Riociguat - Zydus Pharmaceuticals USA Inc | MSN LABORATORIES PRIVATE LIMITED

Riociguat tablets are indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class [ see Clinical Studies (14.1)].

Riociguat tablets are indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening.   
Efficacy was shown in patients on riociguat tablets monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%) [ see Clinical Studies (14.2)].

The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of riociguat tablets, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day. 
Crushed Tablets
For patients who are unable to swallow whole tablets, riociguat tablets may be crushed and mixed with water or soft foods (such as applesauce) immediately before administration [ see Clinical Pharmacology (12.3)].

If a dose is missed, advise patients to continue with the next regularly scheduled dose. 
In case riociguat tablets are interrupted for 3 days or more, re-titrate riociguat tablets. 

Exclude pregnancy before initiating riociguat tablets. [see Contraindications (4.1), Warning and Precautions (5.1), Use in Specific Populations (8.3)].

Consider titrating to dosages higher than 2.5 mg three times a day, if tolerated, in patients who smoke. A dose decrease may be required in patients who stop smoking [see Drug Interactions (7.2)and Clinical Pharmacology (12.3)].

Consider a starting dose of 0.5 mg, three times a day when initiating riociguat tablets in patients receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein (P-gp/BCRP) inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (for example, ritonavir). Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Warnings and Precautions (5.2), Drug Interactions (7.2)and Clinical Pharmacology (12.3)].

• Discontinue sildenafil at least 24 hours prior to administering riociguat tablets [see Contraindications (4.3) and Drug Interactions (7)].
• Discontinue tadalafil at least 48 hours prior to administering riociguat tablets [see Contraindications (4.3) and Drug Interactions (7)].Consider initiating riociguat tablets at a starting dose of 0.5 mg in patients at risk of hypotension [see Dosage and Administration (2.1)].Monitor for signs and symptoms of hypotension on initiation.
• Discontinue riociguat tablets at least 24 hours prior to administering a PDE5-inhibitor [see Dosage and Administration (2.1),Contraindications (4.3),and Drug Interactions (7)].Monitor for signs and symptoms of hypotension on initiation.

Use of riociguat is contraindicated in patients who are pregnant [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

Co-administration of riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated [ see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].

Concomitant administration of riociguat with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE-5 inhibitors (such as dipyridamole or theophylline) is contraindicated [ see Dosage and Administration (2.6), Drug Interactions (7.1)and Clinical Pharmacology (12.2)].Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.

Riociguat is contraindicated in patients with concomitant use of other soluble guanylate cyclase (s GC) stimulators [see Drug Interactions (7.1)].

Riociguat is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

Based on data from animal reproduction studies, riociguat may cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. The available human data for riociguat do not establish the presence or absence of major birth defects related to the use of riociguat. Counsel patients who can become pregnant on the potential risk to a fetus. Exclude pregnancy prior to initiation of treatment with riociguat. Advise females of reproductive potential to use effective contraception prior to initiation of treatment, during treatment with riociguat and for at least one month after the last dose. When pregnancy is detected, discontinue riociguat as soon as possible [see Dosage and Administration (2.3), Contraindications (4.1), and Use in Specific Populations (8.1, 8.3)].

Riociguat reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors [see Drug Interactions (7.2) andClinical Pharmacology (12.3)].Consider a dose reduction if patient develops signs or symptoms of hypotension.

In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking riociguat compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking riociguat compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with riociguat.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety data described below reflect exposure to riociguat in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (riociguat: n = 490; Placebo: n = 214) was between the age of 18 and 80 years [ see Clinical Studies (14.1, 14.2)].
The safety profile of riociguat in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on riociguat than placebo (≥3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of riociguat.
The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for riociguat and 5.1% for placebo (pooled data).
Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Riociguat than Placebo (Pooled from CHEST-1 and PATENT-1)

Other events that were seen more frequently in riociguat compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials.

