Despite several setbacks this year, and a major competitor's withdrawal from further R&D in the field, Merck reiterated its commitment to cardiovascular R&D at its annual business review Dec. 9 and outlined an aggressive cardiovascular development program.

The Dec. 9 briefing was a stage for Merck to fully review its cardiovascular pipeline and present its case for remaining committed to cardiovascular medicine - a primary care area with expensive, risky development and high competition in the marketplace that has been waning as big pharma embraces a specialty strategy. Pfizer made waves when it announced in October that it was stopping R&D in the area, long a major focus for the firm (¹ [A#00700400013], p. 20).

Not long after, Merck seized on the 50th anniversary of the launch of its first major cardiovascular medicine to showcase that it intends to continue investing in the cardiovascular therapeutic area. In a November news release, the company touted its historic contributions to the cardiovascular field and its future strategies, which cover several external collaborations, educational efforts and a full pipeline.

A month later, at the business review, Merck Research Laboratories President Peter Kim reiterated that message: "We are committed to cardiovascular research and we plan to continue our investment to develop new drugs against the number one cause of death in the U.S." He also detailed the cardiovascular pipeline, which includes four drugs in Phase III (two of which it anticipates filing in 2009) and six in phases I and II for atherosclerosis and hypertension.

Projects in development include a drug for acute heart failure, rolofylline, and a range of cholesterol products. Those include Merck's MK-0524 products based on a partnering of niacin with the flushing inhibitor laropiprant, a cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859), and a combination of ezetimibe ( Zetia ) and atorvastatin (Pfizer's Lipitor ) that it "intends to launch with our partner [Schering Plough] upon the expiry of the patent for Lipitor in 2011."

"Another part [of our strategy] is illustrated early in our pipeline, which is to take advantage of the tremendous amount of information that has been gained over the past five years for new mechanisms to treat hypertension," Kim continued. "These go above and beyond the diuretics and drugs that target the rennin-angiotensin system, which is how many of the current hypertensive agents work."

Looking Beyond The Setbacks

New mechanisms will be important for the highly competitive cardiovascular space, which is poised to become even tougher due to the increasing availability of generics. In addition, Merck and others in the field have seen a slew of major regulatory, commercial, and R&D setbacks. Merck's cholesterol-lowering franchise, led by Vytorin (ezetimibe/simvastatin), which it markets through a joint venture with Schering Plough, is still reeling from results of a negative study released last winter.

Merck suffered a further blow in April when the FDA issued a "not approvable" letter for its atherosclerosis combination drug Cordaptive (niacin/laropiprant) (² Also see "Merck’s Cordaptive “Not Approvable,” But Clark Not Giving Up On Combo" - Pink Sheet, 5 May, 2008., p. 13).

Merck is pushing ahead, however, because it sees huge unmet needs. Only 35 percent of hypertensive patients in the U.S. have their high blood pressure under control, Kim said. Furthermore, the number of drug-resistant hypertensive patients - those not at goal when treated with three classes of antihypertensives - has been growing and is now more than 3 million in the U.S. alone.

Merck also sees ongoing opportunities in lipid management. Roughly 25 percent of American adults have low HDL cholesterol levels, which are associated with significantly increased cardiovascular risk, he said.

If Pfizer has withdrawn from cardiovascular research, a handful of others, in addition to Merck, continue to see the field as an opportunity (³ Also see "After Statins, What Next?" - Scrip, 1 April, 2008.). Roche and Novartis are both investing in developing cardiovascular drugs with new mechanisms of action: Novartis largely in the area of hypertension, where it has a best-selling drug that goes off patent in 2012, and Roche in dyslipidemia, a new area for it (⁴ [A#00700500004], p. 9).

Merck's cardiovascular pipeline reflects a mix of caution and risk; while some of the drugs in its late-stage pipeline are combinations of approved drugs, the company is also gambling on a CETP inhibitor that bears a strong chemical resemblance to Pfizer's failed torcetrapib. Plus some of its combinations of approved drugs may not be easy sells - either for FDA (the niacin/laropiprant was already rejected) or for the market, which remains unconvinced that Zetia combinations are worthwhile.

Next Up: Rolofylline For Acute Heart Failure

Merck's next cardiovascular filing is likely to be rolofylline, for which it plans to file an NDA in 2009 for acute heart failure. Heart failure is the leading cause of hospitalization in patients over 65 years of age, Kim said. Current practice guidelines include treatment with diuretics, which help the weakened heart pump blood, but also increase the liquid that kidneys must process. As a result, diuretics often have negative effects on renal function. Patients with acute heart failure who develop worsening renal function are at increased risk for death and re-hospitalization.

Rolofylline, a selective adenosine A1 antagonist, which Merck acquired from NovaCardia in September 2007, is on target to complete enrollment in Phase III studies the first quarter of 2009, Kim told analysts. This drug has the potential to be the first major acute heart failure therapy that preserves renal function and improves outcomes, he emphasized (⁵ Also see "NovaCardia & Domain: New-Model Spec Pharma Investing" - Scrip, 1 September, 2007.).

