Summary Basis of Decision for Adempas

 

Clinical Pharmacology

Adempas (riociguat) is a highly specific stimulator of the soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme enhances synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP), which plays an important role in regulating vascular tone, proliferation, fibrosis, and inflammation.

Adempas has a dual mode of action: it sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. It also directly stimulates sGC via a different binding site, independently of NO. Adempas, as a stimulator of sGC, addresses NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of cGMP. There is a direct relationship between the concentration of Adempas in the plasma and hemodynamic parameters, such as systemic and pulmonary vascular resistance, systolic blood pressure, and cardiac output.

The comprehensive clinical pharmacology program included studies in patients with chronic thromboembolic pulmonary hypertension (CTEPH), or symptomatic pulmonary arterial hypertension (PAH) and in hepatically impaired, renally impaired and healthy subjects.

A total of four safety concerns have been identified with the use of Adempas, namely, hypotension, co-administration with other drugs affecting the nitric oxide-soluble guanylatecyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway, gastro-intestinal disorders and risk of bleeding. As a sGC stimulator, Adempas acts as a vasodilatator, lowering the pulmonary and systemic blood pressures which can cause hypotension. Concomitant use of Adempas with nitrates or phosphodiesterase type 5 (PDE5) inhibitors can also cause hypotension by having a synergistic effect on the NO-sGC-cGMP pathway. Adempas has smooth muscle relaxation properties not only in the arterial wall but also in the gastrointestinal system, which can cause gastrointestinal disorders, such as dyspepsia, nausea, diarrhea and vomiting. Finally, the risk of bleeding with the use of Adempas was a very common adverse event (AE), particularly in patients receiving anticoagulation therapy. Idiopathic bleeding events were observed in 58 (11.8%) of the Adempas treated patients compared to 18 (8.4%) in the placebo group. There were 101 adverse bleeding events in the two controlled trials (CHEST-1 and PATENT-1), 12 of which were serious events (all in the Adempas group). Appropriate warnings and precautions are included in the approved Adempas Product Monograph.

Overall, the clinical pharmacological data support the use of Adempas for the specified indication. Appropriate warnings and precautions are in place in the approved Adempas Product Monograph to address the identified safety concerns.

For further details, please refer to the Adempas Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Adempas was evaluated in one pivotal Phase III study (CHEST-1) and one supportive study (PATENT-1).

The pivotal Phase III study was a randomized, double-blind, placebo-controlled, multicentre, multi-national study to evaluate the efficacy and safety of oral Adempas [1.0 mg, 1.5 mg, 2.0 mg, or 2.5 mg three times daily (TID)] in 261 patients aged from 19 to 80 years old, who were considered not eligible for pulmonary endarterectomy (PEA) (72%), or who had recurrent chronic thromboembolism pulmonary hypertension (CTEPH) (28%) after an unsuccessful PEA. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) CTEPH at baseline and were mostly Caucasians (71%), female (66%), and middle-aged [59 ± 14 standard deviation (SD) years]. The mean baseline 6-minute walking distance (6MWD) for these patients was 347 m.

In total, 173 patients received Adempas and 88 patients received placebo for 16 weeks. During the first 8 weeks, patients were uptitrated to the highest tolerable dose. The dose of Adempas was titrated every two weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension. The 8-week titration phase was followed by an 8-week main study phase.

The primary efficacy endpoint was a measure of exercise tolerance, described as the distance covered in a 6-minute walking test (6MWT) performed after 16 weeks in accordance with the American Thoracic Society guideline. This test reflects an individual's ability to perform daily physical activities The secondary endpoints were the change from baseline in pulmonary vascular resistance (PVR) after 16 weeks, change from baseline in N-terminal prohormone B-type natriuretic peptide (NT-proBNP) after 16 weeks [(NT-proBNP is a neurohormone release by the heart and thought to be a reliable indicator for cardiac failure)], change from baseline in WHO functional class after 16 weeks, time to clinical worsening (TTCW), change from baseline in Borg CR 10 Scale or Modified Borg Dyspnoea Scale (measured at the end of the 6MWT) after 16 weeks, change from baseline in European-quality of life 5-dimensions instrument (EQ-5D) questionnaire after 16 weeks and change from baseline in "Living with Pulmonary Hypertension (LPH)" questionnaire after 16 weeks.

