*Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

Transcription

1 The Relationship between NO Pathway Biomarkers and Response to Riociguat in the RESPITE Study of Patients with PAH Not Reaching Treatment Goals with Phosphodiesterase 5 Inhibitors James R Klinger,* Raymond L Benza, Paul A Corris, David Langleben, Robert Naeije, Gérald Simonneau, Christian Meier, Pablo Colorado, MiKyung Chang, Dennis Busse, Marius M Hoeper *Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA

2 Faculty disclosures: James R Klinger Professor Klinger reports: Research support from Actelion, Bayer, Gilead Sciences, Ikaria, Lung Biotechnology, NIH-NHLBI, Pfizer, and United Therapeutics Travel expenses for consultations from Bayer and United Therapeutics

3 RESPITE study: Rationale and objective A significant proportion of patients (20 60%) with PAH fail to reach or maintain treatment goals with PDE5i 1,2 This may be because PDE5is are dependent on sufficient levels of endogenous NO and cgmp, which are reduced in patients with PAH 3 Riociguat has a dual mode of action, sensitizing sgc to low levels of NO and directly stimulating sgc independently of NO 4,5 Riociguat may therefore be effective in patients with PAH who do not respond to PDE5i treatment RESPITE was designed to investigate whether it is safe, feasible, and beneficial to replace PDE5i therapy with riociguat in patients with PAH who do not respond adequately to PDE5i This analysis explores the relationship between biomarkers, including NT-proBNP, plasma cgmp, ADMA, GDF-15 and ST-2, and response to riociguat 1. Chockalingam A, et al. Int J Cardiol 2005;99:91 95; 2. Leuchte HH, et al. Chest 2004;125: ; 3. Klinger JR, et al. Am J Respir Crit Care Med 2013;188: ; 4. Stasch JP, et al. Circulation 2011;123: ; 5. Mittendorf J, et al. ChemMedChem 2009;4: ADMA, asymmetric dimethylarginine; cgmp, cyclic guanosine monophosphate; GDF-15, growth differentiation factor 15; NO, nitric oxide; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PDE5i, phosphodiesterase type 5 inhibitors; sgc, soluble guanylate cyclase; ST-2, suppression of tumorigenicity-2

4 Design of the RESPITE study Open-label, multicenter, uncontrolled Phase IIIb pilot study Biomarkers were assessed at every visit Right heart catheterization Screening (baseline) Stop PDE5i Right heart catheterization patients screened Time (weeks) Patients with PAH not at goal with PDE5i (n=61) 1- to 3-day PDE5i treatmentfree period Riociguat mg tid Treatment phase Dose adjustment Maintenance Safety follow-up a Patients assessed as not at goal on PDE5i met all the following criteria: WHO FC III 6MWD m Cardiac index <3.0 L/min/m 2 PVR >400 dyn s cm 5 mpap >30 mmhg Exploratory endpoints: NT-proBNP (every visit) WHO FC (every visit) 6MWD ((baseline, Week 12, Week 24) Hemodynamics (baseline, Week 24) Biomarkers (every visit) a Patients may participate in an extended drug supply phase for 18 months or until reimbursement. Baseline = the last documented value while still receiving PDE5i 6MWD, 6-minute walking distance; mpap, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; tid, three times daily; WHO FC, World Health Organization functional class

5 Efficacy: Change from baseline in 6MWD and NT-proBNP over time in RESPITE No. of patients No. of patients b a p-value calculated for relative change from baseline b One patient missing for change from baseline; n=52 for change from baseline at Week 24 due to one patient withdrawal at Day +159 having undergone a Week 24 assessment of NT-proBNP Data are mean±standard error of the mean Baseline = the last documented value while still receiving PDE5i

6 Responder endpoint: Patients without clinical worsening who achieved at least WHO FC II and an improvement in 6MWD of 30 m Patients (%) Week 12 (n=52) Week 24 (n=51) Clinical worsening is defined as death (all-cause mortality), atrial septostomy, lung transplantation, non-planned PAH-related hospitalization, start of new PAH-specific treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of intravenous or subcutaneous prostanoids, persistent decrease of >15% from baseline or >30% from last measurement in 6MWD, persistent worsening of FC, or appearance or worsening of signs/symptoms of right heart failure that do not respond to optimized oral diuretic therapy

