ADEMPAS® (riociguat)

About ADEMPAS^® (riociguat)

Prescribing Information (Great Britain) & Prescribing Information (Northern Ireland) [External links]

Indication

ADEMPAS is a member of a class of therapeutic agents called ‘soluble guanylate cyclase stimulators (sGC stimulators)’, and is used for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).¹

In PAH, ADEMPAS is licenced as monotherapy or in combination with endothelin receptor antagonists (ERAs), for the treatment of adult patients with PAH with WHO functional class (FC) II to III, in order to improve exercise capacity.¹

In paediatric patients aged less than 18 years of age and body weight ≥50 kg, ADEMPAS is licensed for the treatment of PAH in combination with ERAs for patients in WHO FC II to III.¹

In CTEPH, ADEMPAS is licenced for the treatment of adult patients with WHO functional class II to III with:¹

• inoperable CTEPH
• persistent or recurrent CTEPH after surgical treatment

to improve exercise capacity.

Mode of action

ADEMPAS has a dual mode of action. It increases cGMP levels by both sensitising sGC to endogenous NO and directly stimulating sGC independently of NO.^1,2

These images were created for MSD.

NO = Nitric Oxide; sGC = soluble Guanylate Cyclase; cGMP = cyclic Guanosine Monophosphate; GTP = Guanosine Triphosphate.

Why is this important?

• Intracellular cGMP has an important part in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation¹
• Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-sGC-cGMP pathway¹
• ADEMPAS restores the NO-sGC-cGMP pathway, resulting in an improvement of pulmonary vascular hemodynamics and an increase in exercise ability¹

• ADEMPAS in CTEPH
• ADEMPAS in PAH

ADEMPAS is the only oral pharmacological therapy licensed for inoperable CTEPH or persistent or recurrent CTEPH after surgical treatment.^1,4

CHEST-2: improvements in 6MWD were sustained for up to 2 years with ADEMPAS^5,6

*6MWD – distance walked in 6 minutes
Adapted from Simonneau G et al. 2016^6,7

CHEST-2 study overview – CTEPH (open-label extension)

Study design

237 patients entered CHEST-2.⁵ CHEST-2 was a multicentre, open-label, single-group study conducted at 71 out of the 89 centres (across 25 out of the 26 countries) that participated in CHEST-1. CHEST-1 was a randomised, double-blind, multi-national, placebo controlled, phase III study conducted in 261 adult patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) (72%) or persistent or recurrent CTEPH after pulmonary endarterectomy (PEA; 28%). During the first 8 weeks riociguat was titrated every 2-weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg 3 times daily) which was then maintained for a further 8 weeks. The primary endpoint of the study was the placebo adjusted change from baseline in 6-minute walk distance (6MWD) at the last visit (week 16). At the last visit, the increase in 6MWD in patients treated with riociguat was 46 m (95% confidence interval (CI): 25 m to 67 m; p<0.0001), compared to placebo.⁵

Patients in the former riociguat group started CHEST-2 at the riociguat dose they received at the end of CHEST-1, while former placebo patients started CHEST-2 at 1 mg three times daily. During the 8-week double-blind dose-adjustment phase of CHEST-2, patients in the former placebo group were individually adjusted up to a maximum of 2.5 mg three times daily according to systolic blood pressure (SBP) and symptoms of hypotension, and patients in the former riociguat group continued on the dose they were receiving at the end of CHEST-1 while receiving sham titration. During the open-label study phase, investigators could adjust the riociguat dose (up to a maximum dose of 2.5 mg three times daily) according to the patient’s need, considering SBP, side-effects and progression of underlying CTEPH.⁵

Exploratory endpoints

• Primary outcome: safety and tolerability⁵

• Secondary outcome: included change in 6MWD and WHO FC⁵

Long-term results

The long-term results at 2 years from the CHEST-2 trial show that long-term use of ADEMPAS is generally well-tolerated in patients with CTEPH.⁵

