Discussion of FREEDOM-EV Trial
Hello, my name is Jim White, and I'm a professor of medicine, pharmacology, and physiology at the University of Rochester in Rochester, New York.
I founded and still direct the Pulmonary Hypertension Association, accredited triple C in pulmonary hypertension, and I'm here today to talk a little bit about FREEDOM-EV, the culmination of a 15 year development program for the use of oral treprostinil in patients with pulmonary arterial hypertension.
The FREEDOM-EV trial launched in 2013 as the fourth global study looking at pulmonary hypertension patients started on oral treprostinil in what we call an event driven design.
We took this homogenous population and showed that we could reduce the risk of a clinical worsening event by 26 percent over the course of the study. We were surprised to find out after the study closure that our plan to study risk improvement actually showed that the oral treprostinil patients were much more likely to die, statistically significantly more likely to die in the first year as assessed by the non-invasive French risk score. And so once we adjusted for that baseline imbalance and risk we actually had a 39 percent reduction in clinical worsening events.
Of course, this drug is a prostacyclin, and so treprostinil has side effects that are typical for the drugs that you're used to using in parenteral form, Remodulin and Veletri. And so oral treprostinil is no different, and nausea, headache, diarrhea, flushing were common, and in fact, about 18 percent of patients dropped out because of intolerable adverse events.
During the conduct of EV, what became most exciting was that follow-up risk assessment was critical.
So we were incredibly pleased to see that as early as week 12 and clearly at week 24, 36, and 60, we saw very sharp improvements in the risk profile for oral treprostinil treated patients.
Even though a majority of the patients started in functional class two, we were able to show that patients shifted functional class favorably with oral treprostinil compared to placebo, and that meant both there was improvement in the TRE assigned patients as well as decline in the placebo patient.
We started out with relatively high NT-proBNP measurements, and as you'll see in the, in the graph, that's part of that paper, a striking difference in the, in the oral treprostinil treated patients over time, where NT-proBNP marches down at week 12, marches down at week 24, marches further down at week 36 and the placebo patients sort of stay the same or creep up.
The final component of the risk assessment is six-minute walk. And at week 24 there were numeric improvements in six-minute walk in the oral treprostinil group, but the placebo patients remember who started out with an average walk distance of 400 meters, they also stayed about the same or improved by a few meters so we did not have a statistically significant difference at week 24. The oral treprostinil patients had gains at week 12, even further gains at week 24, maintained those gains at week 36, but the placebo patients had finally fallen off and so at week 36, week 48, week 60, the difference in six-minute walk is statistically significant.
Along with the clear reduction in clinical worsening events. Along with the clear improvement in risk profile. Along with the clear reduction in symptoms as measured by functional class and the clear reduction in NT-proBNP.
In summary, FREEDOM-EV represents an exciting step forward in the use of oral treprostinil.
INDICATION Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%). IMPORTANT SAFETY INFORMATION FOR ORENITRAMContraindications
- Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.
- Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
- The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.
- In the 12-week, placebo-controlled, monotherapy study, and an event-driven, placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.
- Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.
- Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
- It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
- Safety and effectiveness of Orenitram in pediatric patients have not been established.
- Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
- There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.