DRUG FORECAST
`
`For the Treatment of Pulmonary
`
`Riociguat (Adempas): a Novel Agent
`
`Arterial Hypertension and
`Chronic Thromboembolic Pulmonary Hypertension
`Diana Khaybullina, PharmD; Ami Patel, PharmD; and Tina Zen’lli, PharmD
`
` Table 1 Clinical Classification of Pulmonary Hypertension"
`
`1. Pulmonary arterial hypertension (PAH; lWHO Group 1]
`1.1 Idiopathic PAH
`1.2 Heritable PAH
`1.2.1 BMPRZ
`1.2.2 AtK—l. ENG. smog. CAIN, KCNK3
`1.2.3 Unknown
`
`INTRODUCTION
`Pulmonary hypertension is a condition
`defined by a mean pulmonary artery pres-
`sure greater than or equal to 25 mm Hg at
`rest measured by right heart catheteriza—
`tion.l Previously classified into two catego-
`ries (primary pulmonary hypertension or
`secondary pulmonary hypertension due
`to identified causes or risk factors), pul-
`monary hypertension is now categorized
`into five groups based on pathological
`findings. hemodynamic characteristics.
`and management (Table 1) .3 Because
`of the multiple etiologies of pulmonary
`hypertension, a thorough diagnostic eval—
`uation is essential in patients who present
`with symptoms (dyspnea, fatigue, chest
`pain, syncope, edema} so that appropriate
`therapy may be initiated.3
`Over the last decade. great strides
`have been made in the understanding
`and management of pulmonary arterial
`hypertension (PAH; WHO Group 1). PAH
`is a chronic, progressive disorder of the
`pulmonary arterial circulation that leads
`to pathological increases in peripheral
`vascular resistance (PVR) and ultimately
`to right heart failure.3 Hemodynamically,
`PAH is characterized by a mean pulmo—
`nary artery pressure greater than or
`equal to 25 mm Hg at rest with a pulmo—
`nary artery wedge pressure less than
`or equal to 15 mm Hg and elevated PVR
`
`Dr. Khayballina is a Stai'ir Pharmacist.
`Nthrlr—Presbyterian/lt‘er'll Camel! Medical
`Center. New York. New York. Dr. Zerrllr ls
`Associate Professor of Pharmacy Pracb‘ce at
`Amold& MorieSchmrtz College olPlronnocy
`and Health Sciences. tong lslond University,
`Brook-int New l'brk.
`
`
`Disclosure: The authors report no commer-
`cial or financial relationships in regard to this
`article.
`
`1.3 Drug- and toxin-induced
`1.4 Associated with:
`1.4.1 Connective tissue disease
`1.4.2 HIV infection
`
`1.4.3 Portal hypertension
`1.4.4 Congenital heart diseases
`1.4.5 Schistosomiasis
`
`1' Pulmonary veno—occlusive disease andlor pulmonary capillary hemangiomatosis
`
`1" Persistent pulmonary hypertension of the newborn
`
`2. Pulmonary hypertension due to left heart disease (WHO Group 2]
`2.1 Left ventricular systolic dysfunction
`2.2 Lefl ventricular diastolic dysfunction
`2.3 Valvular disease
`
`2.4 Congenitallacquired left heart intlowlouttlow tract obstruction and congenital
`cardiomyopathies
`
`3. Pulmonary hypertension due to lung diseases andlor hypoxia [WHO Group 3]
`3.1 Chronic obstructive pulmonary disease
`3.2 Interstitial lung disease
`3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
`3.4 Sleep—disordered breathing
`3.5 Alveolar hypoventilation disorders
`3.6 Chronic exposure to high altitude
`
`3.? Developmental lung diseases
`
`4. Chronic thromboembolic pulmonary hypertension {WHO Group 4]
`
`5. Pulmonary hypertension with unclear multifactorial mechanisms [WHO Group 5]
`5.1 Hematological disorders: chronic hemolytic anemia. myeloproliferative disorders,
`splenectomy
`5.2 Systemic disorders: sarcoidosis. pulmonary histiocytosis, lyrnphangioleiomyomatosis
`5.3 Metabolic disorders: glycogen storage disease. Gaucher disease. thyroid disorders
`5.4 Others: tumoral obstmction, tibrosing mediastinitis, chronic renal failure, segmental PH
`Ant-1: activin receptor-like ldnase11iS'MPli'2 = bone morphogenic protein receptor type II; 64W: caveolin-l:
`ENG : endoglin; HIV : human immunodeficiency virus. WHO : World Health Organization
`' Updated at the Filth mad Symposium on Pulmonary rarper'tenson in Nice. France. 2013. Adapted mom
`
`Simoaneaa et at."
