Back to Nature: Prescription Dietary Supplements Cash in on Cholesterol R&D Setbacks

Between big-name statins going generic and high-profile blow-ups like torcetrapib, Cordaptive and Vytorin, cholesterol drug development has been tough going. Some drug companies think the next big thing in lipid management is something different altogether: prescription-grade supplements. It may be just the thing for a risk-averse FDA.

Between big-name statins going generic and high-profile blow-ups, cholesterol drug development has been tough going. Some drug companies think the next big thing in lipid management is something different altogether: prescription-grade supplements. It may be just the thing for a risk-averse FDA.

By Kate Rawson

Twenty years ago, Merck & Co. Inc.’s lovastatin (Mevacor) ushered in a new era of cholesterol management and launched the largest blockbuster class in the history of the pharmaceutical industry.

In hindsight, though, the Food & Drug Administration’s decision to approve lovastatin for prescription marketing might not have been the most important regulatory action it took on the product. That may have come 10 years later, when FDA blocked the marketing of red yeast rice dietary supplements that contained lovastatin—even though they’d been available for decades before Merck ever entered the picture.

For all its landmark status as a blockbuster of the golden age of Big Pharma, lovastatin has humble roots. The chemical itself was isolated from a fungus and naturally occurs in some yeast products. There is certainly nothing unusual about that: The pharma industry is built on synthetic forms of naturally derived products.

But lovastatin seemed to herald a new era, one where the biological target—in this case, the HMG CoA reductase enzyme—would drive development, not brute force and serendipity.

Now that lovastatin and its successors are going off-patent, it is abundantly clear that things didn’t work out that way. Twenty years after Mevacor, who would have guessed that the most successful attempts would come not from companies that tried to copy the mechanism-of-action based development strategy, but rather from companies that opted to launch branded dietary supplements?

But that’s exactly where industry finds itself these days. Between niacin (a focus of recent cardiovascular drug development) and fish oil (for which GlaxoSmithKline PLC paid $1.65 billion as part of the Reliant Pharmaceuticals Inc. acquisition), supplements are all the rage in lipid-lowering R&D.

That’s not to say there isn’t pipeline activity around novel drugs. The launch of Merck and Schering-Plough Corp.’s ezetimibe (Zetia) marked a new class in lipid management. Merck and Roche continue to tout the promise of cholesterol ester transfer protein inhibitors as the next big thing to raise levels of "good" cholesterol, or HDL. And there’s plenty deeper in the pipeline addressing other novel targets. (Also see "Merck's Cordaptive: Just Another Cholesterol Combo, or More?" - In Vivo, 1 Apr, 2008.)

But there also have been high-profile setbacks: the Vytorin ENHANCE data cast a dark cloud over ezetimibe, prompting questions as to whether its efficacy is any better than generic simvastatin alone. And excitement around CETP inhibitors has certainly cooled since Pfizer Inc.’s torcetrapib blow-up. (Also see "Abbott Rides High After Torcetrapib Collapse: Is Everything Old New Again?" - Pink Sheet, 1 Dec, 2006.)

At least for now, supplements are hot in cholesterol R&D. After the torcetrapib disaster, investors rewarded Abbott Laboratories Inc. for its prescient acquisition of extended-release niacin (Niaspan) via Kos Pharmaceuticals Inc. And GSK is crowing about the prospects for its prescription omega-3 brand Lovaza. (Also see "The Unsung Vytorin Victim: Primary-Care Marketing" - Pink Sheet, 1 Feb, 2008.)

Zetia and Vytorin may be redeemed once data from Merck and Schering’s outcomes study IMPROVE-IT are released in 2010. But for now, the Vytorin experience demonstrates the difficulty in improving upon statins as lipid management.

Is LDL Still a Valid Surrogate?

And for cholesterol drug developers, ENHANCE had an even more ominous finding: the data seemed to support a long-standing suspicion that lower levels of LDL cholesterol don’t translate into better health outcomes. In addition to the potential loss of a very effective marketing message, it also complicates cholesterol drug development: If LDL isn’t the surrogate marker, what is?

