nacf investor event slide deck.pptx

©2014 Vertex Pharmaceuticals Incorporated

The Science of Possibility: Reaching More CF Patients and Enhancing Benefit

NACF Conference | October 9, 2015

Jeff Leiden, M.D., Ph.D. President & CEO

Paul Negulescu, Ph.D. SVP & San Diego Site Head

Jeff Chodakewitz, M.D. EVP & Chief Medical Officer

Stuart Arbuckle EVP & Chief Commercial Officer

Ian Smith EVP & Chief Financial Officer


2

Safe Harbor Statement

This presentation contains forward-looking information pertaining to KALYDECO®, 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, the risk that in vitro responses may not be predictive of clinical results, and the risks and uncertainties listed in the

Company’s October 8, 2015 press release and under Risk Factors in the Company’s

10-K and other filings with the SEC.


3

Agenda

Jeff Leiden, M.D., Ph.D., President & CEO Executing on the Strategy

Paul Negulescu, Ph.D., SVP & Site Head, San Diego Commitment to Patients: Reaching More People and Enhancing the Benefit in the Future

Jeff Chodakewitz, M.D., EVP & Chief Medical Officer Highlights from the Meeting and Our Development Programs

Stuart Arbuckle, EVP & Chief Commercial Officer Reaching More Patients Who Can Benefit Today

Q&A moderated by Ian Smith, EVP & Chief Financial Officer


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2014 – 2015 ü Maximize the potential of KALYDECO ü  Launch ORKAMBI ü Progress a portfolio of medicines to reach more patients with CF ü Enhance the pipeline through internal and external investments

2016 + •  Significant revenues from launching multiple high-value medicines •  An operating expense profile that supports earnings growth •  A pipeline of transformational medicines in CF and beyond

Vertex Strategy G

row

th Build foundation for long-term growth

Sustained revenue and earnings growth

2012 – 2013 ü  KALYDECO approval and launch ü  Advance CF pipeline ü  Invest in research outside CF

Invest to build core business

5

CF Strategy and Opportunity Maintaining Leadership in CF

Add

ress

able

Cys

tic F

ibro

sis

popu

latio

n

Vertex regimens APPROVED OR SUBMITTED CLINICAL TRIALS UNDERWAY

KALYDECO (ivacaftor) ORKAMBI (lumacaftor + ivacaftor) Dual or triple combination

US

R117H & Peds G551D & Ga(ng

US Residual Fn &

EU R117H & Peds

F508del Homozygous

ages 6-11

Vast Majority of all CF patients

US F508del Homozygous

ages 12+

F508del/ Minimal Fn

Ex-US F508del Homozygous

ages 12+

Ex-US Residual Fn

Ongoing clinical trials: •  Ph 3 VX-661 •  Ph 3 F508del homozygous

ages 6-11 •  Next-Gen Correctors

>60,000 2016 & Beyond

Today >25,000

>3,400 June 2015

>2,600 Oct 2014


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2

3

1

Today: CF Complexity Requires Multiple Regimens Multiple CF Medicines and Combinations for Different Patient Populations

Gating Mutations

Homozygous F508del/F508del

ORKAMBI

Potentiator + VX-661 (in trials) +

Next-Gen Corrector(s) (planned)

KALYDECO Heterozygous F508del/Minimal Fn


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Future: Triple Combinations Have Potential to Treat Vast Majority of CF Patients

Nonsense Mutations and others

KALYDECO Monotherapy (no F508del)

Anyone with ≥1 F508del Mutation (Next-Gen Corrector + VX-661 + ivacaftor)

Gating & Residual Fn Mutations

MAXIMIZE THE NUMBER OF PATIENTS TREATED

INCREASE THE BENEFIT FOR ALL and GOAL:


Heterozygous F508del/Minimal Fn


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Other Approaches Such as ENaC Inhibitors Could Provide Additional Benefit

ENaC inhibitor

Next-Gen Corrector + VX-661 + ivacaftor Anyone with ≥1 F508del Mutation

Gating & Residual Fn Mutations

(Next-Gen Corrector + VX-661 + ivacaftor)

MAXIMIZE THE NUMBER OF PATIENTS TREATED

INCREASE THE BENEFIT FOR ALL and GOAL:



Nonsense Mutations

and others


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Agenda







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Enhancing CFTR Protein Function with Next-Gen Correctors: Expanding to Treat More Patient Groups and Enhancing Potential Benefit

Hypothesis: Any CF Patient with at least one F508del mutation should benefit

Mechanism: Next-Gen correctors act with VX-809 or VX-661 to get more CFTR protein to the cell surface

Progress: Vertex is moving 2 Next-Gen correctors, VX-152 and VX-440, into Phase 1 studies in healthy volunteers in 2015



F508del/Gating F508del/Residual Fn

EXPAND ENHANCE ENHANCE

©20

15 V

erte

x P

harm

aceu

tical

s In

corp

orat

ed

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Triple Combinations Show Enhanced CFTR Function In Vitro

