Vertex Pharmaceuticals Incorporated · NASDAQ:VRTX

Vertex Pharmaceuticals — American Society of Nephrology Kidney Week 2025

42 slides from Vertex Pharmaceuticals's conference presentation, Nov 8, 2025

1. Slide 1: Kidney Program Updates at the American Society of Nephrology Kidney Week 2025

   Kidney Program Updates at the American Society of Nephrology Kidney Week 2025 November 8, 2025 Presentation intended for the investment community ©2025 Vertex Pharmaceuticals Incorporated ©2025 Vertex Pharmaceuticals Incorporated

2. Slide 2: Agenda

   Welcome Susie Lisa, CFA, Senior Vice President, Investor Relations, Vertex Pharmaceuticals Kidney portfolio Reshma Kewalramani, M.D., President and Chief Executive Officer, Vertex Pharmaceuticals RUBY-3 late breaking data recap James A. Tumlin, M.D., Professor of Medicine in Nephrology at Emory Univ

3. Slide 3: Safe harbor statement

   This presentation contains forward-looking statements as defined in the Private Securities Safe harbor Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding Vertex's expectations for the kidney programs, including expectations that the company's four renal pr

4. Slide 4: Vertex's disease-first R&D strategy has delivered four renal programs

   Vertex’s differentiated, disease-first R&D strategy has delivered four renal programs each with first-in-class and/or best-in-class potential Immunoglobulin-A nephropathy (IgAN) R+D strategy centered on: • High unmet need​ Primary membranous nephropathy (pMN) • Causal human biology is known​ • Valid

5. Slide 5: Rapid progress across the kidney portfolio in mid- and late-stage development

   Rapid progress across the kidney portfolio with multiple programs now in mid- and late-stage clinical development PATIENTS1 RESEARCH PHASE 1 PHASE 2 PHASE 3 APPROVED Rolling BLA submission Povetacicept – IgAN2 ~300K for AA to begin YE 2025 (>750K China) Full trial enrolled B cell driven ~150K Phase

6. Slide 6: High unmet need + large patient populations = significant opportunity

   High unmet need + large patient populations = significant opportunity Vertex seeks to be a leader in the renaissance in renal medicine +>750K China 3 programs in pivotal development +>300K 4 potential kidney launches by 2030 China ~300K ~300K ~250K ~150K >$B each disease area represents a multi-$B o

7. Slide 7: BAFF and APRIL are central to pathogenesis of B cell driven diseases

   BAFF and APRIL are central to pathogenesis of B cell driven diseases Inhibiting both BAFF and APRIL provides optimal B cell control APRIL-dominant BAFF-dominant Large Small Immature Mature Plasmablast Plasma pre B cell pre B cell B cell naïve B cell cell BAFF APRIL • Important in early B cell develo

8. Slide 8: Pove: dual BAFF + APRIL inhibitor engineered for optimal B cell control

   Pove: dual BAFF + APRIL inhibitor, specifically engineered for optimal B cell control Plus significant advantages that yield desirable, patient-centric features By inhibiting both BAFF and APRIL, Desirable, patient-centric Specifically pove is designed to control B cells across the features and engi

9. Slide 9: Povetacicept is delivering on its pipeline-in-a-product potential

   Povetacicept is delivering on its pipeline-in-a-product potential In pivotal trials IgA Primary Membranous General Warm Autoimmune Other Nephropathy Nephropathy Myasthenia Gravis Hemolytic Anemia B Cell-Driven (IgAN) (pMN) (gMG) (wAIHA) Diseases RAINIER pivotal trial OLYMPUS pivotal trial In FDA dis

10. Slide 10: IgAN: RAINIER Phase 3 trial fully enrolled in ~15 months

    IgAN: RAINIER Phase 3 trial fully enrolled in ~15 months Fastest of any contemporary IgAN trial IgAN and pMN Phase 2 continues to show best-in-class clinical potential IA cohort, for potential U.S. accelerated approval, enrolled Q2:25 Phase 3 trial now fully enrolled FDA Breakthrough Therapy Designa

