The Highs and Lows in Cholesterol

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Every cholesterol drug marketer remembers where they were when the titanic news first broke of the sinking of Pfizer's torcetrapib heart drug. It was the first Saturday evening in December when CEO Jeffrey Kindler announced the firm had pulled the plug due to a surprising number of deaths in the clinical trial. The failure of the HDL-raiser crushed hopes that torcetrapib could replicate the success of Lipitor, the world's best-selling drug. Some claim they saw it coming. Others admitted disbelief. But what about Pfizer's rivals? A cynic may have expected them to rejoice at the news—tactless as it may sound.

Not AstraZeneca's Mike Tilton. As VP cardiovascular, Tilton oversees the US marketing of Crestor, now Pfizer's biggest statin rival with global sales skyrocketing to more than $2 billion last year. But rather than basque in the failure of torcetrapib, Tilton describes it as “a blow” to consumers. “I'm totally committed to patient health,” he says. “Any time something seems so promising and can't be made available to patients who need it most, it's a bit of a disappointment.”
Indeed, a group of thought leaders and physicians believe drugs that boost HDL cholesterol are going to provide additional clinical benefit to patients. Questions remain as to what is the best mechanism for doing that and to what degree.

“What has transpired with torcetrapib thus far makes those more significant questions,” said Deutsche Bank analyst Barbara Ryan. “I don't think we know.” Physicians and analysts expect some answers this month as results are revealed from studies using ultrasound imaging to determine whether the deaths associated with torcetrapib were due to an isolated toxicity or a defect involving all CETP  inhibitors.

While raising HDL, or good cholesterol, holds promise, current therapies do a pretty good job lowering LDL, or bad cholesterol. The major branded cholesterol drugs compete on LDL-lowering ability.

Lipitor (atorvastatin) had global sales of $12.9 billion last year, a 6% rise from 2005, Pfizer said, but the drug is set to go generic as early as 2010 and already is feeling heat from multiple entries of generic Zocor (simvastatin) as well as fierce branded competition from AstraZeneca's Crestor and Merck/Schering-Plough's Vytorin, both of which are growing much faster (Fig. 2).

Pfizer's Ian Read, president, worldwide pharmaceutical operations, said recently that Lipitor this year will hone its sales message to emphasize more aggressive cholesterol targets. The new message stresses a 50% reduction of LDL with a 40 mg. starting dose, a higher starting dose than the company previously discussed. “Higher doses of statins are needed to reach new treatment guidelines,” Read said.

But the fact that Pfizer is stressing potency is a tip of the hat to Crestor, which touts 52% LDL lowering plus an increase of HDL by 14%. That's with a recommended starting dose of only 10 mg. Crestor's LDL potency shoots up to 70% when paired with another drug that blocks cholesterol absorption, Zetia (ezetimibe) from MSP.

While Crestor edges out Lipitor for LDL lowering, the brand still has its work cut out on the efficacy and safety fronts. Crestor has not been determined to prevent heart attacks or strokes; Lipitor has. Last March AstraZeneca released data from a two-year imaging study in 500 patients that showed regression of atherosclerosis. And several outcomes studies are under way to investigate its effect on reducing CV morbidity and mortality.

In the past, safety has been a sensitive topic for Crestor. Tilton says results of two 2006 post-marketing studies of 20,000 patients apiece have “laid to rest” those worries. Yet toxicity concerns plagued the drug in 2005. The FDA, after conducting its own analysis, said it does not appear that risk for serious muscle toxicity is greater with Crestor than with other marketed statins but revised the label to address the risk.

Seeking to turn potency back into a strength, AstraZeneca in 2005 repositioned Crestor to focus on a broad range of high-risk patients—those with two or more risk factors for a cardiovascular event. The new positioning followed the National Cholesterol Education Program's 2004 statement (not a guideline) that those at very high cardiovascular risk “consider” an LDL-C less than 70 mg./dl. Prior to that, the panel had recommended those with established vascular disease or type II diabetes to aim for below 100. “Crestor's profile fit that well,” resonating with cardiologists who in turn exerted a strong impact on primary care physicians, says Tilton.

