Slides
Page 1
global.vrtx.com SUZETRIGINE (VX-548) PHASE 2 RESULTS IN PAINFUL LUMBOSACRAL RADICULOPATHY DECEMBER 19, 2024 ©2024 Vertex Pharmaceuticals Incorporated
Page 2
global.vrtx.com SAFE HARBOR STATEMENT 2©2024 Vertex Pharmaceuticals Incorporated This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding the anticipated benefits of suzetrigine as a treatment for patients with LSR, beliefs that Vertex can demonstrate success in a Phase 3 study of suzetrigine for patients with LSR, including beliefs that trial design may better control for the placebo effect, plans to advance to Phase 3 pending regulatory discussions focused on acceptance of novel study design and requirements to broaden beyond DPN indication, expectations for the LSR patient population in the U.S., expectations for securing a broad PNP label, Vertex's commitment to transforming the treatment of pain, and plans to continue advancing the next wave of NaV1.8 and NaV1.7 inhibitors. While Vertex believes the forward-looking statements contained in this presentation are accurate, these forward-looking statements represent the company's beliefs only as of the date of this presentation and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's pain programs may not support registration or further development of its potential medicines due to safety, efficacy or other reasons, that discussions with regulators may have different outcomes than the company anticipates, that the company may be unable to successfully commercialize suzetrigine as a treatment for pain and other risks listed under “Risk Factors” in Vertex's annual report filed with the Securities and Exchange Commission (SEC) and available through the company's website at www.vrtx.com and on the SEC’s website at www.sec.gov. You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this presentation as new information becomes available.
Page 3
global.vrtx.com©2024 Vertex Pharmaceuticals Incorporated 3 SUZETRIGINE PHASE 2 STUDY IN PAINFUL LUMBOSACRAL RADICULOPATHY (LSR): KEY POINTS • Suzetrigine Phase 2 LSR study met its primary endpoint: -2.02 within-group change from baseline in NPRS scores at week 12 Statistically significant and clinically meaningful reduction in NPRS scores Clearly an active drug, with meaningful treatment effect across pain studies However, treatment curves did not separate; placebo effect: -1.98 within-group change in NPRS to week 12 • Suzetrigine was well tolerated with a lower AE rate than the placebo arm, adding to the safety profile • Vertex believes we can demonstrate success in a Phase 3 study in LSR given: 1. The suzetrigine treatment effect was robust and consistent with prior studies 2. Insights from post hoc analyses regarding site variability and placebo effect 3. Our belief that we can better control for the placebo effect with innovation in clinical trial design • Advancing to Phase 3 pending regulatory discussions, focused on 1. Study design optimization to manage the placebo effect 2. FDA requirements to broaden beyond a diabetic peripheral neuropathy (DPN) indication • Committed to transforming the treatment of pain with innovations in NaV1.8/NaV1.7 research and clinical trial design NPRS = numeric pain rating scale, AE = adverse event. Suzetrigine is an investigational medicine for acute and peripheral neuropathic pain, including lumbosacral radiculopathy.
Page 4
global.vrtx.com©2024 Vertex Pharmaceuticals Incorporated 4 HIGH UNMET NEED AND LIMITED CLINICAL TRIAL EXPERIENCE CREATE SIGNIFICANT OPPORTUNITY IN LSR >4 million LSR patients in the U.S. • Limited LSR studies:* • ~10 published Phase 2 randomized placebo-controlled trials in LSR • No studies with NaV1.8 pain signal inhibitors • No Phase 3 study ever completed in LSR No approved therapies specifically indicated for LSR No defined standard for meaningful between-group difference of change in NPRS *Defined as studies of systemic therapies, does not include devices or procedures
Page 5
global.vrtx.com SUZETRIGINE PHASE 2 STUDY DESIGNED TO UNDERSTAND PERFORMANCE OF SELECTIVE NAV1.8 PAIN SIGNAL INHIBITOR AND PLACEBO IN LSR ©2024 Vertex Pharmaceuticals Incorporated 5 1. Evaluate the magnitude of the treatment effect with suzetrigine, the first selective NaV1.8 pain signal inhibitor to be studied in LSR 2. Evaluate the effect of placebo in patients with LSR 3. Assess safety and tolerability over 12 weeks of treatment Study goals Translate these learnings into next steps for suzetrigine in LSR
Page 6
global.vrtx.com Phase 2, randomized, double-blind, placebo-controlled study in patients with painful LSR lasting over 3 months SUZETRIGINE PHASE 2 LSR STUDY DESIGN 14 days Phase 2 study Run-in to establish baseline Suzetrigine (69mg qd) 7 days Placebo 12 weeks Safety Follow-upScreening N = 218 enrolled Primary Endpoint: • Within-group change from baseline in the weekly average of daily leg pain intensity on the NPRS at week 12 ©2024 Vertex Pharmaceuticals Incorporated 6 N=218 patients*, randomized 1:1 suzetrigine vs. placebo, enrolled across 38 sites. Patients were randomized after a 7-day run-in period to establish baseline. Pain medications, except stable over-the-counter doses of ibuprofen (up to 1600 mg/24-hour) or naproxen (up to 440 mg/24-hour), were stopped at least 14 days prior to first dose. Acetaminophen (up to 500 mg every 4 to 6 hours, as needed) was allowed during the run- in period and throughout the study. Key inclusion criteria: patients with painful lumbosacral radiculopathy lasting over 3 months, ages 18 to 70; moderate-to-severe pain (NPRS≥4 and <10). Key exclusion criteria: painful neuropathy other than LSR, history of prior lumbar spine surgery. Secondary Endpoints: • Within-group change from baseline in the weekly average of the daily sleep interference scale (DSIS) at week 12; • Safety and tolerability *202 patients evaluated for efficacy. One site with 15 patients excluded from the efficacy analysis, due to non-compliance. One patient was randomized but not dosed. All patients dosed were included in the safety analysis.