In a pilot study, patients who were treated once daily for three days with a four-hour infusion of rolofylline and as much diuretics as needed had improved dyspnea (shortness of breath), fewer declines in heart function, and greater weight loss while preserving renal function compared to those treated with diuretics and placebo.

The pilot study also looked at 60-day outcomes and found that patients treated with 30 mg of rolofylline cut the mortality, cardiovascular and renal re-hospitalization rates by 45 percent. Kim observed that the results were remarkable, given that patients were treated only for three days. Nevertheless, the results just missed statistical significance, and Merck is seeking to confirm the trend in a large Phase III study.

Risk of seizures has been a concern with rolofylline, but Kim noted that those are controllable because the drug is administered in the hospital setting.

Still, analysts aren't as excited about the acute care product as Merck scientists. Biopharma forecasting firm EvaluatePharma estimates that if it launches in 2010, the drug is likely to reach sales of $173 million by 2014.

Tredaptive Filing Expected in 2012

Beyond rolofylline, Merck's hopes are pinned on drugs that - if they make it to the market - appear to have much greater commercial opportunities: Tredaptive (the new name for Cordaptive, a name FDA rejected) and, longer-term, on anacetrapib, a CEPT inhibitor that lowers LDL cholesterol and raises HDL cholesterol levels.

Tredaptive combines extended-release niacin and laropiprant - a flushing pathway inhibitor that reduces the amount of flushing often associated with niacin therapy. Niacin has broad lipid effects, both with and without statins, but its use is limited in many patients by its flushing effect. Compliance is extremely poor, even if patients follow a recommended titration schedule that is supposed to reduce flushing.

Tredaptive addresses a need in the lipid management field, which statins dominate. Statins, however, leave room for other approaches to reducing cardiovascular risk - and the market has been primed for an HDL-raising therapy. By reducing the side effect that limits niacin use, Tredaptive offers Merck a chance to harness the efficacy of the mature drug at raising HDL levels, which, Kim noted, are too low in 25 percent of Americans, or 50 million adults (⁶ Also see "Merck's Cordaptive: Just Another Cholesterol Combo, or More?" - In Vivo, 1 April, 2008.).

The drug is already approved in more than 30 countries, but the FDA rejected it in April, demanding longer-term outcomes data. An Oxford University-led outcomes study, HPS2Thrive, is ongoing, but it won't be completed until 2012. Merck expanded the population of that study to accelerate its completion (⁷ 'The Pink Sheet' Dec. 15, 2008, In Brief).

Kim said that the FDA has recommended that Merck wait until completion of that study before re-filing an NDA for Tredaptive, although the company continues to negotiate with the agency for an earlier date.

A Phase III study comparing Tredaptive to placebo alone or with statins found an 18 percent decrease in LDL cholesterol, a 20 percent increase in HDL, and a 26 percent decrease in triglycerides. Flushing was significantly lower compared to niacin alone. Merck is also studying combinations of Tredaptive with statins, such as its own simvastatin (the now generic Zocor ), and atorvastatin.

Combining Tredaptive with the leading generic statin (simvastatin) and having an atorvastatin combination ready for when Lipitor loses exclusivity is a good strategy. Merck is also working on a combination of Zetia with atorvastatin, to have in hand - although it remains to be seen whether Merck and Schering can regain ground lost on the disappointing results of the ENHANCE trial in 2008, which found no benefit for the combination of Zetia and simvastatin over simvastatin alone.

Another Aim At HDL: Anacetrapib

Merck also remains firmly behind anacetrapib, a CEPT inhibitor, although Pfizer's failure with torcetrapib sent the entire CEPT inhibitor field reeling two years ago. Pfizer has yet to recover from the torcetrapib debacle, which contributed to its decision to exit late-stage cardiovascular R&D. The company had hoped that torcetrapib would replace sales lost when Lipitor,its number-one drug, goes off patent, but worse outcomes in a Phase III study forced it to drop development.

Still, other companies working on CETP drugs also have remained committed to the promising mechanism - and focused on learning the lessons from Pfizer's failure (⁸ Also see "Roche Exorcizes Torcetrapib’s Ghost: CETP Candidate Starts Phase III" - Pink Sheet, 1 May, 2008., p. 3).

Merck's message on its drug has been consistent: Pfizer terminated development of its CETP inhibitor because of an increased risk of death and cardiac events that was specific to the torcetrapib molecule. Merck researchers have discovered off-target effects of torcetrapib that might have led to its problems, but they don't see those effects in anacetrapib. Results of a Phase IIb study demonstrated that anacetrapib had favorable lipid changes with no increases in blood pressure or changes in serum aldosterone or electrolytes, which were seen with Pfizer's drug and are associated with an increase in cardiovascular events. The Merck study was published in 2008.

A Phase III program for anacetrapib was initiated in April of this year. The aim is for a once daily dose of the drug to lower LDL cholesterol by 40 percent and increase HDL cholesterol by 100 percent. An independent data monitoring safety board, which met in November, has recommended continuing the trial, Kim said. Results of that trial will lead to a large cardiovascular outcomes study, which is scheduled to begin enrollment in 2010.

- Wendy Diller (w.diller@elsevier.com)

Merck Taking Aggressive Approach To Cardiovascular Development

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