OPSUMIT - Combination Therapy With Riociguat

SUMMARY

• Johnson & Johnson has not conducted any clinical studies on the combination use of OPSUMIT and riociguat.
• An interim analysis of the OPsumit USers (OPUS) registry (data cutoff date of April 2018) evaluated the safety and survival of patients treated with OPSUMIT and riociguat in a real-world setting.¹
• A retrospective study evaluated the efficacy and safety of OPSUMIT and riociguat in 90 patients with idiopathic pulmonary arterial hypertension (IPAH; n=60) or connective tissue disease pulmonary arterial hypertension (PAH; n=30). At the 6-month follow-up, 6-minute walking distance (6MWD) increased from 350±102 to 417±128 m (P<0.001) and NT-pro-brain natriuretic peptide (NT-pro-BNP) levels decreased from 1537±3077 to 465±557 pg/mL (P=0.001). The transplant-free survival rate at the 18-month follow-up was 91%.²
• The upfront combination of OPSUMIT and riociguat in patients with PAH has been evaluated in a single-center study. Initial therapy with OPSUMIT and riociguat improved clinical and hemodynamic parameters and was well tolerated.³
• A search of the scientific literature retrieved a number of published studies in which combination regimens, including OPSUMIT and riociguat, were administered during the course of PAH treatment; relevant information from these publications is summarized in this letter.^4-16
• Overall, the efficacy and safety of dual PAH therapy with OPSUMIT and riociguat vs monotherapy with either agent have not been formally investigated and are currently unknown. Only limited data exist with respect to combining OPSUMIT and riociguat in the treatment of PAH.^4-18

CLINICAL DATA

OPUS Registry

OPUS was a prospective, multicenter, long-term, observational drug registry that aimed to characterize the safety profile of OPSUMIT and describe the clinical characteristics and outcomes of patients newly treated with OPSUMIT in the United States.^1,19 An interim analysis (data cutoff date of April 2018) of enrolled patients treated concomitantly with riociguat and OPSUMIT was presented.¹

Results

As of April 2018, OPUS included 1721 patients with follow-up data. Of these, 151 patients were identified as being treated concomitantly with riociguat and OPSUMIT. The main reasons for OPSUMIT treatment were PAH (n=105 [69.5%]) and chronic thromboembolic pulmonary hypertension (n=27 [17.9%]).¹

Treatment Patterns

OPSUMIT was initiated prior to riociguat in 68 (45%) patients. The treatment patterns at the start of concomitant OPSUMIT and riociguat exposure and 6 months after are presented in the Table: PAH Therapy at the Start of the Concomitant OPSUMIT and Riociguat Exposure Period and 6 Months After. The OPSUMIT and riociguat exposure period was defined as the time from the initiation of OPSUMIT or riociguat (whichever was later) up to the end of OPSUMIT or riociguat treatment (whichever was earlier) or to the last information before the data cutoff date.  OPSUMIT exposure period was defined as the time from OPSUMIT initiation up to the end of OPSUMIT treatment or the last information before the data cutoff date.¹

The median (quartile [Q]1-Q3) exposure to concomitant OPSUMIT and riociguat was 7.4 (2.6-17.1) months, with 31.8% and 23.8% of patients having concomitant exposure of >12 and >18 months, respectively.¹

Safety and Tolerability

In the OPSUMIT and riociguat population, 39 (25.8%) patients discontinued OPSUMIT, with 61.3% discontinuing due to an adverse event (AE). There were no unexpected safety findings with the combination use of OPSUMIT and riociguat.¹ AEs and liver enzyme elevations are described in further detail in the Table: AEs and Liver Enzyme Elevations During the Exposure Period.

Hospitalization and Survival

A total of 593 (34.5%) patients in the overall OPUS population experienced ≥1 hospitalization, while 54 (35.8%) patients in the OPSUMIT and riociguat population experienced ≥1 hospitalization.¹

Kaplan-Meier survival estimates from the start of the concomitant OPSUMIT and riociguat exposure period were 91% (95% confidence interval [CI], 83%-95%) at month 12 and 75% (95% CI, 61%-85%) at month 24. Kaplan-Meier survival estimates from OPSUMIT initiation in the overall population (OPSUMIT exposure period) were 91% (95% CI, 89%-92%) at month 12 and 84% (95% CI, 81%-86%) at month 24.¹

D’Alto et al (2026)² conducted a retrospective study that evaluated the efficacy and safety of the initial combination of OPSUMIT and riociguat in 90 patients with IPAH (n=60) or connective tissue disease PAH (n=30). In the study, hemodynamic and echocardiographic data, NT-pro-BNP levels, World Health Organization functional class (WHO FC), and 6MWD were obtained at baseline and the 6-month follow-up; survival and lung transplantation status were checked at the 18-month follow-up.

The mean (SD) age was 58 (15) years, and 60/90 patients were female. Mild/moderate cardiovascular (CV) comorbidities were recorded in 42 patients, while a lung diffusing capacity for carbon monoxide of <45% was observed in 37 patients.