Publicly, FDA is standing by LDL cholesterol as a surrogate endpoint for heart disease, at least for now. "It would be premature to embark on any systematic change in how we approve lipid-lowering drugs," Office of New Drugs director John Jenkins said at the time the ENHANCE data were released. FDA, he added, has a "long track record" of success in basing approvals on LDL.

But there are signs that the agency is sending a somewhat different message to individual drug sponsors. Genzyme Corp. and Ionis Pharmaceuticals Inc. got word that while LDL lowering is still a suitable endpoint for their Phase III injectable cholesterol drug mipomersen, they’ll need outcomes data to support the broader of two planned indications. (Also see "Genzyme/Isis: Has ENHANCE Dulled Mipomersen's Prospects?" - In Vivo, 1 Feb, 2008.)

Genzyme and Isis aren’t the only companies running into post-ENHANCE roadblocks at FDA. According to an individual who represents drug companies at the agency, high-level FDA officials have advised at least one other sponsor that outcomes data will be needed to support an LDL-lowering endpoint.

That subtle change is indicative of other roadblocks with cardiovascular surrogate endpoints. Between LDL cholesterol, blood sugar levels and blood pressure, "every traditional surrogate endpoint has been blown up," Nissen asserts. And as a result, cardiovascular R&D "has become a lot more complex."

The Trouble with Cordaptive

One sure sign that cardiovascular R&D is becoming more complex is Merck’s experience with Cordaptive.

At first glance, Cordaptive seemed to have a risk-benefit profile that would sail through FDA: Niacin’s long track-record, free of significant safety issues, plus laropiprant’s (theoretically) highly targeted anti-flushing action, were reasons that Merck was confident of a green light. (Also see "CMS' Change of Heart: Niaspan will be Covered Under Medicare Part D" - Pink Sheet, 1 May, 2006.)

Nevertheless, given the high-profile failure of Pfizer’s HDL-targeting CETP inhibitor torcetrapib in late 2006, niacin remains the most effective available drug for raising HDL cholesterol.

The snag with niacin is flushing, a dilation of blood vessels near the skin, accompanied by reddening flesh and uncomfortable tingling sensations. And that, according to Merck, isn’t just a bearable inconvenience: it’s the main reason that fewer than a quarter of patients stay on niacin for a year or more.

Given niacin’s well-known profile, it’s tempting to assume that laropiprant, as the novel half of Cordaptive, is the culprit. Nissen speculates that it is a safety issue related to laropiprant’s mechanism of action as a selective antagonist of the prostaglandin D2 receptor. Prostaglandins (albeit different ones) are also the target of COX-2 inhibitors, which have also had their share of safety concerns, Nissen points out.

Laropiprant acts on the final step in the flushing pathway, thus theoretically reducing the chances of any unwanted additional effects, according to John Paolini, MD, PhD, senior director for Merck’s cardiovascular clinical research.

At the recent American College of Cardiology meeting in Chicago, Merck released Phase III results from a 1,455-patient trial showing significantly fewer flushing events among patients taking Cordaptive versus Niaspan. Based on data from a pooled population of almost 5,000 patients treated for up to one year, Merck boldly ventured that Cordaptive’s safety profile is "similar to that of extended release Niaspan."

But "similar" proved to be not good enough, particularly when you’re tampering with a side effect that, if uncomfortable, is hardly fatal. FDA is treating those kinds of products differently these days—while no formal guidance is in effect, the agency has raised the bar for me-too products for symptomatic treatment. (Also see "Nervous Times for NDA Sponsors: The New Reality of FDA Drug Reviews" - Pink Sheet, 1 Apr, 2007.)

And given the theoretical risk with any new molecule, perhaps the better way to address niacin’s flushing side effect would be to better manage niacin, rather than deal with the unknowns of a novel drug. According to Nissen, 90% of his patients can tolerate niacin, so long as they start with a low dose and slowly titrate to higher doses. Indeed, many patients can tolerate up to 2,500 mg per day "without unacceptable side effects."

