaches and small molecules for the potential treatment of SCD and TDT.

•Acute Pain. We are enrolling and dosing patients in a Phase 2 clinical trial evaluating an oral formulation of VX-993, our next-generation NaV1.8 pain signal inhibitor, for the treatment of moderate-to-severe acute pain. We are also enrolling and dosing healthy volunteers in a Phase 1 clinical trial evaluating an intravenous formulation of VX-993.

•Neuropathic Pain. The FDA has granted suzetrigine Breakthrough Therapy Designation in diabetic peripheral neuropathy and we are enrolling and dosing in the Phase 3 pivotal program evaluating suzetrigine in this population. In addition, we are enrolling and dosing patients in a Phase 2 diabetic peripheral neuropathy clinical trial of the oral formulation of VX-993. In December 2024, we announced results from a Phase 2 clinical trial evaluating suzetrigine in people with lumbosacral radiculopathy (“LSR”). The clinical trial met its primary endpoint, but the suzetrigine arm did not separate from the placebo reference arm. We hypothesize that a high placebo response in this clinical trial led to a lack of separation of the suzetrigine and placebo response curves. We believe we can innovate in pain clinical trial design to better control the placebo effect, and succeed in pivotal development with suzetrigine. Pending discussions with regulators, we plan to initiate a Phase 3 clinical trial of suzetrigine in LSR.

SUMMARY

•APOL-1 Mediated Kidney Disease. Inaxaplin, our small molecule for the treatment of APOL1-mediated kidney disease (“AMKD”) is in pivotal development. We continue to enroll and dose people with AMKD in the Phase 3 portion of the global Phase 2/3 clinical trial. We expect to complete enrollment in the interim analysis cohort in 2025. This cohort requires 48 weeks of follow-up, at which point the interim analysis will be conducted. If the interim analysis is positive, we will apply for potential accelerated approval in the U.S.

•IgA Nephropathy. Povetacicept, a dual inhibitor of the B cell activating factor (“BAFF”) and a proliferation-inducing ligand (“APRIL”) pathways, is a potentially best-in-class approach to treat IgAN and is in pivotal development. We are currently enrolling and dosing patients in the Phase 3 clinical trial and expect to complete enrollment in the interim analysis cohort this year. This cohort requires 36 weeks of follow-up, at which point the interim analysis will be conducted. If positive, we will apply for potential accelerated approval in the U.S. Povetacicept is also being studied in two Phase 2 basket trials of additional B cell-mediated autoimmune diseases: renal conditions in RUBY-3 and hematologic conditions in RUBY-4. We expect data in some of these conditions in 2025.

•Type 1 Diabetes. Zimislecel, formerly known as VX-880, is an allogeneic, stem-cell derived, fully differentiated islet cell therapy in pivotal development for the treatment of type 1 diabetes (“T1D”). We expect to complete enrollment and dosing in the Phase 3 portion of this Phase 1/2/3 clinical trial in 2025 and, assuming positive data, we expect to file for approval in 2026. In March 2025, we announced results from the Phase 1/2 clinical trial evaluating VX-264, our second clinical program in T1D, in which zimislecel is encapsulated in an immunoprotective device. VX-264 was generally safe and well-tolerated, however, efficacy data are not supportive of further clinical development. We plan to conduct further analyses of the VX-264 Phase 1/2 study, including explanted devices, to better understand these findings. In research, we are pursuing development of gentler approaches to immunosuppression for patients receiving zimislecel, as well as gene-editing approaches to develop hypoimmune stem cell-derived allogeneic cells.

•Myotonic dystrophy type 1. We are exploring multiple approaches to address the underlying causal biology for myotonic dystrophy type 1 (“DM1”), including small molecules and VX-670, an oligonucleotide-based approach in-licensed from Entrada Therapeutics, Inc. (“Entrada”). We completed the single ascending dose portion of the global Phase 1/2 clinical trial evaluating VX-670 in people with DM1 and we are currently enrolling and dosing the multiple ascending dose portion of the trial, which will evaluate the safety and efficacy of VX-670.

•Autosomal Dominant Polycystic Kidney Disease. We are nearing completion of a Phase 1 clinical trial in healthy volunteers evaluating VX-407, our first-in-class small molecule corrector that targets the underlying cause of autosomal dominant polycystic kidney disease (“ADPKD”) in people with a subset of variants in the PKD1 gene. We expect to advance VX-407 into a Phase 2 proof-of-concept study in people with ADPKD in 2025.

•In addition to the programs listed above, we have several earlier-stage research programs aimed at diseases that fit our R&D strategy, as well as follow-on programs in diseases already in the clinic.

We will continue investing in scientific innovation through our internal research efforts and by accessing emerging technologies and product candidates through business development transactions.

The following chart represents our approved medicines, clinical stage programs and select pre-clinical programs.

