Statins: Making New Friends

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Statins will continue to dominate the lucrative cholesterol market, but new combinations may see the light of day as early as this year, with a slate of others potentially wading in over the next two to four years. Additionally, current market leaders, specifically Crestor and Vytorin, will have new opportunities to sink or swim following the patent expiry of Pfizer's billion dollar blockbuster drug, Lipitor, in 2011.

Pfizer hoped to counteract the drop-off in Lipitor sales with torcetrapib, but was forced to halt development in 2006, after mortality rates increased during clinical trials. Researchers, cholesterol marketers and analysts alike were disappointed with the news, since torcetrapib would have presented a radically new treatment for patients, and a huge commercial opportunity for manufactures. Torcetrapib, a cholesterol-ester transfer protein (CETP) inhibitor, was founded on emerging high-density lipoproteins (HDL) research suggesting that high levels of HDL (or “good cholesterol”) can assuage the risk of cardiovascular incident. Low HDL levels are considered to be a reliable indicator of increased risk. 

Recent experimental trials seem to suggest that torcetrapib (in combination with atorvastatin) suffered from an isolated toxicity, a drug-specific flaw that may not hold true for all CETP inhibitors. Unlike lowering LDL (known as “bad cholesterol”), which has a dearth of scientific data in its corner, the advantages in increased HDL—to counteract atherosclerosis, specifically—have yet to be solidified, though several ongoing studies are hoping to do just that. 

Tim Anderson, global pharmaceuticals analyst at Sanford Bernstein, acknowledges that most physicians still have questions, but views CETP inhibitors as potentially being “very meaningful in terms of commercial opportunity.” Anderson puts the odds of that outcome at “slightly more than 50%.” Merck is currently developing anacetrapib, and Roche is developing dalcetrapib in a collaboration with Japan Tobacco. Both products are CETP inhibitors. Roche launched Phase III morbidity and mortality trials in April. “A lot of physicians are saying CETP [inhibitors] are the way to go,” says Anderson. 

Gazing into the crystal ball
Results from two key studies could open doors for several new products targeting HDL levels. The first, AIM-HIGH, is scheduled for completion in 2011, and is testing the combination of extended-release niacin and simvastatin (generic Zocor). The second, HPS2-THRIVE, slated for completion in January 2013, looks at cardiovascular outcomes in relation to HDL increases. 

Should these studies yield positive results, extended-release (ER) niacin/statin combinations like Abbott's Advicor (niacin ER/lovastatin) and Simcor (niacin ER/simvastatin) may face competition from fenofibrates and fenofibrate/statin combinations. In 2008, Vytorin outsold the next-best selling combination drug (Advicor) and the third-best seller (Simcor) by over $1 billion dollars combined (Fig. 2), according to IMS Health data. 

Niacin has been shown to raise HDL and lower LDL and triglycerides—high levels of triglycerides have been linked to atherosclerosis. The trouble with niacin single agent drugs like Abbott's Niaspan, as well as niacin/statin combinations, is that facial-flushing, a common side effect, may limit sales. Niaspan's branded website describes flushing as “redness, mostly on the face, neck and chest and/or back, which is caused by local blood flow to the skin.” If niacin can hurdle this challenge it stands to extend profits. “[Niacin] has quite a broad range, and physicians appreciate its mechanism of actions,” notes Graeme Green, an analyst with Decision Resources. 

Abbott's Tricor (fenofibrate) netted over $1 billion in sales in 2008, and newly FDA-approved TriLipix (fenofibric acid), a delayed-release capsule to be taken with or without a statin, may be able to shift patients over to the drug by 2011, when Tricor's patent is set to expire. Both drugs lower triglyceride and LDL levels while bringing HDL levels up. However, occurrences of rhabdomyolysis, or rapid muscle deterioration, increase substantially when fenofibrates are paired with a statin. Abbott is seeking FDA approval for a fixed-dosed combo pill adding AstraZeneca's Crestor to TriLipix. Positive outcomes on HDL from HPS2-THRIVE and AIM-HIGH could help to boost fenofibrate and fenofibrate/statin combos in the market.

According to Green, Sciele Pharma will file an NDA this year for a fenofibrate/pravastatin combination. Green says an onslaught of new cholesterol combos probably won't set off a complete shift away from single agent statins. “There's an interest from payers to control costs,” he says, although cholesterol patients with multiple risk factors, like diabetes for example, will need therapies that “act on more than one pathway.” 

Merck's much-anticipated pair of experimental combos —MK-0524a and MK-0524b – are currently awaiting the results of HPS2-THRIVE, following an FDA's not approvable letter last April. MK-0524a, originally dubbed Cordaptive, pairs extended-release niacin with laropiprant, an anti-flushing agent. MK-0524a is called Tredaptive in Europe, where it received approval last July for the treatment of dyslipidemia and hypercholesterolemia (heterozygous familial and non-familial). The product can be used in combination with a statin when “cholesterol lowering effects of statin monotherapy is inadequate,” Merck said in a release.

