Vertex Pharmaceuticals Investor Presentation — June 2022

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Efficacy and Safety of a Single Dose of

Exagamglogene Autotemcel for Transfusion -Dependent

β-Thalassemia and Severe Sickle Cell Disease

Franco Locatelli ,1Haydar Frangoul,2Selim Corbacioglu,3Josu de la Fuente,4Donna Wall,5Maria Domenica Cappellini,6

Mariane de Montalembert,7Antonis Kattamis,8Stephan Lobitz,9Damiano Rondelli,10Sujit Sheth,11 Martin Steinberg,12

Mark C. Walters,13Yael Bobruff,14Chris Simard,14Yang Song,14Lanju Zhang,14Anjali Sharma,15Suzan Imren,14

Bill Hobbs,14Stephan Grupp16 on behalf of the CLIMB THAL- 111 and CLIMB SCD -121 teams

1Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome, Italy; 2Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial,

Nashville, TN, USA; 3University of Regensburg, Regensburg, Germany; 4Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, UK; 5The Hospital for Sick

Children/University of Toronto, Toronto, Canada; 6University of Milan, Milan, Italy; 7Necker -Enfants Malades Hospital, Assistance Publique -Hôpitaux de Paris (AP -HP),

University of Paris, Paris, France; 8University of Athens, Athens, Greece; 9Gemeinschaftsklinikum Mittelrhein, Koblenz, Germany; 10University of Illinois at Chicago, Chicago, IL,

USA; 11Joan and Sanford I Weill Medical College of Cornell University, New York, NY, USA; 12Boston University School of Medicine, Boston, MA, USA; 13UCSF Benioff Children’s

Hospital, Oakland, CA, USA; 14Vertex Pharmaceuticals Incorporated, Boston, MA, USA; 15CRISPR Therapeutics, Cambridge, MA, USA; 16Children’s Hospital of Philadelphia,

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

27th Congress of the European Hematology Association (EHA) 2022; June 9– 17, 2022

* Exagamglogene autotemcel (exa- cel) is formerly known as CTX001Disclosures

Exa-cel Is a Cell Therapy That Uses Non -Viral, Ex Vivo CRISPR/Cas9 -Mediated

Editing of BCL11A to Increase HbF Levels1

•Naturally occurring genetic polymorphisms in

BCL11A are associated with elevated HbF and

decreased severity of TDT and SCD2-4

•BCL11A suppresses expression of γ-globin and

•Editing of Bcl11a reactivates γ -globin expression

and formation of HbF (α2γ2) in mouse models4

•Exa-celis produced using non- viral, ex vivo editing

of the erythroid -specific enhancer region of

BCL11A in CD34+HSPCs and reduces

erythroid -specific expression of BCL11A

•Infusion of exa- cel leads to an increase in HbF

levels in erythroid cells in vivo

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