Full Year and Fourth Quarter 2015 Financial Results January 27, 2016

Agenda Introduction Michael Partridge, VP Investor Relations Strategy and 2016 Business Priorities Jeff Leiden, M.D., Ph.D., President and CEO Full Year and Fourth Quarter 2015 Financial Results Ian Smith, Chief Financial Officer Q&A 2 ©2016 Vertex Pharmaceuticals Incorporated

Safe Harbor Statement

This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, information pertaining to KALYDECO® and ORKAMBI®, the ongoing discovery, development and commercialization of Vertex’s product candidates and the Company’s future financial performance. While the Company believes that these forward-looking statements are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to differ materially from the Company’s current expectations. These risks and uncertainties include, among others, the risk that data from the Company's development programs may not support registration or further development of its compounds due to safety, efficacy or other reasons, and the risks and uncertainties listed in the Company’s January 27, 2016 press release and under Risk Factors in the Company’s 10-K and other filings with the SEC.

3 ©2016 Vertex Pharmaceuticals Incorporated

Non-GAAP Financial Measures 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 exclude stock-based compensation expense, costs and credits related to the relocation of the company's corporate headquarters including a one-time 2014 cash payment related to a lease agreement, hepatitis C-related revenues and costs, $75.0 million payment related to our collaboration with CRISPR Therapeutics AG and other adjustments. These results are provided as a complement to results provided in accordance with GAAP because 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. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally and to manage the company's business and to evaluate its performance. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the attached financial information.

4 ©2016 Vertex Pharmaceuticals Incorporated

2015: A Transformational Year for Vertex

5

Approval and successful launch of ORKAMBI while continuing to grow KALYDECO

ü  U.S. FDA approval of ORKAMBI; 4,500+ patients treated as of December 31 ü  Approval of ORKAMBI in EU ü  Gating reimbursement for KALYDECO in multiple EU countries ü  Approval for KALYDECO ages 2-5 in US and EU, and R117H ages 18+ in EU ü  sNDA accepted for review for KALYDECO in certain residual function ages 2+

Significantly advanced CF development pipeline

ü  Initiation of VX-661 pivotal program ü  Advancement of next-generation correctors, VX-152 and VX-440, into clinical

Expanded and diversified pipeline outside CF

ü  Oncology: VX-970 and VX-803 Phase 1 studies ongoing; VX-984 ongoing ü  Pain: VX-150 Phase 1 study complete; Phase 2 initiated; VX-241 advancing to

Growing revenues, earnings and cashflow, and >$1B of cash entering 2016

ü  Total CF net product revenues of $983M, >110% increase v. 2014 CF net product

development

ü  In-licensed VX-371 (Parion) as different approach to treat CF

Phase 1 in 2016

ü  Collaboration with CRISPR Therapeutics

revenues of $464M ü  Cash flow positive in 4Q’15

ü  Strong balance sheet ü  2016: Positioned for increasing revenues, earnings and cash flow ©2016 Vertex Pharmaceuticals Incorporated

2016 Business Priorities Cystic Fibrosis (CF) Expand number of eligible patients treated with KALYDECO and ORKAMBI and develop new medicines to potentially treat all people with CF in years ahead

Emerging Financial Profile Positioned for increasing revenues, earnings and cash flow

Pipeline Investing to create new transformative medicines 6 ©2016 Vertex Pharmaceuticals Incorporated ©2015

Residual Function: Basis for sNDA Filing to FDA

•  Approximately 1,500 people ages 2+ in US with CF have residual function mutations represented in sDNA •  Submission based on preclinical and Phase 2a clinical data showing effect of ivacaftor on CFTR function in certain residual function mutations •  Filing supported by more than 4 years of safety data for KALYDECO •  PDUFA date of February 7 7 ©2016 Vertex Pharmaceuticals Incorporated

ORKAMBI Phase 3 Data in Ages 6-11 Study Supports sNDA Submission Study Background

Primary Endpoint: Safety

•  Open-label, ages 6-11, n=58

•  Met primary safety endpoint

•  1 dose group

•  Most common AEs

o  LUM 200mg/IVA 250mg •  24-week duration

Secondary Endpoints: Efficacy •  Treatment demonstrated within-group improvements at week 24 in: o  o  o  o  o 

Absolute change in ppFEV1 LCI (exploratory) Sweat chloride BMI CFQ-R

o  Cough, headache, infective PE, nasal congestion, abdominal pain, increased sputum and elevated liver enzymes

Overall Conclusion •  Regimen was well-tolerated •  Demonstrated improvements in all secondary endpoints •  Demonstrated favorable changes in LCI

8 ©2016 Vertex Pharmaceuticals Incorporated

Maintaining Leadership in CF RESEARCH

CRISPR

PHASE 1

NextGeneration Correctors

PHASE 2

ENaC

PHASE 3

VX-661 + ivacaftor

APPROVED

KALYDECO® ORKAMBI®

RESEARCH

PHASE 1

PHASE 2

PHASE 3

APPROVED

•  Four-year research collaboration with initial focus in CF and Sickle Cell Disease