3 Donor Bronchi 5 Donor Bronchi

Chl

orid

e tr

ansp

ort (

%N

orm

al C

FTR

func

tion)

VX-152

Lumacaftor – – – Ivacaftor –

VX-440

80

70

60

40

20

10

30

50

VX-661

Ussing Chamber studies using bronchial epithelial cells expressing the genotypes indicated; Top of bar charts represent EC90 concentrations

ORKAMBI Untreated ORKAMBI Untreated

+++

F508del F508del

Homozygous

F508del Minimal CFTR function allele

Heterozygous

+++

+++

+++


12

1

2.9

2.5

0

1

2

3

4

F508del/F508del

Fold Increase in Chloride Transport Over ORKAMBI in F508del/F508del and F508del/Minimal Function HBE cells

ORKAMBI

VX-152 +VX-661

+ IVA VX-440

+VX-661 +IVA

Triple Combinations Show Enhanced CFTR Function In Vitro

Fold

incr

ease

rela

tive

to O

RK

AM

BI

Bar charts represent EC90 concentrations

1

3.3

2.8

0

1

2

3

4

F508del/Minimal Fn

ORKAMBI

VX-152 +VX-661

+ IVA VX-440

+VX-661 + IVA


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Triple Combinations Show Enhanced Cilia Beat Frequency in HBE Cells In Vitro


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In epithelial cells •  CFTR transports chloride ions out

•  ENaC transports sodium ions in

•  Balance between CFTR and ENaC activity regulates hydration of the airway surface

In Vitro, Inhibiting ENaC Shows Potential to Amplify Effect of CFTR Modulators in the Lung

Lung Epithelial Cell

Cl-

Na+

H20

CFTR ENaC


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VX-371 Significantly Amplified Cilia Beat Frequency in F508del Homozygous HBE Cells In Vitro

0.3

1

2

0

1

2

3

VX-371 ORKAMBI ORKAMBI + VX-371

F508del/F508del – HBE Cells (Fold increase in cilia beat frequency @ 72 hours in vitro)

Fold

incr

ease

rela

tive

to O

RK

AM

BI

F508del F508del

Homozygous


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Research Activity Supports Our Pipeline Progression

•  Two next-gen CFTR correctors advancing into the clinic in 2015 with potential to extend treatment to all CF patients with the F508del mutation

•  ENaC blocker VX-371 (P-1037) increases cilia beating and airway surface liquid when combined with CFTR modulation in F508del homozygous airway cells

•  Vertex is continuing internal research to identify additional correctors


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Agenda







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Development Plans for VX-152 and VX-440 and Triple Combinations

Results and regulatory input

Phase 2 Triple combination

Phase 1 Monotherapy and triple combination

Healthy volunteers Multiple CF patient groups, including F508del/minimal function

Single and multiple doses up to 14 days

Up to 28 days treatment duration

Initiate Nov 2015 Anticipated 2H 2016 Initiation


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VX-371 (P-1037) Phase 2 Development Plan

VX-371 vs. Saline

ANY CFTR MUTATION 120 patients, Age 12+

14 Days

Follow-up

F508DEL HOMOZYGOUS PATIENTS 150 Patients, Age 12+

ORKAMBI + VX-371 vs. ORKAMBI alone

28 Days, Crossover Design

Follow-up

Data anticipated mid-2016

•  Safety •  Absolute change

in ppFEV1

Key Outcome Measures Recruiting (conducted by Parion)

Starting in 2016 (conducted by Vertex) •  Safety •  Absolute change

in ppFEV1

•  Other exploratory measures

Key Outcome Measures

Vertex plans to explore ENaC inhibition in several other pulmonary indications


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VX-661 + Ivacaftor: Potential to Treat Multiple CF Patient Groups

Phase 3 studies are evaluating efficacy and safety in CF patients 12 and older across 4 groups:

F508del/F508del “homozygous” ~500 patients, 6 months of treatment vs. placebo

F508del/Gating ~200 patients, 8 weeks of treatment vs. ivacaftor

F508del/Residual function ~300 patients, 8 weeks of treatment, crossover design

F508del/minimal function “heterozygous” Initially enroll ~150 patients for 12 weeks of treatment, Potential expansion to 300 patients based on futility analysis

Studies expected to complete enrollment in mid-2016* * Expect to complete enrollment by mid-2016 in first three studies, and in first part of fourth (F508del/Min Fn) study


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KALYDECO sNDA Submission for Residual Function Accepted for Priority Review

sNDA for use of KALYDECO in people with CF ages 2+ who have one of 23 Residual Function mutations accepted for Priority Review by FDA

• KALYDECO currently approved in US to treat patients as young as 2 years old with one of 10 mutations*

