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OPSUMIT® (macitentan)
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OPSUMIT - Combination Therapy With Riociguat
Last Updated: 11/20/2024
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
- The upfront combination of OPSUMIT and riociguat in patients with pulmonary arterial hypertension (PAH) has been evaluated in a single-center study. Initial therapy with OPSUMIT and riociguat improved clinical and hemodynamic parameters and was well tolerated.
2 - 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.3
- 12 - 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.3-12
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,
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
| Patients With Follow-up Data | Start of OPSUMIT and Riociguat Exposure Period (n=151)a | 6 Months After Start of OPSUMIT and Riociguat Exposure Period (n=95)a |
|---|---|---|
| Monotherapy, n (%) | - | 7 (7.4) |
| Double combination therapy, n (%) | 111 (73.5) | 60 (63.2) |
| OPSUMIT+sGC stimulator | 111 (100) | 58 (96.7) |
| OPSUMIT+PDE-5i | - | 1 (1.7) |
| OPSUMIT+oral prostanoid | - | 1 (1.7) |
| Triple combination therapy, n (%) | 34 (22.5) | 25 (26.3) |
| OPSUMIT+sGC stimulator+IV/SC prostanoid | 13 (38.2) | 7 (28.0) |
| OPSUMIT+sGC stimulator+oral prostanoidb | 9 (26.5) | 12 (48.0) |
| OPSUMIT+sGC stimulator+inhaled prostanoid | 6 (17.6) | 3 (12.0) |
| OPSUMIT+sGC stimulator+PDE-5i | 6 (17.6) | 3 (12.0) |
| Abbreviations: IV, intravenous; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase-5 inhibitor; SC, subcutaneous; sGC, soluble guanylate cyclase.aN=number of patients receiving combination therapies. Percentages are calculated out of N or out of the number of patients receiving double or triple combination therapy. Six patients at the start of OPSUMIT and riociguat exposure period and 3 patients at 6 months after the start of OPSUMIT and riociguat exposure period received more than 3 PAH therapies. bIncludes selexipag. | ||
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. AEs and liver enzyme elevations are described in further detail in the Table: AEs and Liver Enzyme Elevations During the Exposure Period.1
| Patients With Follow-up Data | OPSUMIT and Riociguat Population (n=151) | Overall Population (N=1721) |
|---|---|---|
| Patients with ≥1 AE, n (%) | 111 (73.5) | 1276 (74.1) |
| Rate of first AE per person-year (95% CI) | 1.96 (1.63-2.36) | 1.57 (1.49-1.66) |
| Most common (≥5%) AEs,a n (%) | ||
| Dyspnea | 26 (17.2) | 316 (18.4) |
| Peripheral edema | 15 (19.9) | 150 (8.7) |
| Headache | 8 (5.3) | 149 (8.7) |
| Pneumonia | 13 (8.6) | 123 (7.1) |
| Diarrhea | 4 (2.6) | 120 (7.0) |
| Nausea | 7 (4.6) | 117 (6.8) |
| Edema | 18 (11.9) | 117 (6.8) |
| Dizziness | 9 (6.0) | 116 (6.7) |
| Anemia | 12 (7.9) | 116 (6.7) |
| Fatigue | 6 (4.0) | 100 (5.8) |
| Condition aggravated | 9 (6.0) | 94 (5.5) |
| Cough | 5 (3.3) | 93 (5.4) |
| Hypoxia | 5 (3.3) | 92 (5.3) |
| Upper respiratory tract infection | 11 (7.3) | 50 (2.9) |
| Hypotension | 8 (5.3) | 57 (3.3) |
| AEs of special interest,a n (%) | ||
| Syncope | 2 (1.3) | 48 (2.8) |
| Hemoptysis | 3 (2.0) | 16 (0.9) |
| Liver enzyme elevations, n (%) | ||
| Patients with ALT/AST ≥3×ULN | 2 (1.3) | 36 (2.1) |
| Patients with ALT/AST ≥3×ULN and total bilirubin ≥2×ULN | 0 | 5 (0.3) |
| Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; ULN, upper limit of normal.aAEs are not mutually exclusive; patients could have had multiple AEs. | ||