•  Phase 1 underway with Next-Gen correctors VX-152 and VX-440

•  Phase 2 monotherapy results anticipated in mid-2016

•  Broad Phase 3 program underway

•  KALYDECO label expansion for G551D, Gating, R117H & Ages 2-5

•  Phase 2, 28-day triple combination study in patients planned to begin 2H16

•  Phase 2 combination study with luma/iva anticipated in 1H16

•  Additional opportunity to provide further safety data for triple combination

•  ORKAMBI approval for F508del/F508del patients ages 12+ in US and EU •  Additional opportunity for label and geographic expansion 9 ©2016 Vertex Pharmaceuticals Incorporated

Building a Sustainable Business in CF and Beyond

High operating margins

High-value specialty medicines

EPS growth Reinvest in R&D and BD

Low G&A expense

Create high-value breakthrough medicines Allow significant reinvestment in R&D

Maximize shareholder returns Diversified pipeline 10 ©2016 Vertex Pharmaceuticals Incorporated

Continued KALYDECO Growth Based on Geographic and Label Expansion •  4Q’15 KALYDECO net revenues of $181M, an increase of 45% v. 4Q’14

•  Growth in 2015 from geographic and label expansion o 

4,000 patients eligible for KALYDECO as of December 31, 2015

•  2016 Market Dynamics: o  o  o 

Continued label and geographic expansion Growth expected to be offset by ongoing enrollment in VX-661 + ivacaftor pivotal study Residual function PDUFA date February 7; Potential for additional 1,500 patients 11 ©2016 Vertex Pharmaceuticals Incorporated

ORKAMBI Launch Update

•  4Q’15 ORKAMBI net revenues of $220M, an increase of 68% v. 3Q’15 o 

As of December 31, 2015 more than 4,500 patients have started treatment in US

•  2016 Market Dynamics: o 

Gross-to-net adjustments to increase to mid-teens by end of 2016

o 

Expect ex-US revenues from Germany only in 2016; EU pricing and reimbursement discussions ongoing on country-by-country basis

12 ©2016 Vertex Pharmaceuticals Incorporated

Fourth Quarter and FY2015 Financial Highlights 4Q’15

FY2015

KALYDECO Revenues

181

632

ORKAMBI Revenues

220

351

Combined Non-GAAP R&D and SG&A Expense*

282

1,060

204

764

78

296

43

(268)

0.17

(1.11)

(in $M except per share data)

Non-GAAP R&D Expense* Non-GAAP SG&A Expense* Non-GAAP Net Income (Loss)* Non-GAAP Net Income (Loss) Per Share*

Cash Balance at December 31, 2015*

1.04B

*An explanation of the company’s non-GAAP financial measures and a full reconciliation of GAAP to non-GAAP financial results is included in the company’s press release dated January 27, 2016. * Cash includes cash, cash equivalents and marketable securities. As of December 31, 2015 the company had $300M of term debt. *The company’s GAAP net loss was $76M and $558M, respectively, GAAP R&D expense was $310M and $996M, respectively, and GAAP SG&A expense was $97M and $377M, respectively, in 4Q’15 and FY2015.

13

©2016 Vertex Pharmaceuticals Incorporated

2016 Financial Guidance

(in $M)

KALYDECO Revenues

Non-GAAP Operating Expenses

FY 2016 Guidance $670 – 690M $1.18 – 1.23B

Non-GAAP R&D Expense

$850 - 880M

Non-GAAP SG&A Expense

$330 – 350M

Notes •  2016 KALYDECO net revenue guidance excludes any potential revenues from approval for residual function. •  2016 KALYDECO net revenue guidance reflects expectation for approx. 200 patients to enroll in clinical study VX-661 + ivacaftor who would otherwise receive the drug. •  Company expects to provide ORKAMBI net revenues guidance in 2016 based on additional uptake in U.S. and further data on persistence and compliance rates. •  Combined non-GAAP operating expenses exclude stock-based compensation expense and certain other expenses.

14

©2016 Vertex Pharmaceuticals Incorporated

Key Factors for Understanding Revenues from ORKAMBI Launch 1.  Rate of Uptake: How quickly eligible patients initiate treatment o 

Rate of initiation slows as penetration rate increases

2.  Peak Penetration: Proportion of eligible patients initiated on therapy o 

We believe vast majority of eligible patients will initiate treatment by end of 2016

3.  Persistence: Proportion of patients that remain on therapy o 

In clinical study at 48 weeks, discontinuation rate was approx. 15%

4.  Compliance: What percentage of pills patients actually take o 

KALYDECO compliance rate is approximately 85%

o 

Other chronic CF medicines have lower compliance rates

These combined factors drive ORKAMBI revenue

15

©2016 Vertex Pharmaceuticals Incorporated

Building a Sustainable Business in CF and Beyond

High operating margins

High-value specialty medicines

EPS growth Reinvest in R&D and BD

Low G&A expense

Create high-value breakthrough medicines Allow significant reinvestment in R&D

Maximize shareholder returns Diversified pipeline 16 ©2016 Vertex Pharmaceuticals Incorporated