7 Change from baseline in biomarkers at Week 24 in RESPITE Biomarker, mean (SD) Baseline Week 24 cgmp (plasma), pmol/ml ADMA (plasma), μmol/l n Value at baseline n Change from baseline p-value for change from baseline to Week (11.24) (8.00) (0.13) (0.12) NT-proBNP, pg/ml (1828) (1235) a GDF-15, pg/ml (4525) (2977) ST-2, ng/ml (15.17) (9.80) a p-value is for the relative change from baseline in NT-proBNP Baseline = the last documented value while still receiving PDE5i

8 PVR (dyn s cm -5 ) NT-proBNP (pg/ml) Correlation between cgmp at baseline and clinical parameters at Week 24 r= 0.36 p= r=0.36 p= cgmp (pmol/ml) cgmp (pmol/ml) Cardiac index (L/min/m 2 ) RAP (mmhg) r=0.34 p= r=0.45 p= cgmp (pmol/ml) cgmp (pmol/ml)

9 Biomarkers at baseline, and change from baseline at Week 24 in responders and non-responders in RESPITE NT-proBNP (pg/ml) Baseline Change from baseline cgmp (pmol/ml) Baseline Change from baseline GDF-15 (pg/ml) ST-2 (ng/ml) Baseline Change from baseline Baseline Change from baseline

10 Conclusions RESPITE provided preliminary evidence that treatment with riociguat may be beneficial in PAH patients with an insufficient response to PDE5i Changes in NT-proBNP, GDF-15, and ST-2 during treatment may point towards potential cardioprotective effects Further studies are needed to determine if any of the biomarkers measured in this study or other biomarkers are able to identify patients who are more likely to benefit from transition from PDE5i to riociguat

11 Backup slides

12 Riociguat dose adjustment in the RESPITE study Pretreatment phase 1.5 mg tid 2 weeks V3 2.0 mg tid 2 weeks V4 2.5 mg tid 2 weeks V5 2.5 mg tid 2.0 mg tid 1.5 mg tid V6 V6 V6 V7 V7 V7 1.0 mg tid V0 V1 V2 2 weeks 2 weeks 1.0 mg tid V6 V7 0.5 mg tid V6 V7 Screening (baseline) Week 0 (post-pde5i Week 2 Week 4 Week 6 Week 8 treatment-free period) Week 12 Week 24 PDE5i will be stopped 1 3 days prior to the first dose of riociguat (V1) to allow a PDE5i treatment-free period of at least 24 hours for patients receiving sildenafil and 72 hours for patients receiving tadalafil Riociguat will be individually adjusted from a starting dose of 1 mg tid to a maximum dose of 2.5 mg tid based on SBP and signs and symptoms of hypotension Patients were still receiving PDE5i at screening/baseline visits. V1 (Week 0) was post-pde5i treatment-free period SBP, systolic blood pressure; V, visit

13 Study endpoints (exploratory) Change in 6MWD from baseline to Weeks 12 and 24 Change in NT-proBNP from baseline to Weeks 12 and 24 Change in WHO FC from baseline to Weeks 12 and 24 Change in pulmonary hemodynamics at Week 24 Number of patients without clinical worsening who achieved at least WHO FC II and an improvement in 6MWD of >30 m Change in Borg dyspnea score from baseline to Weeks 12 and 24 Change in EQ-5D QoL questionnaire from baseline to Weeks 12 and 24 Change in biomarkers from baseline to Weeks 12 and 24 cgmp (blood) cgmp (urine) ADMA ST-2 GDF-15 Clinical worsening AEs and SAEs Change in SBP and DBP from baseline to Weeks 12 and 24 Frequency and timing of patients with SBP <95 mmhg Baseline = Week 0: the last documented value prior to start of riociguat treatment, after the PDE5i treatment-free period. Where no Week 0 value was available, baseline values were used. Baseline = the last documented value while still receiving PDE5i for 6MWD, NT-proBNP, hemodynamics and, egfr ADMA, asymmetrical dimethyl arginine; DBP, diastolic blood pressure; EQ-5D, EuroQoL 5-Dimensions; GDF-15, growth differentiation factor 15; QoL, quality of life; ST-2, suppression of tumorigenicity 2