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
Upfront Combination With OPSUMIT and Riociguat
Sulica et al (2019)2 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 (World Health Organization [WHO] functional class [FC], 6-
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 idiopathic PAH, 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.2
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; see Table: Summary of 6MWD (Meters) at Baseline, First Follow-up, and Second Follow-up (n=14).2
| Baseline | First Follow-up | Second Follow-up | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean (SD) | Change From Baseline (SD) | P Value | % Change (SD) | P Value for % Change | Mean (SD) | Change From Baseline (SD) | P Value | % Change (SD) | P Value for % Change |
| 281.6 (93.4) | 315.7 (108.4) | 34.1 (56.6) | 0.0421 | 12.3 (20.2) | 0.0397 | 313.9 (108.4) | 32.2 (58.8) | 0.0610 | 13.5 (19.9) | 0.0244 |
| Abbreviations: 6MWD, 6-minute walking distance; SD, standard deviation. | ||||||||||
Mean BNP levels decreased from 318.2 pg/mL at baseline to 122.0 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; see Table: BNP (pg/mL) at Baseline, First Follow-up, and Second Follow-up (n=15).2
| Baseline | First Follow-up | Second Follow-up | ||||
|---|---|---|---|---|---|---|
| Mean (SD) | Mean (SD) | Change From Baseline (SD) | P Valuea for Change | Mean (SD) | Change From Baseline (SD) | P Valuea for Change |
| 318.2 (369.7) | 122.0 (156.2) | -196.2 (365.7) | 0.0566 | 98.6 (62.6) | -219.7 (325.4) | 0.0204 |
| Abbreviations: BNP, brain natriuretic peptide; SD, standard deviation.aP value is calculated from paired t-test to test whether the change is equal to 0. | ||||||
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 were observed at follow-up; see Table: Summary of Hemodynamic Parameters at Baseline and Follow-up.2
Abbreviations: CI, confidence interval; FC, functional class; WHO, World Health Organization.
| Baseline (n=15); Mean (SD) | Follow-up (n=14); Mean (SD) | Change From Baseline; Mean (SD) | P Valuea for Change | |
|---|---|---|---|---|
| Mean blood pressure, mmHg | 100.4 (11.7) | 87.1 (12.0) | -13.3 (12.8) | 0.0019 |
| Heart rate, bpm | 85.1 (15.1) | 79.1 (11.3) | -7.9 (18.9) | 0.1412 |
| O2 saturation, % | 93.9 (2.8) | 93.2 (3.5) | -0.9 (3.2) | 0.3038 |
| RAP, mmHg | 11.2 (4.4) | 8.0 (3.4) | -2.8 (5.1) | 0.0632 |
| SPAP, mmHg | 77.8 (17.9) | 65.2 (12.3) | -11.1 (15.0) | 0.0158 |
| DPAP, mmHg | 33.1 (8.5) | 28.4 (6.3) | -4.9 (6.6) | 0.0157 |
| Mean PAP, mmHg | 47.3 (10.0) | 38.9 (6.9) | -8.1 (8.6) | 0.0039 |
| PA saturation, % | 59.3 (7.5) | 68.5 (3.4) | 9.7 (7.6) | 0.0004 |
| Cardiac output, L/min | 4.1 (0.8) | 5.2 (1.0) | 1.2 (0.6) | <0.0001 |
| Cardiac index, L/min/m2 | 2.3 (0.4) | 3.0 (0.5) | 0.7 (0.4) | <0.0001 |
| PVR, Wood units | 9.2 (3.0) | 5.7 (1.8) | -3.6 (2.5) | 0.0001 |
| PVRI, Wood units/m2 | 16.9 (5.6) | 10.0 (3.5) | -6.9 (4.6) | <0.0001 |
| Abbreviations: DPAP, diastolic pulmonary arterial pressure; O2, oxygen; PA, pulmonary artery; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; PVRI, pulmonary vascular resistance index; RAP, right atrial pressure; SPAP, systolic pulmonary artery pressure.aP value is calculated from paired t-test to test whether or not the change is equal to 0. | ||||
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.2
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.2
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.2
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.
