Vertex Pharmaceuticals Incorporated : Q3 2023 Presentation

THIRD QUARTER 2023 FINANCIAL RESULTS

NOVEMBER 6, 2023

©2023 Vertex Pharmaceuticals Incorporated

AGENDA

Introduction

Susie Lisa, CFA, Senior Vice President, Investor Relations

CEO Perspective and Pipeline Update

Reshma Kewalramani, M.D., Chief Executive Officer and President

Commercial Update

Stuart Arbuckle, Executive Vice President and Chief Operating Officer

Financial Results

Charlie Wagner, Executive Vice President and Chief Financial Officer

©2023 Vertex Pharmaceuticals Incorporated

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SAFE HARBOR STATEMENT & NON-GAAP FINANCIAL MEASURES

This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the information provided regarding expectations for future financial and operating performance, full-year 2023 financial guidance, including expectations for raised 2023 revenue guidance, and statements regarding our (i) expectations, development plans, and timelines for the company's products, product candidates, and pipeline programs, including expectations for potential near-term launches and clinical milestones, anticipated benefits of new products, patient populations, study designs, study enrollment, data availability, anticipated regulatory filings, regulatory approvals, and timing thereof, (ii) expectations to reach all CF patients eligible for CFTRm and the last ~5,000 CF patients (ineligible for a CFTRm) with VX-522, our plans to complete a single ascending dose study and initiate multiple ascending dose study for VX-522 in 2023, and our expectations for KAFTRIO approval in the EU and UK for children 2-5 years of age by end of 2023, (iii) expectations for the benefits of vanzacaftor triple combination therapy, plans to complete Phase 3 studies in 2023, expectations for data in early 2024, and expectations for near-term launch, commercial potential and lower royalty burden, (iv) expectations for the exa-cel program, including the potential of exa-cel to be a one-time, functional cure for patients with SCD and TDT, potential of exa-cel to be the first CRISPR-basedgene-editing treatment to be approved, initial patient targets, expectations regarding regulatory decisions, including timing thereof, expectations for near-term launch and commercial potential, including expected patient population, our launch readiness and expectations regarding providers and payers, expectations that 2024 will be a foundational year for exa-cel, expectations for each phase of the patient process for exa-cel, and plans for the global Phase 3 studies evaluating exa-cel in patients 5-11 years of age with SCD or TDT, (v) expectations for our pain program, including its potential to treat acute and neuropathic pain without the side effects or addictive properties of opioids, expectations to complete Phase 3 pivotal program for VX-548 in acute pain in late 2023 and have data in early 2024, expectations for data from the Phase 2 studies of VX-548 in neuropathic pain, plans to initiate a Phase 2 study evaluating VX-548 in LSR by end of 2023, commercial potential and plans for near-term commercial launch in moderate-to-severe acute pain, (vi) our expectations and beliefs regarding our pivotal program for inaxaplin, including its potential to treat the underlying cause of AMKD, plans regarding enrollment in Phase 2B portion of studies, expectations to select a dose and move to Phase 3 of the study in the first quarter of 2024, and our beliefs regarding anticipated results of the study, (vii) expectations for the development of our T1D programs, including the patient population, potential curative benefits and safety of VX-880, expectations for our VX-264 study, and expected use of CRISPR/Cas9 gene editing in our hypoimmune program, (viii) plans for continued advancement of VX-634 and VX-668, (ix) plans and expectations for our programs for muscular dystrophies, and (x) expectations regarding the company's tax rates, revenue growth, and the impact of foreign exchange rates on revenue growth. While Vertex believes the forward-looking statements contained in this presentation are accurate, these forward-looking statements represent the company's beliefs only as of the date of this presentation and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the company's expectations regarding future financial and operating performance may be incorrect (including because one or more of the company's assumptions underlying its expectations may not be realized), that our products may not receive regulatory approval on expected timelines, or at all, that external factors may impact the company's business or operations differently than the company currently expects, that data from preclinical testing or clinical trials, especially if based on a limited number of patients, may not be indicative of final results, that patient enrollment in our trials may be delayed, that actual patient populations able to participate in our trials or eligible for our products may be smaller than anticipated, that reimbursement for our therapies may be more difficult to obtain or maintain than expected, that data from the company's development programs may not be available on expected timelines, or at all, and may not support registration or further development of its potential medicines due to safety, efficacy or other reasons, and other risks listed under "Risk Factors" in Vertex's annual report filed with the Securities and Exchange Commission (SEC) and available through the company's website at www.vrtx.com and on the SEC's website at www.sec.gov. You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this presentation as new information becomes available.