14 Patient disposition Screened (n=79) Treated (n=61) Discontinued a (n=10) (16%) AE 4 (7%) Death b 1 (2%) Lack of efficacy 1 (2%) Physician decision 1 (2%) Withdrawal by patient 3 (5%) Riociguat up to 2.5 mg tid (n=61) Completed 24 weeks of treatment (n=51) (84%) a Primary reason for discontinuation b Two patients died during the main study. Causes of death were subdural hematoma and pneumonia. The patient who died of pneumonia was recorded as withdrawal by patient Prior PDE5i therapy for these patients was tadalafil for the patient who experienced a subdural hematoma and sildenafil for the patient who died of pneumonia AE, adverse event

15 PAH-specific medication received prior to study Treatment, n (%) Riociguat up to 2.5 mg tid (n=61) Transitioned from PDE5i a Sildenafil 20 mg tid Tadalafil 40 mg qd Concomitant ERAs at baseline Ambrisentan Bosentan Macitentan 61 (100) 40 (66) 21 (34) 50 (82) 23 (38) 16 (26) 11 (18) a PDE5is discontinued before start of study qd, once daily

16 Riociguat dose and duration Mean±SD duration of treatment: 154±44 days Cumulative treatment exposure: 25.7 patient-years (n=61) Riociguat dose at Week 24 a (n=51) 8% 92% 2.0 mg tid 2.5 mg tid a Does not include any dose adjustments made at Week 24 for patients entering the extended drug supply phase

17 Correlation between biomarkers and clinical parameters Baseline BL 6MWD RAP SvO 2 Cardiac index W 24 Δ BL W 24 Δ BL W 24 Δ BL W 24 Cardiac output Δ BL W 24 PVR Δ BL W 24 NT-proBNP cgmp GDF-15 mpap Δ BL W 24 ST-2 Week 24 NT-proBNP cgmp GDF-15 ST-2 Δ NT-proBNP cgmp GDF-15 ST-2 Δ BL, baseline; W24, Week 24; Δ, change from baseline to Week 24. Baseline = last value while still receiving PDE5i

18 Baseline clinical parameters for responders and nonresponders Responders (n=16) Non-responders (n=38) 6MWD, m 391 (72) 352 (80) PVR, dyn s cm (296) 870 (272) Cardiac index, L/min/m (0.38) 2.34 (0.44) Data are mean (SD) Combined responder endpoint: free from clinical worsening, WHO FC I/II, and 30 m increase in 6MWD

19 Change from baseline in WHO FC at Weeks 12 and * * Patients (%) WHO FC III WHO FC II WHO FC I 10 0 Baseline (n=61) Week 12 (n=54) 2 2 Week 24 (n=52) *Sign test for change from baseline p< Baseline = the last documented value while still receiving PDE5i

20 Biomarker signaling pathways Amended from Buglioni and Burnett. Annu Rev Med 2016; 67: ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CD-NP, CD natriuretic peptide; cgmp, cyclic guanosine monophosphate; CNP, C-type natriuretic peptide; CU-NP, CU natriuretic peptide; DNP, Dendroaspis natriuretic peptide; GC-A, particulate guanylate cyclase A; GTP, guanosine triphosphate; NO, nitric oxide; NOS, nitric oxide synthase; MANP, mutant atrial natriuretic peptide; PDE, phosphodiesterase; PKG, cgmp-dependent protein kinase; sgc, soluble guanylate cyclase.

