Clinical Study Synopsis

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Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 1 of 11

Date of report: 12 Dec 2018

Study title: Multi-center, randomized, placebo-controlled, double-blind group comparison study to investigate safety, tolerability and blood pressure of 2.5 mg, 5.0 mg and 10 mg vericiguat each given over 14 ± 3 days together with isosorbide mononitrate (ISMN) 60 mg extended release formulation after a pretreatment phase (ISMN-starting dose: 30 mg) in stable coronary artery disease (CAD) patients with or without heart failure aged 30 to 80 years - Vericiguat ISOsoRbide mononitrate interaction (VISOR) study

Sponsor’s study number: 18582

NCT number: NCT03255512

EudraCT number: 2016-005178-36

Sponsor: Bayer AG Collaborator: Merck Sharp & Dohme Corp.

Clinical phase: Ib

Study objectives: The primary objective of this study was to - evaluate the pharmacodynamic drug-drug interaction between ISMN extended release (ER) given once daily at steady state and vericiguat titrated up from 2.5 mg to 5.0 mg and 10 mg The secondary objective of this study is to - assess safety and tolerability of the co-administration of ISMN and vericiguat

Test drug: Vericiguat IR tablet

Name of active ingredient(s): Vericiguat (BAY 1021189)

Dose: Day 0 to Day 13 ± 3 (11 – 17 days): 2.5 mg vericiguat Day 14 ± 3 to Day 27 ± 3 (11 – 17 days): 5 mg vericiguat Day 28 ± 3 to Day 41 ± 3 (11 – 17 days): 10 mg vericiguat

Route of administration: Once daily oral administration

Duration of treatment: 42 days (Range: 33-51 days)

Reference drug: Placebo

Name of active ingredient(s): not applicable Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 2 of 11

Dose: 0 mg (matching placebo of 2.5 mg, 5 mg and 10 mg vericiguat)

Route of administration: oral

Duration of treatment: 42 days (Range: 33-51 days)

Interaction drug: Isosorbide mononitrate ER tablet

Name of active ingredient(s): Isosorbide mononitrate

Dose: Day -14 to Day -8 ± 2 (at least 5 days): 30 mg ISMN ER Day -7 ± 2 to day -1 (at least 5 days): 60 mg ISMN ER (reduced to 30 mg in case of intolerance; then 30 mg were given throughout the entire remaining administration period) Day 0 to Day 13 ± 3 (11 – 17 days): 60 mg ISMN ER Day 14 ± 3 to Day 27 ± 3 (11 – 17 days): 60 mg ISMN ER Day 28 ± 3 to Day 41 ± 3 (11 – 17 days): 60 mg ISMN ER

Route of administration: oral

Duration of treatment: 56 days (Range: 43-69 days)

Indication: Not applicable (Clinical Pharmacology study)

Diagnosis and main criteria for inclusion: Patients with stable CAD defined by • coronary artery stenosis in any of the 3 main coronary vessels ≥ 50% documented by coronary angiography within last 36 month or • history of myocardial infarction Clinically stable for at least 3 months prior to the first screening examination Age: 30 to 80 years (inclusive) at the first screening examination Body mass index (BMI): above/equal 18.0 and below/equal 36.0 kg/m2

Study design: Multi-center, randomized, placebo-controlled, double-blind parallel group design. Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 3 of 11

Methodology The pharmacodynamic drug-drug interaction was assessed based on seated oscillometric systolic and diastolic blood pressure and heart rate measurements during the hemodynamic profiles from 1 h 45 min prior to 4 h 15 min after vericiguat administration on profile days Day 0, Day 13, Day 14, Day 27, Day 28 and Day 41. Safety and tolerability were assessed based on adverse events, reported spontaneously and in response to non-systematic, non- leading questions, clinical laboratory, vital signs and electrocardiograms, determined at defined time points throughout the study.