MK-0524b adds simvastatin to the ER niacin/laropiprant formula. Merck's laropiprant, a DP1 antagonist, reduces vasodilation and could potentially make strides, depending on its performance, says Green. Green and his colleague at Decision Resources, analyst Nikhil Mehta, note two other emerging cholesterol therapies worth keeping an eye on. The first is mipomersen, an injectable in development through an Isis Pharmaceuticals/Genzyme collaboration. Mipomersen reduces the production of apoB-100, a protein critical in the body's production of LDL, and targets patients with familial hypercholesterolemia, a disease that increases the risk of cardiovascular disease and death. Preliminary data saw the weekly injection reduce cholesterol and other atherogenic lipids beyond levels achieved by statins, said Mehta, though mipomersen will initially be used only in high-risk patients. “There's an oral formulation further down the line,” adds Green, which could see significant sales figures, as it will assuredly be priced significantly above other treatments.

The second drug, Livalo (pitavastatin), has already been launched in Japan, says Green, adding that Livalo, should it get a nod from FDA, would surpass AstraZeneca's Crestor as the most potent statin on the market. Livalo is manufactured by Japan-based Kowa, which filed an NDA in late 2007. The product could receive approval this year, though Green doesn't expect it to make significant inroads with physicians immediately.

The big three
Of the top sellers (Fig. 2) in 2008—Lipitor ($7.7 billion), Crestor ($2.1 billion) and Vytorin ($1.9 billion)—Crestor saw the biggest gains, in both market share and sales, according to IMS Health. In fact, Crestor was the only product of the trio to net growth across the board, despite trailing Lipitor (and simvastatin) by a large margin in Rx dispensed. Crestor's recent success owes to solid clinical trials and a new indication. Results of the JUPITER trials were released last November, and showed a 44% reduction in major cardiovascular events compared to placebo among patients with elevated CRP but low to normal cholesterol levels on 20 mg doses of Crestor. “That was the missing piece for AstraZeneca,” says Green.

AstraZeneca quickly launched new campaign materials touting the drug's atherosclerosis-fighting power. “With Crestor's high efficacy, it has the momentum behind it and will continue to do well,” says Anderson. Combined with Merck/Schering-Plough's ENHANCE trial for Vytorin, which showed no benefit in fighting atherosclerosis, Crestor was able to leverage its new indication successfully. With agency partners Saatchi, Digitas and Edelman, AstraZeneca upped its DTC spend from $56.6 million in 2007, to $98.2 million through October of 2008, according to SDI Health data.

Crestor represents the biggest competition for Vytorin, according to Mehta, since both lower cholesterol levels more than Lipitor. Merck/Schering-Plough is currently recruiting participants for a new Vytorin outcomes study called IMPROVE-IT. That study will pit Vytorin (ezetimibe/simvastatin) against simvastatin, in relation to patients with acute coronary syndrome. IMPROVE-IT is scheduled to be completed in 2012. “Vytorin will have to ride out the storm in the US market for at least another three years,” says Green. FDA has reviewed the data from ENHANCE, and announced in January that the existing evidence shouldn't prevent patients from using the drug. Anderson says Vytorin should consider restarting its DTC campaign, put on hold after ENHANCE. Only professional ads are currently running. “Once a brand is damaged, it's hard to regain confidence [in the product], says Anderson, noting that Vytorin will most likely continue to “drift slowly, and continue to decline, but at a much slower rate.”

Pfizer just launched a consumer ad campaign behind Lipitor last September, after taking heat from federal regulators over a DTC campaign featuring Robert Jarvik, inventor of the artificial heart. Controversy stemmed from the presentation of Jarvik, and whether or not the ads misrepresented him and his credentials. Jarvik is not a cardiologist and not licensed to practice medicine. The new campaign features testimony from John Erlendson, who suffered a heart attack at 57. “My doctor told me I should have been doing more for my high cholesterol. What was I thinking? But now I trust my heart to Lipitor,” Erlendson says in the TV spot. Despite spending over $153 million on DTC efforts through October 2008, Lipitor continues to yield scripts to simvastatin. Launched as a generic in 2006, simvastatin immediately chopped into Lipitor prescriptions—in 2005 Lipitor garnered 54.3% of the total scripts among single agent statins. In 2008, simvastatin claimed 38.7% in the category, besting Lipitor's 33.6%.

In the news
Hoping to curb heart disease, the American Academy of Pediatrics recommended active screening for cholesterol last summer—and subsequent drug regimens—in children as young as eight. These new guidelines, which contradicted the Academy's previous stance, touched off fierce debate among nation's pediatricians, with vociferous opinions on both sides. A study in AHA's Circulation on February 16, and picked up by news outlets, may put those fears to rest. The study looked at data from the National Health and Nutrition Examination Survey for children 6 to 17 years of age, and concluded that only a small number of adolescents may need pharmacological treatment for elevated concentrations of LDL. 
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