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The first and only hypertension therapy targeting the endothelin pathway TRYVIO in the difficult-to-control treatment landscape | August 2025
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TRYVIO (aprocitentan): The only approved therapy for difficult-to-control hypertension 1 Difficult-to-control hypertension 2 The optimal endothelin blocker 3 Compelling efficacy & safety data 4 Differentiated profile in high-risk populations 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 20252
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The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as “intend”, "estimates", "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment and research and development programs, business development activities and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. Rounding differences in the numbers presented may occur. TRYVIO in the difficult-to-control treatment landscape | August 20253
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TRYVIO (aprocitentan): The only approved therapy for difficult-to-control hypertension 1 Difficult-to-control hypertension 2 The optimal endothelin blocker 3 Compelling efficacy & safety data 4 Differentiated profile in high-risk populations 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 20254
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Hypertension is the number one modifiable risk factor of cardiovascular morbidity and premature death – Risk is even greater in patients whose blood pressure is difficult-to-control The Global Burden of Disease 2021, The Lancet 2024 1 Difficult-to-control hypertension TRYVIO in the difficult-to-control treatment landscape | August 20255
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Difficult-to-control versus resistant hypertension References: 1. Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease 2021: Findings from the GBD 2021 Study. Seattle, WA: IHME, 2024. 2. Whelton PK, et al. Hypertension. 2018;71(6):1269-1324. Hypertension guidelines recommend less than as a blood pressure goal 130/80 mmHg2 Resistant hypertension Patients whose blood pressure remains high, despite receiving at least three antihypertensives of different pharmacological classes, including a diuretic, at optimal dose. TRYVIO in the difficult-to-control treatment landscape | August 20256
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Morbidity and mortality risk is greater in patients whose hypertension is difficult-to-control 1. Muntner P, et al. Hypertension. 2014;64(5):1012-1021. 23%Peripheral artery disease 30%All-cause mortality 44%Coronary heart disease Stroke 57% Heart failure 88% End-stage renal disease 95% Increased risks when comparing individuals with vs. without difficult-to-control hypertension TRYVIO in the difficult-to-control treatment landscape | August 20257
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Significant medical need in difficult-to-control hypertension ~26 million US patients are not adequately controlled on other drugs despite treatment and are amenable to TRYVIO according to the US indication *Source: Komodo claims; 3-Year Dx: Sep’20 - Aug’23; 1-Year Rx: Sep’22 - Aug’23. L1 16 million L2 15 million L3/4+ 12.9 million Total drug treated patients in the US* L1 L2 L3/4+ *1 40.2 million 14.4million12.7 million TRYVIO in the difficult-to-control treatment landscape | August 20258 13.1million
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TRYVIO (aprocitentan): The only approved therapy for difficult-to-control hypertension 1 Difficult-to-control hypertension 2 The optimal endothelin blocker 3 Compelling efficacy & safety data 4 Differentiated profile in high-risk populations 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 20259
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Aprocitentan targets the endothelin system and represents the first drug from the established ERA class – optimized for patients with difficult-to-control hypertension 2 The optimal endothelin blocker TRYVIO in the difficult-to-control treatment landscape | August 202510