`
`
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`DRUG FORECAST
`
`(greater than 3 mm Hg/l*min) .1 Though
`PAH may be idiopathic in nature, it may
`also be heritable, acquired via drug expo-
`sure, or the result of disorders ranging
`from connective tissue disease and human
`
`immunodeficiency virus (HIV) infection
`to portal hypertension, among others.2
`Based on data from the Registry to Evalu-
`ate Early and LongTerm PulmonaryArte
`rial Hypertension Disease Management
`(REVEAL), the incidence of PAH in U.S.
`adults is 2.0 per million, with approxi-
`mately equal numbers of patients with
`idiopathic or heritable PAH versus PAH
`due to associated disorders.4 Survival
`rates progressively decline from the time
`of diagnosis {85% at one year versus 49% at
`seven years}.5 However, data from various
`registries indicate that Overall survival
`rates have improved in recent years, likely
`as a result of improved treatment options.6
`The treatment of PAH is difficult,
`largely because of the multiple pathophys-
`iological processes involved, including
`excessive vascular proliferation, reduced
`apoptosis, thrombosis, inflammation, and
`vasoconstriction.3 General measures rec?
`ommended for all PAH patients include
`supervised exercise training, avoidance of
`pregnancy, routine immunizations (influ-
`enza and pneumococcal), psychosocial
`support, and referral to expert centers.7
`Additional supportive therapy includes
`the use of oral anticoagulants. diuretics,
`oxygen, and digoxin. Calciumchannel
`blocker therapy is recommended in those
`patients exhibiting a positive response to
`an acute vasoreactivity test? In those with-
`out such a response, and in patients who
`cannot sustain a response to calcium-chan-
`nel blocker therapy, a PAH-approved drug
`should be selected, taking into account
`multiple variables—including the patient‘s
`functional class, the medication‘s route
`of administration, sideeffect and drug—
`interaction profiles, patient preference,
`physician experience, and cost of therapy.T
`PAH-specific therapy includes endo-
`thelin receptor antagonists (ambrisentan,
`bosentan, macitentan), phosphodiester-
`ase type-5 {FDR-5} inhibitors (sildenafil,
`tadalafil), and prostanoids (iloprost,
`treprostinil, epoprostenol). Such drugs
`may cautiously be considered in non-
`PAH pulmonary hypertension as well.
`although there are few data to guide the
`decision—making process.3 Typically,
`treatment for the other more prevalent
`forms of pulmonary hypertension (WH0
`
`750 P&To - November 2011 - vans m. 11
`
`Groups 2—5) is directed at the underlying
`disease state, whether it is cardiac, pul—
`monary, or thromboembolic in nature.3
`Notably, for chronic thromboembolic pul—
`monary hypertension {CTEPH; WHO
`Group 4) the treatment of choice is sur-
`gical; the first—line therapy, pulmonary
`endarterectomy, is potentially curative.3
`In October 2013, the Food and Drug
`Administration approved riociguat
`(Adempas, Bayer Healthcare Phar—
`maceuticals), the first agent in a novel
`therapeutic class called soluble guanyl—
`ate cyclase (sGC) stimulators.8 Riociguat
`was approved for the treatment of adults
`with PAH, thereby adding to the treat-
`ment armamentarium of this condition.
`Notably, riociguat was also approved for
`the treatment of adults whose CTEPH
`persists or recurs following pulmonary
`endarterectomy, and in those with inoper-
`able C'I‘EPH.9 Approval for use in patients
`with CTEPH is unique to riociguat, as no
`other PAH-approved agent is indicated
`for other forms of pulmonary hyperten-
`sionJW The purpose of this article is to
`review the pharmacological and clinical
`characteristics of riociguat and discuss
`their implications for its use.
`
`CHEMICAL STRUCTURE9
`Chemically, riociguat is methyl 4,6
`diamino2—[1—(2—fluorobenzyl)—lH—pyrazolo
`[3,4—b]pyridin-3-yl]-5-pyrimidinyl(methyl)
`carbamate. The molecular formula
`and molecular weight of riociguat are
`CmngFNSOZ and 422.42 g/mol, respec—
`tively. The chemical structure is shown
`in Figure 1.
