United Therapeutics' recently approved pulmonary arterial hypertension drug Adcirca threatens to close in on the vast lead held by Actelion's Tracleer , though surpassing the market pioneer seems nearly impossible. Not to mention, the Swiss-based biotech has an ace up its sleeve with the expansive REVEAL patient registry.

Tracleer (bosentan), an endothelin receptor antagonist, has been marketed since 2001 for patients with moderate to severe PAH (WHO Class III-IV symptoms) and has become a $1 billion drug. Actelion raised awareness of this relatively rare disease among physicians during its early push to expand use of Tracleer; PAH was a little-talked-about disease seven years back.

But as Actelion proves how lucrative a specialist market can become, competitors have quickly jumped on the bandwagon. Many drug makers - large and small - are developing PAH drugs. EvaluatePharma estimates that the U.S. PAH market will grow 10 percent annually, and that the overall PAH market, growing at about the same rate, could reach $3.8 billion by 2014.

By that time, however, United Therapeutics may well edge ahead of Actelion in the U.S. market, with its PAH franchise comprising currently marketed Remodulin (treprostinil), soon-to-launch Adcirca (tadalafil), an inhaled form of treprostinil, Tyvaso, pending at FDA and UT-15C (sustained-release treprostinil) in the pipeline.

EvaluatePharma predicts that by 2014, United Therapeutics' combined products will have 45 percent of the U.S. market, ahead of Tracleer's projected 30 percent share (see chart: " ¹ Change Of Power: PAH Market Expects New Entrants By 2014 "). Not that Tracleer is going to stand still: that drug could reach $2.8 billion before it's expected to face generics in 2015, the data analysis group surmises.

Indeed, Tracleer has succeeding in staving off the competition so far: it has retained an undisputed lead among oral treatments, even with the introduction in 2007 of Gilead Science's Letairis (ambrisentan), also an endothelin receptor antagonist.

Lofty Plans For Adcirca

United Therapeutics' anticipated launch of its phosphodiesterase type 5 inhibitor Adcirca in August may yet prove a more formidable competitor, however.

Adcirca has a once-daily dosing benefit and, unlike Tracleer, does not require liver enzyme testing. FDA approved the oral drug in 40 mg (two 20 mg tablets) at the end of May (² Also see "FDA Approves Adcirca (Tadalafil) For PAH; United Therapeutics Ready For U.S. Launch" - Pink Sheet, 26 May, 2009.). Lilly retains marketing rights for tadalafil ex-U.S. and the Cialis brand.

Adcirca's main competitor in its class, Pfizer's Revatio (sildenafil), also does not require liver toxicity testing. Adcirca is cheaper, though, according to Deutsche Bank, which cites an annual wholesale acquisition cost of $11,096 for Adcirca versus a WAC of $15,201 for Revatio. ERAs are priced much higher, typically at more than $40,000 per year.

United Therapeutics anticipates that Adcirca will become the preferred oral treatment for PAH, given its dosing convenience. The specialty pharma has a marketing team ready for Adcirca, which it hopes to establish as a front line therapy.

That's not to say United Therapeutics does not intend the drug be used in combination; PAH often requires a varied treatment regime. Typically, physicians start patients with an oral therapy, such as an ERA, and add on another class of oral drug to better target the disease as it progresses. The most severe PAH patients then receive inhaled or subcutaneous therapy and may progress to an intravenous analog. In a call following the drug's approval, execs said Adcirca has a favorable drug-to-drug interaction profile compared to some competitors.

But gaining share is challenging for any new PAH entrant, given the reluctance of physicians to switch patients from one treatment to another in the market, said Nikhil Mehta, therapeutic area director for Decision Resources, a firm that conducts market analysis.

Reluctance to switch is one reason why Letairis has not managed to catch Tracleer in scripts, Mehta said. "But, if physicians see a new patient coming in they are more likely to prescribe Letairis," he added, noting Letairis' dosing advantage.

