National Editor

In its second deal of the week, Merck & Co. Inc. tapped Swiss firm Actelion Inc. for a potential $272 million agreement to develop new classes of renin inhibitors for cardio-renal diseases.

Actelion, of Allschwil, gets $10 million up front, plus potential research, development and approval milestone payments related to the first product (plus royalties) totaling as much as $262 million. It could be in line for more if additional products from the collaboration hit the market.

Actelion's work is still in the preclinical stage, said Peter Engel, media relations spokesman for the company, and how soon Phase I might begin "depends on how lucky we are - how good the thing is." Merck and Actelion will decide together.

Under the terms, the parties will form a joint committee and initially share development costs, with Merck paying for pivotal Phase III and outcome studies, leading and funding commercialization as well. Actelion retains a worldwide option to co-promote any product resulting from the deal - with a sales force Whitehouse Station, N.J.-based Merck would pay for.

Engel said he could not be more specific about how far downstream in the development process more milestones might come, but the arrangement is said to include "substantial" royalties for Actelion if a product is approved.

Renin, a component of the renin-angiotensin system, is an enzyme that catalyzes formation of angiotensin I, which is then transformed by the angiotensin-converting enzyme to angiotensin II, which acts on specific receptors to increase blood pressure and modulate long-term processes such as arteriosclerosis and remodeling of heart and kidney.

More simply, it triggers a cascade that makes blood vessels narrow, thereby causing hypertension.

Renin inhibitors have been available for years, but they interrupt the renin-angiotensin cycle later than would be ideal, may fail over time, and, in any case, lack the convenience of once-per-day dosing, since patients often end up taking multiple drugs.

"A lot of companies have worked on developing a [better] renin inhibitor," Engel said, but bioavailability has proved problematic, often as low as 5 percent to 20 percent. "We think ours is up to 70 percent."

Merck's pipeline could use some beefing up, analysts have noted. Whether the upgraded renin inhibitors, hailed as potential blockbusters, will become a growth driver for Merck and Actelion is unclear - especially since Novartis AG, of Basel, Switzerland, has a product candidate in the same class but further along.

That drug, Aliskiren (better known as SPP100), was developed in its first stages by The Speedel Group, also of Basel, with help from Blue Bell, Pa.-based Locus Pharmaceuticals Inc.'s computational technology. Speedel in-licensed Aliskiren from Novartis in 1999 and conducted fast-track development through Phase I and Phase II. Then Novartis licensed it back.

At its "R&D Day" in New York last month, Novartis said a 650-patient study showed Aliskiren significantly reduced blood pressure in patients with essential hypertension at all doses tested and was either as good as or statistically better than irbesartan in lowering diastolic blood pressure. Irbesartan is the angiotensin II inhibitor marketed worldwide by Bristol-Myers Squibb Co. (as Avapro) and Sanofi-Synthelabo SA (as Karvea).

How serious the Aliskiren threat might be to Merck/Actelion's plans is "at the moment pretty hard to say," Engel told BioWorld Today. "The only thing we know about the Novartis drug is what they let out on R&D Day. They told us they are about to enter Phase III, but there's no head-to-head data available, so it's very hard to compare the compounds."

Novartis, which said it expects to file a new drug application for Aliskiren by the end of 2005, already has the blockbuster Diovan (valsartan), an angiotensin II antagonist for high blood pressure that sold $615 million in the third quarter of this year.

Actelion's Tracleer (bosentan), an orally available dual endothelin receptor antagonist for pulmonary arterial hypertension, sold CHF208.3 million (US$161 million) during the first nine months of 2003.

Merck's first deal of the week was with Neurogen Corp. to discover and develop pain medications that target the vanilloid receptor. Neurogen is guaranteed $42 million and could get milestone payments totaling up to $118 million if a drug is approved and sold in a single therapeutic indication. The Branford, Conn.-based company is in line for milestone payments and royalties on additional indications. (See BioWorld Today, Dec. 2, 2003.)

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