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Last week s new deal between Aradigm Corp. and existing partner United Therapeutics Corp. through its wholly owned subsidiary Lung Rx Inc. to develop Remodulin (treprostinil) using the former s AERx Essence approach could provide the needed boost to put prostacyclins at the forefront of pulmonary arterial hypertension therapy (PAH), thanks to the metered-dose inhaler.

As an indication, PAH is undeniably hot. The latest landscape-changing news came in June when just as the FDA cleared Gilead Sciences Inc. s Letairis (ambrisentan), an oral endothelin receptor antagonist for PAH Encysive Pharmaceuticals Inc. made public another approvable letter from the agency regarding Thelin (sitaxsentan). (See BioWorld Financial Watch, June 25, 2007.)

Under the terms of the just-made Aradigm/Lung Rx arrangement, centered on AERx s palm-sized inhaler that delivers medications in two to four breaths, Aradigm gets an up front fee of $440,000, followed by another payment in the same amount four months down the road.

Aradigm will pay for and conduct a bridging trial that compares AERx to the bulkier OptiNeb nebulizer about the size of a large can of stewed tomatoes, notes analyst Andrew Fein, of Unterberg, Towbin that is used in the ongoing Phase III TRIUMPH-1 (Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension) study.

When the bridging trial is finished next year, Aradigm gets license fees that are expected to be paid within three years of signing the agreement, totaling up to $9.65 million. As part of the deal, Lung Rx also will buy $3.47 million of Aradigm stock at the average closing price for the 30-day period ahead of specified events, and would be responsible for costs to commercialize and make treprostinil with AERx.

Lung Rx parent UTC already had a pact with Aradigm to come up with a liposomal-based inhaled version of Remodulin that might work with AERx, a technology licensed to Novo Nordisk A/S for diabetes and undergoing Phase III trials in that indication. Remodulin, a tricyclic benzidine analog of epoprostenol, is approved for intravenous and subcutaneous use in PAH.

Last June, UTC entered a deal to develop oral treprostinil with Supernus Pharmaceuticals Inc., as the firm continues its bid to wean doctors off prescribing GlaxoSmithKline plc s prostacyclin Flolan (epoprostenol) haunted, like Remodulin, by risk of Gram-negative sepsis.

Coming up with an easy-to-use, portable, inhaled version of Remodulin could be the ticket for UTC or half a ticket. Look at Exubera, Pfizer Inc. s inhaled insulin, developed by Nektar Therapeutics Inc. and cleared at the start of last year. Once hailed as a potential blockbuster, Exubera so far has proven a bust instead. Pfizer has not disclosed sales numbers, but Nektar CEO Howard Robin, in a conference call with investors, said Exubera s launch was one of the worst ever and Pfizer s team has done poorly with the product.

Could this bode ill for inhaled Remodulin? Stephen Dunn, analyst with Dawson James, said Remodulin s long-term promise lies elsewhere. Inhaled is the bridge between IV and oral, he told BioWorld Financial Watch.

A new delivery route would come none too soon, given the sepsis issue with the IV version and another threat: a potential generic form of Flolan that could grab more market share. Making that drug, which involves a complicated synthesis process, would challenge any generic firm, but the rewards could be deemed worthwhile.

Tricky to diagnose, PAH comes in two forms. Primary PAH is rare and the cause is unknown. The more common secondary PAH often derives from such conditions as emphysema, bronchitis, or congenital heart disease.

Though the AERx bridging trial will take longer, many analysts expect top-line data from the pivotal TRIUMPH-1 study by the end of the year, and recently installed UTC management is guiding Wall Street to a new drug application filing as early as the second quarter of next year, with a filing in Europe to follow, possibly as soon as the fourth quarter of 2008.

UTC likely will be cleaning up the TRIUMPH-1 data in hopes of making the American Heart Association meeting in early November, and could hit the mark. Witness Myogen Inc. (bought by Gilead Sciences Inc. for $2.5 billion) with its PAH drug Letairis (ambrisentan), an oral endothelin receptor antagonist approved in June. The firm released tidy top-line data in about 10 weeks after the final patients went through the ARIES-1 and ARIES-2 trials, and UTC s electronic data collection system could provide an edge, allowing the company to present results at the important AHA event.

TRIUMPH-1 completed enrollment in mid-July, listing 235 patients with a dropout rate of about 6 percent, significantly below the 10 percent rate assumed when the study was designed. Investors are hopeful, though some are less sanguine about the chances for the oral form of Remodulin, undergoing Phase III trials under the name Freedom.

Near the start of last month, 115 of the targeted 300 patients had been enrolled in the combination arm testing Remodulin as an addition to background therapy with Tracleer (bosentan), the endothelin receptor antagonist from Actelion Ltd., and 62 of the planned 150 patients had been signed up for the twice daily monotherapy arm. Getting enough oral prostacyclin into a patient without causing side-effect trouble might prove daunting, but investors could know more by the end of this year, with an interim peek at data due when 150 are enrolled in the combo arm and 90 are signed up for the monotherapy arm.

Overall, investors have cause for fewer jitters about the once-iffy UTC, at least for now. The firm handily beat second-quarter earnings estimates, reporting $51.8 million in revenues, compared to the consensus number of $43.2 million, although fully diluted earnings per share came in at 26 cents, fully 10 cents below consensus, because of expenses. Research and development topped out at $18 million, due to the TRIUMPH-1 and Freedom trials.

Lung Rx, gearing up for a possible launch of inhaled Remodulin, is hiring 25 salespeople who also will sell the subcutaneous version (usage of which makes up about half of all prescriptions), probably in an effort to get even more physicians accustomed to the idea of trying prostacyclins. n