•  sNDA based on:

o  Preclinical data for ivacaftor in the 23 residual function mutations

o  The established clinical profile of KALYDECO, and

o  Previously reported data from an exploratory Phase 2a study

•  >1,500 people in the US have one of these mutations; PDUFA date of February 6

* G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H


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Key Clinical Goal: Understand Value of Starting Treatment Early

•  KALYDECO approved in US to treat patients as young as 2 years old with one of 10 mutations*

•  Initiating study in 1Q16 to evaluate the safety of treating infants and toddlers <24 months

KALYDECO

ORKAMBI

•  ORKAMBI approved in US to treat patients who are F508del homozygous as young as 12 years old

•  Studies ongoing to evaluate the safety and efficacy of treating F508del homozygous patients age 6 – 11

•  Planning a study to evaluate the safety of treating ages 2 – 5

CLINICAL DEVELOPMENT PLANS

* G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H

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17 Data Presentations at NACFC

HIGHLIGHTS

Long-Term Safety Data on Ivacaftor Treatment •  Annual risk of death, organ transplantation, hospitalization and frequency of pulmonary exacerbation

were all significantly lower in the ivacaftor group compared to matched controls from the CF Patient Registry (Poster #246)

Rate of Lung Function Decline Not Associated with Acute Improvements in ppFEV1 in PERSIST Study •  Results indicate that KALYDECO produces separate and independent effects on lung function: acute

improvement in ppFEV1, and a reduction in the rate of ppFEV1 decline (Poster #221)

Reduction in Pulmonary Exacerbations in Traffic and Transport Studies Not Correlated to Acute Improvements in Lung Function •  ORKAMBI pulmonary exacerbation benefit was independent of the acute change in lung function at Day

15 (Poster #241)

Improvements in Lung Function, Pulmonary Exacerbations and BMI Observed Across Sub-Groups in TRAFFIC and TRANSPORT Studies, Regardless of Baseline Lung Function •  Efficacy and safety of ORKAMBI were generally similar across lung function subgroups (Poster #245)

The effects of CFTR modulators on treating the underlying cause of disease can be measured in multiple ways


24

Agenda






25

CF Strategy and Opportunity Maintaining Leadership in CF

Add

ress

able

Cys

tic F

ibro

sis

popu

latio

n

Vertex regimens APPROVED OR SUBMITTED CLINICAL TRIALS UNDERWAY

KALYDECO (ivacaftor) ORKAMBI (lumacaftor + ivacaftor) Dual or triple combination

US

R117H & Peds G551D & Ga(ng

US Residual Fn &

EU R117H & Peds

F508del Homozygous

ages 6-11

Vast Majority of all CF patients

US F508del Homozygous

ages 12+

F508del/ Minimal Fn

Ex-US F508del Homozygous

ages 12+

Ex-US Residual Fn

Ongoing clinical trials: •  Ph 3 VX-661 •  Ph 3 F508del homozygous

ages 6-11 •  Next-Gen Correctors

>60,000 2016 & Beyond

Today >25,000

>3,400 June 2015

>2,600 Oct 2014


26

KALYDECO Reaching More Patients Based on Geographic and Label Expansion

US: •  Patients ages 2+ with Gating mutations*

•  R117H (approved Dec 2014)

Ex-US: •  Strong Australian uptake in Gating patients

following reimbursement in late 2014 •  International reimbursement approval for

non-G551D Gating mutations received in Italy, France, UK and the Netherlands during 2Q15

•  R117H (ages 18+) and G551D/Gating (ages 2-5) CHMP positive opinion received Sept 2015

o  Marketing Authorization expected in EU in 4Q15

Our goal is to provide access to KALYDECO as quickly as possible for patients who may benefit

Approval of the Residual Function sNDA in the US for ages 2+ could potentially benefit >1,500 additional patients

* G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R


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ORKAMBI Has Potential to Benefit Many More People with CF Homozygous for F508del

•  US FDA approval received July 2 for patients ages 12+ who are homozygous for the F508del mutation

•  EU MAA decision expected in 4Q15

o  CHMP Positive Opinion in Sep

o  Country-by-country reimbursement discussions to follow

•  Planned sNDA submission for ages 6-11 in US in 2016

~5,500 6-11 in US + EU

~12,000 12+ in EU

~8,500 12+ in US


28

2014 – 2015 ü Maximize the potential of KALYDECO ü  Launch ORKAMBI ü Progress a portfolio of medicines to reach more patients with CF ü Enhance the pipeline through internal and external investments

2016 + •  Significant revenues from launching multiple high-value medicines •  An operating expense profile that supports earnings growth •  A pipeline of transformational medicines in CF and beyond

Vertex Strategy G

row

th Build foundation for long-term growth

Sustained revenue and earnings growth

2012 – 2013 ü  KALYDECO approval and launch ü  Advance CF pipeline ü  Invest in research outside CF

Invest to build core business

nacf investor event slide deck.pptx

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