FDA Endpoint Development For Pediatric Pulmonary Arterial Hypertension Focuses On Pfizer's Revatio

The standard exercise test is a problem for many pediatric patients, and FDA's Cardiovascular and Renal Drugs Advisory Committee will assess alternatives.

How to develop drugs for pediatric pulmonary arterial hypertension will be the focus of an upcoming FDA advisory panel meeting, with Pfizer's Revatio (sildenafil) as the star exhibit - even though Pfizer has yet to submit an sNDA for that population.

FDA will ask the Cardiovascular and Renal Drugs Advisory Committee July 29 whether it should ask Pfizer to assess a hemodynamic endpoint, and what the appropriate study endpoint should be in PAH patients who can't perform exercise testing.

"We've conducted extensive work in this area and they're aware of it," Pfizer spokeswoman Gwen Fisher said.

"The discussion will help the agency determine what studies to request for products intended to treat pediatric PAH," FDA said in a statement scheduled for publication in the Federal Register June 22.

There is no drug currently approved to treat pediatric PAH, and the exercise test is a problem for many pediatric patients still learning to walk. The agency approved Revatio for PAH in adult patients in June 2005. Revatio, which has the same active ingredient as the erectile dysfunction dug Viagra , is indicated for improving exercise ability in patients suffering from "World Health Organization Group I" PAH ( (Also see "Viagra’s Second Wind: Pfizer Revatio Approved For Pulmonary Hypertension" - Pink Sheet, 13 Jun, 2005.).

The primary efficacy endpoint for the clinical trial listed in the label was "the change from baseline at week 12 in six-minute walk distance at least four hours after the last dose."

Different Ages, Similar Endpoints

Pfizer used a similar endpoint in a placebo-controlled Phase III pediatric clinical trial that concluded last year, which was designed to evaluate the efficacy of three different doses of Revatio for PAH in children one to 17 years old.

The summary on ClinicalTrials.gov says that "efficacy [was] measured by exercise and hemodynamics," with the primary outcome measures being percent change from baseline in peak volume of oxygen consumed in the intent-to-treat and per protocol populations. "That's a measure of exercise capacity performed through cardiopulmonary exercise testing," Fisher explained. "We used a six-minute timed walk."

For all three doses combined, the peak volume of oxygen consumed was 7.71 percent. But the improvement was greatest at the medium dose - 11.3 percent.

Another exercise-related endpoint in this trial was a secondary outcome measure: change from baseline to week 16 in WHO pulmonary hypertension functional class. Revatio showed efficacy in this area as well, with 32 out of the 120 patients who got a dose of the drug improving by one functional class and one improving by two functional classes, while four out of the 35 placebo patients improved by one functional class.

[Editor's note: This story has been updated to correct the description of the Phase III pediatric clinical trial of Revatio that concluded in 2009.]

Other companies likely to be interested in what the advisory committee says are GlaxoSmithKline and Merck, who market Bayer's ED drug Levitra (vardenafil) in the U.S. That product is being studied in a Phase III clinical trial by Tongji University, Shanghai, China, for PAH in patients age 12-65. According to the listing on Clinical Trials.gov, that trial had concluded by February 2010, but no results are available yet.

Side Effect Profile May Prove Troublesome

When Pfizer or other sponsors are ready to submit their sNDAs for pediatric PAH, they will have to contend with a number of known side effects of phosphodiesterase type 5 inhibitors, a class to which both Revatio and Levitra, as well as Lilly's Cialis (tadalafil), belong.

For example, in October 2007 FDA revised the labeling for PDE-5 inhibitors to display the risk of sudden hearing loss more prominently, though the agency did not assert a causal link ('The Pink Sheet,' Oct. 22, 2007).

Two years before that, FDA asked for ED drug labeling revisions that added language about vision loss, although again, no causal link was asserted (Also see "Erectile Dysfunction Class Labeling Does Not Assert Causal Link To Vision Loss" - Pink Sheet, 8 Jul, 2005.).

- Martin Berman-Gorvine ([email protected])