Study center(s)/countries: 6 study centers in Germany

Publication(s) based on the study (references): None at the time of report completion

Study period: First subject, first visit: 17 Aug 2017

Last subject, last visit 07 Feb 2018

End of study: 23 Mar 2018

Early termination No

Number of subjects: Planned: 36 subjects

Actual (randomized/assigned to treatment): 41

Criteria for evaluation Clinical pharmacology: Seated blood pressure and heart rate

Safety: Adverse events, clinical laboratory, vital signs, electrocardiography

Other: Not applicable

Statistical methods: Interaction of vericiguat and ISMN at vericiguat steady state and after first dose of next dose was analyzed based on the change in seated systolic blood pressure, diastolic blood pressure and heart rate using analysis of covariance (ANCOVA) including treatment, time, and treatment*time effects with baseline SBP as a covariate. Based on these analyses point estimates (LS-Means) and exploratory 90% confidence intervals for the differences “vericiguat - placebo” were calculated. Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 4 of 11

Substantial Amendment 1, dated 18 Jul 2017, was globally implemented protocol changes: prior to study start to satisfy requirements raised by the German competent authority and ethics committee; it specified the following modifications: • Deletion of previous exclusion criterion 15 (“hypotension [SBP <90 mmHg]”) • Modification of exclusion criterion 31 from “alanine aminotransferase (ALT) > 3 x ULN and bilirubin > 2 x upper limit of normal laboratory values (ULN)” to “ALT > 3 x ULN or bilirubin > 2 x ULN” • Deletion of reference to ‘legally acceptable representative’ from withdrawal criteria text, as legally acceptable representatives did not apply for patients planned to be enrolled in this study. • The number of subjects that could be replaced was limited to 6.

Study subjects Overall, fifty-nine (59) subjects with CAD were screened in 6 centers in Germany. Of them, 41 subjects (36 males and 5 females) in the age range of 49 to 79 years were randomized in a double-blinded fashion to treatment with either vericiguat + ISMN (28 subjects) or placebo + ISMN (13 subjects). All of these subjects started ISMN intake, 35 of them completed the study. 3 subjects dropped out during the run-in phase between Day -14 and Day -1 of the study, 1 due to adverse events, for 2 further subjects the primary reason for study discontinuation was “withdrawal by subject”. During the escalating treatment with 2.5, 5 and 10 mg vericiguat / placebo in addition to ISMN treatment, 3 further subjects terminated study participation: 1 subject due to an adverse event, 1 due to non-compliance with the study-drug regimen and 1 further subject based on a sponsor decision. All three subjects were treated in the vericiguat arm. The average age of the 41 subjects of the safety analysis set of this study was 64.6 ± 6.9 years (range: 49 to 79 years). All of the subjects were white. There were 36 (87.8%) male and 5 (12.2%) female subjects randomized into the study. All 5 female subjects were randomized into the vericiguat arm. The overall mean BMI was 28.2 ± 3.9 kg/m2. Accordingly the mean weight of the subjects was 85.9 ± 14.6 kg and the mean height was 174.4 ± 6.4 cm. Subjects with systolic blood pressure (SBP) values below 110 mmHg and above 160 mmHg or with diastolic blood pressure (DBP) values below 50 or above 100 mmHg at screening were excluded as defined in the protocol. During screening, sitting and standing blood pressures were taken, supine baseline blood pressure values were measured prior to first study drug administration on Day -14. At this time, values were ranging between 106 and 159 mmHg for SBP and between 52 and 94 mmHg for DBP after 15 min in supine rest. There were no major differences between the demographic distributions in the vericiguat and the placebo group. Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 5 of 11

All of the subjects had at least one medical history finding, as all of them were included with a cardiac disease as defined by the inclusion criteria. Apart from this lead diagnosis, there were further medical history findings, especially surgical and medical procedures, mostly in direct relationship to the cardiac disorders, reported by approximately half of the subjects, including coronary arterial stent insertion in 7 subjects (17.1%) and stent placement in 9 subjects (22.0%). Hypertension was reported for 32 subjects (78.0%), hyperlipidemia for 23 subjects (56.1%), hypercholesterolemia in 11 subjects (26.8%), diabetes mellitus in 10 subjects (24.4%), and hyperuricemia in 6 subjects (14.6%). Concomitant medication was taken by all subjects randomized. As recommended for the indication CAD, antithrombotic agents were taken by almost all subjects (n=40, 97.6%), especially acetylsalicylic acid (38 subjects, 92.7%). Serum lipid reducing agents were taken by 38 subjects (92.7%), mostly atorvastatin or simvastatin (17 subjects, 41.5% each). The most common antihypertensive drugs taken were agents acting on the renin-angiotensin system (39 subjects, 95.1%), especially ramipril, taken by 29 subjects (70.7%), and beta- blocking agents (35 subjects, 85.4%), especially metoprolol, taken by 16 subjects (39.0%) in different formulations, and bisoprolol, taken by 14 subjects (34.1%) in different formulations.