AZ's strategy really turned a corner when new generic versions of Merck's Zocor and Bristol-Myers Squibb's Pravachol (pravastatin) became available last year. Thanks to discount generic programs of retailers like Kmart, generics are making statins even more accessible, but Crestor doesn't see that as a threat.

“You've seen managed care embrace that value proposition by saying, ‘Put [mild-to-moderate patients who can't get to goal] on generics and, if they need more aggressive therapy, Crestor can be made available,'” says Tilton. “We totally embrace generics, and that's been a big commercial differentiation between Crestor and the other branded statins.”

On the patient front, last year AstraZeneca laid out $165.5 million on Crestor TV, print and radio promotion through November, outspending rivals MSP and Pfizer by 30%, according to Nielsen Monitor-Plus. Tilton predicts the same spend level this year. Our current promotional campaign has been effective,” he says, calling Saatchi & Saatchi Consumer Healthcare's DTC campaign “one of the most responsible” ever. “We didn't bury the side effects.”

Those tactics have had a tremendous impact on US sales, which surged to $1.06 billion last year, a 56% rise over 2005, according to Verispan. That's the best performance of any monotherapy statin. Crestor also led branded statins in new prescription market share as of December. Tilton sees growth potential in targeting those that need very aggressive LDL reduction. “Thirty percent of all patients on statins don't attain the LDL goal agreed upon by their physician,” he says. “There's a huge unmet need out there.”

Combination pills offer yet another treatment option, apparently a very popular one. Vytorin sales are rising quicker than any cholesterol drug. Last year worldwide sales boomed 90% vs. 2005 to $1.96 billion ($1.47 billion US). That's well ahead of the next best-selling branded combo drug, Kos Pharmaceutical's Advicor. Advicor, which pairs niacin with Merck's off-patent statin Mevacor (lovastatin), had 2006 US sales of $121.5 million.

Launched in 2004, Vytorin is the newest of the big three cholesterol drugs. Its two active ingredients inhibit lipid production in the liver (Zocor) and absorption in the small intestine (Zetia). Creative has played off the theme of dual inhibition of cholesterol “from food and family” in consumer ads from DDB Worldwide. The brand spent $128.7 million through November 2006 on DTC media, a 26% rise vs. the same period in 2005.

As a standalone product, Zetia is also more than holding its own. According to MSP, that's a function of each drug's distinct segment: Vytorin offers 52% LDL-C reduction from the start (10/20-mg dose) and is often used as a monotherapy for patients who can't get cholesterol down through lifestyle changes. Zetia has found a home as an add-on therapy for additional LDL-lowering, a more effective tack than titrating a statin.

While these clinical benefits are impressive, scientists say it gets even better—25-35% better. That's the amount of gain in HDL people can expect with niacin, a type of B vitamin. Figure the average LDL decrease via statins equals 30-40%, and you have a net 70% cardiovascular risk reduction. That straight-line relationship between the sum of HDL-raising, the change in LDL and cardio risk reduction was noted in a recent meta-analysis by Greg Brown, MD, a cardiologist at the University of Washington in Seattle. “That data are incredibly compelling,” Brown says.

A study published in the Journal of the American Medical Association last month raised the level of interest in HDL therapy further by showing that patients who took statins and had small changes in good cholesterol ended up with less arterial plaque.

Some of the most dramatic results in raising HDL—26% in patients with low HDL—have been seen with Niaspan, an extended-release version of niacin launched in 1997. (The only other FDA-approved Rx niacin is an immediate-release form called Niacor, from Upsher-Smith.) Sold by Kos, Niaspan had $473.8 million in US sales in 2006, a 24% increase over the year-prior period (Fig. 3). The growth was “due to growing recognition that raising good cholesterol is an important part of managing heart health and decreasing [cardiovascular disease] risk,” said a spokesperson for Abbott Labs, which last year entered a deal to buy Kos for $3.7 billion and with it Niaspan and Advicor.