| Reference | Patient Characteristics | Treatmenta |
|---|---|---|
| Sulica et al (2015)3 Case series | Case 1: 44-year-old male patient diagnosed with PAH secondary to Sjögren’s syndrome, WHO FC III Case 3: 51-year-old male patient diagnosed with IPAH, WHO FC III | Case 1: Received different treatment modalities over time before finally receiving triple combination therapy with OPSUMIT, riociguat, and epoprostenol several years after diagnosis (while at FC II). Case 3: After diagnosis, OPSUMIT was initiated and then riociguat was added on after several weeks. |
| Raina et al (2017)4 Case series | Case 2: 62-year-old female patient diagnosed with SScPAH, WHO FC III Case 3: 67-year-old female patient diagnosed with SScPAH, WHO FC III-IV | Case 2: Switched to riociguat after approximately 6.5 years sildenafil treatment and then OPSUMIT was added on after 2 years of riociguat monotherapy. Case 3: Approximately 1.5 years after diagnosis, OPSUMIT was added to prior treatment with tadalafil and inhaled treprostinil; tadalafil was subsequently switched to riociguat after 4 months (while WHO FC III). |
| Yanagisawa et al (2017)5 Case study | 57-year-old female patient diagnosed with PAH associated with sclerodermapolymyositis; concomitant severe aortic stenosis with heart failure, WHO FC IV | After diagnosis, OPSUMIT and riociguat were initiated in short succession, in addition to beraprost. |
| Hirata et al (2018)6 Case study | 23-year-old female patient diagnosed with MCTD-PAH, WHO FC II; concomitant cardiovocal syndrome likely associated with MCTD-PAH | After diagnosis, initial treatment with bosentan was transitioned to OPSUMIT (3 mg/day) after 2 weeks due to liver enzyme elevations, which was gradually increased to 7.5 mg/day. Riociguat was subsequently added on to OPSUMIT. |
| Chan et al (2018)7 Case study | 20-year-old female patient diagnosed with severe PH (IPAH suggested by post-mortem examinationb) | After diagnosis, sildenafil was initiated and OPSUMIT was added on after 3 weeks. Sildenafil was subsequently switched to riociguat after 8 months.b |
| Okamoto et al (2021)8 Case study | 53-year-old Japanese woman diagnosed with CTD-PAH and right-sided heart failure (WHO FC IV) | Treatment of PH was initiated with dobutamine, followed by sildenafil, tadalafil, OPSUMIT, and selexipag; sildenafil and tadalafil were later replaced with riociguat. These drugs were added sequentially, and dosages were increased with uptitration of each drug. |
| Kanai et al (2021)9 Case study | 41-year-old female patient diagnosed with ventricular septal defect complicated by severe PAH | Initial treatment with bosentan was transitioned to OPSUMIT. Riociguat was subsequently added on to OPSUMIT and was later switched to tadalafil. To control the increased pulmonary artery flow due to intensive PAH treatment, PAB was performed. After PAB, selexipag was added to OPSUMIT and tadalafil but was later switched to a continuous epoprostenol infusion. |
| Momoi et al (2021)10 Retrospective study | 26 patients underwent combination therapy with OPSUMIT, selexipag, and riociguat | Four patients (15.0%) discontinued any of the 3 drugs because of AEs, and 17 patients (65.4%) reached the maximum dose of all 3 drugs. The mPAP, PVR, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days), and similar improvements were observed in treatment-naïve patients at baseline. |
| El-Kersh et al (2023)11 Case study | 48-year-old male patient diagnosed with severe high-risk PAH | The patient was initiated on a triple combination therapy, including OPSUMIT, riociguat (titrated to 2.5 mg thrice daily), and inhaled treprostinil (titrated to 12 breaths 4 times daily). At 2.5 months, the patient went from WHO FC III to I, NT-proBNP levels decreased from 2882 pg/mL to 45 pg/mL, 6MWD improved from 274 m to 487 m, and right ventricular reverse remodeling was noted. RHC was repeated at 4 months and showed normalization of hemodynamics. |
| Nair et al (2024)12 Case study | 37-year-old female patient with a history of IPAH (WHO Group 1 PH) diagnosed with serous retinal detachment due to increased systemic venous pressure in the setting of PH | The patient was taking OPSUMIT, SC treprostinil, and riociguat. Supplemental oxygen was administered, and diuretics were adjusted following the diagnosis of serous retinal detachment due to increased systemic venous pressure. Riociguat was switched to sildenafil, OPSUMIT was continued, and the treprostinil dose was increased. |
| Abbreviations: 6MWD, 6-minute walking distance; AE, adverse event; CTD-PAH, pulmonary arterial hypertension associated with connective tissue disease; FC, functional class; IPAH, idiopathic pulmonary arterial hypertension; MCTD-PAH, pulmonary arterial hypertension associated with mixed connective tissue disease; mPAP, mean pulmonary arterial pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAB, pulmonary artery banding; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RHC, right heart catheterization; SC, subcutaneous; SSc, systemic sclerosis; WHO, World Health Organization.aUnless otherwise specified, treatment with OPSUMIT was 10 mg daily or not specified in the publication. bPatient died following lower respiratory tract infection with equivocal mycoplasma pneumoniae serology 12 months after diagnosis. | ||
Literature Search
References
| 1 | McLaughlin V, Chin K, Kim N, et al. Real-world experience with concomitant macitentan and riociguat treatment in patients with pulmonary hypertension (PH) in the OPsumit USers (OPUS) Registry. Poster presented at: European Society of Cardiology (ESC) Congress; August 25-29, 2018; Munich, Germany. |
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