Building on the results of CHEST-I the 2-year data from CHEST-2 further show that treatment with ADEMPAS leads to sustained benefits in 6MWD and WHO FC in patients with inoperable CTEPH and persistent/recurrent PH after PEA.⁵

At 2 years, overall survival was 93% (95% Cl 89-96) and clinical worsening-free survival was 82% (77-87).⁵

Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±SD 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236).⁷

In patients who received placebo during CHEST-I, although the incidence of clinical worsening events was similar compared with former riociguat patients, improvements in 6MWD and WHO FC after transitioning to riociguat treatment did not fully catch up to the former riociguat group by the 1-year cut-off. This highlights the importance of initiating the appropriate treatment as early as possible.^5,7

Adverse events/safety information

Safety results of ADEMPAS in CHEST-2 were consistent with previously reported findings from CHEST-1. The incidence of AEs during CHEST-2 was generally similar in patients with inoperable CTEPH and those with persistent or recurrent pulmonary hypertension after PEA. The most common serious AEs were syncope (23 [10%] of 237), worsening pulmonary hypertension (18 [8%] ), and right ventricular failure (16 [7%]).^5,7

There were 13 deaths during CHEST-2, none of which were considered to be study drug-related by the investigators.^5,7

ADEMPAS provides an alternative treatment option for stable patients receiving a PDE5i who are not achieving low-risk WHO functional class I/II⁸

REPLACE is the first head-to-head study suggesting a higher treatment response with ADEMPAS versus PDE5is⁸

Adapted from Hoeper M M, Al-Hiti H et al. 2021⁸

REPLACE study overview – PAH

Study design

A clinical study in 224 adult patients with PAH at intermediate risk demonstrated the efficacy of transitioning from a PDE5i to ADEMPAS^8,a

Prospective, open-label study in which patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil (≥60 mg per day) or oral tadalafil (20-40 mg per day) or switch to ADEMPAS (up to 2.5 mg three times a day).⁸

Statistically powered to evaluate the efficacy of ADEMPAS in adult patients with symptomatic PAH at intermediate risk who were receiving a stable dose of a PDE5i with or without an ERA and not at treatment goal^8,a

Efficacy endpoints

Primary endpoint^9,a

Clinical improvement in the absence of clinical worsening at 24 weeks:^8,c

• Prespecified improvements in at least 2 out of 3 parameters:
• Improvement in 6MWD of ≥10% or ≥30 m
• Improvement to WHO FC I or II
• Decrease in NT-proBNP of ≥30%

Secondary endpoints^8,a,d

• Change from baseline to Week 24 in
• 6MWD
• NT-proBNP
• WHO FC
• Time to first clinical worsening event

Exploratory endpoints^8,a

• Risk assessment at baseline, 16 weeks, and 24 weeks using 3 risk score calculators:
• RRS
• COMPERA
• FPHN non-invasive

^aIntermediate risk determination based on WHO FC and 6MWD.
^bRequired washout period of 24 hours after last dose of sildenafil and 48 hours after last dose of tadalafil.
^cClinical worsening defined as death from any cause; hospitalization for worsening PAH (non-elective hospitalization due to PAH or initiation of parenteral prostanoid therapy); or disease progression (decrease in 6MWD ≥15% on two separate days plus either worsening WHO FC, need for new PAH-targeted medication, or decompensated right-sided heart failure).
^dSecondary endpoints were tested hierarchically in the following order: 6MWD, NT-proBNP, WHO FC, and clinical worsening.