For now though, most patients using an ERA are using Tracleer, notwithstanding Gilead EVP of commercial operations Kevin Young's statement at a June 9 William Blair & Co. Growth Stock Conference in Chicago that "over a third of ERA-treated patients for pulmonary arterial hypertension are taking Letairis." Letairis sales were $113 million in 2008, up from $21 million year on year.

Gilead may find it has some tailwind after FDA recently relaxed its monitoring requirements for Letairis. Until recently, PAH patients taking Letairis had to be enrolled in Gilead's restricted distribution program, initially, and then re-enrolled six months later and annually thereafter. Now, labeling requires re-enrollment after the first 12 months of treatment and annually thereafter.

Meanwhile, though, Actelion has plans to broaden Tracleer's use into less severe PAH, for which it has an sNDA pending at FDA. Actelion is still finalizing its Risk Evaluation and Mitigation Strategy for Tracleer in this indication, (³ Also see "Review Decision On sNDA For Actelion’s Tracleer Awaits Finalized REMS" - Pink Sheet, 2 March, 2009.). Actelion's follow-on ERA candidate, macitentan, is another potential shield against competitors. This drug's tissue specificity could make it more potent than Tracleer and, ultimately, more effective, Kirk Taylor, Actelion U.S. medical group head, said in an interview.

REVEAL: 3,300 PAH Voices

Not all physicians are convinced by the tissue-targeting concept, though, according to analysts, who add that Tracleer will be a hard act to follow. Therefore REVEAL may prove Actelion's most effective weapon, enabling the company to be the first to lay its hands on a wide array of patient use data.

REVEAL currently collects information from 3,300 patients, though Actelion hopes to expand enrollment to 3,500 patients, Taylor said. Both patients and physicians are engaged in tracking PAH therapy. Patients registered in REVEAL can fill out case report forms, which collect, for example, a patient's demographic data, medical history, past diagnoses and diagnostic test history.

"This information allows physicians to follow a patient over a period of time, and with a large number of patients available, they can compare them," Taylor said. An external committee of global experts has been appointed to review the data.

Actelion isn't talking up REVEAL as a commercial tool, but the registry does have distinct marketing advantages. Other companies could conceivably set up similar databases, but they would need time to build the historical data. REVEAL is "important for prescribing to know what the characteristics of the PAH population are," points out Decision Resources' Mehta.

Additionally, the PAH market is relatively compact, making it easier to target specialist centers and physicians familiar with the disease, especially aided by REVEAL data.

Big Pharma Candidates In The PAH Pipe

Biotech and specialty pharmas aren't the only ones battling in PAH, however. This once-niche condition has generated growing interest from big pharma companies - most compelled to move into specialist areas anyway - that see a fruitful opportunity given high pricing potential for PAH drugs.

Bayer is developing an oral agent in Phase III studies called riociguat - a new class of therapy for PAH that stimulates the enzyme soluable guanylate cyclase (sGC). One pivotal study is evaluating the candidate in PAH and the other in Chronic Thromboembolic Pulmonary Hypertension in the U.S.

Novartis' imatinib ( Glivec ) is also in Phase II clinical trials for PAH. Imatinib works by inhibiting the activity of several tyrosine kinases, such as Bcr-Abl, c-KIT and platelet-derived growth factor receptor (PDGER), all thought to be involved in the progression of PAH. Novartis hopes to publish further results later this year.

With several candidates in development for PAH, drug makers may springboard efforts to evaluate therapies for combination use in first line treatment pairings, rather than later add-ons. This approach could more aggressively attack the disease, early on.

Drug makers have been talking up combination therapy as the next step for PAH treatment for some time, but they have yet to generate significant data on this use.

- Carlene Olsen (c.olsen@elsevier.com)

PAH Market Snapshot: Actelion’s Tracleer Faces Stiffer U.S. Competition

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