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The endothelin system Abbreviations: ETA and ETB, endothelin receptor A and B; ET, endothelin END-ORGAN DAMAGE ET-1 Hypertension Fibrosis and inflammation Cell proliferation and Vascular hypertrophy Aldosterone Salt VASOCONSTRICTION VASODILATION ETA ETA ETA ETA ETB ETBETB ETB ETB ETB ETB ETB Increased expression of ETB in smooth muscle cells amplifies vasoconstriction effects of endothelin ET-1 TRYVIO in the difficult-to-control treatment landscape | August 202511
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Difficult-to- control hypertension Endothelin is upregulated and it is the key driver of difficult-to-control hypertension in these patients High body weight Black Post-menopausal women Obstructive sleep apnea Type 2 diabetes Heart failure Chronic kidney disease Chronic kidney disease Heart failure Stroke Consequently, patients are at significant risk of several life- threatening diseases Comorbidities that are at high risk for difficult to control hypertension TRYVIO in the difficult-to-control treatment landscape | August 202512
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Blockade of the RAAS pathway is the focus of current marketed and developmental therapies Abbreviations: ACEi , angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ERA, endothelin receptor antagonist; ET, endothelin; MRA, mineralocorticoid receptor antagonist; RAAS, renin-angiotensin-aldosterone system; RI, renin inhibitor; VSMC, vascular smooth muscle cells. Endothelin System PreProET-1 Big ET-1 Endothelin-1 ERA High blood pressure RAAS System Angiotensinogen Angiotensin I Angiotensin II Renin VSMC constriction ACEi ARB RI or Increased water and sodium retention Aldosterone MRA Converting enzyme Stimulation of aldosterone secretion • Vasoconstriction • Potentiation of growth factors • Profibrotic • Stimulation of sympathetic system Stimulation of aldosterone secretion L. Naseralallah, Blood Pressure 2024; ESH Guidelines 2023 TRYVIO in the difficult-to-control treatment landscape | August 202513
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TRYVIO (aprocitentan): The only approved therapy for difficult-to-control hypertension 1 Difficult-to-control hypertension 2 The optimal endothelin blocker 3 Compelling efficacy & safety data 4 Differentiated profile in high-risk populations 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 202514
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Aprocitentan demonstrated compelling efficacy, safety and tolerability in difficult-to-control / resistant hypertension 3 Compelling efficacy & safety data TRYVIO in the difficult-to-control treatment landscape | August 202515
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Phase 2 trial in patients with essential hypertension Aprocitentan as monotherapy in systemic hypertension Mean change from baseline to Week 8 in systolic and diastolic blood pressure – AOBPM. -7.7 -10.3 -15 -18.5 -15.1 -12.8 -4.9 -6.3 -9.9 -12 -10 -8.4 Placebo 5mg 10mg 25mg 50mg Lisinopril Aprocitentan N=69 149.8/96.8 N=68 148.6/98.2 N=67 151.2/97.8 N=71 149.8/97.7 N=68 149.4/97.8 N=66 149.2/97.5 DBPDBPDBPDBPDBPDBP SBPSBPSBPSBPSBPSBP Verweij P, et al. Hypertension. 2020 Abbreviations: SBP, Systolic blood pressure; DBP, Diastolic blood pressure TRYVIO in the difficult-to-control treatment landscape | August 202516
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PRECISION: Investigated onset and durability of blood pressure reduction Selection of patients with uncontrolled hypertension on existing therapy Efficacy and safety of aprocitentan over 48 weeks Up to 8 weeks 4 weeks 4 weeks 4 weeks 32 weeks 12 weeks 30 days Screening Screening Run-in Part I Double blind Part II Single blind Part III Double blind Safety Follow- up Individual background anti- hypertensive therapy Standardized background antihypertensive therapy (SBAT): Single pill: ARB (valsartan) CCB (amlodipine) Diuretic (hydro- chlorothiazide) +/- betablockers Stabilization on SBAT 25mg Aprocitentan 25mg Aprocitentan 25mg Aprocitentan 12.5mg Aprocitentan Placebo Placebo N = 1,965 Week 0 Week 4 Week 36 Week 40 Week 48 Randomization 1° Endpoint Re-randomization Key 2° End of N = 730 N = 678 N = 614 Endpoint Treatment End of study confirmation Week 40 Key 2° Endpoint N = 528 Continue standardized background antihypertensive therapy Schlaich MP, et al. The Lancet, 2022 TRYVIO in the difficult-to-control treatment landscape | August 202517
