A spate of news at the start of this year regarding therapies for pulmonary arterial hypertension (PAH) threw fresh light on the disorder - and might put eventual pressure on the Swiss firm Actelion Ltd., which markets the only approved oral therapy: Tracleer (bosentan), the dual endothelin receptor antagonist given market clearance by the FDA in 2001.
Say hello, world, to Ventavis. An inhaled product for PAH from CoTherix Inc., Ventavis (iloprost) was in-licensed from Schering AG in the fall of 2003 and approved at the very end of 2004. Piper Jaffray & Co. said Ventavis sales are expected to total about $7.5 million in 2005, $40 million in 2006, and reach a peak of $250 million in 2010.
PAH is characterized by high blood pressure in the pulmonary arteries of the lungs and affects about 50,000 U.S. patients, but only about 15,000 are diagnosed and treated, which means there's plenty of room for drug newcomers, notes a recent research report by Decision Resources. The firm predicts an increase in "polypharmacy" (i.e., multi-drug) approaches.
"Physicians want to see more compounds on the market, because obviously bosentan isn't suitable for all patients," said Ruth Brown, analyst with Decision Resources. "They want to increase their armamentarium of compounds." Actelion's drug, though, is well established and will be difficult to challenge in the near term.
The cause of the disease is unknown, but PAH might result from diseases that cause a restriction of blood flow to the lungs, such as scleroderma, HIV and lupus.
Symptoms include fatigue, shortness of breath or exertion, chest pain and dizziness. If it is not treated, the median survival time could be as short as three years.
Ventavis, a prostacyclin, could provide a less-invasive alternative to current drugs in the class that are intravenously or subcutaneously delivered. Such treatments require surgical implantation of a catheter, or they lead to painful site reactions, so severe that some patients need narcotics.
In March, CoTherix launched Ventavis for PAH in patients with New York Heart Association Class III or IV symptoms. The firm also is studying the compound - which targets PAH directly because of its inhaled route of administration - in combination with Tracleer in a 60-patient Phase II study, which started in June. Physicians often talk about augmenting an endothelin with a prostacyclin, CoTherix noted, and results seem sure to draw interest.
Another PAH therapy on deck is Remodulin (treprostinil sodium), a prostacyclin from United Therapeutics Corp., which won marketing approval 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).
More would-be PAH players are lining up. Encysive Pharmaceuticals Inc. reported in mid-February that its Phase III, small-molecule endothelin blocker Thelin (sitaxsentan) met its primary endpoint against PAH.
Encysive's compound not only showed a statistically significant improvement in six-minute walk distance at the 100-mg dose, but it proved to have safety benefits, as well as a positive trend in the time to clinical worsening endpoint, compared with placebo and a control arm - Tracleer.
Thelin surpassed Tracleer numerically in terms of the six-minute workout and time to clinical worsening, while coming up with a better safety profile in terms of liver toxicity. The 246-patient trial called STRIDE-2 (Sitaxsentan To Relieve Impaired Exercise) was conducted at 55 centers around the world and gave patients one of four treatments: Thelin at 50 mg or 100 mg once daily, placebo once daily, or bosentan twice daily.
The bosentan group had more clinical worsening events, totaling 15 in nine patients, as compared to five events seen in four patients on 100 mg of Thelin, to which Encysive owns all rights. There were seven events in Thelin's 50-mg group and 13 events in the placebo group. Liver trouble arose in 3 percent of patients in Thelin's 100-mg group, 5 percent in the 50-mg group, 11 percent in the bosentan group and 6 percent in the placebo group.
If there's a drawback to Thelin, it's that the drug inhibits metabolism of the blood thinner warfarin. When the two are co-administered, warfarin dosage must go down. Tracleer also interacts with warfarin, however, and calls for an increased dose of the blood thinner.
Punk, Ziegel & Co. estimated Thelin could pull down U.S. sales of $200 million-plus by 2010, or worldwide sales of $365 million, based on a conservative market of about 50,000 people each in the U.S. and in Europe.
Not doing as well in its race for a PAH drug was Myogen Inc., which is dealing with a six-month delay in enrolling its Phase III trials with ambrisentan, because of problems finding the right patients.
The work of recruiting patients began in January 2004 for Myogen's pair of 186-patient studies with the Type A selective endothelin receptor antagonist. The ARIES-2 trial, being conducted in Europe and South America, remains on schedule, with enrollment to be completed in the middle of the year and results available around the end of 2005. But enrollment in ARIES-1 met a slowdown because of a decline in available treatment-na ve patients. Enrollment probably won't finish until the end of the year, with data six months later.
Her firm was "bearish" on ambrisentan, Brown said.
"The Myogen compound is very interesting, because it's been shown not to have a warfarin interaction," she said. "We haven't seen any large-scale trials for it yet, but it has a good side effect profile."
Another contender coming down the pike is Pfizer Inc.'s sildenafil citrate, now sold as the blockbuster erectile dysfunction drug Viagra. The PAH drug version, brand named Revatio, has been submitted to the FDA - which has granted expedited review - and to regulatory authorities in Canada, the Netherlands and Spain, as well as the European Medicines Agency.
The Revatio dosing regimen is different from that for Viagra, and, to avoid confusion, Revatio tablets will have a color and shape different from those of Viagra tablets, Pfizer has said.
"I do think that sildenafil has the potential to challenge bosentan in less severely ill patients," Brown told BioWorld Financial Watch, pointing to the drug's already proven side effect profile. Sildenafil also might be used in combination with other PAH drugs, since it's less expensive.
The Decision Resources report predicted that, "of all the drug classes used to treat PAH, the [endothelin-receptor antagonist] class will experience the greatest sales growth" over the next several years.
"Factors fueling this growth will be the publication of long-term efficacy studies for [Tracleer], the expected launch of two new class members [Thelin and ambrisentan], and the long-awaited approval of [Tracleer] in Japan in 2005."
In the endothelin class, Brown projected ambrisentan's launch in 2008, with Thelin ahead of it in 2006.
"We've got Actelion losing patient share by 2013 [with Tracleer]," she said. Until then, despite a market surely to widen, "these agents are going to have a tough time competing."