In this presentation, Vertex's financial results and financial guidance are provided in accordance with accounting principles generally accepted in the United States (GAAP) and using certain non-GAAP financial measures. In particular, non-GAAP financial results and guidance exclude from Vertex's pre-tax income (i) stock-based compensation expense, (ii) gains or losses related to the fair value of the company's strategic investments, (iii) increases or decreases in the fair value of contingent consideration, (iv) acquisition-related costs, (v) an intangible asset impairment charge, and (vi) other adjustments. The company's non-GAAP financial results also exclude from its provision for income taxes the estimated tax impact related to its non-GAAP adjustments to pre-tax income described above and certain discrete items. These results should not be viewed as a substitute for the company's GAAP results and are provided as a complement to results provided in accordance with GAAP. Management believes these non-GAAP financial measures help indicate underlying trends in the company's business, are important in comparing current results with prior period results and provide additional information regarding the company's financial position that the company believes is helpful to an understanding of its ongoing business. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally, to manage the company's business and to evaluate its performance. The company's calculation of non-GAAP financial measures likely differs from the calculations used by other companies. The company provides guidance regarding combined R&D, Acquired IPR&D and SG&A expenses and effective tax rate on a non-GAAP basis. Unless otherwise noted, the guidance regarding combined GAAP and non-GAAP R&D, Acquired IPR&D and SG&A expenses does not include estimates associated with any potential future business development transactions, including collaborations, asset acquisitions and/or licensing of third-party intellectual property rights. The company does not provide guidance regarding its GAAP effective tax rate because it is unable to forecast with reasonable certainty the impact of excess tax benefits related to stock-based compensation and the possibility of certain discrete items, which could be material. Non-GAAP financial measures are presented compared to corresponding GAAP measures in the appendix hereto. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the company's Q3 2023 press release dated November 6, 2023.

©2023 Vertex Pharmaceuticals Incorporated

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STRONG THIRD QUARTER: CONTINUE TO DRIVE EXECUTION ACROSS THE COMPANY

Continue the journey in cystic fibrosis (CF)

• Serially innovate to bring highly efficacious therapies to all CF patients

Prepare for potential near-term commercialization opportunities

• Exa-cel:SCD PDUFA: December 8, 2023; TDT PDUFA: March 30, 2024; regulatory decisions in the EU and U.K. expected in the coming months
• Vanzacaftor triple in CF: all Phase 3 studies expected to complete by end of 2023; data in early 2024
• VX-548in moderate to severe acute pain: all Phase 3 studies expected to complete by end of 2023; data in early 2024

Accelerate diversified R&D pipeline

• VX-548in peripheral neuropathic pain:
• • Phase 2 DPN trial has completed; data by end of 2023
  • Phase 2 LSR trial to initiate by end of 2023
• Inaxaplin in AMKD: completion of enrollment in Phase 2B portion of Phase 2/3 trial this year
• VX-880in T1D: completed enrollment in Part C of Phase 1/2 study
• VX-522in CF: expect to complete the single ascending dose (SAD) portion in CF patients and initiate the multiple ascending dose (MAD) portion of the study by the end of 2023

Deliver financial performance

• Raising full year 2023 CF product revenue guidance to ~$9.85B; specialty model sustains strong operating margins while allowing for significant investments in pipeline and commercial capabilities

©2023 Vertex Pharmaceuticals Incorporated

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CONTINUING OUR SERIAL INNOVATION IN CYSTIC FIBROSIS

ON TRACK TO COMPLETE VANZACAFTOR TRIPLE STUDIES BY THE END OF 2023 WITH DATA IN EARLY 2024

Vanzacaftor Triple

• Next-in-classCFTR modulator triple therapy
• On track to complete all three Phase 3 studies by the end of 2023: SKYLINE 102 and SKYLINE 103 in patients ages 12+, RIDGELINE in patients ages 6-11 years
• Expect to share results from all three pivotal studies in early 2024
• Convenient, once-daily dosing
• Meaningfully lower royalty burden

VX-522

• CFTR mRNA therapy in development for ~5,000 CF patients who cannot benefit from CFTR modulators
• On track to complete single ascending dose (SAD) portion in CF patients in 2023 and initiate multiple ascending dose (MAD) portion of the study by the end of 2023
• Program developed in partnership with Moderna

©2023 Vertex Pharmaceuticals Incorporated

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NEAR-TERM LAUNCH POTENTIAL: EXA-CEL

FDA ADVISORY COMMITTEE COMPLETED FOR SCD, NOW APPROACHING REGULATORY DECISIONS FROM U.S., U.K., AND EU IN THE NEAR TERM

Exa-cel holds potential for one-time, functional cure

The first CRISPR-basedgene-editing treatment potentially to be approved

Plans to initially target the

most severe patients

(~32,000) across the U.S.

and Europe

SCD PDUFA: December 8, 2023

TDT PDUFA: March 30, 2024

Expect regulatory decisions from the U.K. and the EU in the

coming months

Submitted MAA to the Kingdom of Saudi Arabia; exa-cel is first ever to receive Breakthrough Medicines designation in

KSA

Updated clinical data in TDT and SCD accepted for oral presentation at ASH

Continue to enroll and dose two global Phase 3 studies in patients 5-11 years of age with SCD or TDT

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©2023 Vertex Pharmaceuticals Incorporated

VX-548 FOR ACUTE AND NEUROPATHIC PAIN HOLDS THE PROMISE OF EFFECTIVE PAIN RELIEF WITHOUT THE SIDE EFFECTS OR ADDICTIVE PROPERTIES OF OPIOIDS

