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Bayer Submits Riociguat for EU and US regulatory approval to treat treat patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH)

File:Riociguat structure.svg

Methyl N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminate

625115-55-1 CAS NO

Riociguat (BAY 63-2521) is a novel drug that is currently in clinical development by Bayer. It is a stimulator of soluble guanylate cyclase (sGC). At the moment Phase III clinical trialsinvestigate the use of riociguat as a new approach to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) andpulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of a novel class of sGC stimulators.[1]

Sunday, February 10, 2013

Bayer HealthCare has submitted the oral investigational drug riociguat to treat patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) for regulatory approval in the United States and in the European Union.

“These regulatory submissions for two distinct forms of pulmonary hypertension not only represent important progress in our cardiovascular pipeline but also fuel our hope to bring this much-needed new treatment option for these serious and potentially fatal diseases to patients and doctors soon,” said Kemal Malik, member of the Bayer HealthCare Executive Committee and Head of Global Development.Riociguat was discovered by Bayer and represents the first member of a novel class of compounds, the stimulators of soluble guanylate cyclase (sGC). Riociguat is the first drug to demonstrate clinical efficacy in a placebo controlled phase III trial in inoperable CTEPH patients.

In CHEST-1 patients treated with riociguat showed a statistically significant improvement from baseline in the six-minute walking test (6MWT) after 16 weeks, compared to those receiving placebo. The study included both patients with inoperable CTEPH and those with persistent or recurrent disease after a surgical procedure called pulmonary endarterectomy (PEA). The PATENT-1 study met its primary endpoint by demonstrating a statistically significant improvement  from baseline in the 6MWT, after 12 weeks compared with placebo. PATENT-1 included both treatment naïve symptomatic PAH patients and those pre-treated with ERAs or non-iv prostanoid monotherapy.

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Phase I clinical trials

One of the first studies was designed to test the safety profile, pharmacokinetics andpharmacodynamics of single oral doses of riociguat (0.25–5 mg). 58 healthy male subjects were given riociguat orally (oral solution or immediate-release tablet) in a randomised, placebo-controlled trial. Doses of riociguat were increased stepwise, and riociguat was well tolerated up to 2.5 mg.[7]

Phase II clinical trials

proof-of-concept study, reported by the University of Gießen Lung Center, was the first small study (in 4 PAH patients) to investigate safety, tolerability, pharmacokinetics and efficacy parameters.[8] The drug was well-tolerated and superior to NO in efficacy and duration.

An open-label, non-controlled phase II trial of riociguat in 75 adult patients (42 with CTEPH and 33 with PAH, all in World Health Organization (WHO) functional class II or III) evaluated the safety and tolerability, and the effects on hemodynamics, exercise capacity and functional class. Riociguat was given three times daily for 12 weeks. Doses were titrated at 2-week intervals from 1.0 mg three times daily to a maximum of 2.5 mg three times daily. Riociguat had a favourable safety profile, and also significantly improved exercise capacity and hemodynamic parameters such as pulmonary vascular resistance, cardiac output and pulmonary arterial pressure compared to baseline values.[9]

In addition, a phase II study of riociguat is underway in patients suffering from other forms of PH such as associated with interstitial lung disease (PH-ILD). First results from this study are expected in 2011.[10]

Phase III clinical trials

The phase III trials on riociguat are multi-center studies. The study program includes large randomized, double-blind, placebo-controlled pivotal trial phase (CHEST-1 and PATENT-1), and open-label extensions of these studies (CHEST-2 and PATENT-2). Details of these studies are reported on, a register of studies maintained by the National Institutes of Health (NIH).[6]

  1.  “Background Riociguat”. Bayer HealthCare. Retrieved 15 December 2009.
  2. Yoshina S, Tanaka A, Kuo SC (March 1978). “Studies on heterocyclic compounds. XXXVI. Synthesis of furo[3,2-c]pyrazole derivatives. (4) Synthesis of 1,3-diphenylfuro[3,2-c]pyrazole-5-carboxaldehyde and its derivatives (author’s transl)” (in Japanese). Yakugaku Zasshi 98 (3): 272–9. PMID 650406.
  3. Stasch JP, Becker EM, Alonso-Alija C, et al. (March 2001). “NO-independent regulatory site on soluble guanylate cyclase”.Nature 410 (6825): 212–5. doi:10.1038/35065611.PMID 11242081.
  4. Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HH, Stasch JP (September 2006). “NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential”Nature Reviews. Drug Discovery 5 (9): 755–68. doi:10.1038/nrd2038PMC 2225477.PMID 16955067.
  5. Mittendorf J, Weigand S, Alonso-Alija C, et al. (May 2009). “Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension”. Chemmedchem 4 (5): 853–65.doi:10.1002/cmdc.200900014PMID 19263460.
  6. ClinicalTrials.govRiociguat
  7. Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G (December 2008). “Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers”. Journal of Clinical Pharmacology 48 (12): 1400–10. doi:10.1177/0091270008322906.PMID 18779378.
  8. Grimminger F, Weimann G, Frey R, et al. (April 2009). “First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension”. The European Respiratory Journal 33 (4): 785–92.doi:10.1183/09031936.00039808PMID 19129292.
  9.  “ATS International conference”. American Thoracic Society. 2009.
  10. NCT00694850 Impact of Multiple Doses of BAY 63-2521 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Patients With Interstitial Lung Disease (ILD) Associated Pulmonary Hypertension
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