LOS ANGELES – Pulmonary artery hypertension patients who have an insufficient response to phosphodiesterase inhibitors may benefit from a switch to riociguat (Adempas), based on results from a 24-week, open-label investigation from the drug’s maker, Bayer.
The 61 patients – mean age 54 years, 74% of whom were women – had World Health Organization functional class 3 disease, with 6-minute walking distances of 165-440 meters, and cardiac indices below 3 L/min/m2 despite being on a phosphodiesterase inhibitor (PDEi) for 90 days or more, 40 (66%) on sildenafil (Viagra) and 21 (34%) on tadalafil (Cialis).
After PDEi washout, the researchers swapped them for riociguat titrated to a maximum oral dose of 2.5 mg t.i.d. The 50 patients (82%) on concomitant endothelin receptor antagonists (ERA) were allowed to stay on them. At week 24, 16 patients (34% of the 47 evaluable patients) achieved the combined endpoint of no clinical worsening, functional class 1 or 2, and 30 meters or more improvement on their walk test.
Dr. James Klinger
“The key point is that it was safe to switch people from a [PDEi] to riociguat, and it seemed to have improved efficacy, but we hesitate on these conclusions because it was an open-label trial, and the results need to be confirmed,” lead investigator James Klinger, MD, professor of medicine at Brown University, Providence, R.I., said at the annual meeting of the American College of Chest Physicians. A randomized, controlled trial is underway, he added.
The usual approach to PAH is to start patients on a PDEi, often with an ERA. If that doesn’t work, a prostacyclin is added. The cost can exceed $200,000 a year.
“This is a study that says, wait a minute, before you add a third drug to the first two, maybe it would be worthwhile to” switch out the PDEi. “You would save the person the addition of a third drug,” and the cost would be comparable or less than a three-drug regimen, Dr. Klinger said.
The researchers also found that after 24 weeks on riociguat, mean plasma cyclic guanosine monophosphate (cGMP) increased by 4.6 pmol/mL, urinary cGMP by 1,005 pmol/mL, and asymmetric dimethylarginine (ADMA) by 0.004 micromol/L.
The biomarkers were important because the team is trying to find a way to identify patients who would benefit most from riociguat. “As a field, we still don’t understand the disease well enough to know” how to best match patients and drugs. “We are trying to find a biomarker that would identify patients who are more likely to respond to one medication versus another,” Dr. Klinger said.
ADMA inhibits the production of nitric oxide, and is a bad player in PAH. The study results were reassuring because riociguat didn’t have much of an effect on ADMA levels, although the “slight difference was not enough to identify people who might do better with” it, Dr. Klinger said.
As for cGMP, “when we raise [levels] with riociguat, patients get better, so we think riociguat is raising cGMP in the right place, which we think is the lungs. Unfortunately, we don’t’ have a biomarker that can distinguish lung cGMP from total body cGMP,” he said.
The work was funded by Bayer, maker of riociguat. Dr. Klinger is an unpaid consultant, and also receives research support from the company.