Clinical pharmacology evaluation Pharmacodynamics Mean supine SBP, DBP and heart rate (HR) at before start of treatment on Day -14 were 130.7 ± 13.2 mmHg, 74.9 ± 8.9 mmHg and 61.0 ± 9.8 beats/min, respectively, for the vericiguat group and 126.1 ± 10.6 mmHg, 69.7± 7.0 mmHg and 58.9 ± 6.6 beats/min, respectively, for the placebo group. For blood pressure, a slight group difference with approximately 5 mmHg higher mean values in the vericiguat group was more or less stable throughout the study In all profiles, a decrease in blood pressure and an increase in heart rate approximately 1 h after ISMN administration were observed. The effect was similar in the vericiguat and the placebo group. Vericiguat, given 1h after ISMN administration, had only a slight additive blood pressure lowering effect, resulting in mean maximum SBP decreases (calculated from area under the effect-time-curve) of -25.7 to -32.2 mmHg in the vericiguat group and -21.0 to -30.2 mmHg in the placebo group. Mean maximum DBP decreases during the hemodynamic profiles ranged from -18.4 to -22.3 mmHg in the vericiguat group and from -14.0 to -20.0 mmHg in the placebo group. Most extreme mean changes for SBP/DBP throughout all profile days were -18.6/-12.7 mmHg for in the vericiguat group, and -15.0/-10.1 mmHg in the placebo group. There was no trend of higher decreases with up-titration of the vericiguat dose. An ANCOVA analysis indicates statistically significant differences to placebo for SBP at Day 13, Day 27 and Day 28, i.e. for 2.5 mg vericiguat at steady state, 5 mg vericiguat at steady state and the first day of 10 mg vericiguat administration, since for these estimates the 90% confidence intervals are completely below “0”. Point estimates for the difference to placebo on these profile days range between -4.13 mmHg and -5.08 mmHg. For SBP on Day 0, Day 14 and Day 41, i.e. for the first dose of 2.5 mg vericiguat, the first up-titrated dose of 5 mg Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 6 of 11 vericiguat and 10 mg vericiguat at steady state, and for all DBP profiles, no differences were indicated. An additional ANCOVA comparing the three vericiguat doses at steady state (Day 13, Day 27 and Day 41) indicate a 2.4 mmHg higher SBP for 2.5 mg vericiguat at steady state than for 5 mg vericiguat at steady state, and a 2.0 mmHg lower DBP for the 10 mg vericiguat dose compared to the 2.5 mg vericiguat dose. For heart rate, mean maximum increases ranged from 10.3 to 14.2 beats/min in the vericiguat group and from 9.6 to 13.6 beats/min in the placebo group. Most extreme mean changes throughout all profile days were 7.7 beats/min in the vericiguat group and 5.6 beats/min in the placebo group. For heart rate, there were no statistically significant differences to placebo at all in the explorative ANCOVA analysis. However, the comparison of the 5 and 10 mg vericiguat dose steps to the 2.5 mg dose step indicated increases in heart rate by 2.1 beats/min for the 5 mg dose and by 1.4 beats/min for the 10 mg dose. No consistent relationship between dose and amount of change in blood pressure or heart rate was observed under escalated multiple dose treatment with 2.5 to 10 mg vericiguat once daily on top of ISMN. Pharmacokinetics Concentrations of vericiguat in plasma increased with duration of treatment within one dose step and with up-titration of the dose. Overall, the pharmacokinetics of vericiguat in this patient population were in line with prior knowledge for vericiguat and overall comparable to the pharmacokinetics observed in the Phase IIb studies. Concentrations of ISMN in proximity to trough concentrations were in the expected range and ensured treatment compliance of the evaluated subjects. Safety evaluation Adverse events Of the 41 subjects in the safety analysis set, 37 (90.2%) had at least one treatment-emergent adverse event (TEAE), 29 of all 41 subjects (70.7%) during treatment with ISMN alone in the run-in phase, 24 of the 26 subjects (92.3%) randomized to vericiguat + ISMN and 8 of 12 subjects (66.7%) randomized to placebo + ISMN in the 6-week treatment phase. The most common treatment emergent adverse event was headache, occurring in almost one half of the subjects. The highest incidence rate of headache was seen after start of the run-in treatment with 30 mg ISMN from Day 14 to Day -7, where more than one third of the subjects complained headache, tension headache or dizziness, which can be reasonably related to the mode of action of ISMN. Despite of introduction and up-titration of vericiguat every two weeks, the incidence rate of headache decreased in the following course of treatment. Gastrointestinal disorders like dyspepsia and gastroesophagal reflux were reported almost exclusively in the vericiguat group during treatment with vericiguat on top of ISMN (7 subjects in total), with maximum intensity of up to severe, however all reported events were transient and may have also occurred due to other reasons in the treated group of multimorbid CAD patients with extensive concomitant medication. Incidence decreased with duration of treatment, and the events appeared controllable with antacidic therapy if used.