11. Slide 11: pMN: Pove is the first BAFF/APRIL inhibitor in pivotal development

    pMN: Pove is the first BAFF/APRIL inhibitor in pivotal development Single adaptive Phase 2/3 study of povetacicept versus SOC Dose selection Randomization 2:3 Anti-PLA2R at Week 12 Population: Double-blinded • Adults with pMN diagnosis by biopsy Povetacicept • UPCR ≥3.5 g/g 80mg SC Q4W • eGFR: ≥40 m

12. Slide 12: AMKD: Leading the way with inaxaplin for patients with significant unmet need

    AMKD: Leading the way with inaxaplin for patients with significant unmet need On track to achieve major milestones over the next 12 months First and only drug to achieve Innovation recognized by On track for First and only drug to achieve Innovation recognized by On track for proof of concept in AMK

13. Slide 13: ADPKD: Leveraging our CF expertise through protein correction and serial innovation

    ADPKD: Leveraging our CF expertise and seeking to transform patient lives through protein correction and serial innovation Cystic fibrosis ADPKD First asset VX-407 in Phase 2 POC CFTR correctors promote proper folding of CFTR PC1 correctors aim to promote proper folding and restore trafficking to th

14. Slide 14: Vertex's disease-first R&D strategy has delivered four renal programs

    Vertex’s differentiated, disease-first R&D strategy has delivered four renal programs each with first-in-class and/or best-in-class potential Immunoglobulin-A nephropathy (IgAN) R+D strategy centered on: • High unmet need​ Primary membranous nephropathy (pMN) • Causal human biology is known​ • Valid

15. Slide 15: Efficacy and Safety of Povetacicept in IgAN and pMN at 48 Weeks (RUBY-3)

    #SA-OR091 Efficacy and Safety of Povetacicept in IgA Nephropathy and Primary Membranous Nephropathy at 48 Weeks of Treatment (RUBY-3 Study) James Tumlin1; Rajesh Yalavarthy2; Dong Ki Kim3; Ju-Young Moon4; Inwhee Park5; Sung Gyun Kim6; Sreedhar Mandayam7; Frank Cortazar8; Amanda Enstrom9; Heather Tho

16. Slide 16: Author Disclosures

    Author Disclosures Research Support • AbbVie • Epizon Pharma • Novartis • Achillion Pharmaceuticals • Gilead Sciences • Novo Nordisk (Chinook) • Akebia Therapeutics • Horizon • Otuska Pharmaceutical • Alexion • Johnson & Johnson • Relypsa • Argenyx • La Jolla Pharmaceutical Company • Roche • AstraZe

17. Slide 17: BAFF + APRIL: Central to the Pathogenesis of Autoimmune Glomerulonephritis

    BAFF + APRIL: Central to the Pathogenesis of Autoimmune Glomerulonephritis • BAFF primarily regulates earlier B cell stages; APRIL-dominant and promotes pathogenic T and innate BAFF-dominant immune cells, aberrant IgA glycosylation leading to Gd-IgA1 (IgAN), pathogenic autoantibodies against PLA2R (

18. Slide 18: Povetacicept is a Dual BAFF + APRIL Inhibitor Engineered for Superior Potency

    Povetacicept is a Dual BAFF + APRIL Inhibitor Engineered for Superior Potency, Affinity, and Enhanced Tissue Distribution WT-TACI Fc Povetacicept • Superior potency against BAFF and APRIL • Modest BAFF, weak APRIL • Superior BAFF and APRIL binding potency affinity • Modest BAFF binding affinity • En

19. Slide 19: RUBY-3 Study Design

    RUBY-3 Study Design Ongoing Phase 1/2 open-label study in adults with IgAN and pMN receiving povetacicept o IgAN: 80 mg (N=21 dosed; N=17 at Week 48) or 240 mg (N=33 dosed; N=30 at Week 48) o pMN: 80 mg (N=10 dosed; N=5 at Week 48) Note: ClinicalTrials.gov ID: NCT05732402; date of data cut is 13 Jun

20. Slide 20: IgAN Baseline Characteristics

    IgAN Baseline Characteristics: Participants With Moderate/Large Hematuria (>50%) Povetacicept 80 mg SC Q4W Povetacicept 240 mg SC Q4W Parameter N = 21 N = 33 Age; mean (SD) yr 47.6 (11.7) 45.1 (12.1) Male; n (%) 7 (33) 18 (55) Female; n (%) 14 (67) 15 (45) Race (Asian/White/Other); n (%) 10 (48)/10

