Six weeks of treatment with levosimendan significantly lowered pressure on the heart and improved physical capacity among people with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF), findings from a Phase 2 trial show.
The investigational treatment, by Tenax Therapeutic, however, did not reduce pressure on the heart’s upper left chamber during exercise, failing to meet the trial’s main endpoint.
Still, several secondary goals were met, supporting a future Phase 3 trial of levosimendan in a patient population without any disease-specific treatments.
“Levosimendan is the first drug to ever show a favorable mechanism of action with biventricular [on both left and right ventricles, the lower chambers of the heart] effects in patients with PH-HFpEF,” Stuart Rich, a professor of medicine at the Bluhm Cardiovascular Institute at Northwestern University, said in a press release.
People with this type of PH cannot pump blood properly because their heart muscles are too weak, even though their heart beats normally. PH-HFpEF represents an area of very high unmet medical need, with no currently approved or effective therapies.
Levosimendan belongs to a class of compounds known as calcium sensitizers. It is designed to help improve heart muscle contraction without increasing the need for oxygen.
The multicenter Phase 2 HELP trial (NCT03541603) evaluated the efficacy and safety of levosimendan in PH-HFpEF. These patients still pump enough blood, but at the cost of higher pressure in their heart chambers.
The trial had an open-label, lead-in phase. To take part, patients had to show a reduction of at least 4 mmHg in their pulmonary capillary wedge pressure (PCWP, a measure of pressure on the left side of heart) during supine (laying down) exercise, 24 hours after a single infusion of levosimendan.
HELP’s primary goal was to determine whether levosimendan was better than placebo at lowering left heart pressure — assessed as changes from baseline (study start) to week six in PCWP — during exercise (25 watts for three minutes or until the patient was tired).
Secondary measures included changes in PCWP at rest and with legs up, pulmonary artery pressure, right atrial pressure, and functional capacity, assessed via the six minute walk test — the distance that can be walked in six minutes.
Changes seen from baseline to week six in PCWP during exercise were not significantly different between the levosimendan and placebo groups, meaning that HELP failed its primary goal, the release stated.
But levosimendan led to significant improvements in PCWP at six weeks when a composite measure of pulmonary capillary wedge pressure was used — one that combined assessments at rest, with legs up, and during exercise. Changes in this measure from baseline to week six were again significantly better on levosimendan than on a placebo, it noted.
Levosimendan-treated patients also showed significant reductions in other measures of heart pressure, pulmonary arterial pressure and right atrial pressure assessed at rest and with legs up over the trial’s six weeks.
Treatment also significantly improved functional capacity, with patients being able to walk 29 meters (about 95 feet) more at the end of treatment compared to the study’s start.
“The consistency of the hemodynamic [blood flow] data and improvement in 6-minute walk demonstrates that levosimendan has great promise as a treatment for PH-HFpEF which has a serious unmet need,” Rich said.
The incidence of adverse events or serious side effects was similar between those given levosimendan or placebo. No signs of arrhythmias were seen in a 72-hour monitoring after five weeks of treatment.
“The positive outcome of this Phase 2 trial represents a major milestone for Tenax and our development of levosimendan for the treatment of patients suffering from this debilitating illness,” Anthony DiTonno, CEO of Tenax, said in the release.
“We believe these results support a Phase 3 trial that will translate into the first approved therapy to treat these patients,” DiTonno added.
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