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PRECISION population mirrors clinical reality of resistant hypertension with comorbidities and lack of response to prior therapies • North America origin (29%) − Of which 38.9% were Black or African American • Type 2 Diabetes (54%) • Obese (55%; 30 to <40) and severely obese (15%; ≥40) • Congestive heart failure (20%) − Of which, 40% had elevated NT-proBNP • CKD stage 3 or 4 (22%) − Of which,13% had macroalbuminuria Older patients • ≥65 years old (34%) − Of which, 10% were ≥75 years old High-risk and patients with comorbidities Schlaich MP, et al. The Lancet, 2022 TRYVIO in the difficult-to-control treatment landscape | August 202518
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On top of three antihypertensives: valsartan, amlodipine and hydrochlorothiazide Regulatory approved promotional material 130 135 140 145 150 155 160 0 2 4 Sitting systolic blood pressure (mmHg) 3.8 mmHg (P=0.0042) 15.4 mmHg* Triple combination + Aprocitentan 12.5 mg Triple combination + Placebo Schlaich MP, et al. The Lancet, 2022* Measured at trough Rapid double-digit reduction in BP seen as early as 2 weeks with continued benefit over time Primary endpoint measurement at 4 weeks TRYVIO in the difficult-to-control treatment landscape | August 202519
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Double-digit BP decrease was sustained BP reduction confirmed up to 48 weeks Key secondary endpoint after 4 weeks of withdrawal 25 mg* vs placebo: - 5.8 mmHg, P<0.0001 @week 40 of treatment 130 135 140 145 150 155 0 4 8 12 16 20 24 28 32 36 40 44 48 SiSBP (mm Hg) +/- SE PART 2 Single-blind PART 3 Double-blind withdrawal PART 1 Double- blind Randomization Re-randomization Triple combination + Aprocitentan 12.5 mg Triple combination + Placebo Triple combination + Aprocitentan 25 mg* Time (weeks) Schlaich MP, et al. The Lancet, 2022 -15.3 mmHg -19.2 mmHg -17.7 mmHg *The 25 mg dose of aprocitentan is not approved for use in the US TRYVIO in the difficult-to-control treatment landscape | August 202520
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Major night-time BP decrease • Insufficient BP decrease at night is a very strong predictor of poor outcome in hypertension. • Unique nighttime efficacy of aprocitentan is an important feature and may be due to sympatholytic effects in addition to long half-life. -2.3 -6.2 -10 -8 -6 -4 -2 0 Change in ambulatory systolic blood pressure (mmHg) Daytime -2.6 -8.1 -10 -8 -6 -4 -2 0 Nighttime # Patients 179 175 178 174 P=0.003 P=0.0002 Placebo Aprocitentan 12.5 mg Schlaich MP, et al. The Lancet, 2022; ESH Guidelines 2023 TRYVIO in the difficult-to-control treatment landscape | August 202521
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US Prescribing Information Broader indication – difficult-to- control hypertension – compared to the resistant hypertensive patients included in PRECISION TRYVIO in the difficult-to-control treatment landscape | August 202522
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Edema: mild, peripheral, early and transient 0% 2% 4% 6% 8% 10% -8 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 New edema and/or fluid retention events Weeks Pre-randomization (switched to SBAT) Part 1 Part 2 (all patients received aprocitentan 25 mg) Part 3 After 8 weeks of treatment, incidence returns to levels observed before randomization Aprocitentan 12.5 mg -> 25 mg Edema discontinuation rate <1% over 48 weeks Schlaich MP, et al. The Lancet, 2022 TRYVIO in the difficult-to-control treatment landscape | August 202523
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Demonstrated safety and tolerability profile No drug-drug interactions No increased incidence of hyperkalemia No hypotension, No heart rate increase, No headaches Very low overall discontinuation rate due to adverse events over 48 weeks: only 7.3% Schlaich MP, et al. The Lancet, 2022; L. Nasaralallah, Blood Pressure 2024 with or without food No dose adjustments Half-life of 41 hours One dose can be missed TRYVIO in the difficult-to-control treatment landscape | August 202524
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TRYVIO (aprocitentan): The only approved therapy for difficult-to-control hypertension 1 Difficult-to-control hypertension 2 The optimal endothelin blocker 3 Compelling efficacy & safety data 4 Differentiated profile in high-risk populations 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 202525