21. Slide 21: IgAN: Povetacicept Reduced Proteinuria 64% at Week 48

    IgAN: Povetacicept Reduced Proteinuria 64% at Week 48 Percent Change from Baseline to Week 48 (Mean ± SE) in 24-hour UPCR – 80 mg Q4W Mean 24-hour UPCR decreased substantially at 48 weeks with 80 mg Q4W: • 64% decrease from baseline (1.3 g/g to 0.5 g/g) • ~2/3 participants achieved UPCR <0.5 g/g Wit

22. Slide 22: IgAN: Povetacicept Stabilized eGFR Through Week 48

    IgAN: Povetacicept Stabilized eGFR Through Week 48 Change from Baseline to Week 48 (Mean ± SE) in eGFR – 80 mg Q4W With 240 mg Q4W: 3.2 mL/min/1.73 m2 change from baseline at Week 48 Note: date of data cut is 13 June 2025

23. Slide 23: IgAN: Early Gd-IgA1 Reduction Continued at Week 48

    IgAN: Early Gd-IgA1 Reduction at Week 12 Continued at Week 48 (77%) Percent Change from Baseline to Week 48 (Mean ± SE) in Gd-IgA1 – 80 mg Q4W Mean Gd-IgA1 decreased substantially with 80 mg Q4W: • Declined early by 57% at Week 12 • Reduction continued at Week 48 by 77% With 240 mg Q4W: 77% decrease

24. Slide 24: IgAN: Hematuria Resolution and Clinical Remission

    IgAN: Substantial Proportion of Participants on Povetacicept Achieved Hematuria Resolution (90%) and Clinical Remission (53%) Clinical Hematuria Resolution and Clinical Remission from Week 12 to Week 48 – 80 mg Q4W With 240 mg Q4W: 94% achieved hematuria resolution at Week 48 34% achieved clinical r

25. Slide 25: pMN Baseline Characteristics

    pMN Baseline Characteristics: Participants Had Nephrotic Range Proteinuria (60%) and High Anti-PLA2R Autoantibody Titer Povetacicept 80 mg SC Q4W Parameter N = 10 Age; mean (SD) yr 58.2 (18.1) Male; n (%) 8 (80) Female; n (%) 2 (20) Race (Black or African American/White/Asian); n (%) 4 (40)/4 (40)/2

26. Slide 26: pMN: Povetacicept Reduced Proteinuria 82% at Week 48

    pMN: Povetacicept Reduced Proteinuria 82% at Week 48 Percent Change from Baseline to Week 48 (Mean ± SE) in 24-hour UPCR – All Participants with pMN Note: date of data cut is 13 June 2025

27. Slide 27: pMN: Povetacicept Stabilized eGFR through Week 48

    pMN: Povetacicept Stabilized eGFR through Week 48 Change from Baseline to Week 48 (Mean ± SE) in eGFR – All Participants with pMN Note: date of data cut is 13 June 2025

28. Slide 28: pMN: Anti-PLA2R Autoantibody Reduction and Immunologic Remission

    pMN: Povetacicept Reduced Anti-PLA2R Autoantibody 83% Leading to Immunologic Remission in All Participants at Week 48 Percent Change from Baseline to Week 48 Immunologic Remission from (Mean ± SE) in Anti-PLA2R Autoantibody Week 12 to Week 48 – All Participants with pMN – All Participants with pMN N

29. Slide 29: pMN: Partial and Complete Clinical Remission at Week 48

    pMN: All Participants on Povetacicept Achieved Partial Remission and 40% Achieved Complete Clinical Remission at Week 48 Complete and Partial Clinical Remission from Week 12 to Week 48 – All Participants with pMN Note: Complete clinical remission is defined as UPCR <0.5 g/g. Partial clinical remissi

30. Slide 30: Povetacicept Was Generally Safe and Well Tolerated in Both IgAN and pMN

    Povetacicept Was Generally Safe and Well Tolerated in Both IgAN and pMN IgAN IgAN pMN Povetacicept Povetacicept Povetacicept • Most AEs were mild to 80mg SC Q4W 240mg SC Q4W 80mg SC Q4W N = 21 N = 33 N = 10 moderate in severity Parameter Any AE; n (%) 16 (76) 27 (82) 8 (80) Grade 1/mild 6 (29) 7 (21