Brown is leading a federal study of Niaspan plus Zocor to test the benefit of add-on niacin therapy. Despite the fiasco with torcetrapib, he and others say that a statin combined with a drug that raises HDL would mark a significant advance. (Pfizer had planned to sell Lipitor with torcetrapib in a single pill.) “The real question,” says Brown, “is when the NCEP panel will recommend raising HDL.” If it does, marketers of these drugs could be well positioned. Merck is also betting on niacin-based therapy, testing an extended-release niacin combined with a prostaglandin blocker—MK-524A—aimed at reducing flushing, the only side effect of niacin (Fig. 4). Merck said it expects MK-524A can be used with any statin. But there are uncertainties with niacin, namely whether flushing will limit sales. “Doctors have a difficult time getting patients to take 2 grams of niacin,” Ryan says. “Reducing the incidence and severity of the flushing a significant advance.”

That speaks to the potential of a more tolerable form of niacin. Lehman Bros. analyst Tony Butler said MK-524A, which may reach the market in 2008, could earn between $800 million and $1 billion “or substantially more, if the clinical outcome suggests a mortality benefit.” Kos also says it's working on a modified form to prevent flushing. A study published last month showed that patients who took aspirin 30 minutes before Niaspan had improved tolerance. Fenofibrate, the active ingredient in Abbott's TriCor, also raises HDL. AstraZeneca and Abbott are testing a Crestor-Tricor combo that addresses patients who have low HDL and elevated LDL and triglycerides, as well as another pill coupling Crestor with Abbott's next-generation fenofibrate. The firms expect to decide which of the two to bring to market by 2009 and to file for approval the same year.

There are other promising mechanisms for raising HDL-C. One is intravenous infusion of recombinant HDL. In animal models, this experimental treatment has been shown to dramatically inhibit artheroscerlosis progression. A compound is with Pfizer, and human studies are being planned. Another molecular treatment on the horizon involves using an orally effective peptide designed to mimic apolipoprotein A-I, the major protein component of HDL. Novartis has the peptide, code named D-4F, and it's said to have gone through a phase I study, with the company planning phase II studies in humans.

But the experimental lipid therapy generating the most buzz these days is CETP inhibition. No one knows for sure whether the CETP mechanism of raising HDL is viable, but imaging trials to be read in March at the American College of Cardiology meeting should offer an indication. (Fig. 5) If torcetrapib reduces atherosclerosis, that could “breathe a small ray of hope” that this mechanism works, says Brown. Worsening atherosclerosis, combined with the deaths seen in the trial canceled by Pfizer, would suggest worsening clinical outcomes, prompting other companies like Merck, Roche, Bayer and Pfizer to take a hard look at their CETP programs. Companies trying to get such a drug approved would be forced to show favorable clinical outcomes first. That means a trial lasting five to 10 years and involving 10,000-20,000 patients. What's more, if the imaging studies are positive, it would imply a disconnect between imaging and clinical outcomes, possibly hurting the imaging industry. “Then the imaging trials will no longer be accepted by the FDA for approval of a new class of drugs,” Brown explains.

“Either way, it's going to be a bombshell,” says Prediman Shah, MD, a cholesterol expert at Cedars Sinai Medical Center, of the impending results. “But it doesn't in any way negate the HDL hypothesis.” HDL therapies “look quite bright…This will be the new frontier in lipid-modifying therapies. There's only so much you can get from LDL lowering.” He doesn't expect that new frontier to come through CETP inhibition. Shah says it's unlikely that the deaths seen in Pfizer's abandoned ILLUMINATE trial were due to the agent's slight blood-pressure effect. “Something else is going on”—perhaps that inhibition of CETP may lead to a kind of dysfunctional HDL that may not do its job of carrying plaque away from the arterial wall.

The Cleveland Clinic Foundation's Steven Nissen, MD, who is leading an intravascular ultrasound (IVUS) study on torcetrapib, declined to comment for this story. “Since I am the only individual with unrestricted access to all of the data, it would not be appropriate,” Nissen told MM&M by e-mail. “In addition, I'm not eager to occupy the Martha Stewart memorial jail cell.” The comparison with Stewart, the domestic diva convicted of insider stock trading, is not a bad one; the upcoming studies are expected to jolt the investment community.

Certainly the December report from Pfizer was a shock. Should more negative news be in store, “it's a sad thing for our patients,” said Shah. “But, unfortunately, many good ideas get killed by ugly facts.”

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