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The blood pressure-lowering effect of TRYVIO was consistent among subgroups – defined by age, sex, race, body mass index, baseline eGFR, baseline UACR, and medical history of diabetes 4 Differentiated profile in high-risk populations TRYVIO in the difficult-to-control treatment landscape | August 202526
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Unprecedented BP reduction in CKD 3/4 patients 2.2 -3.4 -6.9 -10.7 -12.0 -10.0 -8.0 -6.0 -4.0 -2.0 0.0 2.0 4.0 Daytime Nighttime Ambulatory SBP Mean change in ambulatory systolic blood pressure (mmHg) -5.9 -13.4 -16.0 -14.0 -12.0 -10.0 -8.0 -6.0 -4.0 -2.0 0.0 SiSBP Mean change in sitting systolic blood pressure from baseline to W4 (mmHg) Schlaich MP, et al. The Lancet, 2022; Data on file Triple combination + Aprocitentan 12.5 mg Triple combination + Placebo (n = 162) TRYVIO in the difficult-to-control treatment landscape | August 202527
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Major reduction of UACR at week 36 UACR change from baseline to Week 36 Aprocitentan 25 mg -56% -67% -80% -70% -60% -50% -40% -30% -20% -10% 0% Microalbuminuria UACR 30-300 mg/g Macroalbuminuria UACR >300 mg/g Schlaich MP, et al. The Lancet, 2022; Data on file UACR: Urine Albumin-to-Creatinine Ratio TRYVIO in the difficult-to-control treatment landscape | August 202528
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Stable eGFR in CKD 3/4 at 25 mg over 48 weeks 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (weeks) Mean values in eGFR (mL/min/1.73mˆ2) Aprocitentan 25 mgeGFR mean observed values for patients treated with aprocitentan 25 mg over 48 weeks – CKD stage 3/4 (eGFR = 15 to <60 ml/min/1.73m2) subgroup (n = 162) Schlaich MP, et al. The Lancet, 2022; Data on file TRYVIO in the difficult-to-control treatment landscape | August 202529
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TRYVIO (aprocitentan): The only approved therapy for difficult-to-control hypertension 1 Difficult-to-control hypertension 2 The optimal endothelin blocker 3 Compelling efficacy & safety data 4 Differentiated profile in high-risk populations 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 202530
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Prescribers are seeing the benefits of TRYVIO in real-world practice. 5 Strong advocacy – ready to launch TRYVIO in the difficult-to-control treatment landscape | August 202531
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Commercially available in the US and ready for launch with the right partner TRYVIO in the difficult-to-control treatment landscape | August 202532
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Strong advocacy and interest for patients with difficult-to-control hypertension Early positive outcomes with TRYVIO in US • ~5 to 20 mmHg drop in BP • Close monitoring based on patient type, preferred in CKD • ~10 to 15 mmHg drop in BP • Well tolerated, plans to expand use within CKD population • Endothelin MOA is needed for these difficult to treat patients • ~10 to 15 mmHg drop in BP • Patients on multiple other medications are tolerating TRYVIO well “Resistant hypertension has complexities... One patient had a clear need for additional medication, he normalized with adding TRYVIO!" We continue to build advocacy and real-world evidence ID Cardiologist ID Cardiologist ID Cardiologist ID Nephrologist Key institutions we are engaged with on these efforts include Columbia, Cedars Sinai, Stanford, and Duke TRYVIO in the difficult-to-control treatment landscape | August 202533
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TRYVIO: first systemic hypertension treatment to target a new pathway in over 30 years Once daily, single dose tablet eGFR down to 15 No risk of hyperkalemia, hypotension and no clinically relevant drug-drug interactions TRYVIO is the first and only dual endothelin receptor antagonist (ERA) approved for systemic hypertension TRYVIO is well tolerated and delivers rapid, durable blood pressure reduction when added on top of any existing treatment regimen for patients with difficult-to-control hypertension The endothelin pathway is a key driver in difficult-to-control hypertension TRYVIO in the difficult-to-control treatment landscape | August 202534