The increasingly crowded field of therapies for pulmonary arterial hypertension (PAH) added another player last week with the approval of Pfizer Inc.'s Revatio, a compound that may either compete with or supplement the only other approved oral therapy in the U.S. - Tracleer (bosentan), from Swiss firm Actelion Ltd., which was cleared for marketing in the U.S. in 2001.
Tracleer is a dual endothelin receptor antagonist, while Revatio's active ingredient is sildenafil citrate, the magic bullet in Viagra, Pfizer's blockbuster drug for erectile dysfunction that chalked up $1.7 billion in sales last year, despite competition from generic versions shipped into the U.S. from overseas.
Viagra works by blocking the enzyme phosphodiesterase 5, thus allowing the blood-vessel expander cyclic guanosine monophosphate to work more fully. Revatio, which will be sold this summer in a lower dose than Viagra (and as a white, round pill rather than the familiar blue, diamond-shaped one) works by similarly opening the blood vessels that lead from the heart to the lungs.
And that's where PAH creates its problems. Rare but aggressive and deadly, PAH afflicts about 100,000 people worldwide, who suffer symptoms that include difficulty breathing, dizziness and fatigue. Without treatment, they survive an average of less than three years after diagnosis.
The FDA gave Revatio priority review, basing clearance of the drug on results from a 277-patients trial that measured the exercise capability of patients after 12 weeks of treatment. Participants got 20 mg, 40 mg, or 80 mg of Revatio three times a day or placebo, and all three treatment groups showed highly significant improvements in the six-minute walk distance, which is the standard measure of efficacy in PAH trials, compared to patients on placebo.
Since researchers found no differences among the Revatio doses studied, the approved dosage is limited to 20 mg three times daily.
Patients on the drug also showed improvements in mean pulmonary artery pressure and other measures of cardiac function, and in a long-term non-placebo-controlled extension trial, and at the end of one year, walk distance remained stable, with 94 percent of patients still alive. The compound was generally well tolerated at all doses, and the most common side effects included headache, dyspepsia, flushing, epistaxis (nosebleed) and insomnia.
As the first oral treatment for PAH to be approved in patients with an early stage of PAH (Tracleer, approved in November 2001 and given twice a day at 125 mg, is indicated for worsening PAH patients), where does that put Revatio in the landscape of emerging therapies?
A report at the start of the year by analyst Ruth Brown at Decision Resources hailed Revatio's side effect profile. Brown told BioWorld Financial Watch the drug "has the potential to challenge bosentan in less severely ill patients," and - because it's likely to be less expensive - could find a place for itself in combination with other PAH drugs. Pfizer said nothing about pricing in its disclosure of approval, but predicted the drug would be in the hands of pharmacists in July. (See BioWorld Financial Watch, April 4, 2005.)
Last week, Brown noted Revatio is "a nice alternative to using an invasive treatment," and might go well with oral Tracleer. "You can target more than one pathway and also treat more severe disease with two pills rather than move onto an injectable more quickly," she said.
Still, her report forecast the major growth in PAH drugs over the next several years will be in the endothelin receptor antagonist class, where Tracleer resides. Levels of endothelin, a blood vessel constrictor, are elevated in the plasma and lung tissue of patients with PAH. The report looked ahead to publication of long-term efficacy studies for Tracleer and the launch of two new class members - Thelin and ambrisentan.
The small molecule Thelin (sitaxsentan), from Encysive Pharmaceuticals Inc., hit its primary endpoint against PAH in February of this year, and late last month the company filed a new drug application with the FDA.
Ambrisentan, from Myogen Inc., has fared less well. The firm expects results from Phase III studies with the compound later this year, after declaring in February that results from one of its trials would be delayed six months due to difficulty finding treatment-na ve patients.
Other drugs for PAH include the widely hailed Ventavis (iloprost), an inhaled prostacyclin from CoTherix Inc. approved at the end of last year. CoTherix in-licensed the compound from Schering AG in the fall of 2003, and analysts at Piper Jaffray & Co. said Ventavis sales are expected to total about $7.5 million this year, $40 million in 2006, and $250 million in 2010. Prostacyclins are often discussed by physicians as good partners with the endothelin drugs.
The remaining available PAH therapies are more invasive and painful to administer. United Therapeutics Corp. has the prostacyclin Remodulin (treprostinil sodium), cleared in 2002 as a continuous subcutaneous infusion. Late last year, the FDA extended the Remodulin label to include an IV formulation and help the most severely ill PAH patients. Remodulin is said to be more stable and thus more convenient than GlaxoSmithKline plc's IV drug Flolan (epoprostenol).
PAH is a tricky disease. Decision Resources estimated that diagnosis rates will increase as a result of physicians' increased awareness, but the rates will remain low - less than 50 percent - in the near term, since the symptoms are so non-specific even in the later stages of the disease.
Whatever the available patient size, watch for Pfizer to gobble a significant portion, Brown said, especially in early stage patients.
"Actelion has launched Tracleer in Japan at a much higher price than we were expecting, so the company may feel challenged by the approval of Revatio" and could lose sales, Brown said, noting that "others available are already very highly priced. For products entering the marketplace post-Revatio, companies will have to look very closely at their strategies."