Results

Efficacy

• Systemic vascular resistance and systolic blood pressure showed no significant changes during follow-up.
• European Society of Cardiology (ESC)/European Respiratory Society (ERS) 3-strata model (baseline)
  • Intermediate risk: 74 of 90 patients (82%)
  • Low risk: 16 of 90 patients (18%)
• ESC/ERS 4-strata model (follow-up)
  • Low risk: 47 of 90 patients (52%)
  • Intermediate-low risk: 28 of 90 patients (31%)
  • Intermediate-high risk: 14 of 90 patients (16%)
  • High risk: 1 of 90 patients (1%)
• Among 90 patients, 51 presented with the worst echocardiographic (ECHO) phenotype (right ventricle [RV] > left ventricle [LV] and low tricuspid annular plane systolic excursion [TAPSE]/pulmonary artery systolic pressure [PASP]) at baseline. At follow-up, 8 of these 51 patients (16%) attained the best ECHO phenotype (RV < LV and high TAPSE/PASP), while 22 of 51 patients (43%) remained in the worst ECHO phenotype category. Improvements in ECHO phenotypes were observed across all ECHO risk strata. See Table: Efficacy Endpoints

Safety

• Three of the 90 patients discontinued double oral therapy because of fluid retention, including 1 discontinuation within the first 3 months and 2 between months 3 and 6.
• The transplant-free survival rate at the 18-month follow-up was 91%.
• Eight deaths were reported, including 4 unrelated to PAH (malignancy and pneumonia) and 4 attributed to PAH worsening.

Upfront Combination With OPSUMIT and Riociguat

Sulica et al (2019)³ conducted an open-label study that evaluated the upfront combination of OPSUMIT and riociguat in patients with newly diagnosed PAH. In the study, demographic, clinical (WHO FC, 6MWD, Borg score, brain natriuretic peptide [BNP]), and hemodynamic data were collected at baseline, the first follow-up (median 4 months), and the second follow-up (median 12 months). This combination was defined as upfront if the decision was to start both medications upon the diagnostic right heart catheterization without a waiting period to assess the effect of the medication started first and if logistical considerations allowed medication initiation within less than 3 months from each other.

Overall, 15 consecutive newly diagnosed PAH patients from 2014 to 2016 who received upfront OPSUMIT and riociguat combination therapy were evaluated in the study. There were 11/15 (73.3%) women, and the mean age was 55.8 years (range, 27-82 years). Six patients (40%) had IPAH, and 9 patients had associated PAH (6 patients with connective tissue disease and 5 associated with other risk factors). All patients had WHO FC III (n=14) or IV (n=1) symptoms at baseline. The 1 patient classified as WHO FC IV was due to a history of exertional syncope; she was started on OPSUMIT, riociguat, and subcutaneous treprostinil. Treprostinil was uptitrated to a dose of 16 ng/kg/min but was stopped at the patient’s request.³

Results

Efficacy

6MWD data were available for 14/15 patients since 1 patient was wheelchair bound. The 6MWD increased from a mean of 281.6 m at baseline to 315.7 m at the first follow-up and was maintained at 313.9 m at the second follow-up, which represents an increase in 6MWD of 34 m and 32 m, respectively.³ See Table: Summary of 6MWD (Meters) at Baseline, First Follow-up, and Second Follow-up (n=14).

Mean BNP levels decreased from 318.2 pg/mL at baseline to 122 pg/mL at the first follow-up and 98.6 pg/mL at the second follow-up, with changes from baseline of -196.2 pg/mL and 219.7 pg/mL, respectively.³ See Table: BNP (pg/mL) at Baseline, First Follow-up, and Second Follow-up (n=15).

There was an improvement in WHO FC in 8 patients (53%; 95% CI, 27%-79%), and no patients had FC deterioration; see Figure: WHO FC Improvement. Additionally, improvements in hemodynamic parameters, including mean blood pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, pulmonary vascular resistance index, pulmonary artery saturation, systolic pulmonary artery pressure, and diastolic pulmonary arterial pressure, were observed at follow-up.³

Kaplan-Meier analysis showed a survival of 100% at 1 year, 92.9% at 2 years, and 85.1% at 3 years. When the risk of disease progression and adverse outcomes (as defined by the 2015 European guidelines) were examined for the group at baseline and at follow-up, approximately 50% of the patients achieved low-risk status at the first follow-up, which had been maintained at the second follow-up. At baseline, 14 patients (93%) were at intermediate risk and 1 patient (7%) was at high risk. At the second follow-up visit, 7 patients (47%) had a risk reduction (6 [40%] patients from intermediate to low and 1 [7%] patient from high to low) and 8 patients (53%) had no change and maintained intermediate status.³

Safety

Five patients experienced medication-related side effects. Two patients had increased nasal congestion, 2 had headaches, and 1 had increased lower extremity edema; all resolved with supportive therapy. Riociguat uptitration was stopped in 3 patients due to hypotension and in 1 patient due to headache, but the medication had been continued at a lower dose, with 73% of the patients achieving and maintaining the maximum Food and Drug Administration-approved dose of 2.5 mg thrice daily.³

By the end of the second follow-up period, 1 patient required hospital admission for right heart failure/fluid overload, which was resolved with intravenous diuretics. Four patients required the addition of a third medication (1 patient for hemodynamic optimization due to impeding cholecystectomy and the 3 other patients for insufficient therapeutic response). One patient with scleroderma received bilateral lung transplant. There were 3 deaths at 19, 32, and 51 months since the initiation of dual therapy, all from causes unrelated to pulmonary hypertension: 1 intra-abdominal sepsis in a patient with cirrhosis, 1 hypoxic respiratory failure due to aspiration pneumonia in a patient with scleroderma, and 1 with acute respiratory distress syndrome from bacterial pneumonia in an 84-year-old patient with rheumatoid arthritis. Of the 11 non-transplanted patients alive at 36 months, 7 patients were still on dual OPSUMIT and riociguat therapy.³

Information From the Literature

A number of case reports/series and other studies of relevance were identified from the scientific literature. A brief description of the patients and the circumstances of combination treatment with OPSUMIT and riociguat is provided in the Table: Patient Characteristics and Treatment Regimens in Case Reports/Series and Other Studies Describing the Administration of OPSUMIT in Combination With Riociguat to Treat PAH. Please refer to the full text publications for full details including outcomes of patients.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 September 2026.