`
`
`
`
`
`
`Figure 1 Chemical Structure of
`Riociguat9
`
`CLINICAL PHARMACOLOGY
`In healthy subjects, endothelial cell-
`derived nitric oxide {NO} induces vase
`
`dilation in vascular smooth muscle cells
`through the activation of sGC and the sub
`sequent increase in production of cyclic
`guanosine monophosphate (cGM P). The
`production of endothelial cellderived NO
`is reduced in patients with PAH, so tar-
`geting the NO/sGC/cGMP pathway is a
`logical therapeutic approach? Riociguat
`does so via a dual mechanism of action:
`It sensitizes sGC to endogenous N0,
`and it directly stimulates sGC receptors
`independent of N0 availability, resulting
`in vasorelaxation and antiproliferative
`effects.” This is in contrast to PDE-5
`inhibitors, which target a component of
`the N0 signaling pathway further down-
`stream and have restricted efficacy in the
`presence of reduced NO levels.”
`
`PHARMACODYNAMICS AND
`PHARMACOKINETICS
`In an early hemodynamic study evalu-
`ating doses of 1 mg or 2.5 mg of riociguat
`in patients with pulmonary hypertension,
`riociguat significantly reduced PVR,
`mean pulmonary arterial pressure, sys-
`tolic blood pressure. and systemic vasctr
`lar resistance in addition to increasing the
`cardiac index in a dosedependent man—
`ner.22 Comparable hemodynamic effects
`were subsequently seen in a phase 2
`study.23 The effects of riociguat on PVR
`and N—terminal probrain natriuretic pep—
`tide (NT-proBNP) were further evaluated
`in phase 3 clinical studies as prespeci—
`fied secondary outcomes (whereas the
`impact on other hemodynamic variables
`was exploratory in nature) .9‘35 Com-
`pared with placebo, statistically signifi-
`cant reductions in PVR were evident in
`riociguat-treated patients; least-squares
`mean differences {LSMD} from baseline
`were —226 dyn‘*sec*cm“5 in patients with
`PAH“ and —246 dyn*sec*cm* in patients
`with CTEPH (P < 0.001}.25 Similarly,
`NT—proBNP levels were significantly
`lower (P < 0.001) in riociguat—treated
`patients with PAH (LSMD, —432 Dg/ml.)
`and CTEPH (LSMD, 4144 Dg/mL}.W$
`Riociguat is readily absorbed. with an
`absolute oral bioavailability of approxi-
`mately 94% that is not affected by food.9 At
`doses ranging from 0.5 mg to 2.5 mg, rio-
`ciguat exhibits dose-dependent increases
`in plasma concentrations with pronounced
`variability among individuals.ms Peak
`plasma concentrations occur within
`1.5 hours after oral intakes”-2 Riociguat is
`not extensively distributed; its volume of
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`distribution is approximately 30 L in both
`healthy subjects and patients with pulmo-
`nary hypertensionm Riociguat is approxi-
`mately 95% bound to human plasma pro
`leins, mainly serum albumin and (11' acidic
`glycoprotein. ”37 Several cytochrome P450
`(CYP) enzymes are involved in the metab
`olism of riociguat (CYP1A1, CYP3AA/5.
`CYP2C8. and CYP2J2), though the forma—
`tion of the major active metabolite. M1. is
`largely catalyzed by CYP1A1. Clinically,
`this is noteworthy because CYP1A1 is
`inducible by exposure to polycyclic aro-
`matic hydrocarbons such as those found
`in cigarette smoke, thereby warranting
`dosage adjustments in smokers”? Fur-
`thermore, riociguat is a substrate of the
`efflux transporters P—glycoprotein (P—gp)
`and breast cancer resistance protein
`(BCRP). making the compound prone
`to drug interactions. The drug is elimi-
`nated in the urine (40%) and feces (53%).
`largely as metabolites.” The elimination
`half-life is longer in patients with PAH
`(approximately 12 hours} than in healthy
`subjects (approximately seven hours),
`likely because of impaired elimination
`in PAH patients?”m Average systemic
`clearance is 1.8 [flu in patients with PAH,
`approximately half of that seen in healthy
`subjects (3.4 L/hr).9-zm
`Dose adjustments based on sex. age.