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Number of subjects with treatment-emergent adverse events by primary system organ class, preferred term by treatment group Primary System Organ Class ISMN alone Vericiguat Placebo Total Preferred Term + ISMN + ISMN MedDRA version 20.1 N=41 (100%) N=26 (100%) N=12 (100%) N=41 (100%) Number of subjects (%) with at least 29 (70.7%) 24 (92.3%) 8 (66.7%) 37 (90.2%) one such adverse event Blood and lymphatic system disorders 0 0 1 ( 8.3%) 1 ( 2.4%) Leukopenia 0 0 1 ( 8.3%) 1 ( 2.4%) Monocytosis 0 0 1 ( 8.3%) 1 ( 2.4%) Cardiac disorders 3 ( 7.3%) 4 (15.4%) 2 (16.7%) 8 (19.5%) Acute coronary syndrome 0 1 ( 3.8%) 0 1 ( 2.4%) Angina pectoris 0 1 ( 3.8%) 0 1 ( 2.4%) Angina unstable 0 1 ( 3.8%) 0 1 ( 2.4%) Atrioventricular block first degree 2 ( 4.9%) 1 ( 3.8%) 1 ( 8.3%) 3 ( 7.3%) Bradycardia 0 1 ( 3.8%) 1 ( 8.3%) 2 ( 4.9%) Tachycardia 1 ( 2.4%) 0 0 1 ( 2.4%) Ventricular extrasystoles 0 1 ( 3.8%) 0 1 ( 2.4%) Ear and labyrinth disorders 0 5 (19.2%) 0 5 (12.2%) Vertigo 0 5 (19.2%) 0 5 (12.2%) Gastrointestinal disorders 5 (12.2%) 10 (38.5%) 1 ( 8.3%) 15 (36.6%) Abdominal discomfort 0 1 ( 3.8%) 0 1 ( 2.4%) Abdominal pain upper 0 2 ( 7.7%) 0 2 ( 4.9%) Constipation 0 1 ( 3.8%) 1 ( 8.3%) 2 ( 4.9%) Diarrhoea 2 ( 4.9%) 3 (11.5%) 0 5 (12.2%) Dyspepsia 0 6 (23.1%) 0 6 (14.6%) Faeces soft 1 ( 2.4%) 0 0 1 ( 2.4%) Gastrooesophageal reflux disease 1 ( 2.4%) 1 ( 3.8%) 0 2 ( 4.9%) Nausea 2 ( 4.9%) 2 ( 7.7%) 0 4 ( 9.8%) Toothache 0 1 ( 3.8%) 0 1 ( 2.4%) Vomiting 1 ( 2.4%) 1 ( 3.8%) 0 2 ( 4.9%) General disorders and administration 3 ( 7.3%) 4 (15.4%) 3 ( 25.0%) 9 (22.0%) site conditions Catheter site pain 0 0 1 ( 8.3%) 1 ( 2.4%) Discomfort 0 0 1 ( 8.3%) 1 ( 2.4%) Fatigue 2 ( 4.9%) 2 ( 7.7%) 0 3 ( 7.3%) Gait disturbance 0 1 ( 3.8%) 0 1 ( 2.4%) Medical device site exfoliation 1 ( 2.4%) 0 0 1 ( 2.4%) Oedema peripheral 0 2 ( 7.7%) 2 ( 16.7%) 4 ( 9.8%) (continue)

