Riociguat for chronic thromboembolic pulmonary hypertension This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research
Riociguat for chronic thromboembolic pulmonary hypertension Target group Chronic thromboembolic pulmonary hypertension (CTEPH): inoperable, or recurrent or persisting pulmonary hypertension (PH) after surgical pulmonary endarterectomy. Background PH is a diverse group of rare diseases characterised by a progressive increase in pulmonary vascular resistance (PVR), which, in the absence of aggressive treatment, may lead to right-heart failure and premature death 1,2. The current clinical classification system identifies five major groups and causes PH 3. Chronic thromboembolic pulmonary hypertension (CTEPH) is represented by group five 4,5 and is a life-threatening condition characterised by single or recurrent pulmonary thromboemboli that obstruct the pulmonary arteries 6. The consequence is an increase in pulmonary vascular resistance (PVR) resulting in progressive pulmonary hypertension and right-heart failure 3. The underlying cause of CTEPH remains unclear, but it is thought to be the result of previous pulmonary embolism (PE) 7. However, many people with CTEPH have no clear history of an acute thromboembolic event 8. People with CTEPH may present initially with nonspecific symptoms, such as breathlessness, fatigue and lightheadedness 1. Diagnosis is usually in the late stages of the disease when there is progressive dyspnoea on exertion, with or without signs of right heart dysfunction including fatigue, palpitations, syncope or oedema 4,6,7. Surgical pulmonary endarterectomy, to remove the obstructing thromboembolic material is recommended in suitable patients as it can restore near-normal cardiorespiratory function 9,10. Technology description Riociguat (BAY63-2521) is a soluble guanylate cyclase (sgc) stimulator which works via the same vasodilating signaling pathway as nitric oxide (NO) 11,12. Riociguat is intended as an alternative to current treatment options. It is administered orally and is currently being trialled at a dose of 1.5mg titrated to a maximum of 2.5mg three times daily (4.5 to 7.5 mg per day). Innovation and/or advantages Riociguat is the first in a new class of drugs which if successful at licensing, will offer a treatment option for patients with inoperable CTEPH, or recurrent or persistent symptoms after surgery. Developer Bayer plc. Availability, launch or marketing dates, and licensing plans In phase III trials. NHS or Government priority area This topic is relevant to The NHS National Service Framework for Long Term Conditions (2005) and The NHS National Service Framework for Coronary Heart Disease (2005). 2
Relevant guidance European Society of Cardiology and European Respiratory Society. Guidelines for the diagnosis and treatment of pulmonary arterial hypertension. 2009 7. National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. 2008 13. Clinical need and burden of disease Due to its nonspecific symptoms and variable disease course, CTEPH is often misdiagnosed and the number of people with the disease is thought to be significantly underestimated 6,9. The incidence of CTEPH in people surviving an acute PE is an estimated 0.5-3.8% 10,14, and the incidence of PE is approximately 60-70 cases per 100,000 population 15. Therefore an estimated 164 1,457 people will have resulting CTEPH per year in England. Estimates suggest that up to the same number of people may have CTEPH with no prior clinical episode of acute PE. The eligible patient group for riociguat will be a subset of these, with either inoperable disease or symptoms postsurgery. In England in 2008-09, there were 71 admissions for pulmonary endarterectomy (OPCS L04.1), accounting for 1,557 bed days 16. Existing comparators and treatments Current guidelines for management of CTEPH recommend the following 10 : Lifelong anticoagulation usually vitamin K antagonists e.g. warfarin. Surgical pulmonary endarterectomy if patients are suitable and the lesion is accessible. PAH-specific drug therapy e.g. bosentan (unlicensed) for patients not suitable for surgery or with residual PH after pulmonary endarterectomy. Efficacy and safety Trial NCT00454558; dose titration; CTEPH or PAH; phase II and phase II extension. CHEST-1; NCT00855465; adults; riociguat vs placebo; phase III. CHEST-2; NCT00910429; adults; riociguat; phase III extension. Sponsor Bayer. Bayer. Bayer. Status Published. Ongoing. Ongoing. Source of Published 17, trial registry 18, 19 Trial registry, 20 Trial registry, information manufacturer. manufacturer. manufacturer. Location Germany. EU (inc UK), USA, Canada and other countries. EU (inc UK), USA, Canada and other countries. Design Participants and schedule Open-label, uncontrolled, dose titration. n=75; adults; PAH (n=33) or CTEPH (n=42), NYHA class II or III; treatment-naive or pre-treated with bosentan and/or calcium channel blockers. Received riociguat 3-7.5mg/day for 12 weeks. Dose titrated to systolic blood pressure (SBP) response. n=68 entered extension study. Randomised, placebocontrolled. n=270 (planned); adults; CTEPH; inoperable or with persistent or recurrent PH after surgery. Randomised to riociguat 3-7.5mg/day or placebo for 16 weeks. Open-label extension. Adults; completed CHEST-1 (NCT00855465). Received riociguat 3-7.5mg/day to end of study. 3