`weight. or race/ethnicity are not neces—
`sary because these factors have not dem—
`onstrated a clinically relevant effect on
`the pharmacokinetics of riociguat and its
`active metabolite”? Despite significant
`hepatic metabolism and renal elimina—
`tion. studies indicate that impairment
`in hepatic or renal function also do not
`necessitate dosage adjustments?” Of
`note, the effect of riociguat in patients
`with end—stage renal disease (ereatinine
`clearance less than 15 mL/min) or severe
`hepatic impairment (Child Pugh C) has
`not been evaluated.‘3
`
`CLINICAL STUDIES
`The efficacy of riociguat was estab-
`lished in two pivotal phase 3 studies involv—
`ing patients with PAH (WHO Group 1) or
`CTEPH (WHO Group 413‘“?-5 Addition—
`ally, phase 2 studies evaluating the effect
`of riociguat in patients with pulmonary
`hypertension associated with systolic
`left ventricular dysfunction (PH—sLVD;
`WHO Group 2) and interstitial lung dis—
`ease (WHO Group 3) have been published
`and are briefly summarized here.21m
`
`Pulmonary Arterial Hypertension
`The PATENT-1 trial was an interna-
`tional. multicenter. randomized. double-
`blind, placebocontrolled. 12—week study
`evaluating the efficacy and safety of rio-
`ciguat in patients with symptomatic PAH
`who were either not receiving treatment
`for the condition or were being treated
`with endothelin receptor antagonists or
`nonintravenous prostanoids.“ A total of
`443 patients received placebo (r1 = 126),
`riociguat administered orally at individu—
`ally adjusted doses up to 2.5 mg three
`times daily (n = 254). or riociguat at doses
`adjusted up to 1.5 mg three times daily
`(11 = I). The latter tr'eatment arm was
`included solely for exploratory purposes
`and was therefore excluded from the effi—
`cacy analysis. Most randomized patients
`were white (61%) and female (79%) with
`idiopathic PAH (61%) or PAH associated
`with connective tissue disease (25%).
`Almost all patients were in WHO flinc—
`tional class II or III (42% and 53%, respec-
`tively) and half were receiving treatment
`with other PAH therapies, largely endo~
`thelin receptor antagonists.31
`1With respect to the primary end—
`point, the change from baseline to the
`end of week 12 in six-minute walk dis-
`tance (6MWD). there was a statistically
`significant difference in the riociguat
`2.5mg—maximum group versus the plat
`cebo group (LSMD, 36 m; P< 0.001).“
`The effect was consistent across numer-
`ous subgroups of patients, including
`those who were treatment—naive and
`those on concomitant endothelin recep
`tor antagonists or prostanoids. Patients
`with more advanced disease (WHO
`functional class III or IV) experienced
`greater improvements in exercise capac—
`ity than those in WHO functional class I
`or II. Statistically significant improve
`ments from baseline were also noted with
`riociguat therapy in several secondary
`endpoints, including PVR (P < 0.001),
`NT—proBNP levels (P < 0.001), WHO
`functional class (P = 0.003), Borg dys-
`pnea score (P= 0.002). and time to clinical
`worsening (P = 0005). Quality of life, as
`assessed by the EuroQol Group 5Dimen
`sion Self—Report Questionnaire. did not
`significantly differ between groups.“
`Study discontinuation because of
`adverse events occurred in 3% of the
`riociguat 2.5—mg—maximum group ver—
`sus 7% in the placebo group?“ The most
`frequently occurring serious adverse
`
`DRUG FORECAST
`
`events in the riociguat 2.5-mg-maximum
`gmup and placebo group were syncope
`(1% versus 4%. respectively), worsening
`pulmonary hypertension (less than 1%
`versus296. respectively). chest pain {1% in
`both groups), and right ventricularfailure
`(1% in both groups) 5’” Additional adverse
`events data are discussed in the Safety
`and Tolerability section.
`Ninety—eight percent (N = 396) of
`patients who completed the PATENT-1
`study entered PATENT—2, an ongoing.
`open-label. long-term extension study.“
`An exploratory analysis of the first
`12 weeks revealed additional improve-
`ments in GMWD in patients receiv-
`ing riociguat up to 2.5 mg three times
`daily; there was a mean increase of
`53 m over the baseline distance noted in
`PATENT-1.“ Sustained benefits in
`SMWD and functional class were also
`noted in an interim one-year unpublished
`analysis of this study.30
`
`Chronic Thromboembolic
`
`Pulmonary Hypertension
`Ghofrani et al‘*5 evaluated the efficacy
`and safety of riociguat in patients with
`CTEPH in an international. multicenter.
`randomized. double-blind, placebo-
`controlled study (CHEST—l). Patients
`(N = 261) with inoperable CTEPH or
`persistent or recurrent pulmonary hyper—
`tension after pulmonary endarterectomy
`were randomly assigned to receive pla-
`cebo (n = 88) or riociguat (n = 173) up
`to 2.5 mg three times daily for 16 weeks.
`Clinical outcome measures were similar
`to those in PATENT—1.