Results at the 6MWT, which measures the distance a patient can walk on a flat, hard surface in 6 minutes, showed improvements from week 2 onward. At week 16, the mean increase in the 6MWD within the Adempas group was 46 m (least-squares) [95% Confidence Interval (CI): 25 m to 67 m; p<0.0001] compared to placebo. Improvements of Adempas over placebo were observed in all sub-groups evaluated, such as the inoperable patients [number of patients (n) = 189], who demonstrated an increase in 6MWD of 54 m (95% CI: 29 m to 79 m), and patients with recurrent or persisting CTEPH following PEA (n = 72), who demonstrated an increase in 6MWD of 27 m (95% CI: -10 m to 63 m). In patients with a WHO functional class of III/IV at baseline, Adempas led to a 53 m (95% CI: 27 m to 79 m) improvement in the 6MWD from baseline to week 16. In patients with a WHO functional class of I/II at baseline, the treatment effect was 26 m (95% CI: -9 m to 59 m). A larger proportion of patients in the Adempas group (1.0 to 2.5 mg) had an improvement in 6MWD of at least 30 m by week 16 compared to the placebo group: [63% versus (vs.) 30%].

Improvements across all the secondary efficacy endpoints were observed in the Adempas treatment group. A reduction of PVR against placebo of 246 dyn·sec/cm⁵(95% CI: -303 to -190, p<0.0001) was observed in the intent-to-treat (ITT) population. The baseline for PVR was 791 ± 432 dyn·sec/cm5 in the Adempas group and 779 ± 401 dyn·sec/cm5 in the placebo group. Levels of NT-proBNP were significantly reduced in the Adempas group; placebo-corrected mean change from baseline was -444 pg/mL (95% CI -843 to -45, p<0.0001). A total of 32.9% of patients in the individual dose titration group (riociguat 1.0 to 2.5 mg) compared to 14.9% patients in the placebo group had an improvement of at least one WHO functional class (p = 0.0026). The secondary endpoint of Time To Clinical Worsening (TTCW) was a combined endpoint of death (all-cause mortality) and events reflective of residual clinical worsening. The sum of events leading to clinical worsening had a lower event rate in the Adempas group (2.3%) than in the placebo group (5.7%), but the difference was not considered statistically significant (p = 0.1724). Benefit was observed in both inoperable and operable CTEPH patients. Baseline values for the Borg CR 10 Scale were comparable in both treatment groups. Between baseline and week 16, the mean Borg CR 10 Scale decreased in the Adempas group (mean change of -0.83), but remained almost unchanged in the placebo group (mean change of 0.17). The treatment difference between the Adempas group and the placebo group was statistically significant (p = 0.0035). However, since the Borg Scale was below clinical worsening in the hierarchical testing order for secondary variables, statistical significance cannot be formally claimed for this variable. Also for EQ-5D, although statistical significance in the improvement of an individual's perceived quality of life cannot be formally claimed, the self-reported score improved for the Adempas group while it worsened for the placebo group (+0.0615 ± 0.2768 vs. -0.0819 ± 0.3446 placebo; p<0.0001). The last secondary variable, the LPH questionnaire, is a self-report measuring the effects of pulmonary hypertension (PH) and PH-specific treatments on an individual's quality of life. The results showed that, at the last visit, patients in the Adempas group had a statistically nonsignificant improvement in perceived quality of life compared to patients in the placebo group (-6.72 ± 18.62. vs. -2.09 ± 19.31 placebo; p = 0.1220).

Supportive Studies

Supportive evidence regarding efficacy comes from a Phase III, randomised, double-blind, placebo-controlled, multicentre, multinational study (PATENT-1) to evaluate the efficacy and safety of Adempas in patients with symptomatic pulmonary arterial hypertension (PAH). A total of 586 patients were enrolled in the 12 week study. Of the 586 patients enrolled, 445 were randomized and 443 received study medication (254 in the Adempas individual titration (IDT) group, 126 in the placebo group and 63 in the Adempas 1.0-1.5 mg group).

In PATENT-1, the patients on Adempas significantly improved their walking distance in the 6MWT from baseline to week 12 compared to the patients on placebo. The estimated, placebo-corrected overall treatment effect was 35.78 m (95% CI: 20.06 m to 51.51 m; p<0.0001). Pulmonary hemodynamic and clinically important secondary endpoint variables (CO, PVR, Borg dyspnea scale and change in WHO functional class) also pointed at statistically significant improvements of patients on Adempas.

The long-term maintenance of efficacy was confirmed by 2 ongoing long-term studies (CHEST-2 and PATENT-2). At 18 months, the improvements in the 6MWD, pulmonary hemodynamic variables and clinical scales seen at Weeks 12 and 16 of the short-term controlled studies were maintained (data cut-off April/May 2012).