SCD: sickle cell disease; TDT: transfusion-dependent beta thalassemia; alt. IS: alternative immunosuppression; CF: cystic fibrosis; AMKD: APOL-1 mediated kidney disease; ADPKD: autosomal dominant polycystic kidney disease; LSR: lumbosacral radiculopathy; PNP: peripheral neuropathic pain; DPN: painful diabetic peripheral neuropathy; CFTR mRNA: cystic fibrosis transmembrane conductance regulator messenger RNA; DM1: myotonic dystrophy type 1; pMN: primary membranous nephropathy; LN: lupus nephritis; AAV: ANCA-associated vasculitides; ITP: idiopathic thrombocytopenia; AIHA: warm autoimmune hemolytic anemia; CAD: cold agglutin disease.

SUMMARY

Increasing Shareholder Value

We expect that execution of our differentiated serial innovation strategy will continue to create shareholder value over the long-term. The biotechnology sector is subject to short-term volatility and many biotechnology companies experienced stock price fluctuations in 2024, including Vertex, where our stock price reached an all-time high of $519.88. We believe, however, that biotechnology companies are best measured over the long term as opposed to one-year or other shorter-term increments. The following chart shows our total shareholder return relative to the Nasdaq Biotechnology Index and S&P 500 index since 2012, when our first CF medicine was approved.

SUMMARY

Corporate Responsibility

We are a leading global biotechnology company that serially innovates to bring transformative medicines to people with serious diseases. We are committed to operating our business responsibly and disclosing our progress to stakeholders on an annual basis. Our progress and efforts with respect to environmental, social, and governance topics, including community engagement and workplace practices, were recognized broadly in 2024. A selection of awards and recognitions include Forbes’ America’s Best Companies, Fortune 100 Best Companies to Work For® 2024, TIME 100 Most Influential Companies, U.S. News & World Report Best Companies to Work For, Points of Light’s Civic 50, Science Magazine’s Top Employers, Fast Company’s 2024 World’s 50 Most Innovative Companies list, TIME Magazine’s Best Inventions of 2024 for CASGEVY, and many others.

Our corporate responsibility priorities relate to four objectives fundamental to our business: improving the lives of people with serious diseases; fostering a culture of innovation, integrity, and belonging; carefully managing our operations and environmental footprint; and making a positive impact in our communities.

SUMMARY

Director Nominees

The following table provides summary information regarding our eleven director nominees. For detailed information about each nominee’s background and areas of expertise, please see Proposal No. 1: Election of Directors.

SUMMARY

2024 Compensation Decisions and Pay-for-Performance

In 2024, our executive compensation program received substantial support, with approval by approximately 91% of the votes cast at the annual meeting. We believe this support is consistent with our shareholders’ understanding of our business model, our pay-for-performance compensation philosophy, and the long-term value we are creating. Our management development and compensation committee (“MDCC”) and our board of directors reviewed our compensation programs and made the following key decisions with respect to 2024 compensation:

•We increased the base salary and the target cash bonus as a percentage of base salary for Dr. Reshma Kewalramani, our CEO and President, based on a comparative analysis of companies in our peer group, and maintained her target equity level.

•Based on a comparative analysis of companies in our peer group, we increased the base salaries and target cash bonuses as a percentage of base salary for Dr. David Altshuler, Mr. Stuart Arbuckle, Dr. Nia Tatsis, and Mr. Charles Wagner, and maintained their target equity levels.

•Our outstanding performance in 2024 resulted in the MDCC determining that we had achieved a leading rating for 2024 (142 out of a total potential score of 150), with the payment of annual cash bonuses commensurate with this high level of performance.

•Our total revenue exceeded the board’s pre-approved financial targets for 2024, resulting in maximum payout achievement for our 2024 financial-based performance stock units (“PSUs”). In addition, the MDCC determined that our non-financial PSUs with a three-year performance period ending December 31, 2024 achieved maximum payout based on achieving all three milestones associated with each award.

•We maintained the mix of equity granted to our named executive officers (each, a “NEO”) with 50% of the awards consisting of PSUs that vest upon achievement of specific performance goals and 50% consisting of time-vesting restricted stock units (“RSUs”). This mix incentivizes both shorter-term financial accomplishments and longer-term strategic objectives, long-term tenure, and the creation of shareholder value.

•We extended the term of the employment agreement of our Executive Chairman, Dr. Jeffrey Leiden, until 2027. Under his amended employment agreement, Dr. Leiden continues to receive no cash compensation for his role as Executive Chairman other than an annual cash payment intended to facilitate participation in the Company’s benefit plans, and he will continue to receive equity awards for his service as Executive Chairman.