`The majority of randomized patients
`(mean age, 59 years; 66% female) had
`inoperable CTEPH (72%) and. as in
`PATENT—1, most were in WHO func—
`tional class II (31%) or III (64%).” Simi—
`lar to the findings seen in patients with
`PAH. there was a statistically signifi-
`cant improvement from baseline in the
`6MWD (LSMD. 46 m; P < 0.001). This
`effect was consistent across all subgroups
`of patients, though less pronounced in
`patients with persistent/ recurrent pul-
`monary hypertension. Riociguat—ti'eated
`patients also experienced statistically sig—
`nificant improvements in several second-
`ary endpoints, notably PVR (P < 0.001).
`NT—proBNP level (P < 0.001), and WHO
`functional class (P = 0.003); clinical wors—
`ening was not significantly delayed. Few
`patients discontinued the study because
`continued on page 755
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`crmtimredfi'om page 75}
`of adverse events (3% in the riociguat
`group versus 2% in the placebo group}.
`Right ventricular failure {3% of patients in
`each group). syncope (2% in the riociguat
`group and 3% in the placebo group), and
`hemoptysis (2% in the riociguat group)
`were the most frequent serious adverse
`events.25 The most commonly reported
`adverse events are summarized in the
`
`Safety and ’I‘olerability section. Prelimi-
`nary data from the long-term extension
`study (CHEST-2}, which have been pre-
`sented but not yet published, suggest that
`effects on 6MWD and functional class are
`sustained in this patient population and
`that riociguat is generally well tolerated
`with a good long-term safety profile.3|
`As with PATENT-2. these data must be
`viewed cautiously until the full results of
`the study are available.
`
`Unlabeled Uses
`Bonderman et a1” evaluated the effects
`of riociguat on hemodynamic and clinical
`outcomes in heart failure patients with
`PH—sLVD in a doubleblind, multicenter,
`phase 2b study. Eligible patients (N = 201)
`were randomized in a 2:1:1:2 fashion to one
`of four treatment arms: placebo, riociguat
`0.5 mg, riociguat 1 mg, or riociguat 2 mg,
`three times daily for a 16-week treatment
`period. In addition, participants received
`standard medical treatment (angiotensin—
`converting enzyme inhibitors/angioten-
`sin-receptor blockers, beta blockers,
`and aldosterone antagonists) or cardiac
`device therapy. The primary endpoint,
`placebocorrected change from baseline
`to week 16 in mean pulmonary artery
`pressure. was not significantly different
`between the riociguat 2-mg group and the
`placebo group (LSMD, —2.7, P= 0.10). Use
`of riociguat did. however, result in sig-
`nificant improvements in several hemo
`dynamic variables (cardiac index. stroke
`volume index, PVR, and systemic vascular
`resistance) without significantly affecting
`heart rate and blood pressure. Notably,
`echocardiographic parameters and explor—
`atory clinical outcomes. such as 6MWD,
`clinical worsening events, and change in
`functional class. were also not improved,
`although an improvement in health-related
`quality of life was found.” More studies
`are needed to better characterize the role
`of riociguat in this patient population.
`In another phase 2. open-label, uncon-
`trolled pilot trial, Hoeper et a1” evaluated
`the efficacy of riociguat (target dose of
`
`DRUG FORECAST
`
`2.5 mg three times daily) in patients with
`pulmonary hypertension due to inter—
`stitial lung disease (N = 22), though the
`study was primarily designed to assess
`safety and tolerability. Although cardiac
`output and PW improved, this did not
`translate into substantial improvements
`in clinically relevant outcomes. There
`was only a slight increase in BMWD.
`while functional class and Quality of life
`measures remained unchanged. During
`the initial 12 weeks of treatment and at
`the interim 12—month mark of the long—
`tenn extension phase, 104 adverse events
`were repor ted, 70% of which were consid—
`ered drug—related. Dyspnea, peripheral
`edema, dySPePsia, headache, and "feeling
`hot” were the most frequently reported
`adverse events.29 The clinical relevance
`
`and applicability of this data is limited
`owing to the small, uncontrolled, open—
`label design of this study.
`
`SAFETY AND TOLERABILITY
`Adverse Effects
`Information on the adverse-event pro-
`file of riociguat is restricted to what is
`known from the fairly short—term phase 3
`clinical trials involving patients with
`PAH and C’I‘EPH. The most commonly
`reported adverse events in PATENT-1
`and CHEST—l were headache, dizziness,
`dyspepsia, peripheral edema, nausea,
`vomiting, diarrhea, and nasopharyngi—
`tis (Table 2) .2135 Hypotension was also
`frequently reported and significantly
`greater in riociguat-treated patients
`enrolled in PATENT—1: this would be
`
`Table 2 Adverse Events Reported in at Least 5% of Riociguat-Treated Patients
`
`And at a Frequency Greater Than Placebo in Phase 3 Clinical Trials“-25
`
`Number of Patients [9.2]
`
`PilTENT-1
`CHEST-1
`
`Adverse Events
`
`Placebo
`[n = 126]
`
`Placebo
`(n = 88]
`
`Riociguat.
