Veletri’s dosing important to achieve beneficial results: Small study

Higher doses might be needed to ensure Veletri's effectiveness

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Note: The headline of this article was updated Feb. 27, 2023, to better reflect that Veletri is considered a safe and effective therapy at the approved and recommended dosing levels. 

Treatment with Veletri (epoprostenol AS) infusion was generally well-tolerated and safe, but did not lead to clinical improvements for most patients with severe pulmonary arterial hypertension (PAH) in a small German study.

About half — seven of 15 — patients died across the six-month study and its approximately 1.5-year follow-up.

The researchers noted that the dose of Veletri used in the study may not have been high enough for these severely affected patients.

“In future applications/trials the up-titration process should be pushing for higher dosages of [Veletri] in the occurrence of side effects, as the achievement of a high and effective dosage is crucial for the clinical benefit of the patients,” the team wrote.

The study, “Tolerability, safety and survival in patients with severe pulmonary arterial hypertension treated with intravenous epoprostenol (Veletri): a prospective, 6-months, open label, observational, non-interventional study,” was published in the journal Respiratory Research.

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No improvements seen with Veletri infusion therapy

Veletri is an approved into-the-vein (intravenous) treatment for PAH now marketed by Janssen. Its active ingredient, epoprostenol, mimics the activity of prostacyclin, a naturally occurring substance in the body that helps blood vessels widen.

It’s the same active ingredient found in Flolan (epoprostenol GM), a version of the medication developed by GlaxoSmithKline. However, Veletri’s formulation contains arginine and sucrose, two ingredients meant to help stabilize epoprostenol, making it easier to store at room temperature and prepare for infusions.

Because symptoms may significantly worsen if treatment is stopped abruptly, Veletri is delivered via a continuous infusion into the bloodstream through a catheter, or tube, placed into one of the body’s veins. The infusion is controlled via an external pump.

Eepoprostenol, including Veletri’s formulation, is the only approved intravenous treatment that’s highly recommended for patients who have severe PAH, defined as those with a World Health Organization (WHO) functional class of 3 or 4, according to researchers.

Still, the treatment “was under-used in clinical practice at the time the study started and still remains so to present day, despite available data suggesting a survival benefit if applied early as a part of combination therapy,” the researchers wrote.

In the study, the research team in Germany aimed to “expand clinical experience and knowledge” related to the real-world use of Veletri in 15 patients with severe PAH. Among the patients, 80% were women.

All but one patient were receiving dual therapy with phosphodiesterase-5 inhibitors (e.g. Revatio) and endothelin receptor antagonists (e.g. Letairis) at the study’s start. However, they either had an unsatisfactory long-term clinical response or were still at an intermediate to high risk of PAH worsening.

Four patients also had been previously using other prostacyclin analogues (e.g. Orenitram, Remodulin) but were transitioned to Veletri during the study.

Each of the participants — all of whom were recruited between March 2018 and August 2020 — were started on Veletri, which was titrated to the appropriate dose over a one-week period in the hospital. The mean maximum dose was 7.9 nanograms per kilogram per minute (ng/kg/min).

The safety and efficacy of Veletri were monitored for six months. This was followed by an additional period lasting a mean of 19.1 months, or about 1.5 years, to monitor survival.

Safety findings were generally similar to previous reports. Non-serious side effects considered related to Veletri treatment included nausea (three people), flushing (two people), diarrhea, and headaches, which each occurred in one person.

Three serious side effects were deemed related to Veletri — two cases of catheter infection and one of a blockage in the catheter.

A single participant withdrew from the study due to treatment intolerance and therapy resistance after the three-month visit.

Overall, across the main study and the follow-up phase, three patients were listed for a lung transplant and seven people died. Three deaths occurred in the six-month trial, and four patients died during follow-up. Reasons for death included acute renal failure, cancer, and right heart failure.

Taken together, transplant-free survival rates at one and two years were 73.3% and 52.4%, respectively.

Future applications/trials … should be pushing for higher dosages of [Veletri] in the occurrence of side effects, as the achievement of a high and effective dosage is crucial for the clinical benefit of the patients.

In terms of efficacy, no consistent improvements were observed, including in measures of exercise capacity, breathlessness, heart function, lung function and functional classification. But “most patients remained stable under Veletri therapy,” the researchers wrote.

The lack of efficacy could be due to the severity of the patients’ disease at the study’s start, the team noted — reflected by the fact that about half of patients died during the study and follow-up.

On the other hand, it’s possible the dose of Veletri was too low.

“Possibly we did not increase the dosage enough after the in-hospital start of the therapy,” the researchers wrote.

Larger and longer studies are needed  “to optimize titration, dosing and dose escalation and to determine efficacy in terms of (transplant-free) survival,” the team wrote, noting that such studies will serve as a “guide standardization of long-term therapy.”

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