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Number of subjects with treatment-emergent adverse events by primary system organ class, preferred term by treatment group (continued) Primary System Organ Class ISMN alone Vericiguat Placebo Total Preferred Term + ISMN + ISMN MedDRA version 20.1 N=41 (100%) N=26 (100%) N=12 (100%) N=41 (100%) Hepatobiliary disorders 0 0 1 ( 8.3%) 1 ( 2.4%) Cholelithiasis 0 0 1 ( 8.3%) 1 ( 2.4%) Hydrocholecystis 0 0 1 ( 8.3%) 1 ( 2.4%) Infections and infestations 2 ( 4.9%) 8 (30.8%) 2 ( 16.7%) 11 (26.8%) Conjunctivitis 0 1 ( 3.8%) 0 1 ( 2.4%) Gastroenteritis 0 1 ( 3.8%) 0 1 ( 2.4%) Nasopharyngitis 2 ( 4.9%) 5 (19.2%) 2 ( 16.7%) 8 (19.5%) Urinary tract infection 0 1 ( 3.8%) 0 1 ( 2.4%) Injury, poisoning and procedural 0 5 (19.2%) 0 5 (12.2%) complications Fall 0 1 ( 3.8%) 0 1 ( 2.4%) Humerus fracture 0 1 ( 3.8%) 0 1 ( 2.4%) Skin abrasion 0 2 ( 7.7%) 0 2 ( 4.9%) Subcutaneous haematoma 0 1 ( 3.8%) 0 1 ( 2.4%) Tooth fracture 0 1 ( 3.8%) 0 1 ( 2.4%) Investigations 5 (12.2%) 4 (15.4%) 2 ( 16.7%) 8 ( 19.5%) Amylase increased 0 0 1 ( 8.3%) 1 ( 2.4%) Blood creatinine increased 0 1 ( 3.8%) 0 1 ( 2.4%) Blood glucose increased 1 ( 2.4%) 0 0 1 ( 2.4%) C-reactive protein increased 0 1 ( 3.8%) 1 ( 8.3%) 2 ( 4.9%) Electrocardiogram QT prolonged 1 ( 2.4%) 1 ( 3.8%) 0 2 ( 4.9%) Glycosylated haemoglobin increased 1 ( 2.4%) 0 0 1 ( 2.4%) Lipase increased 1 ( 2.4%) 0 1 ( 8.3%) 2 ( 4.9%) Pancreatic enzymes increased 1 ( 2.4%) 0 0 1 ( 2.4%) Troponin increased 1 ( 2.4%) 0 0 1 ( 2.4%) Metabolism and nutrition disorders 0 1 ( 3.8%) 0 1 ( 2.4%) Hyperkalaemia 0 1 ( 3.8%) 0 1 ( 2.4%) Musculoskeletal and connective tissue 1 ( 2.4%) 5 (19.2%) 0 6 ( 14.6%) disorders Back pain 0 4 (15.4%) 0 4 ( 9.8%) Bursitis 0 1 ( 3.8%) 0 1 ( 2.4%) Muscle spasms 1 ( 2.4%) 0 0 1 ( 2.4%) Musculoskeletal pain 0 1 ( 3.8%) 0 1 ( 2.4%) Nervous system disorders 20 (48.8%) 9 (34.6%) 3 ( 25.0%) 23 ( 56.1%) Dizziness 2 ( 4.9%) 3 (11.5%) 3 ( 25.0%) 8 ( 19.5%) Dizziness postural 1 ( 2.4%) 0 0 1 ( 2.4%) Headache 16 (39.0%) 6 (23.1%) 1 ( 8.3%) 18 ( 43.9%) Orthostatic intolerance 2 ( 4.9%) 0 0 2 ( 4.9%) Somnolence 0 1 ( 3.8%) 0 1 ( 2.4%) Tension headache 1 ( 2.4%) 0 0 1 ( 2.4%) Renal and urinary disorders 0 4 (15.4%) 1 ( 8.3%) 5 ( 12.2%) Acute kidney injury 0 1 ( 3.8%) 0 1 ( 2.4%) Leukocyturia 0 1 ( 3.8%) 0 1 ( 2.4%) Renal impairment 0 1 ( 3.8%) 1 ( 8.3%) 2 ( 4.9%) Renal pain 0 1 ( 3.8%) 0 1 ( 2.4%) (continue)