`Riociguat.
`Riociguat.
`maximum
`maximum
`maximum
`2.5 mg t.i.d.
`1.5 mg t.i.d.
`2.5 mgt.i.d.
`
`[n = 254}
`[n = 63]
`[n =1‘r‘3]
`
`Headache
`69 [2?]
`20 (32]
`25 (20]
`43 [25]
`12 [14]
`
`Dyspepsia
`43 {19}
`8 [13]
`10 (8]
`31 [18]
`7 [8]
`
`Peripheral edema
`44 [1?]
`14 [22]
`14 [11]
`2? [16]
`18 [20]
`
`Dizziness
`40 [16]
`15 [24]
`15 [12]
`39 (23]
`11 [12]
`
`Nasopharyngitis
`26 [10]
`6 [10}
`14 [11]
`26 [15]
`8 [9]
`
`Nausea
`40 [16]
`1t} [16]
`16 [13]
`19 [11)
`i' [8]
`
`Diarrhea
`35 [14}
`6 [10]
`13 [10)
`17 (10)
`4 [5]
`
`Vomiting
`26 [10]
`7 [11]
`11 [9]
`1? [10]
`3 [3]
`
`Pyrexia
`3 {3]
`6 [10]
`4 [3]
`—
`—
`
`Hypotension
`25 [10}‘
`2 (3}
`3 (2]
`16 [9]
`3 [3]
`
`Anemia
`21 {8}
`1 [2]
`3 (2]
`—
`—
`
`Palpitations
`20 [8}
`5 (8}
`6 [5]
`—
`—
`
`
`
`
`
`
`
`
`
`Gastroesophageal
`14 [6}
`4 [6]
`4 (3]
`—
`—
`
`reflux disease
`
`Gastritis
`4 {2]
`4 [6]
`0
`—
`—
`
`Nasal congestion
`11 [4]
`4 [6]
`3 [2)
`—
`—
`Upper respiratory
`—
`—
`—
`10 [6]
`41:5]
`
`tract infection
`
`Increase in INR
`—
`—
`—
`10 (6)
`4 [5]
`
`Constipation
`
`—
`
`—
`
`—
`
`10(6)
`
`1 [1]
`
`2 [2]
`8 [5]
`—
`—
`—
`Prolonged aPTT
`aPTT = activated partial-tn romboplastin time; INR = intemarional normalized ratio; t.i.d. = three times daily
`
`° P: 0.005
`
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`DRUG FORECAST
`
`expected because of the drug‘s vaso—
`dilatory actions. Notably, this did not
`translate into an increased incidence of
`
`syncope. Syncope was more frequently
`reported in the placebotreated patients in
`both PATENT-1 and CHEST-1 (4% and 3%,
`respectively) than in patients treated with
`riociguat (1% and 2%, respectively).mfi
`It is worth noting that various bleeding
`events were reported more frequently in
`riociguat—treated patients than in the pla—
`cebo groups in both studies.” Treatment-
`emergent bleeding events were reported
`for 11.0% of subjects in the riociguat 2.5mg
`group versus 9.5% of subjects in the pla—
`cebo group in the PATENT-1 study, and
`13.396 of subjects in the riociguat group
`compared with 11.4% of subjects in the pla—
`cebo group in the CHEST-1 trial. The most
`frequently reported bleeding events were
`epistaxis and hemoptysis.32 The occur-
`rence of serious bleeding events during
`the clinical development of riociguat,
`albeit low {2.4% versus 0% in placebo),
`prompted the inclusion of a warning in
`the prescribing information.9 Ultimately,
`the longterm extension studies and posts
`marketing reports will shed more light on
`the overall safety of this agent.
`
`Contraindications
`
`Because of teratogenicity documented
`in preclinical studies. riociguat is classi—
`fied as pregnancy category X and con-
`traindicated for use during pregnancy.9 A
`restricted distribution program is in place
`(the Adempas REMS Program) for all
`females on riociguat therapy. irrespective
`of reproductive potential. The program
`requires all prescribers and pharmacies
`dispensing riociguat to be to certified with
`the program, and in females of reproduc-
`tive potential, pregnancy must be ruled
`out prior to initiation of therapy. monthly
`during treatment, and one month after
`drug discontinuation. Acceptable meth—
`ods of contraception must be utilized dur—
`ing and for one month after treatment.”