31. Slide 31: Conclusions

    Conclusions • Povetacicept 80 mg Q4W led to early, substantial, and sustained improvements in IgAN o Proteinuria declined 64% at Week 48 o eGFR was stable through Week 48 o Gd-IgA1 declined early by 57% at Week 12 and continued at Week 48 with a 77% decline o Hematuria resolution was achieved by 90%

32. Slide 32: Acknowledgments

    Acknowledgments Thank you to the participants and their families, investigators, sites, and the RUBY-3 team Alexander Nimiri Arizona Kidney Disease and Hypertension Center Ju-Young Moon Kyung Hee University Hospital at Gangdong Angus Ritchie Concord Repatriation General Hospital Rajesh Yalavarthy We

33. Slide 33: Richard Lafayette, M.D. RAINIER pivotal study

    Richard Lafayette, M.D. Professor of Medicine (Nephrology) at the Stanford University Medical Center; Founder and Director of the Stanford Glomerular Disease Center Areas of Expertise: Nephrology, glomerular disease, amyloidosis, kidney and pancreas transplantation, pathogenesis of IgA nephritis  R

34. Slide 34: RAINIER pivotal trial for povetacicept in IgAN is fully enrolled

    RAINIER pivotal trial for povetacicept in IgAN is fully enrolled ~15 months to complete full enrollment of ~600 patients Population: Phase 3 • Adults with IgAN (biopsy-verified) Randomization 2:1, double-blinded • 24-hour proteinuria excretion ≥1 g/day or 24-hour uPCR ≥0.75 g/g Povetacicept 80 mg SC

35. Slide 35: Brad Rovin, M.D.

    Brad Rovin, M.D. Director, Division of Nephrology, Vice Chair of Research, Professor of Internal Medicine, Ohio State University Wexner Medical Center Areas of Expertise: Nephrology, glomerulonephritis, kidney disease  Evolving standard of care in IgAN  Role of guidelines in the treatment of IgAN

36. Slide 36: Treatment of IgAN now recommends shift from sequential to simultaneous intervention

    Treatment of IgAN now recommends shift from sequential to simultaneous + early and more aggressive intervention, with a redefined proteinuria threshold for “high-risk” From sequential to simultaneous first line Reduce glomerular hyperfiltration and the impact of proteinuria on the tubulointerstitium

37. Slide 37: Q&A Session

    Q&A Session ©2025 Vertex Pharmaceuticals Incorporated ©2025 Vertex Pharmaceuticals Incorporated

38. Slide 38: Appendix: Disease area backgrounders

    Appendix: Disease area backgrounders ©2025 Vertex Pharmaceuticals Incorporated • PUBLIC 38

39. Slide 39: IgAN: A serious autoimmune disease due to uncontrolled B cell activity

    IgAN: A serious autoimmune disease due to uncontrolled B cell activity; most patients are at risk of The 4-hit hypothesis kidney failure within their lifetimes 1 2 3 4 • IgAN is a global disease with >300k diagnosed patients in U.S. and Europe1 (>1M patients globally) Generation of Formation of Mesa

40. Slide 40: pMN: A rare autoimmune disease; Pathogenesis of pMN

    pMN: A rare, autoimmune disease caused by pathogenic antibodies that Pathogenesis of pMN target kidney podocytes, leading to long-term kidney damage • ~150k individuals diagnosed with pMN in the US and Europe (~500K patients globally) • Less than 50% of people with pMN achieve complete remission wit

41. Slide 41: AMKD: toxic gain-of-function APOL1 variants lead to proteinuria and kidney failure

    AMKD: toxic gain-of-function AMKD causal human biology APOL1 variants lead to proteinuria, kidney function decline and kidney failure • ~250,000 people in the U.S. & Europe living with AMKD, majority not diagnosed; occurs in people of African ancestry • AMKD is a genetic, rapidly progressive, protei

42. Slide 42: ADPKD: Kidney cysts lead to kidney function decline and kidney failure

    ADPKD: Kidney cysts lead to kidney function decline and kidney failure Over time, kidney cysts lead to kidney function (eGFR) decline and • ~300,000 people in the U.S. & kidney failure Europe diagnosed with ADPKD Normal Hyperfiltration Impairment Failure • Most common genetic cause of kidney failure

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