Page 7
global.vrtx.com©2024 Vertex Pharmaceuticals Incorporated 7 DEMOGRAPHICS AND BASELINE CHARACTERISTICS GENERALLY BALANCED Suzetrigine N = 102 Placebo N = 100 Demographics Age in years, Mean (SD) 53.4 (11.2) 50.9 (12.7) Female, % 59.8% 63.0% Race, % White Black or African American Asian Other 74.5% 21.6% 1.0% 2.9% 69.0% 27.0% 1.0% 3.0% Baseline Characteristics BMI in kg/m2, Mean (SD) 30.0 (5.5) 29.3 (5.2) Years since LSR diagnosis, Mean (SD) 5.2 (6.5) 7.3 (8.8) Back Pain associated with LSR, % 92.2% 89.0% Baseline NSAID use, %* 43.1% 42.0% Dermatome with pain, % L4 L5 S1 23.5% 27.5% 49.0% 24.0% 31.0% 45.0% Baseline Weekly average of NPRS, Mean (SD) 6.33 (1.22) 6.05 (1.07) Baseline Weekly average of NPRS category, % <7 ≥7 67.6% 32.4% 78.0% 22.0% *Note: Acetaminophen, up to 500 mg every 4 to 6 hours, as needed, was allowed during the run-in period and as rescue throughout the study. Acetaminophen use was balanced in both arms.
Page 8
global.vrtx.com PRIMARY ENDPOINT: TREATMENT WITH SUZETRIGINE SHOWED STATISTICALLY SIGNIFICANT & CLINICALLY MEANINGFUL REDUCTION IN LEG PAIN INTENSITY ©2024 Vertex Pharmaceuticals Incorporated 8 Mean (SD) Placebo N=100 6.05 (1.07) Baseline leg pain intensity (NPRS score) LS Mean 95% CI P value Placebo N=100 -1.98 (-2.36, -1.60) <0.0001 PRIMARY END POINT: Within group change from baseline in the weekly average of daily leg pain intensity on NPRS at week 12; study not powered or designed for between group comparison NPRS = numeric pain rating scale, LS Mean = least square mean, SD = standard deviation, CI = confidence interval Suzetrigine 69 mg QD N=102 6.33 (1.22) Suzetrigine 69 mg QD N=102 -2.02 (-2.40, -1.64) <0.0001
Page 9
global.vrtx.com SUZETRIGINE WAS WELL TOLERATED Suzetrigine N = 109 n (%) Placebo N = 108 n (%) Subjects with any AEs 25 (22.9) 35 (32.4) Subjects with AEs by strongest relationship Not related 16 (14.7) 20 (18.5) Unlikely related 1 (0.9) 6 (5.6) Possibly related 6 (5.5) 8 (7.4) Related 2 (1.8) 1 (0.9) Subjects with AEs by maximum severity Grade 1/Mild 15 (13.8) 17 (15.7) Grade 2/Moderate 10 (9.2) 17 (15.7) Grade 3/Severe 0 1 (0.9) Grade 4/Life-threatening 0 0 Grade 5/Death 0 0 Subjects with serious AEs 1 (0.9) 2 (1.9) Subjects with AEs leading to treatment discontinuation 0 1 (0.9) Subjects with AEs leading to death 0 0 9 All AEs in subjects who received suzetrigine were mild or moderate; no related SAEs; no clinically significant trends or patterns in labs, ECGs, or vital signs AE = adverse event, ECG = electrocardiogram
Page 10
global.vrtx.com LEG PAIN INTENSITY DECLINED FOR PATIENTS TREATED WITH SUZETRIGINE OVER 12 WEEKS ©2024 Vertex Pharmaceuticals Incorporated 10 VERTEX INTERPRETATION 1) Suzetrigine is active in LSR • Statistically significant improvement • Clinically meaningful ≥2 point reduction • Consistent magnitude of pain reduction for both • VRTX NaV1.8 inhibitors in neuropathic pain • medicines approved for neuropathic pain 2) Placebo response of equal magnitude to suzetrigine in this study • High overall placebo response • High site-to-site variability in placebo response -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 LS MEAN CHANGE FROM BASELINE IN WEEKLY AVERAGE OF NPRS ± SE WEEK Placebo Suzetrigine (VX-548) Reduction in Pain • Results for secondary and other endpoints were consistent with the primary endpoint Placebo had similar response HYPOTHESIS: The high placebo response was driven by some sites, leading to lack of separation of suzetrigine and placebo curves
