High-Throughput Screening Speeding Up CF Drug Discovery >10,000 Primary assays/day High-throughput screening CFTR Modulator Drug SAR based Medicinal Chemistry Prioritize hits Screening Assay Courtesy of Vertex Pharmaceuticals

VX-770 Phase III Study Design Randomized, double-blind, placebo-controlled Recruitment: 161 subjects Key inclusion criteria –G551D mutation on at least one CFTR allele –Aged ≥ 12 years –FEV 1 40% to 90% predicted Run-in Screening Randomization (1:1) Or 2-yr Follow-up VX mg q12h Open-label rollover study Placebo Day Week 24 VX mg q12h VX-770 Treatment period Extension period Primary analysis Elborn JS, 34th ECFC (NCT )

Change from Baseline in Sweat Chloride Treatment effect through Week 24 – 47.9 mmol/L P < Treatment effect through Week 48 – 48.1 mmol/L P < Elborn JS, 34th ECFC 2011 Vertex press release June 10, 2011

Absolute Change in FEV 1 % Predicted Treatment effect through Week % P < Treatment effect through Week % P < Elborn JS, 34th ECFC 2011 Vertex press release June 10, 2011

Time to First Pulmonary Exacerbation Week 24 Hazard Ratio 0.40 P = Week 48 Hazard Ratio 0.46 P = Hazard Ratio: 0.45 ( 0.28, 0.73) P= PLACEBOVX-770 Event-Free Rate At Week PLACEBOVX-770 Event-Free Rate At Week 48 Placebo VX-770 Proportion of event-free subjects Study day Modified Fuchs’ criteria Elborn JS, 34th ECFC 2011 Vertex press release June 10, 2011

Change from Baseline in CFQ-R Respiratory Domain * MCID, minimal clinically important difference (Quittner et al 2009) MCID = 4* Treatment effect through Week P < Treatment effect through Week P < Elborn JS, 34th ECFC 2011;Vertex press release June 10, 2011

Change from Baseline in Weight Treatment effect at Week kg P < Treatment effect at Week kg P = Elborn JS, 34th ECFC 2011 Vertex press release June 10, 2011 See talk by M Drumm: S1 (Thursday 2:00 PM)

Summary of VX-770 Phase III Study in CF Patients with the G551D Mutation Rapid onset and sustained improvement in lung function (primary endpoint: absolute change in % predicted FEV 1 ) Parallel improvement in CFTR function and lung function Sustained improvements in other outcomes including risk of exacerbation, respiratory symptoms and weight gain No important safety concerns KALYDECO was approved by the FDA on January 31, 2012 for patients with CF who are 6 years of age and older and who have a G551D mutation For more information on other VX-770 studies, see posters by R Ahrens, E McKone & P Flume: #s 203, 204 & 206, respectively

5 Classes of CFTR Mutations I Defective Production II Defective Processing III Defective Regulation IV Defective Conductance V Reduced Amounts G542X R553X W1282X F508delG551D N1303K R117H R334W kbC>T A>G CFTR is made & in proper Location, but Does not function normally

2011 Clinical Studies with CFTR Modulators Rowe SM et al., New Engl J Med 2005 CFTR potentiator VX-770: Phase III study in CF patients with the G551D CFTR mutation CFTR corrector VX-809: Phase IIa study in CF patients with the  F508 CFTR mutation