With Schering-Plough's research now tucked snugly in with Merck, the combined company met with analysts and investors for its widely anticipated R&D overview May 11. Even as management laid out a deep mid- to late-stage pipeline especially rich in cardiovascular products, executives provided little in the way of scientific news.

Top on the agenda, Merck unveiled plans to file five new molecular entities and combination products with regulatory authorities by the end of the year - that's in addition to four NMEs currently pending with either U.S. or European regulators. The five new submissions include the protease inhibitor boceprevir for hepatitis C; a long-acting combination of sitagliptin and metformin, Janumet XR ; the oral contraceptive NOMAC/E2; a sitagliptin/simvastatin combination, MK-0431D; and ridaforolimus, an mTOR inhibitor for sarcoma.

The four drugs already under review in the U.S. and Europe include mometasone/formoteral in combination for asthma in the U.S. and EU, Brinavess (vernakalant IV) for atrial fibrillation in the EU, NOMAC/ED in the EU, and asenapine for schizophrenia and bipolar in the EU (already on the market in the U.S. as Saphris ).

Schering gave Merck's pipeline a significant boost and added two of the company's most important near-term opportunities: boceprevir and vorapaxar, a protease activated receptor-1 antagonist for thrombosis, targeted for regulatory filing in 2011. Other late-stage drugs Schering brought to the company are the mometasone/formoteral combination, NOMAC/E2 and Saphris. About 55 percent of the molecules in the pipeline originated from Merck and the other 45 percent from Schering. Merck unveiled the combined pipeline earlier this year, and said only two drugs in the late-stage pipeline were culled due to overlap (Also see "Merck's Backbone Is Cardiovascular, Infectious Disease After Pipeline Integration" - Pink Sheet, 1 March, 2010.).

"We have consistently said what sets us apart in this merger is the fact that it is not just about the synergies, it is about the science," CEO Dick Clark maintained in his opening remarks.

In Cardiovascular Disease, Many Long-Term Opportunities

But most of Merck's highest potential late-stage drug candidates are in the high-risk cardiovascular disease area and are in the midst of lengthy- and costly - Phase III clinical trials. Thus, significant news won't be coming for many months until data from those trials reads out. Recently, Merck has emerged as a leader in cardiovascular drug development, with management consistently reaffirming Merck's commitment to the space while competitors like Pfizer have backed away from the therapeutic area, citing expenses and risks.

"Cardiovascular disease is an incredibly important unmet medical need with overwhelming morbidity and mortality worldwide," Global Scientific Strategy Head Luciano Rossetti said. "The market segments that Merck is most involved in, hypertension, thrombosis and dyslipidemia, are and will continue to be the largest unmet medical needs worldwide."

Indeed, highlighting just how deeply involved Merck is in the space, the company said it currently has 90,000 patients enrolled in cardiovascular outcomes trials.

One of the key cardiovascular contenders is vorapaxar. The drug is currently being studied in two Phase III studies for acute coronary syndrome and the secondary prevention of thrombosis, with an NDA filing targeted in the U.S. in 2011. "We believe vorapaxar has major blockbuster potential," President Kenneth Frazier said. But first the drug will need to demonstrate efficacy in Phase III as an add-on to anti-platelet therapy without an increase in major bleeding.

Both studies are event-driven trials with a minimum of one-year follow up. The secondary prevention study has completed enrollment of more than 26,000 patients and is continuing on track after a recent interim analysis, Rossetti said. The ACS study has enrolled approximately 12,000 of the targeted 12,500 patients.

Other cardiovascular opportunities are further out, including the cholesterol drug Tredaptive (MK-524A), a combination of niacin with a novel anti-flushing agent laropiprant, and MK-524B, which is Tredaptive with the addition of simvastatin. The niacin/laropiprant combination was rejected by FDA in 2008 as "not approvable," but Merck then initiated a Phase III cardiovascular outcomes trial that has since been completed. Merck is targeting a filing for both drugs in 2012.

Another opportunity is anacetrapib for atherosclerosis. The cholesterol ester transfer protein inhibitor is part of same class of drugs as Pfizer's failed torcetrapib - which contributed to increased blood pressure and deaths in patients in a Phase III study - and it is therefore one investors are cautious of. Roche, too, is continuing with development of its CETP inhibitor, dalcetripib (Also see "With Genentech Fully Integrated, Roche Lays Out Pipeline" - Pink Sheet, 22 March, 2010.). Both Merck and Roche have maintained that they have not seen the same safety side effects with their drugs. Anacetrapib is currently being evaluated in a Phase III study, with enrollment in a cardiovascular outcomes trial expected to begin in 2011.

Betrixaban, an oral Factor Xa inhibitor in development as an anticoagulant for stroke prevention in patients with atrial fibrillation or flutter is on track for filing in 2012, Merck said. Positive data from a Phase IIb study of the drug was released at the American College of Cardiology annual scientific session.

Merck's pipeline is chock full of drug candidates in other areas of research as well, including in migraine, osteoporosis, insomnia, asthma and chronic obstructive pulmonary disease, and Parkinson's disease.

-Jessica Merrill (j.merrill@elsevier.com)

Merck R&D: A Jam-Packed Pipeline But Much Of It Wait-And-See

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