Merck believes it will be able to submit its developmental atherosclerosis therapies targeting HDL cholesterol without conducting major outcomes trials, Merck Research Lab President Peter Kim said during the firm's annual business review in Whitehouse Station, N.J. Dec. 15.

The two HDL products, which Merck is bringing into Phase III trials, include a combination of a novel inhibitor of the niacin flushing pathway with the company's extended-release niacin, and a version adding Merck's Zocor (simvastatin).

Due to the availability of cardiovascular outcomes data on niacin, "historically...niacin products have been registered with the FDA without clinical outcomes studies," Kim said. Labels for those products include mention of the clinical outcomes studies with niacin, he noted.

"Whereas we don't think there is going to be a requirement for such studies for registration, we certainly are committed to demonstrating proven outcomes with our drugs," Kim added.

Niacin, which has been shown to increase HDL-cholesterol levels and have a positive effect on cardiovascular outcomes, is accompanied by flushing in approximately 90% of patients, Kim said. By adding the anti-flushing agent to minimize the side effect, Merck intends to leverage niacin's established efficacy.

The HDL products would augment Merck's traditional franchise of LDL-cholesterol agents at a time when the company is expecting to take a significant hit from the loss of exclusivity for Zocor; simvastatin faces patent expiry in June 2006.

Could Merck Beat Pfizer To Market?

The first of the two HDL products, MK-0524a, is the basic niacin/flushing inhibitor combo product. The company began Phase III trials of MK-0524a in December, and expects to file an NDA in 2007.

The second product, MK-0524b, adds Zocor to the MK-0524a combo, thus providing a treatment that targets both HDL and LDL cholesterol. Merck plans to start Phase III studies of the MK-0524b combination in the first quarter of 2006, with NDA submission anticipated in 2007.

The 2007 filing timeline could give Merck an edge over Pfizer's headline HDL-raising/LDL-lowering cholesterol combination of torcetrapib and Lipitor (¹ Also see "Pfizer’s Torcetrapib/Lipitor Raises HDL Cholesterol, But Blood Pressure Too" - Pink Sheet, 21 November, 2005., p. 14).

Pfizer expects to have data from imaging studies of torcetrapib/atorvastatin in the fourth quarter of 2006, which it may use as the basis for submission. Traditional morbidity/mortality results from the Phase III program will not be available for another two years.

Kim suggested that Merck's niacin product may have a more clearly defined regulatory pathway than Pfizer's torcetrapib combo because of niacin's proven benefit on cardiovascular outcomes.

Competitive Differences vs. Torcetrapib

The exec also maintained that Merck's product will have a different competitive profile than Pfizer's: torcetrapib, a cholesterol-ester transfer protein (CETP), targets a different type of HDL particle than niacin.

"CETP is a very interesting mechanism for increasing the levels of HDL cholesterol, however, the benefits of that mechanism have not been proven in outcomes studies," he noted.

"Unlike LDL lowering, where there is a general consensus in the field that lower is better and it doesn't matter how you lower it, there are different HDL particles - different in composition and size - and the question of whether or not a particular mechanism for raising HDL will necessarily lead to outcomes benefits is one that is not commonly accepted in the field."

In addition to MK-0524a and MK-0524b, Merck plans to move three other compounds into Phase III in 2006: the integrase inhibitor MK-0518 for treatment of HIV, the insomnia therapy gaboxadol and MK-0431a for diabetes.

Merck To Rejuvenate Diabetes Care With Januvia

MK-0431a is a fixed-dose combination of the firm's investigational dipeptidyl peptidase IV (DPP-4) inhibitor MK-0431 and metformin. The company expects to submit an NDA for the combo product, which will be dosed twice-daily, in 2007.

MK-0431 as monotherapy (proposed trade name Januvia ) is one of three compounds Merck expects to file in 2006. The firm also plans to submit NDAs for the oncologic vorinostat and the antiemetic MK-0517, a prodrug of aprepritant ( Emend ).

During the annual business review, Kim said he envisioned Januvia as one component of a diabetic treatment regimen.

