Adempas Review Gives First Glimpse Of FDA Benefit-Risk Framework In Action

Graphic presentation of the evidence, uncertainties, conclusions and risks of a drug could become more complex for therapies with major efficacy or safety questions.

Sponsors’ first glimpse of a drug reviewer’s implementation of FDA’s benefit-risk assessment framework came in briefing documents for an advisory committee review of Bayer HealthCare LLC’s vasodilator Adempas (riociguat) to treat two pulmonary arterial hypertension indications.

Clinical Reviewer Preston Dunnmon was succinct in presenting the evidence, uncertainties, conclusions and risks in the five framework categories – analysis of condition, unmet need, clinical benefit, risk and risk management – including a summary of pivotal trial results in the evidence column. The one missing component from the graphic display of riociguat’s benefits and risks was an overall summary that FDA designers put at the bottom of the framework.

Filling out the framework could become more complex with drugs that pose major concerns about safety and or efficacy. The efficacy for riociguat is robust, its indications can be life-threatening, and Dunnmon said that the potentially worst consequence of the drug, hypotension, could be addressed by cautious dose escalation (Also see "FDA Review Of Bayer’s Riociguat Suggests It’s All About The Dose" - Pink Sheet, 2 Aug, 2013.).

The framework is part of an international effort to have benefit-risk assessments proceed in a similar fashion across the globe (Also see "Benefit-Risk Assessment Framework Pushes Into Post-Approval Arena" - Pink Sheet, 2 Sep, 2013.).

Riociguat Benefit-Risk Assessment Framework
Decision Factor	Evidence and Uncertainties	Conclusions and Risks
Analysis of Condition	Summary of evidence: Pulmonary Artery Hypertension (Dana Point, 2008) WHO Group 1 (PAH) – idiopathic, familial, associated with other diseases (collagen vascular disease), congenital heart disease, diet therapies or other drugs WHO Group II – Left Heart Dz WHO Group III – Lung Dz (COPD, ILD, sleep disorders, high altitude, developmental lung abnormalities WHO Group IV – chronic thrombotic/embolic disease (CTEPH) WHO Group V - miscellaneous Clinical manifestations include poor exercise tolerance, shortness of breath, marked elevation of pulmonary artery pressures due to vasoconstriction of and fibromuscular obstruction within pulmonary arteries Symptoms include debilitating shortness of breath, exercise intolerance, chest pain Natural history – average survival 4-5 years after diagnosis in adults	Conclusions (implications for decision): Life threatening condition in patients with no remaining medical options other than lung transplantation
Unmet Medical Need (Current Treatment Options)	Summary of evidence: There are no approved therapies for CTEPH. Available PAH therapies include ERA, PDE5-i, and Prostanoids that target vasoconstriction When drug therapy fails, the only remaining option is lung transplantation	Conclusions (implications for decision): On average, the prognosis of PAH patients is worse than that of many patients who are diagnosed with cancer. Lung transplantation is a suboptimal option for many patients due to limited supply of donor organs, cost, and complexity of post-operative care. Riociguat, if approved, would be the first non­surgical therapy approved for the treatment of CTEPH in the United States. According to the results of CHEST-1, less than 1/3 of CTEPH patients are not surgical candidates, leaving the rest with no approved therapeutic options at all. Even for those patients who undergo surgical pulmonary thromboembolectomy/endarterectomy, elevated pulmonary pressures may persist or recur, leaving these patients without medical options as well.
Clinical Benefit	Summary of evidence: The 6MWD has been the accepted endpoint measure on which prior PAH drugs have been approved in adults. Bayer completed two pivotal trials in support of the riociguat NDA – one in patients with CTEPH (CHEST-1) and another in patients with PAH (PATENT-1) in which the placebo-corrected change from baseline 6MWD was utilized as the primary efficacy variable. Adding to the robustness of the evidence for benefit were secondary analyses of time to clinical worsening (TTCW), hemodynamics, chemical biomarkers, and five different measures of functionality and/or quality of life. A summary table of the results for each of these pivotal trials is shown in the table below: PATENT-1 Trial (PAH), p-values 6MWD: <0.0001 PVR: <0.0001 NT-proBNP: 0.0001 WHO FC: 0.0033 TTCW: 0.0285* Borg: 0.0022 EO^-5D: 0.0663 LPH: 0.0019 CHEST-1 Trial (CTEPH) p-values 6MWD: <0.0001 PVR: <0.0001 NT-proBNP: <0.0001 WHO FC: 0.0026 TTCW: 0.2180** Borg: 0.0035 EO^-5D: <0.0001 LPH: 0.1220 * ANCOVA – stratified Wilcoxon (non-parametric) p=0.0046 * ANCOVA – stratified Wilcoxon (non-parametric) p=0.1724	Conclusions (implications for decision): The combination of two positive pivotal trials with coordinate and positive results across multiple measures of clinical benefit in two different populations of pulmonary hypertension patients is a robust data set supporting the benefit of riociguat and its mechanism of action in the therapy of both PAH and CTEPH patients. The benefit-risk balance is probably optimized at the lower dose of 1.5 mg TID.
Risk	Summary of evidence: Hypotension. Riociguat causes dose-dependent decreases in blood pressure, both systolic and diastolic. Events of renal failure. Serious TEAEs of renal failure (renal failure, renal failure acute, renal failure chronic, renal impairment) were observed in 10 subjects (1.3%) in the pooled riociguat group in the main studies in Pool 3 (all riociguat studies), and in 1 subject (0.3%) in the pooled placebo group. I suspect a secondary effect of blood pressure reduction may play a mechanistic role in the occurrence of these infrequent events. Bleeding. There were a total of 10 treatment emergent serious hemorrhages across both pivotal studies, all of which occurred in riociguat-IDT-treated patients.	Conclusions (implications for decision): Hypotension may have the worse consequences in real-world use, especially among patients with underlying CV disease. I recommend more cautious dose escalation than the trials employed. Bleeding risk is probably an unavoidable consequence of vasodilator therapy.
Risk Management	Summary of evidence: The sponsor has proposed a REMS	Conclusions (implications for decision): The reviewer agrees with modifying the proposed REMS to align with other known teratogens used to treat pulmonary hypertension.
Source: FDA briefing document for riociguat advisory committee