CHMP Says No to Serelaxin But Yes to Riociguat

Disclosures

January 24, 2014

LONDON, UK – The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) made a decision this week on two cardio-related drugs, saying yes to one drug and no to another.

In its first decision, the committee has taken a negative stand against serelaxin (Reasanz, Novartis) for the treatment of acute heart failure (AHF)[1].

Serelaxin is a first-in-class recombinant form of human hormone relaxin 2. During pregnancy, the hormone modulates cardiovascular responses by increasing vasodilation and renal function. Relaxin can also modulate various hemodynamic and neurohormonal effects, such as increases in cardiac output and decreases in systemic vascular resistance, pulmonary capillary wedge pressure, and N-terminal pro–brain natriuretic peptide (NT-proBNP).

"Although the safety of Reasanz seemed acceptable, in view of the uncertainties about the benefits of treatment, the CHMP was of the opinion at that point in time that the benefits of Reasanz did not outweigh its risks and recommended that it be refused marketing authorization," according to the committee.

The CHMP review was based on the results of the Relaxin for the Treatment of Acute Heart Failure (RELAX-AHF) study. Reported by heartwire when it was presented at the American Heart Association 2012 Scientific Sessions, treatment reduced shortness of breath as assessed using one of two dyspnea end points. Days alive out of the hospital at day 60 and cardiovascular death or heart-failure/renal-failure hospitalizations up to day 60, the secondary end points, were not significantly improved with serelaxin.

In its review, the CHMP questioned the effect of serelaxin for the short-term relief of dyspnea beyond 24 hours. It also had concerns about the trial's analysis and calculations of the number of patients who died or who required additional treatment for worsening heart failure. Finally, it also questioned whether the differences in the background treatment in the placebo and serelaxin arms might have influenced the results.

RELAX-AHF was the sole trial submitted to CHMP for review in support of the serelaxin indication, so the EMA said further studies will be needed.

Yes to Riociguat for CTEPH and PAH

In contrast to serelaxin, CHMP issued a favorable opinion on riociguat (Adempas, Bayer) and recommended marketing authorization of the drug for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH)[2].

Riociguat is a vasodilator that restores the nitric-oxide–soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway by directly stimulating sGC independent of NO and sensitizing sGC to low levels of NO. In two phase 3 trials, which were reported by heartwire , treatment with riociguat resulted in significant improvements in exercise capacity and pulmonary hemodynamics in patients with pulmonary hypertension.

"The CHMP, on the basis of quality, safety, and efficacy data submitted, considers there to be a favorable benefit-to-risk balance for Adempas and therefore recommends the granting of the marketing authorization."

The intended indication is for CTEPH patients with World Health Organization (WHO) functional class 2 or 3 and inoperable CTEPH or persistent or recurrent CTEPH after surgery. For PAH patients with WHO functional class 2 or 3, riociguat's intended indication is as monotherapy or in combination with endothelin-receptor antagonists. Both indications are for the improvement of exercise capacity.

In October 2013, the US Food and Drug Administration (FDA) approved riociguat for the treatment of PAH and the treatment of chronic CTEPH.

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