Executive Transitions

In February 2025, we announced the retirement of Mr. Arbuckle, our Chief Operating Officer, and the appointment of Mr. Wagner as Chief Operating Officer, each effective as of July 1, 2025. Mr. Wagner will remain our Chief Financial Officer following his appointment. We also announced the appointment of Duncan McKechnie as Chief Commercial Officer effective July 1, 2025. In connection with his appointment, we entered into a new employment agreement and a new change of control agreement with Mr. Wagner. Under his new employment agreement, Mr. Wagner will receive a base salary of $1,000,000 and a target annual bonus of 100% of his base salary effective July 1, 2025. In connection with his retirement, the MDCC considered Mr. Arbuckle as eligible for the retirement vesting provisions of his equity awards.

Shareholder Engagement

Shareholder Outreach and Engagement

We believe that a robust shareholder outreach program is an important component of maintaining our strong corporate governance practices. We strive for a collaborative approach with shareholders to solicit and understand a variety of perspectives and interests, and our practice has been to engage with our shareholders regularly over the course of the year.

In 2024, we solicited feedback regarding our corporate governance practices from shareholders representing approximately 70% of our outstanding shares. Our integrated outreach team included leaders from our Investor Relations, Human Resources, Corporate Responsibility, and Legal teams, and we discussed numerous topics of shareholder interest, including our business strategy, R&D approach, human capital management, corporate governance, political and lobbying disclosures, executive compensation, shareholder proposals, and environmental sustainability matters.

SUMMARY

Response to 2024 Shareholder Proposal

Among the topics our outreach team discussed with shareholders in 2024 was the advisory proposal (the “Advisory Proposal”) presented to shareholders at our 2024 annual meeting. The Advisory Proposal sought to lower the ownership threshold required to call a special shareholder meeting (such ownership threshold, the “Special Meeting Threshold”) from 40% to 10%. The Advisory Proposal was approved by holders of a majority of shares represented at the 2024 Annual Meeting.

We asked shareholders for their perspectives about the appropriate Special Meeting Threshold. Shareholders representing approximately 60% of our outstanding shares responded, including those who voted for and against the Advisory Proposal. Some investors shared their concerns that a 10% Special Meeting Threshold would be too low, allowing a small number of shareholders to call a special meeting. This would potentially allow holders of a small minority of outstanding shares of the company to advance their own special interests at the expense of other shareholders while also distracting directors and management to the detriment of the company. Other investors indicated that, while they supported the Advisory Proposal when the Special Meeting Threshold was at 40%, they would be supportive of an alternative Special Meeting Threshold higher than 10% and lower than 40%. More than half of respondents expressed the view that a 25% Special Meeting Threshold would be appropriate.

After careful consideration of the views expressed during our shareholder outreach, in February 2025, our board amended our by-laws to reduce the Special Meeting Threshold from 40% to 25%. Consistent with the feedback we received from many of the shareholders with whom we engaged, our board believes that a 25% Special Meeting Threshold is a reasonable threshold that strikes an appropriate balance between ensuring that shareholders have a meaningful right to call a shareholder meeting and protecting against the risk that a small minority of shareholders could trigger a special meeting that is not in the best interest of all shareholders, requiring significant corporate resources and disrupting our business.

SUMMARY

Corporate Governance

We are committed to maintaining strong corporate governance practices that promote the long-term interests of our shareholders and strengthen board and management accountability.

Voting Roadmap

TABLE OF CONTENTS

PROXY STATEMENT

This proxy statement is being made available to shareholders of Vertex Pharmaceuticals Incorporated in connection with the solicitation by our board of directors of proxies to be voted at our 2025 annual meeting of shareholders and at any postponement or adjournment thereof. The annual meeting will be held on Wednesday, May 14, 2025, at 9:00 a.m. (Eastern Time) as a virtual meeting conducted exclusively via live webcast at https://meetnow.global/MXD5MZM. See Frequently Asked Questions Regarding the Annual Meeting - How May I Attend the Annual Meeting? below for information regarding attending the virtual annual meeting.

Our board of directors has nominated the following current directors - Sangeeta Bhatia, Lloyd Carney, Alan Garber, Reshma Kewalramani, Michel Lagarde, Jeffrey Leiden, Diana McKenzie, Bruce Sachs, Jennifer Schneider, Nancy Thornberry, and Suketu Upadhyay - for election at our 2025 annual meeting of shareholders to hold office until our 2026 annual meeting of shareholders.

Each of the nominees has agreed to be named in this proxy statement and to serve if elected. We believe that all of the nominees will be able and willing to serve if elected. However, if any nominee should become unable or unwilling to serve for any reason, proxies may be voted for another person nominated as a substitute by our board or our board may reduce the number of directors.

Our board of directors is our company’s ultimate decision-making body, except with respect to those matters reserved to the shareholders. Our board selects our senior management team, which in turn is responsible for the day-to-day operations of our company. Our board acts as an advisor and counselor to senior management and oversees its performance.