`Concurrent administration of riociguat
`with nitrates or NO donors as well as with
`PDE-S or nonspecific PDE inhibitors (e.g.,
`dipyridamole. theophylline) is also con-
`traindicated because of additive hemody-
`namic effects resulting in hypotension.9
`
`Warnings and Precautions
`As a result of its blood—pressurelower—
`ing effects. the riociguat label warns of
`the potential for symptomatic hypoten—
`
`756 P&To - November 2011 - Vol.39 No. 11
`
`Slot] or ischemia when riociguat is used
`in patients with hypovolemia. severe left
`ventricular outflow obstruction, resting
`hypotension, and autonomic dysfunction,
`and when it is used concurrently with
`antihypertensive or strong CYP and P—gp/
`BCRP inhibitors (see the Drug Inter—
`actions section).9 Initial lower doses in
`those at risk for hypotension and/or dose
`reductions in those developing hypoten-
`sion while on riociguat therapy are war—
`ranted. As previously noted, the labeling
`also warns of the increased incidence of
`bleeding noted with riociguat.“ Further-
`more, since the cardiovascular status of
`patients with pulmonary veno-occlusive
`disease may be significantly worsened
`by agents with vasodilatory effects on
`the pulmonary vasculature, administra-
`tion of riociguat to such patients is not
`recommended. ’Ihe possibility of associ-
`ated pulmonary vaso-occlusive disease
`should be considered in the event that
`pulmonary edema develops while on rio-
`ciguat therapy?
`
`DRUG INTERACTIONS
`Both riociguat and N0 delivered
`by nitrates act on sGC to generate an
`increase in cGMR PDFz5 inhibitors also
`increase cGMP by inhibiting its break—
`down. Because of their mechanisms
`of action on the NO/sGC/CGMP path—
`way, an additive hypotensive effect is
`expected. This has been demonstrated
`with concurrent administration of rio-
`ciguat and nitrates or NO donors {such
`as arnyl nitrate) and FDR-5 inhibitors.”
`As a result, concurrent use is contraindi-
`cated. With respect to pharmacokinetic
`interactions. in who and in vivo studies
`suggest that riociguat is unlikely to appre-
`ciably induce or inhibit CYP enzymes
`and drug transporters, lowering its
`interaction potential as a precipitant
`drug.M435 However, plasma concentra—
`tions of riociguat are affected by other
`precipitant compounds, warranting dos-
`age and administration adjustments {see
`the Dosage and Administration section}.
`As alluded to previously, plasma concen-
`trations of riociguat are reduced by 5056
`to 60% in smokers because of induction
`of the CYP1A1 enzyme by polycyclic
`aromatic hydrocarbons.9 Strong CYPBA
`inducers (eg, rifampin, phenytoin, car-
`bamazepine, phenobarbital, St. John's
`wort) may also significantly decrease rio-
`ciguat exposure, although data to guide
`
`dose adjustments are lacking.El Concur-
`rent administration of ketoconazole, a
`strong CYP and P—gp/BCRP inhibitor.
`led to a 150% increase in riociguat's mean
`area under the curve (AUC) .32 A similar
`increase in riociguat exposure is expected
`with HIV protease inhibitors? Concur—
`rent administration with antacids such
`as aluminum hydroxide/magnesium
`hydroxide resulted in reduced riociguat
`bioavailability (mean Cmam decrease of
`56% and mean AUC decrease of 34%), an
`effect that was also seen, although to a
`lesser extent, with proton-pump inhibi-
`tor coadministration (decrease in mean
`Cm, of 35% and mean AUC of 26%)?-32
`Importantly. riociguat demonstrates no
`clinically relevant interactions with war—
`farin and aspirin. agents that are typically
`used in patients with PAH.9m
`
`DOSAGE AND ADMINISTRATION”
`Riociguat is available as oral tablets
`in five different strengths (0.5, 1, 1.5, 2,
`and 2.5 mg} to allow for dosage flexibil-
`ity. The recommended starting dose is
`1 mg taken three times a day. In patients
`at risk for hypotension, consideration
`should be given to initiating treatment
`at 0.5 mg three times a day. The dose
`may be increased no sooner than every
`two weeks to a maximum dose of 2.5 mg
`three times a day if tolerated, though
`patients who smoke may require higher
`doses. Uptitration should occur in incre—
`ments of 0.5 mg taken three times a day
`and only if the patient‘s systolic blood
`pressure remains above 95 mm Hg and
`there are no signs or symptoms of hypo-
`tension. Should hypotension occur, a
`decrease in dose (by 0.5 mg taken three
`times a day) is recommended. In patients
`concomitantly using riociguat with strong
`CYP and P—gp/BCRP inhibitors (e.g.,
`azole antifungals and protease inhibitors) ,
`a starting dose of0.5 mg three times daily
`should be considered and close monitor—
`ing for signs and symptoms of hypoten-
`sion is necessary. Because of the impact
`on riociguat absorption, antacids should
`not be taken within one hour of riociguat.