For more information, refer to the Adempas Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety evaluation was based primarily on data from one pivotal study (CHEST-1) and one supportive study (PATENT-1) previously described in the Clinical Efficacy section. The safety of Adempas was also assessed in two long term open-label extension studies (CHEST-2 and PATENT-2).

CHEST-2 was a long-term extension, multicentre, multinational study to evaluate the safety and tolerability of Adempas (1.0 mg, 1.5 mg, 2.0 mg or 2.5 mg TID) in patients with CTEPH (n = 237 patients from CHEST-1). The mean treatment duration at the cut-off date was 388 days with a median duration of 336 days (range 15 to 989 days) and a total treatment exposure of 206 person years. PATENT-2 was a long-term extension, multi-centre, multi-national study to evaluate the safety and tolerability of Adempas (1.0 mg, 1.5 mg, 2.0 mg or 2.5 mg TID) in patients with symptomatic PAH (n = 396 patients from PATENT-1).

The safety analyses included evaluation of adverse events (AE), serious adverse events (SAE), and deaths. In the pooled controlled studies (CHEST-1 and PATENT-1), 490 patients were exposed to Adempas and 214 to placebo. In the pooled extension studies (CHEST-2 and PATENT-2), 557 patients were treated with Adempas.

Considering Adempas is a vasodilator, common AEs observed in the Phase III clinical studies were dizziness (19.8% of patients in the Adempas group compared to 13.1% in the placebo group), (pre)syncope and hypotension (10% of patients in the Adempas group compared to 3.7% in the placebo group). Bleeding was also a very common AE. Idiopathic bleeding events were observed in 58 (11.8%) of the Adempas-treated patients compared to 18 (8.4%) in the placebo group. Of the 58 cases, 10 cases were considered serious adverse events (SAE) and 1 case was fatal. Pulmonary hemorrhage was reported in less than 1% of patients treated during long-term extension studies with Adempas. Anemia also occurred commonly in the pooled Phase III studies. Anemia (or respective changes in laboratory values reported as an AE) was noted in 33 (6.7%) of the Adempas-treated patients, in 2 of these cases as an SAE. Anemia occurred in 5 (2.3%) of the patients on placebo, once as an SAE.

The overall rates of discontinuation due to an AE in the pooled Phase III studies (CHEST 1 and PATENT 1) were 2.9% for Adempas and 5.1% for placebo.

Treatment-emergent adverse events (TEAEs) were defined as any AE occurring after the first dose administration until 48 hours after the last dose administration. The most frequent TEAEs (> 10%) in each treatment group of CHEST-1 and PATENT-1 studies were headache (26.9%), dizziness (19.8%), dyspepsia (18.6%), peripheral edema (17.3%), nausea (14.1%), diarrhea (12.0%), bleeding (11.8%), and vomiting (10.2%).

There were 11 deaths in the pooled controlled studies (CHEST-1 and PATENT-1); 5 in the Adempas groups and 6 in the placebo groups. In both groups, most fatal events were due to progression of the disease. Sepsis occurred in one fatal case, and death from hemorrhage or hemoptysis occurred in 2 patients on Adempas. There were 23 deaths in the pooled extension studies (CHEST-2 and PATENT-2). Most fatalities (n = 15) were due to progression of the disease: pulmonary arterial hypertension (PAH), cardiac arrest, right ventricular failure, cardiac failure and cardiogenic shock. Hemorrhage was the cause of 3 deaths. Other causes of death were: sudden cardiac death, sepsis, shock, and lung cancer.

Frequencies of adverse events were comparable between the CHEST-1 and PATENT-1 studies, with the exception of a lower rate of anemia in the CTEPH patients and a higher rate of dizziness.

Overall, Adempas is well-tolerated. The submitted data support the safety of Adempas for use in patients with CTEPH who are not considered candidates for surgical treatment, or who have persistent or recurrent pulmonary hypertension post-operatively. There were no signs of cardiac, renal or hepatic toxicity. The risk of hypotension is minimized by a gradual individual dose titration to the highest tolerated dose, and by contraindicating concomitant use with other drugs affecting the NO-sGC-cGMP pathway. Gastrointestinal disorders occurred very commonly, but seemed to be manageable, as few subjects discontinued from the clinical studies. The apparent increased risk of bleeding has been addressed in the label by means of a prominent warning and a description of bleeding events in the adverse reactions section of the Product Monograph. The risk of pulmonary bleeding and hemoptysis may be avoided by contraindicating its use in patients with a history of hemoptysis. As stated in the Product Monograph, patients with a history of serious hemoptysis should avoid the use of Adempas. For more information, refer to the Adempas Product Monograph, approved by Health Canada and available through the Drug Product Database.