Merck isn’t giving up on Cordaptive. "This particular product is critically important," CEO Richard Clark told Morgan Stanley’s "unplugged" conference May 1. "It gives physicians the ability to face the lipid management issues that their patients face in a completely different way. And niacin is approved to be able to do that. And with our product, it’s at higher doses."

The Power of Niacin

Not all companies see niacin as a wonder drug that is perfectly suited for combination therapy.

Start with Merck’s cholesterol partner, Schering-Plough. During Schering’s first quarter conference call April 23—which was held a few days before Cordaptive’s user fee date and subsequent "non-approvable" letter—the company was asked by investors what impact the niacin/laropiprant combination might have on Vytorin and Zetia.

The answer? Not much, according to Schering global pharmaceuticals president Carrie Cox. "While the niacin component is certainly an interesting one in the marketplace, those products do tend to be relatively niche because of the difficulty patients have with flushing and side effects in taking the niacin compound."

"They can be important options to add to overall therapy, but the niacin portion of the market is unlikely to become a major portion of the overall cholesterol management market," Cox said.

While FDA is keeping Cordaptive on the sidelines, Abbott would dispute Schering’s dismissal of niacin. Abbott’s stock is up 50% since the Kos acquisition, and first quarter 2008 sales for Niaspan were up more than 24%. At $650 million in annual sales, Niaspan isn’t a bona fide blockbuster—yet. But it’s not a mere "niche" product, either.

GSK Loves Lovaza

The same goes for GSK’s omega-3 supplement, marketed as Lovaza, which the company is increasingly highlighting as a perfect antidote to its own drug-safety woes.

During the company’s fourth quarter earnings call, J.P. Garnier (who retired as CEO May 22) singled out the prescription-grade supplement as a product to watch. "I think it’s a sleeper," he told investors. "This is a product that is going to do well."

GSK has a lot riding on Lovaza’s success. Lovaza was the highlight of the company’s $1.65 billion acquisition of Reliant Pharmaceuticals [See Deal] in November 2007—a price tag four times Reliant’s annual sales. GSK called Lovaza a "new driver of sales growth" for the US business, and a "strong strategic fit" with the rest of the company’s cardiovascular franchise, including the hypertension drug carvedilol (Coreg CR).

The deal was also a lifesaver for Reliant Pharmaceuticals, which had hoped to raise money—albeit significantly less—through an initial public offering filed a few months before. Reliant had tested the IPO waters earlier but withdrew the filing due to unfavorable market conditions; the company’s second attempt was hoped to raise $270 million—a fraction of GSK’s purchase price.

Was Lovaza worth $1.65 billion? According to GSK, so far, the answer is yes. Garnier told investors in February that Lovaza sales are on a "spectacular" track, with an uptake similar to that of TriCor, a $1.2 billion drug.

Lovaza certainly has a long way to go, but is expected to ring up $500 million in sales this year. First quarter sales were $100 million, up 72%, helped in large part by a tripling of the sales representatives on the product to 1,500. And that comes despite any loss of sales stemming from an FDA-requested name change in August 2007: Reliant changed the name from Omacor to prevent confusion with Wyeth’s Amicar.

GSK’s positioning of Lovaza is simple enough. Branding issues aside, the drug is—essentially—risk-free. "This is a product that is basically a natural product," Garnier said. "It’s the only product approved by the FDA, a product with no warnings."

And given that patients on a triglyceride product usually take an LDL-lowering agent as well, Lovaza is ideally positioned for combination therapy, Garnier said. "This is a product for people who take multiple medications. Every time you add a new pharmaceutical, you’ve got to worry...about potential interactions and side effects." While that’s a concern with Abbott’s triglyceride-lowering fenofibrate (TriCor), he said, it’s "not with Lovaza."

That is exactly the kind of low-risk, high-reward profile that developers are missing right now. It may be fish oil, but if Lovaza pays off the way GSK expects it to, expect plenty of other cholesterol drug developers to find out if there are any more fish in that sea.