`Any treatment interruption for three days
`or more warrants retitration of the rio-
`ciguat dose.
`
`COST
`The average wholesale price of a 30—day
`supply {90 tablets) of riociguat, regard-
`less of the strength. is $9,270.36This is in
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX- 2070
`
`Page 5 of 7
`
`

`

`Table 3 Cost of Therapy With Orally Administered Or Inhaled PAH-Approved Agents
`
`
`Drug
`Usual Adult Maintenance Dose“?
`Costa
`
`Soluble guanylate cyclase [56C] stimulator
`
`Riociguat tAdempas. Bayer}
`2.5 mg by mouth three times daily
`$9.270
`
`Endothelin receptor antagonists
`
`Ambrisentan tLetairis, Gilead}
`5—10 mg by mouth once daily
`$8,2i2
`
`Bosentan [Tracleer, Actelion]
`125 mg by mouth twice daily
`$9.126
`
`Macitentan [Opsumit Actelion]
`10 mg by mouth once daily
`$8,208
`
`Phosphodiesterase type!) [PDEJS] inhibitors
`
`Sildenatil tRevatio, Pfizer]
`20 mg by mouth three times daily
`$2,751
`
`(generic: multiple manufacturers)
`$1.710”
`
`Tadalafil [Adcirca. Eli Lilly}
`40 mg by mouth once daily
`$2.436
`
`Prostanoids
`
`Iloprost Wentavis, Actelion]
`2.5—5 mcgiinhalation
`$21.04?
`
`six to nine times per day
`
`Treprostinil vaaso. United
`Therapeutics)
`
`Nine inhalations [54 mcg}
`four times daily
`
`$15,622u
`
`$9323"
`Oral dosing. individualized
`Treprostinil [0renitram. United
`
`Therapeutics)
`according to response9
`
`
`
` " Cost is calculated for a 30-day supply unless otherwise specified. Cost is based on average wholesale
`
`price {AWPJ at the usual adult maintenance dose and rounded to the nearest dollar.
`" The lowest AWP noted in Red Book Unline is provided.
`‘ Cost is based on 180 ampules of either the 10-mcgtmL or 20-mcgtmL ampule.
`‘ Cost for a 28-day supply ofthe refill kit containing seven foil pouches each with tour 2.9-mL ampules.
`“ The mean dose in a 12—week study was 3.4 mg twice daily." Cost is based on a dose of 3.5 mg twice daily
`
`[2.5mg and 1-mg tablets}.
`
`line with the cost of endothelin receptor
`antagonists. but significantly greater than
`the cost of PDES inhibitors. A cost com—
`parison of agents approved for PAH that
`are administered orally or via inhalation is
`provided in Table 3. Parenterally admin-
`istered prostanoids are excluded from
`the table because use of these agents
`results in additional indirect costs asso-
`ciated with continuous subcutaneous or
`intravenous administration.
`
`P&T COM M ITTEE
`CONSIDERATIONS
`The efficacy of riociguat in PAH is
`comparable to that seen with other PAH-
`approved agents; riociguat improved
`BMWD by 36 m. whereas this endpoint
`was improved by 33 m and 35 m with
`tadalafil and bosentan. respectively“»14
`This effect size has been characterized
`as modest. as only 21% of patients had
`improvement in functional class and the
`improvement in BMWD just about sur-
`passed the minimal clinically important
`
`difference [33 ml.” Still. the current
`evidence-based treatment algorithm
`for PAH recommends riociguat as one
`of several agents that may be used as
`initial therapy in patients of WHO func-
`tional class II or III or as a component of
`combination therapy (except with PDEvS
`inhibitors) in cases of inadequate clini-
`cal response? Since there are no studies
`comparing the different PAH—approved
`compounds, no evidencebased first—line
`treatment is proposed; instead. treatment
`selection must be based on patient— and
`medication-specific factors.7
`As an additional point to consider. rio
`ciguat is the only medication to be shown
`in a randomized, controlled clinical study
`to be effective in improving SMWD in
`select patients with CTEPH. Hence.
`recommend