Reviva’s Pulmonary Hypertension Therapy Works Even Better in Combos, Study Shows

Combinations of Reviva Pharmaceuticals’ RP5063 and other pulmonary arterial hypertension treatments improved rats’  lung blood vessel structure and lung function, a study reports.

Previous research in rats indicated that RP5063 could improve these measures as a stand-alone therapy. The latest study showed that it worked even better as a combo therapy.

The research appeared in the European Journal of Pharmacology. The title of the article is “Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model.”

Doctors often add medications to PAH patients’ initial treatment. But the therapies may target overlapping biological pathways, leading to inconsistent results.

This means patients need newer, more effective approaches to managing their disease, researchers say.

The neurotransmitter serotonin, or 5-HT, contributes to PAH by narrowing lung blood vessels. These arteries contain serotonin receptors and the serotonin transporter SERT, whose activation leads to tightening of pulmonary artery muscle cells and to an increase in these cells. The result is narrowing of the arteries.

Animal studies have shown that using compounds that can block the 5-HT_2B receptor could be a way to treat PAH.

RP5063 acts on both the serotonin and dopamine neurotransmitter systems. Previous studies in a rat model of PAH showed that 10 mg/kg doses of RP5063 twice a day improved the animals’ lung function and the structure and thickness of their pulmonary blood vessels. It also reduced inflammation.

Studies also showed that RP5063 improved blood vessel structure problems, lung blood flow and respiration.

Researchers decided to compare how well RP5063 would work as a stand-alone PAH therapy versus how it would work in combination with other drugs. The other medications were bosentan, which Actelion sells under the brand name Tracleer; treprostinil, which United Therapeutics sells as Remodulin, Orenitram and Tyvaso; and sildenafil, which Pfizer  sells as Revatio and under other brand names.

Again researchers used a rat model of PAH. The animals received 28 days of either RP5063, bosentan (100 mg/kg), treprostinil (100 ng/kg/min) or sildenafil (50 mg/kg) alone, or in a one-drug combination with RP5063.

RP5063, bosentan and sildenafil were given orally twice a day. Treprostinil was administered by intravenous 24-hour infusion.

Compared with untreated controls, RP5063 by itself improved the rats’ lung blood flow, right ventricular (RV) hypertrophy — a hallmark of PAH — and the structure of their pulmonary blood vessels.

The other PAH medications offered similar effects, with sildenafil showing more benefits than the other two.

Importantly, when RP5063 was given as an add-on treatment, the rats exhibited lower mean pulmonary arterial and RV pressures, as well as improved values of the vasodilator sulfur dioxide, in comparison with untreated controls.

A combination of PR5063 and sildenafil offered the best benefits on blood flow, respiratory parameters, and PAH-related tissue alterations. This might have been due to complementary biological effects induced by the two compounds, the researchers hypothesized.

“These results corroborate earlier preclinical findings supporting the efficacy of single-agent [RP5063] in PAH,” the researchers wrote.

The improved benefits with RP 5063 as an add-on therapy “might be of clinical importance, as greater than 50% of patients with PAH will be on an additional treatment co-administered with the original therapy within 2 years of the PAH diagnosis,” the team concluded.