"Diabetics end up with polypharmacies," he explained. "While metformin is the most commonly prescribed drug...adding on MK-0431 results in substantial improvements in glucose control so I think there is definitely going to be a role for both drugs."

The positioning of DPP-4 inhibitors has come under scrutiny since Novartis's developmental DPP-4 agent, vildagliptin, failed to demonstrate superiority to metformin monotherapy in an interim analysis from an ongoing Phase III trial (² Also see "Novartis Sticks With Heart Of Pipeline: Growth Is In Cardio-Metabolic Sector" - Pink Sheet, 26 September, 2005., p. 22).

Kim would not comment on the Novartis trial: "What I'll speak to is the fact that our drug is once-a-day and we are confident that we have titrated the dose to the point where we are inhibiting the DPP-4 enzyme."

Side-effect profile will also be an important point of differentiation for diabetes agents going forward, Kim said. "I am very pleased with the safety and tolerability profile that we have observed so far with Januvia."

The company is refocusing its R&D efforts as part of a larger restructuring program in the wake of the Vioxx withdrawal and in the face of patent exclusivity losses (see ³ Also see "Merck Sales Restructuring Sacrifices Physician Detailing To Payer Marketing" - Pink Sheet, 19 December, 2005.). While Merck is initiating broad cost-cutting measures in its selling and manufacturing activities, the company said it is committed to single digit growth in R&D expenditure through 2010.

Merck To Focus On Nine Disease Categories...

Atherosclerosis and diabetes are two of nine diseases that will be the focus of Merck's R&D efforts going forward. The other "priority" disease areas are Alzheimer's disease, cardiovascular, novel vaccines, obesity, targeted oncology, pain and sleep disorders.

During the investor meeting, CEO Richard Clark explained that "in the past, Merck pursued all areas of unmet medical need. If we saw an opportunity, we took it," he said. Under the new R&D paradigm, however, "we are now prioritizing our areas of research based on scientific opportunity and value to our customers."

"We will commit the resources necessary to invest both broadly and deeply in these areas across the company," Clark maintained. "Our goal is clear: to remain or become the leader in the treatment of these nine disease categories."

In addition to investing in research conducted in its own laboratories, Merck will pursue complementary acquisitions and licensing opportunities, he added.

...But Will Look At Other Areas Too

While the primary emphasis will be on the nine priority areas, Clark noted that the company will continue to invest on a smaller, more focused scale in other targeted areas in which market leadership is less likely.

These other "selected" disease areas include antibiotics, antifungal, antiviral, asthma, chronic obstructive pulmonary disease, neurodegeneration, ophthalmology, osteoporosis, schizophrenia and stroke.

Merck also will continue to pursue research already underway in its labs regardless of whether or not it falls into a priority disease category.

"Furthermore, if we find attractive external licensing opportunities, where clinical proof of concept exists, we will pursue them, regardless of therapeutic area," Clark added.

Merck is also focused on streamlining the development process. Clark said the effort will focus on building partnerships with scientific leaders, increasing external sourcing capabilities, maximizing speed and efficiency and increasing rate of success by early development and use of biomarkers.

Merck hopes to increase R&D throughput by 20% without increasing operating costs, he said. "Increasing productivity means expanding our pipeline both through work in our own labs and through licensing," he said. "It also means making the best use of our talents by outsourcing non-core R&D activities."

One way Merck has already begun to accelerate the development process is by shortening the time between first-in-man trials and Phase III, Kim said. The typical timeline between first-in-man and Phase III initiation is 3.5 years, but Merck has been able to shorten that period to 2.1, 2.3 and 1.8 years for MK-0431, MK-0524a and MK-0518, respectively, he said.

Merck also hopes to reduce cycle time between protocol approval and last-patient-enrolled, and between last-patient-out and final analysis. The company anticipates the initiative will decrease late development cycle time by nine months by 2007.

Merck Expects Expedited Filing Of HDL-Cholesterol Drugs Using Existing Data

More from Archive

More from Pink Sheet