Riociguat use in sickle cell related chronic thromboembolic pulmonary hypertension: A case series

Abstract

Adults with sickle cell disease can develop pulmonary hypertension from a multitude of etiologies. Classified as WHO Group 5, there are no therapies approved for the treatment of sickle cell disease-pulmonary hypertension. Thromboembolic disease is prevalent in sickle cell disease and can lead to pulmonary hypertension. The only approved medical therapy for chronic thromboembolic pulmonary hypertension is riociguat. We report the experience, safety and tolerability of riociguat use in a series of sickle cell disease patients with chronic thromboembolic pulmonary hypertension.

Chronic Thromboembolic Pulmonary Hypertension in a Child With Sickle Cell Disease

“…Once the diagnosis was established, he was also started on targeted PH therapy, including macitentan, an endothelin receptor antagonist, and riociguat, a soluble guanylate cyclase stimulator, while awaiting definitive surgery. Riociguat was chosen because it has been shown to improve exercise capacity and pulmonary vascular resistance in patients with CTEPH, and because it is safe and well-tolerated in patients with SCD (21,22). PTE is the treatment of choice for operable patients, and its success has been demonstrated in children (9,23).…”

<p>Riociguat in the Treatment of Chronic Thromboembolic Pulmonary Hypertension: An Evidence-Based Review of Its Place in Therapy</p>

“…In a select group of SCD-related CTEPH, riociguat was well tolerated in four of six participants. 28 Increased VOC was reported in one participant with riociguat doses of 1.5 mg TID, however improved following down titration to 1 mg TID. Notably, it ultimately lacked efficacy in the aforementioned participant and was discontinued.…”

“… 3-year survival was comparable to CHEST-2 McLaughlin et al 26 (2017). Open-label, uncontrolled, single-arm, Phase IIIb long-term surveillance study 300 CTEPH that was deemed technically inoperable or persistent/recurrent PH after PEA, who were not satisfactorily treated and could not participate in another CTEPH trial Median 47 weeks I–IV Safety and tolerability of riociguat Safety consistent with CHEST1 & 2 No new safety signals in treatment naive or if switched from PAH therapy 6MWD increased by 33±42 meters WHO FC improved Weir et al 28 (2018) Retrospective, case series 6 Inoperable CTEPH in adults (22–64 yrs) 1–3 years II–IV Safety and tolerability of riociguat Well tolerated Improved 6MWD Improvements in RVSP Improved WHO functional class Improved NT-pro-BNP Wiedenroth et al 27 (2018). Prospective, observational cohort study; sequential treatment with riociguat and BPA 36 CTEPH inoperable, mPAP ≥25 mmHg and BPA eligible Median interval from riociguat to BPA=5 months, median duration from 1st BPA to 6 month f/u was 14 months ≥ II Pulmonary hemodynamic parameters and WHO FC Significant improvement in WHO FC, 6MWD, and hemodynamic parameters with riociguat Significant improvement in WHO FC, 6MWD, and hemodynamic parameters when combination riociguat and BPA compared to riociguat alone Kirson et al 30 (2011) Prospective cohort study; CTEPH patients with demographically matched controls without PH 289 CTEPH with private insurance claims between 2002–2007 in the US Mean follow-up 21.5 months N/A Estimate excess direct costs associated with privately insured patients with CTEPH CTEPH mean direct patient month costs (2007 values) US$4782 vs...…”

“…Riociguat use was assessed in a small retrospective case series of patients with sickle cell disease (SCD) related CTEPH. 28 Following initiation of standard of care for SCD-PH: hydroxyurea or blood transfusion, supplemental oxygen to maintain oxygen saturation of 90% and diuretics, PH therapy with riociguat was commenced. Initial concerns about riociguat safety in view of a negative trial with sildenafil in Walk-PHaSST was discussed with participants.…”

cGMP modulation therapeutics for sickle cell disease

“…129 Use of riociguat in a small case series of SCD patients with chronic thromboembolic pulmonary hypertension was recently reported; riociguat therapy was found to be safe overall and well tolerated, and showed clinical efficacy in some of the patients evaluated. 98 Riociguat, however, has a short-half life in humans and requires thrice-daily dosing. 99 Other sGC stimulators in clinical development, include vericiguat (BAY 102-1189), which has a longer half-life than riociguat and is in development for the treatment of chronic heart failure 130 and olinciguat (IW-1701), which is currently in clinical development specifically for use in SCD, and also achalasia.…”