Results

In patients on a PDE5i and at intermediate risk^a, transitioning to ADEMPAS helped more PAH patients achieve clinical improvement compared to continuing treatment with a PDE5i^8,b

Adapted from Hoeper M M, Al-Hiti H et al. 2021⁸

1% of patients receiving ADEMPAS experienced a clinical worsening event vs 9% of patients who continued PDE5i treatment^8,c

^aIntermediate risk determined based on WHO FC and 6MWD.
^bClinical improvement at 24 weeks defined as prespecified improvements in at least 2 out of 3 parameters (6MWD, WHO FC, and/or NT-proBNP) and absence of clinical worsening.
^cPatients who experienced clinical worsening are a subgroup of those who did not achieve the endpoint. Clinical worsening defined as death from any cause; hospitalization for worsening PAH (non-elective hospitalization due to PAH or initiation of parenteral prostanoid therapy); or disease progression (decrease in 6MWD ≥15% on 2 separate.

Adverse events

The safety results from patients switching to ADEMPAS were consistent with the known safety profile of ADEMPAS.⁸

ADEMPAS was generally well-tolerated by patients who switched from a PDE5i:⁸

• Overall adverse event (AE) rates were similar between treatment groups (71% [79/111] in the ADEMPAS group vs. 66% [75/114] in the PDE5i group), with a higher incidence of serious AEs in the PDE5i group than in the ADEMPAS group (17% vs. 7%, respectively)
• Most frequently reported AEs were hypotension, headache and dyspepsia with ADEMPAS, and headache, cough and upper respiratory tract infections with PDE5is

Refer to the Summary of Product Characteristics for full information on adverse reactions.

If you are initiating an eligible patient on ADEMPAS, we have the home monitoring pack service available to support. To order a home monitoring pack for your patients, please visit the below link.

Additional safety information¹

Contraindications

• Co-administration with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil)
• Severe hepatic impairment (Child-Pugh C)
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the ADEMPAS SmPC
• Pregnancy
• Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form including recreational drugs called ‘poppers’
• Patients ≥12 years with systolic blood pressure <95 mmHg at treatment initiation
• Children aged 6 to <12 years with systolic blood pressure <90 mmHg at treatment initiation
• Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP)
• Concomitant use with other soluble guanylate cyclase stimulators

Side effects

In adults

Very common: dizziness, headache, dyspepsia, diarrhoea, nausea, vomiting, peripheral oedema.

Common: gastroenteritis, anaemia, palpitations, hypotension, haemoptysis, epistaxis, nasal congestion, gastritis, gastro-oesophageal reflux disease, dysphagia, gastrointestinal and abdominal pains, constipation, abdominal distension.

Uncommon: pulmonary haemorrhage (incl. cases with fatal outcome).

In children

Most common adverse reactions including the long-term extension phase were hypotension and headache.

Overall, the safety data is consistent with the safety profile observed in adults.

References

1. ADEMPAS Summary of Product Characteristics.
2. O’Callaghan DS, Savale L, Montani D, et al. Treatment of pulmonary arterial hypertension with targeted therapies. Nature Rev Drug Cardiol. 2011;8:526–538.
3. Stasch J-P, Pacher P, Evgenov OV, et al. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123:2263–2273.
4. Wilkens, H et al. Chronic thromboembolic pulmonary hypertension (CTEPH) Updated Recommendations from the Cologne Consensus Conference 2018. Int J Cardiol. 2018;1;272S:69-78.
5. Simonneau G, D’Armini AM, Ghofrani H-A, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;10.1016/S2213-2600(16)30022–4.
6. Simonneau G, D’Armini AM, Ghofrani H-A, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Supplementary appendix. Lancet Respir Med. 2016;10.1016/S2213-2600(16)30022–4.
7. Simonneau G, D’Armini A, Ghofrani H, et al 2015. Riociguat For The Treatment Of Chronic Thromboembolic Pulmonary Hypertension: A Long-Term Extension Study (CHEST-2). [online] Available at: https://erj.ersjournals.com/content/45/5/1293.long.
8. Hoeper M M, Al-Hiti H et al. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(6):573-584.

Supporting documentation

Prescribing Information (Great Britain) & Prescribing Information (Northern Ireland)
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