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Overall, 15 subjects of the vericiguat group (57.7%) had vericiguat-related adverse events, however, a similar rate was reported in the placebo group, with TEAEs considered vericiguat- related reported for 6 subjects (50.0% of the treatment group). Vericiguat-related TEAEs with a maximum intensity of moderate were reported for 4 subjects (15.4%) in the vericiguat group and 1 subject (8.3%) in the placebo group. One subject in the vericiguat group and one subject in the placebo group had vericiguat-related TEAEs with the maximum intensity of severe: gastroesophagal reflux of severe intensity was reported for a subject in the vericiguat group under treatment with 5 mg and 10 mg vericiguat + ISMN and dizziness of severe intensity for a subject in the placebo group. Both cases were also possibly related to ISMN. TEAEs related to ISMN by assessment of the investigator were reported for 21 subjects (51.2%) in the ISMN run-in phase, for 14 subjects (53.8%) under vericiguat + ISMN treatment and for 5 subjects (41.7%) under treatment with placebo +ISMN. In total, ISMN- related TEAEs were reported for 26 subjects (63.4%). ISMN-related TEAEs of moderate intensity were reported for 1 subject (2.4%) under ISMN alone and 2 subjects (7.7%) in the vericiguat group. For 4 subjects in total (2 in the ISMN run-in phase, one in the vericiguat group and one in the placebo group) severe ISMN-related TEAEs were documented. Two SAEs reported in this study, acute coronary syndrome of moderate intensity and unstable angina pectoris of severe intensity were occurring in relationship with the underlying disease of the subjects included in this study and were not considered related to vericiguat or ISMN. The reason for classification as SAE was because both events required hospitalization. No deaths or drug-related SAEs were reported in this study. Laboratory parameters For this population of CAD patients, clinically relevant deviations from the normal ranges in the observed safety laboratory parameters were transient or related to the concomitant Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 10 of 11 diseases of the included subjects. No trends or specific patterns of deviation were revealed that could be attributed to the intake of study drug. Other safety parameters Measured values for supine BP and HR in both groups were highly variable but showed no relevant longitudinal change during treatment with vericiguat and ISMN. A slight trend towards systolic blood pressure decrease and heart rate increase was observed for co- administration of vericiguat at doses of 5 mg and higher and ISMN compared placebo and ISMN. A symptomatic blood pressure drop with a SBP value below 90 mmHg with orthostatic intolerance of severe intensity was only seen for 1 subject during the up-titration of ISMN in the run-in phase of the study. For several other subjects, seated and standing SBP values below 90 mmHg were commonly seen during the hemodynamic tests on profile days, but no further clinical symptoms were reported. These non-symptomatic decreases were seen for both groups. With mean increases of SBP and DBP values when changing from seated to standing position in the hemodynamic profiles and a comparable incidence of orthostatic hypotension in the vericiguat and the placebo group, there was no impact of vericiguat on the orthostatic tolerability of standing blood pressure procedures. In the ECG measurements, no effect of vericiguat or ISMN on electrocardiographic parameters was revealed. In summary, treatment with vericiguat and ISMN was safe and tolerated, though intake of ISMN over 6 weeks caused side effects in the majority of treated subjects. With both drugs acting on the same pathway, concomitant intake should be well-considered.

Overall conclusions • Concomitant treatment with vericiguat up to 10 mg and 60 mg ISMN was safe and generally tolerated. The observed adverse event profile was in line with the mode of action of both drugs and gave no hint for a more than additive adverse effect of both drugs. • Overall, the statistical analysis did not reveal a statistically significant effect of vericiguat compared to placebo, as most of the (exploratory) confidence intervals did not indicate differences between blood pressure or heart rate in the vericiguat and in the placebo group. Statistically significant differences in systolic and diastolic blood pressure of 2 to 5 mmHg and of 1 to 2 beats/min in heart rate were not deemed clinically relevant. • There is no obvious effect of increasing doses of vericiguat compared to placebo on blood pressure and heart rate. • Under concomitant treatment with up to 10 mg of vericiguat and 60 mg ISMN, no symptomatic decreases in blood pressure with systolic values below 90 mmHg and symptoms of hypotension were observed. • In summary, the observed overall effect size of treatment with up to 10 mg of vericiguat together with 60 mg ISMN on blood pressure and heart rate was in a Clinical Trial Results Synopsis 28-Feb-2019 Study no. 18582 Page: 11 of 11

clinically acceptable range for the pharmacodynamic as well as for the safety evaluation. • Vericiguat plasma concentrations in CAD patients were in accordance with observations in previous studies.