Sotatercept_HYPERION_Full_Presentation (1).pptx

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1. Title Slide Sotatercept for Pulmonary Arterial Hypertension within the First Year after Diagnosis HYPERION Trial – NEJM 2025 Presenter: [Your Name] PG Dept. of General Medicine, PSIMS Institution: PSIMS & RF Date: [Insert Date]

2. Introduction PAH is progressive, life-threatening Leads to RV failure and death Despite therapy, outcomes remain poor Need for novel disease-modifying approach

3. Therapeutic Landscape ERAs PDE5 inhibitors sGC stimulators Prostacyclin analogues/receptor agonists Combination regimens improve outcomes

4. Sotatercept – Mechanism Activin-signaling inhibitor Targets TGF-β superfamily ligands Restores vascular signaling balance Reduces remodeling and resistance

5. Study Rationale Prior trials enrolled chronic PAH Early PAH may be reversible Unclear efficacy early Aim: Assess sotatercept <1 year from diagnosis

6. Study Design Phase 3 RCT Parallel-group, event-driven Add-on sotatercept vs placebo Subcutaneous every 21 days Median follow-up 13.2 months

7. Ethics & Oversight Good Clinical Practice Independent committees Merck Sharp & Dohme sponsor ClinicalTrials.gov: NCT04811092

8. Randomization 1:1 (WHO FC II vs III; double/triple therapy) 0.3→0.7 mg/kg every 3 wks Adjusted for Hb, platelets Option for open-label SOTERIA study

9. Inclusion Criteria Adults ≥18 yrs, WHO FC II/III Group 1 PAH (idiopathic, CTD, drug-induced) Diagnosis <1 year Intermediate/high risk (REVEAL ≥6 or COMPERA ≥2)

10. Exclusion Criteria Portal HTN, HIV, veno-occlusive PAH LV EF <50%, valve disease Severe comorbidities Bleeding or abnormal labs

11. Primary Endpoint Time to first clinical worsening event Composite: death, hospitalization, septostomy, transplant, or ↓ exercise capacity

12. Secondary Endpoints Multicomponent improvement @24w Low REVEAL ≤5 Low French risk Change in NT-proBNP, 6MWD, WHO FC Overall survival

13. Statistics Planned 444 pts, 121 events (90% power) HR target 0.55 Early stop after ZENITH results Alpha 0.025 (1-sided)

14. Baseline Demographics N=320 (160 each) Mean age 56, 73% female Idiopathic 59%, CTD 30% Mean duration 7 months

15. Clinical Profile Double therapy 72%, triple 28% 6MWD 355 m NT-proBNP 956 pg/mL 78% WHO FC III

16. Primary Results Clinical worsening 10.6% vs 36.9% HR 0.24 (95% CI 0.14–0.41, P<0.001) Follow-up 13.2 months Benefit seen by 12 wks

17. Components 6MWD decline + symptoms 5% vs 29% Hospitalization 2% vs 9% Death 4.4% vs 3.8% No transplants or septostomy

18. Kaplan–Meier Summary Early curve separation by 12 wks Sustained benefit ARR 22% NNT = 5 for one event/year

19. Secondary Outcomes Multicomponent improvement 29% vs 15% (P=0.003) REVEAL ≤5 60% vs 48% (P=0.04) French risk NS NT-proBNP ↓199 vs ↓10

20. Functional Outcomes WHO FC I/II 55% vs 39% 6MWD ↑21 m Mortality 4.4% vs 3.8% Suggests disease-modifying potential

21. Safety Summary Any AE ~90% Serious AE 24% vs 28% Discontinuation 3% (sotatercept) Deaths 2.5% vs 3.1%

22. Common AEs Epistaxis 31.9% vs 6.9% Telangiectasia 26.2% vs 11.2% ↑Hb 11% vs 1% Bleeding 41% vs 16% (mostly mild)

23. Lab Findings Hb ↑1.2 g/dL Platelets stable BP ↑6.9% vs 1.9% No hepatic/renal toxicity

24. Mechanistic Insights Activin inhibition → SMAD1/5/8 activation ↓ endothelial proliferation ↑ repair, ↓ RV strain ↓ NT-proBNP parallels improvement

25. Discussion – Efficacy 76% reduction in clinical worsening Consistent across subgroups Early measurable benefit (3 doses) Comparable to STELLAR/ZENITH

26. Discussion – Safety Consistent with prior data Epistaxis, telangiectasia manageable Hb rise expected Overall tolerable profile

27. Limitations Early termination → shorter follow-up 33 pts <24w Limited QoL data Secondary endpoints underpowered

28. Clinical Implications First disease-modifying therapy Safe addition to standard therapy Delays progression, reduces hospitalizations Supports early initiation

29. Future Directions Long-term SOTERIA data awaited Evaluate 1st-line use Hb & safety monitoring Cost-effectiveness, real-world validation

30. Key Takeaways (1) HR 0.24; 76% risk reduction Early benefit @12 wks Safe and consistent efficacy NNT = 5 (1 event prevented per 5 treated)

31. Key Takeaways (2) Main AEs: epistaxis, telangiectasia, ↑Hb Integrable early in therapy Validates TGF-β pathway target Potential paradigm shift

32. Limitations Recap Early stop limited duration Mortality underpowered QoL data insufficient Need for ongoing safety data

33. Research Gaps Long-term effect durability Hb/bleeding risk trends Efficacy in FC IV or low-risk PAH Affordability/access studies needed

34. Conclusion Sotatercept early in PAH ↓ clinical worsening HR 0.24 vs placebo Safe, effective, paradigm-shifting New era in PAH therapy

35. References McLaughlin VV et al. NEJM 2025 STELLAR Trial – NEJM 2023 ZENITH Trial – NEJM 2024 ESC/ERS Guidelines 2022