Follow-up Initial active treatment period 12 weeks then optional open-ended extension. Primary Safety and tolerability of titration outcomes Secondary outcome according to SBP. 6 minute walking distance (6MWD), Borg dyspnoea score, WHO functional class. Active treatment period 16 weeks. 6MWD. Change in: PVR, N- terminal prohormone brain natriuretic peptide, WHO functional class, time to clinical worsening, Borg dyspnoea score, quality of life, time to clinical worsening. - 3 years. Safety and tolerability. 6MWD. Key results Hypotension (SBP <90 mmhg): 11 cases; change in PVR: -215 dyn.s.cm -5 a, p<0.0001; median - 6MWD increased in all participants (+55m; p<0.0001); greater improvement in 6 minute walking distance in participants taking riociguat with bosentan than riociguat alone: 90m (p=0.500) vs 57m (p<0.0001). Expected - Q4 2011. Not reported. reporting date Adverse - - effects (AEs) AEs experienced in 65/75 (87%), 42 (56%) were drug-related; incidence of AEs not related to riociguat dose. Most common AEs included: dyspepsia 24%, headache 16%, hypotension 15%, peripheral oedema 12%, tachycardia 12%, fatigue 9%, upper abdominal pain 9%. Estimated cost and cost impact The cost of riociguat is not yet known. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use Service organisation Staff requirements Decreased use Other: None identified a dyn.s.cm -5 = dyne second per cm -5, unit of vascular resistance. 4
Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: costs of drug Savings: Other: Other issues Clinical uncertainty or other research question identified: The place of riociguat in the management of obstructive vascular pathology needs further consideration in particular the characteristics of patients who might benefit. None identified References 1 Regional Drug and Therapeutics Centre. Current Therapeutic Strategies for Pulmonary Arterial Hypertension. Wolfson Unit, Newcastle upon Tyne; March 2009. 2 Rubin L, Badesch B, Robyn M et al. Bosentan therapy for pulmonary arterial hypertension. New England Journal of Medicine 2002; 346:896-903. 3 Simonneau G, Robbins I, Beghetti M et al. Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 2009; 54(sS):S43-S54. 4 Humbert M. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology. European Respiratory Review 2010; 19: 59-63. 5 Simonneau G, Robbins I, Beghetti M et al. Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 2009; 54(S):S43-S54. 6 Tapson VF and Humbert M. Incidence and prevalence of chronic thromboembolic pulmonary hypertension. From acute to chronic pulmonary embolism. Proceedings of the American Thoracic Society 2006; 3:564-567. 7 Peacock A, Simonneau G and Rubin L. Controversies, uncertainties and future research on the treatment of chronic thromboembolic pulmonary hypertension. Proceedings of the American Thoracic Society 2006; 3: 608 614. 8 Auger WR, Kim KM, Kim NH, et al. Chronic thromboembolic pulmonary hypertension. Cardiology Clinics 2004;22:453 66. 9 McNeil K and Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Heart 2007;93:1152 1158. 10 Nazzareno G, Hoeper M, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension-the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society(ERS) endorsed by the International Society of Heart and Lung Transplantation (ISHLT). European Heart Journal 2009;30: 2493-2537. 11 Mittendorf J, Weigand S, Onso-Alija C et al. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009;4(5):853-865. 12 Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. European Respiratory Journal 2009;33(4):785-792. 13 National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart 2008;94 Suppl 1:i1-41. 14 Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. New England Journal of Medicine. 2004;350:2257 64. 15 British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003;58:470-84. 16 NHS. Hospital episode statistics. NHS England 2008-09. HES data 2008-09. www.hesonline.nhs.uk. 17 Ghofrani HA, Hoeper MM, Halank M et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. European Respiratory Journal 2010 36;792-799. 18 ClinicalTrials.gov. An open multiple dose titration study in patients with pulmonary hypertension. http://clinicaltrials.gov/ct2/show/nct00454558. Accessed 27 August 2010. 19 ClinicalTrials.gov. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with CTEPH. http://www.clinicaltrials.gov/ct2/results?term=nct00855465 Accessed 7 September 2010. 20 ClinicalTrials.gov. BAY63-2521 Long-term extension study in patients with chronic thromboembolic pulmonary hypertension. http://www.clinicaltrials.gov/ct2/results?term=nct00910429. Accessed 7 September 2010. 5
The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon 6