Page 11
global.vrtx.com TO EVALUATE THIS HYPOTHESIS, POST HOC ANALYSES WERE CONDUCTED OF SITES WITH LOWER PLACEBO RESPONSE ©2024 Vertex Pharmaceuticals Incorporated 11 • Post hoc analyses were conducted to evaluate the placebo response, which varied across sites, a known issue in pain studies • Approximately 40% of the clinical trial sites had a lower placebo response • Analyses of the primary and other endpoints at these sites showed suzetrigine arm within-group reduction in pain was consistent with the overall study and had greater separation from the placebo arm • As such, we believe that innovation in clinical trial design could allow us to control for the placebo response and separate the treatment effect of suzetrigine from placebo -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 MEAN CHANGE FROM BASELINE IN WEEKLY AVERAGE OF NPRS ± SE WEEK Placebo (n = 36) Suzetrigine (VX-548) (n = 47) Post hoc analysis of leg pain intensity over time at sites with lower placebo response Sites that had either no placebo patients or no suzetrigine patients are excluded.
Page 12
global.vrtx.com VERTEX IS COMMITTED TO TRANSFORMING THE TREATMENT OF PAIN WITH INNOVATIONS IN NAV1.8/NAV1.7 RESEARCH AND PAIN CLINICAL TRIAL DESIGN: LSR TAKEAWAYS AND NEXT STEPS 12©2024 Vertex Pharmaceuticals Incorporated EFFICACY: • Suzetrigine met its primary endpoint with a clinically meaningful and statistically significant reduction in pain scores in LSR • Suzetrigine is an active drug: magnitude of the treatment effect was consistent with our experience with selective NaV1.8 pain signal inhibitors and the overall treatment effect in the field of neuropathic pain • Placebo effect in this study was high and treatment curves did not separate SAFETY: • Today’s results add to the body of evidence on the well tolerated safety profile of suzetrigine and the selective NaV1.8 pain signal inhibitor class NEXT STEPS: • Move into Phase 3, pending regulatory discussions focused on 1) acceptance of novel study design and 2) requirements to broaden beyond DPN indication OUTLOOK FOR PHASE 3 SUZETRIGINE LSR SUCCESS DRIVEN BY: • Robust and consistent treatment effect with suzetrigine • Insights from post hoc analyses regarding site variability and placebo effect • Potential for innovative clinical trial design to better control for placebo effect
Page 13
global.vrtx.com Serial innovation, broad/deep pipeline for leadership in multiple pain states VERTEX IS COMMITTED TO INNOVATING TO TRANSFORM THE TREATMENT OF PAIN ©2024 Vertex Pharmaceuticals Incorporated 13 VX-548 NaV1.8 inhibitor* - Acute Oral VX-548 NaV1.8 inhibitor - DPN Oral VX-548 NaV1.8 inhibitor - LSR Oral VX-993 NaV1.8 inhibitor - Acute Oral VX-993 NaV1.8 inhibitor - DPN Oral VX-993 NaV1.8 inhibitor IV VX-973 NaV1.8 inhibitor Oral Additional NaV1.8 inhibitors Oral and IV NaV1.7 inhibitors Oral FORMULATION RESEARCH PHASE 1 PHASE 2 PHASE 3 APPROVED DPN: diabetic peripheral neuropathy; LSR: lumbosacral radiculopathy; IV: intravenous. All molecules are investigational for acute and peripheral neuropathic pain. Acute Pain Peripheral Neuropathic Pain (PNP) PDUFA Date 1/30/25
Page 14
global.vrtx.com SUZETRIGINE (VX-548) PHASE 2 RESULTS IN PAINFUL LUMBOSACRAL RADICULOPATHY DECEMBER 19, 2024 ©2024 Vertex Pharmaceuticals Incorporated