21 Correlation between plasma cgmp at baseline and clinical parameters at baseline r= 0.29 p= r=0.32 p= MWD (m) RAP (mmhg) r=0.55 p< cgmp (pmol/ml) cgmp (pmol/ml) cgmp (pmol/ml) NT-proBNP (pg/ml)

22 Change from baseline in hemodynamics at Week 24 Parameter, mean (SD) n Baseline n Week 24 Change from baseline to Week 24 a PVR, dyn s cm (272) (379) 103 (296) b Cardiac index, L/min/m (0.4) (0.6) +0.3 (0.5) c mpap, mmhg (11.9) (13.2) 2.8 (8.8) RAP, mmhg (4.9) (4.3) 0.83 (4.2) SvO 2, % (6.9) (7.6) +1.0 (6.3) a Change from baseline calculated using patients with hemodynamic data available at baseline and Week 24 b p= (95% CI: 188 to 18.2) c p= (95% CI: 0.16 to 0.47) Baseline = the last documented value while still receiving PDE5i Data are mean (SD)

23 Borg CR-10 and EQ-5D Parameter, mean (SD) n Week 0 n Week 12 n Week 24 Change from Week 0 to Week 24 Borg CR-10 score (2.1) (2.1) (2.2) 0.7 (2.0) EQ-5D Visual Analog Scale (18) (16) (17) +7 (19) EQ-5D utility score (0.23) (0.25) (0.20) (0.28) Week 0: the last documented value prior to start of riociguat treatment, after the PDE5i treatment-free period (where no Week 0 value was available, baseline values were used) CR, Category Ratio

24 Clinical worsening Event, n (%) Patients with clinical worsening a 6 (10) Appearance or worsening of signs/symptoms of right heart failure that did not respond to optimized oral diuretic therapy Death Pneumonia b Subdural hematoma c 1 (2) 2 (3) 1 (2) 1 (2) Persistent worsening in 6MWD due to PH d 2 (3) Start of new PAH treatment 2 (3) Deaths were not considered study drug-related a Patients could experience more than one event b Withdrew from the study on study Day 28 and died of pneumonia on Day 55 c Chronic subdural hematoma in an anticoagulated patient following a fall; falls were reported during the preceding days d Persistent decrease of >15% from baseline or >30% compared with the last study-related measurement One of the two patients who started a new PAH-specific treatment also experienced persistent worsening of 6MWD due to PAH Clinical worsening is defined as death (all-cause mortality), atrial septostomy, lung transplantation, non-planned PAH-related hospitalization, start of new PAH-specific treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of intravenous or subcutaneous prostanoids, persistent decrease of >15% from baseline or >30% from last measurement in 6MWD, persistent worsening of FC, or appearance or worsening of signs/symptoms of right heart failure that do not respond to optimized oral diuretic therapy

25 Safety AE, n (%) Any Dyspepsia Headache Hypotension a Symptomatic hypotension Hemoptysis b Most frequently reported AEs ( 20% of patients) AEs of special interest Other AEs of interest Riociguat up to 2.5 mg tid (n=61) 58 (95) 14 (23) 12 (20) a Six AEs of hypotension were considered mild, three moderate, and one severe. b Event was considered mild, not study drug-related, and was described as a cough with occasional blood spots. c Three patients experienced more than one SAE; AE, adverse event; SAE, serious adverse event 10 (16) 7 (11) 1 (2) Syncope 0 (0) Any Headache Dyspepsia Hypotension Dizziness Any c Right ventricular failure Any Right ventricular failure Asthenia Study drug-related AEs in 10% of patients SAEs in 5% of patients Study drug-related SAEs 32 (52) 10 (16) 9 (15) 7 (11) 7 (11) 10 (16) 3 (5) 2 (3) 1 (2) 1 (2)

26 Summary Transition from PDE5i to riociguat in patients not responding adequately to previous PDE5i treatment was well tolerated and improved 6MWD, WHO FC, NT-proBNP, and pulmonary hemodynamics (including PVR, cardiac index, mpap, and RAP) The severity of pulmonary hypertension at baseline and Week 24 correlated with: Plasma cgmp levels Plasma NT-proBNP levels Plasma GDF-15 and ST-2 levels Treatment with riociguat: Increased plasma cgmp levels Decreased plasma NT-proBNP levels

27 Summary Patients who had a more favorable response to riociguat (responders vs non responders) had lower baseline levels of: Plasma cgmp Plasma NT-proBNP GDF-15 There was no correlation between improvement in PAH or functional capacity with change in any biomarker from baseline to Week 24