ACUTE PAIN: PIVOTAL PROGRAM TO COMPLETE BY END OF 2023 WITH DATA IN EARLY 2024

PNP: PHASE 2 DPN TRIAL COMPLETE, PHASE 2 LSR TRIAL TO INITIATE BY END OF 2023

Significant Unmet Need

Validated Target

• Millions in the U.S. each year suffer from acute and peripheral neuropathic pain
• Existing therapies have challenging side effects and/or abuse potential
• NaV1.8 is genetically and pharmacologically validated
• 5 successful proof-of-concept studies across both VX-150 and VX-548 in major pain types

Acute pain

Near-term launch potential:

• On track to complete pivotal program by end of 2023
• • Completed Ph 3 trial in abdominoplasty
  • On track to complete Ph3 bunionectomy and single arm safety and effectiveness trial by end of 2023
• Results from all three Phase 3 studies expected in early 2024
• Granted Fast Track and Breakthrough Therapy designations

Peripheral neuropathic pain

Diabetic peripheral neuropathy (DPN):

• Completed the Phase 2, 12-week,dose-ranging,proof-of- concept study
• Expect to share results by the end of 2023

Lumbosacral radiculopathy (LSR):

• Expect to initiate a Phase 2 study in LSR, pain caused by impairment of nerve roots in the area of the lumbar spine, by the end of 2023

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©2023 Vertex Pharmaceuticals Incorporated

TYPE 1 DIABETES: ADVANCING POTENTIALLY CURATIVE TREATMENTS FOR ~2.5M PATIENTS IN NORTH AMERICA & EUROPE

PART C FULLY ENROLLED IN VX-880 TRIAL

EDITED, FULLY DIFFERENTIATED, HYPOIMMUNE CELLS

• The same cells as VX-880

• Research program continues to progress

VX-264: FULLY DIFFERENTIATED CELLS + DEVICE

• The same cells as VX-880
• Encapsulates cells in a device that is designed to eliminate the need for immunosuppressants
• Part A of Phase 1/2 trial enrolling and dosing (partial dose with staggered enrollment)

VX-880: FULLY DIFFERENTIATED CELLS WITH STANDARD IMMUNOSUPPRESSION

• Phase 1/2 trial:
• • Part A and Part B complete
  • • Presented positive updated clinical data at EASD in October 2023
  • Part C fully enrolled

VCTX-211, a hypoimmune program that originated under ViaCyte, has finished enrollment and dosing in Group 1 of the Phase 1/2 trial.

EASD: European Association for the Study of Diabetes

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©2023 Vertex Pharmaceuticals Incorporated

INAXAPLIN: FIRST POTENTIAL MEDICINE TO TARGET THE UNDERLYING CAUSE OF AMKD

100,000

patients in the U.S. and Europe

APOL1-MEDIATED

KIDNEY DISEASE

• Two APOL1 variants
• Proteinuric kidney disease
• Rapid progression to ESKD

©2023 Vertex Pharmaceuticals Incorporated

PIVOTAL TRIAL

UNDERWAY

• Phase 2B dose-ranging portion of the study continues to enroll and dose patients
• Expect to select a dose and move to Phase 3 of the study in the first quarter of 2024
• Path to accelerated approval with interim analysis at 48 weeks of treatment
• Final analysis at ~2 years of treatment

Image TBD

RAISING DISEASE AWARENESS

AND ONGOING GENETIC TESTING EFFORTS

• Education outreach with physicians and patients
• Building trust with historically underserved communities
• Multiple ongoing initiatives to increase awareness of the importance of genetic testing for AMKD

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CLINICAL PORTFOLIO IS BROAD, DIVERSE AND RAPIDLY ADVANCING

Select, Next Wave	Phase 1	Phase (1)/2
Research-stage Programs	in Healthy Volunteers	in Patients

Pivotal	Regulatory Submissions	Launched
Development	Completed

Vertex hypoimmune cells

Type 1 diabetes

Huntington's

ADPKD

Exa-cel

Improved conditioning

NaV 1.7

Pain

DMD

DM1

Follow-on programs:

• CF
• Pain
• AMKD
• AATD

VX-880

Type 1 diabetes

PoC achieved

VX-264 cells + device

Type 1 diabetes

VCTX-211 (ViaCyte) hypoimmune cells Type 1 diabetes

VX-548

Peripheral Neuropathic Pain - DPN

VX-548

Peripheral Neuropathic Pain - LSR*

VX-522**

CFTR mRNA

VX-548		Exa-cel
Acute Pain		Sickle Cell Disease
Vanzacaftor triple		Exa-cel
Cystic Fibrosis		TD Beta Thalassemia

Inaxaplin

AMKD

©2023 Vertex Pharmaceuticals Incorporated

ADPKD: Autosomal Dominant Polycystic Kidney Disease; DM1: Myotonic Dystrophy Type 1; DPN: diabetic peripheral neuropathy; FIH: First In Human; LSR: painful lumbosacral radiculopathy.	11
*Trial to initiate by YE 2023. **Phase 1, single ascending dose study in patients with CF.