Other Soluble Guanylate Cyclase Stimulators: Co-administration of riociguat is contraindicated in patients with use of other soluble guanylate cyclase (sGC) stimulators [see Contraindications (4.4)].
Nitrates: Co-administration of riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension
[see Contraindications (4.2)and Clinical Pharmacology (12.2)].
PDE Inhibitors: Co-administration of riociguat with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil [see Dosage and Administration (2.6)]. Clinical experience with co-administration of riociguat and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited.

Smoking: Plasma concentrations in smokers are reduced by 50% to 60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of riociguat doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)].
Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat [see Dosage and Administration (2.5), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered [ see Clinical Pharmacology (12.3)].
Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking riociguat [ see Clinical Pharmacology (12.3)].

Risk Summary
Based on data from animal reproduction studies, riociguat may cause fetal harm, including birth defects and fetal death, and miscarriage when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1)]. Available data from published literature and post-marketing surveillance over a decade of use with riociguat have not identified an increased risk of major birth defects. However, these data are limited and do not establish the presence or absence of a drug-associated risk of major birth defects or miscarriage. Methodological limitations of these postmarketing reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal riociguat use.
In animal reproduction studies, oral administration of riociguat to pregnant rats during organogenesis was teratogenic and embryotoxic at exposures approximately 8 times and 2 times, respectively, the human exposure. In reproduction studies with pregnant rabbits, oral administration of riociguat during organogenesis caused abortions and fetal toxicity at exposures approximately 4 times and 13 times, respectively, the maximum recommended human dose (MRH-D). Advise pregnant patients of the potential risk to a fetus [see Contraindications (4.1)].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data

In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.

Risk Summary

There are no data on the presence of riociguat in human milk, the effects on the breastfed infant, or the effect on milk production. Riociguat is present in rat milk. Because of the potential for serious adverse reactions from riociguat, such as hypotension, in breastfed infants, advise women not to breastfeed during treatment with riociguat.

Based on data from animal reproductive toxicity studies, riociguat may cause fetal harm, including birth defects and fetal death, and miscarriage when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications (4.1), Use in Specific Populations (8.1)].
Pregnancy Testing
Exclude pregnancy prior to starting treatment with riociguat in females of reproductive potential. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus [ see Boxed Warning, Dosage and Administration (2.3) and Use in Specific Populations (8.1)].
Contraception
Females
Female patients of reproductive potential should use effective contraception prior to initiation of treatment, during treatment with riociguat and for 1 month after treatment with riociguat to prevent pregnancy [see Boxed Warning].

Safety and effectiveness of riociguat in pediatric patients have not been established [ see Nonclinical Toxicology (13.2)].

Of the total number of subjects in clinical studies of riociguat, 23% were 65 and over, and 6% were 75 and over [ see Clinical Studies (14)].No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients showed a higher exposure to riociguat [see Clinical Pharmacology (12.3)].

Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3)].

Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3)].

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO).
When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation.
Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway.
Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO.
Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.
The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output [ see Clinical Studies (14) ].
Hemodynamic parameters were assessed in CTEPH patients in CHEST-1 [see Clinical Studies (14.1)]. Right heart catheterization was performed at the beginning and the end of the study period in 233 patients. A statistically significant reduction of PVR (-246 dyn*s*cm^-5) was shown in the riociguat group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below.

Table 2: CHEST-1, Change In Hemodynamic Parameters from Baseline to Last Visit (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus placebo)  

Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%.
Absorption and distribution
The absolute bioavailability of riociguat is about 94%. Peak plasma riociguat concentrations were observed within 1.5 hours after tablet intake. Food does not affect the bioavailability of riociguat.
Bioavailability (AUC and C_max ) of riociguat administered orally as a crushed tablet suspended in applesauce or in water is similar to that of a whole tablet.
The volume of distribution at steady state is approximately 30 L. Plasma protein binding in humans is approximately 95%, with serum albumin and α1–acidic glycoprotein being the main binding components.
Riociguat is a substrate of P-gp and BCRP.
Metabolism and excretion
Riociguat is mainly cleared through metabolism by CYP1A1, CYP3A4, CYP3A5 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with PAH are about half those for riociguat.
Following oral administration of radiolabeled riociguat in healthy individuals, about 40 and 53% of the total radioactivity was recovered in urine and feces, respectively. There appears to be considerable variability in the proportion of metabolites and unchanged riociguat excreted, but metabolites were the major components of the dose excreted in most individuals.
Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects. The terminal elimination half-life is about 12 hours in patients and 7 hours in healthy subjects.
Specific Populations: The effect of intrinsic factors on riociguat and M1 are shown below in Figure 1. There are no clinically relevant effects of age, sex, weight, or race/ethnicity on the pharmacokinetics of riociguat or M1. No dose adjustment is warranted.
Figure 1: Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics

Drug interactions: The effect of extrinsic factors on riociguat and M1 were studied in healthy subjects and are shown in Figure 2.
Figure 2: Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics

*HIV protease inhibitors are strong CYP3A inhibitors and may increase riociguat plasma concentrations to levels similar to those seen with ketoconazole. ** AUC only, estimated using population pharmacokinetics methods *** AUC only for metabolite, estimated using population pharmacokinetics methods. **** Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.2) and Drug Interactions (7.2)].
Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered [see Drug Interactions (7.2)].
Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil [see Contraindications (4.3) and Clinical Pharmacology (12.2)].
Riociguat (2.5 mg three times per day) did not affect the systemic exposure of combined oral contraceptives containing levonorgestrel and ethinyl estradiol when concomitantly administered to healthy female subjects.

Carcinogenesis: Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure. 
In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure. 
Mutagenesis: Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse. 
Impairment of fertility: In rats, no effects on male or female fertility were observed. 
In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. 
In female rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and during mating and continuing to gestation Day 7 had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area.

In growing rats, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis [ see Use in Specific Populations (8.4)].

A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they:

• were technically inoperable for pulmonary endarterectomy, with PVR >300 dyn*sec*cm^-5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or
• had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm^-5 measured at least 180 days following pulmonary endarterectomy. 

Patients were randomized to riociguat titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline).
The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively.
Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3.
 Figure 3: CHEST-1 Mean Change from Baseline in the 6-Minute Walk Distance
fig-03 
The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used.
Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the riociguat group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m).
Figure 4 illustrates the results of the riociguat and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with riociguat benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving riociguat (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo.
Figure 4: CHEST-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance 
fig-04

A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dyn*sec*cm^-5 and a PAP_mean >25 mmHg.
Patients were randomized to one of three treatment groups: Riociguat titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to riociguat were initiated at 1.0 mg three times a day. The dose of riociguat was up-titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; riociguat was added in combination to these background therapies.
The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2, 1.5, 1, and 0.5 mg 3 times a day, respectively.
Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6.
Figure 6: PATENT-1 Mean Change from Baseline in the 6-Minute Walk Distance

fig-06

The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used.
Figure 7 illustrates the results of the riociguat and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with riociguat benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving riociguat (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo.
Figure 7: PATENT-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance

Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the riociguat group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m). There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day.
Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (see Figure 8).
Figure 8: PATENT-1 Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance (meter) by Prespecified Subgroups

WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5.

Table 5: Effects of Riociguat on the Change in WHO Functional Class in PATENT-1 from Baseline to Week 12

Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO Functional Class. Effects of riociguat in PATENT-1 on events of clinical worsening are shown in Table 6. Table 6: Effects of Riociguat in PATENT-1 on Events of Clinical Worsening (ITT analysis set)

_{* p-value=0.0285 (Mantel-Haenszel estimate)}

Note: Patients may have had more than one event of clinical worsening.
Riociguat-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with riociguat (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate).
The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9.
Figure 9: PATENT-1 Time (in Days) to Clinical Worsening (ITT analysis set)

Riociguat Tablets, USP are film-coated, round, and debossed with the M 0.5, M 1, M 1.5, M 2 and M 2.5 on one side and plain on other side for 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg respectively.

Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].