Earlier this month, the spotlight shone brightly on what's been a rather quiet race for renin inhibitors against high blood pressure, when Merck & Co. Inc. entered a deal with the Swiss firm Actelion Inc. to develop drugs for blocking the enzyme as a way of treating cardiorenal diseases.

And what a deal. Though Actelion has its program only in the preclinical stage, Merck forked over $10 million up front and promised as much as $262 million more in milestone payments related to development and approval of the first product (plus royalties, which analysts have estimated in the 13 percent to 15 percent range).

Not only is Merck paying for a pivotal Phase III and outcome studies as part of the deal, but also Actelion keeps a worldwide option to co-promote the resulting product, with a sales force Merck will pay for. Until then, a joint committee is overseeing the work and the two companies are sharing development costs.

Why would Merck sink big money into such an early stage project - one that might not reach the market for another seven to 10 years - especially when Novartis AG has a renin inhibitor nearing Phase III trials that already has demonstrated efficacy in a study with 650 patients?

"Merck has a lot of cash, and the price of deals has gone up," said Timothy Anderson, analyst with the Prudential Equity Group. "You price what the market will bear."

Other analysts have grumbled about Merck's pipeline, but Anderson noted Merck has six drugs in Phase III trials, "so it's not exactly empty, like some companies."

He said the mainstream press "keeps beating up on Merck" and "certain publications seem to have it in" for the company. "People have jumped on the bandwagon," he said, acknowledging four recent clinical failures the company has recorded.

At a briefing last week, Merck offered the happy news that its human papillomavirus vaccine could be the subject of a regulatory filing as early as the second half of 2005, earlier than analysts had been predicting. That would be just in time, or almost, to offset the loss due when the company's cholesterol-reducing drug Zocor (simvastatin) goes off patent, which will happen the following year. Merck recently estimated 2004 sales of Zocor at $5.1 billion.

The company also has Arcoxia (etoricoxib) for chronic low-back pain, approved outside the U.S. and expected to be the subject of a new drug application filing with the FDA by the end of the year. Still, in October, less-than-stellar earnings prompted the pharmaceutical giant to change its "cost structure" and reduce its work force by 4,400 positions. Analysts have said they would like to see more in Merck's basket of drug candidates, and the HPV vaccine's progress is likely to improve perceptions.

"That could be the monster," Anderson said.

Multiple Drugs Still Likely, Analyst Says

In November, the FDA accepted the filing of an NDA for a Zocor/Zetia tablet for lowering cholesterol. The drug combines Zocor, which reduces production of cholesterol in the liver, with Zetia (ezetimibe), which inhibits cholesterol absorption. The NDA was submitted by Merck/Schering-Plough Pharmaceuticals, a joint venture between Merck and Schering-Plough Corp.

Anthony Butler, analyst with Lehman Brothers, said early stage deals such as the one with Actelion are worthy, even if they don't build the pipeline near term.

"You're talking about enriching your portfolio in 2009 and 2010," he said.

The main, and obvious, reason for the Actelion deal is the opportunity. Market research firm Datamonitor forecasts sales for antihypertensive drugs will grow to about $52 billion by 2007.

Anderson noted that hypertension is "a huge category. If those [Actelion] mechanisms were to have competitive profiles, they could easily be billion-dollar-plus products," even if none turn out to be single agents.

"The trend is to use multiple drugs on top of each other," he said. "You'll still use diuretics and calcium channel blockers [with renin inhibitors]," but angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers may be replaced.

If, as Actelion claims, its once-per-day renin inhibitor has bioavailability superior to the drug being developed by Novartis, the wait through developmental stages will be more than worthwhile for Actelion and Merck, not to mention hypertensive patients.

Renin is secreted by the kidney in response to various cardiovascular events - lowered blood pressure, reduced plasma volume, sodium depletion - and boosts the conversion of angiotensinogen to angiotensin I, which is then changed into angiotensin II. As the cascade goes on, aldosterone levels jump, which increases peripheral vascular resistance and blood pressure.

Drugs to break up the renin-angiotensin cycle have been around for years, but they work later in the process than is ideal, carry unpleasant side effects and might fail to get the job done over time. Many patients end up taking several drugs to control blood pressure.

Angiotensin II antagonists such as Novartis' blockbuster Diovan (valsartan), which sold $615 million in the third quarter of this year, are getting more attention as a step beyond the traditional treatments cited by Anderson: inhibitors of ACE (which transforms angiotensin I to angiotensin II), beta blockers, calcium channel blockers, alpha-blockers and diuretics.

Actelion already is in the blood-pressure game, too. 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. Approval in Japan is expected by the end of this year but could be delayed until early 2003.

No Faith' In Preclinical Animal Data

Renin inhibitors to stop the hypertensive cascade at the place where it begins might be the answer for a patient population whose dangerous condition long has been difficult to attack. Which renin inhibitor will prove better, though, is still up in the air.

Novartis isn't saying much about its drug, called Aliskiren (or SPP100), except that it boasts improved availability and, in the 650-patient trial, significantly reduced blood pressure in patients with essential hypertension at all doses tested - proving 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).

Aliskiren was developed in its first stages by The Speedel Group, also Switzerland-based, with help from Locus Pharmaceuticals Inc. Speedel had in-licensed Aliskiren from Novartis in 1999 and pursued fast-track development through Phase I and Phase II trials, after which Novartis licensed it back. Novartis plans to file a new drug application for Aliskiren by the end of 2005.

Actelion has been less shy, boasting 70 percent absorption rates, compared to bioavailability between 5 percent and 20 percent of other hypertensive drugs (typically peptide mimetics, unlike Actelion's compounds). Even taking into account that the 70 percent result was gained in rats, with their higher-than-humans metabolism, Merck found the result promising.

Butler is not convinced. "I'm never clear what [animal data] mean at all," he said. "I don't have any faith in it until you get the first pass in somebody's stomach."

Actelion's first four orally active, nonpeptide renin inhibitors are known as Act-A, Act-B, Act-C and Act-D. They're being studied for renal failure, heart failure and hypertension. Preclinical experiments showed they work about as well as Diovan in lowering blood pressure and last longer. It's up to the Merck/Actelion panel to decide which compound advances first.

"Even if Novartis is first to the market and they really have a drug, it's not unfair to say the future market could get split" if an Actelion/Merck compound wins approval later, Butler said.

Anderson agreed. "Looking at this class of drugs, if you came out with a novel mechanism with enough promotion behind it, I think it could be a pretty interesting product," he said.