Major Accomplishments

The story of SINGULAIR^® began in 1938, when a British researcher named Charles Halliley Kellaway discovered slow-reacting substance anaphylaxis (SRS-A) in the lungs of animals. More than 40 years later, in 1979, Swedish researcher Bengt Samuelsson from the Karolinska Institute announced that SRS-A was a combination of the leukotrienes LTC4, LTD4 and LTE4. Dr. Samuelsson hypothesized SRS-A to be a biochemical mediator of the asthma response. Dr. Samuelsson went on to receive the Nobel Prize in 1982 for related research.

The announcement galvanized the scientists at Merck Frosst, who had already been working on SRS-A and its involvement in asthma. Clearly, there was now the potential for a medicine that would block the activity of these leukotrienes and relieve the symptoms of asthma.

First the researchers had to find a way to synthesize leukotrienes, to understand how they worked and provide a target for potential inhibitors. The competitors of Merck Frosst included Dr. Elias Corey from Harvard University, a former colleague of Dr. Samuelsson's, who would win the Nobel Prize for chemistry in 1990.

The two competing teams succeeded in synthesizing leukotrienes almost at the same time-during the 1979 Christmas holidays-and were the first to publish articles on leukotriene synthesis. By 1981 Merck Frosst was producing sufficient leukotrienes to distribute them to researchers around the world, to speed up progress on understanding their mechanism of action.

During the years that followed, Merck Frosst scientists in Montréal were able to confirm the pivotal role of leukotrienes in respiratory disease. They were one of the first teams in the world to define leukotriene activity and to show clinically that leukotriene receptor antagonists were effective for treating asthma.

Leukotrienes are produced in the body by leukocytes (white blood cells) from the essential fatty acid, arachidonic acid. This conversion, known as the arachidonic acid cascade, is mediated by a series of enzymes including 5-lipoxygenase.

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Once released into the tissues, leukotrienes attach to receptors on the outside of airway cells. Like an ignition key, they turn on the cellular responses that lead to the asthma reaction: contraction of the airway muscles, swelling of the airway lining and flooding of the remaining airway space with sticky mucus.

Merck Frosst researchers pursued a two-pronged approach to blocking this dangerous sequence of events.

The first approach was to prevent the biosynthesis of leukotrienes in the lungs, by inhibiting 5-lipoxygenase (inhibition strategy). The second approach aimed to prevent the leukotrienes from stimulating the target receptor and turning on the asthmatic reaction (antagonist strategy).

Both approaches yielded good results over the next 10 years; however, by 1991 it was clear that montelukast sodium (later to become SINGULAIR^®) was the superior drug and the inhibition approach was finally dropped.

As a starting point in their search for an effective antagonist for the target receptor, Merck Frosst scientists hand-screened tens of thousands of compounds from the Merck & Co. sample collection.

Any compound capable of blocking the action of leukotrienes on tissues and cells was analysed, chemically manipulated and tested again by the scientists until they had created a workable antagonist. During this painstaking creative process, which lasted several years, over 14,000 compounds were examined in detail. Seven of these were eventually tested in clinical trials in humans.

The team finally chose quinolein as the basis for their compound, because it has affinities with the LTD4 (leukotriene) region.

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During the course of their research, the Merck Frosst scientists identified, quantified and synthesized metabolites of leukotrienes in animals and humans; identified and characterized leukotriene receptors; were instrumental in cloning, expressing and characterizing the 5-lipoxygenase enzyme, and became world experts in its metabolism. They were also the first to identify a co-factor necessary for leukotriene synthesis in cells, the 5-lipoxygenase activating protein (FLAP).

In 1985, there were the first clinical trials, with compounds L-648,051 and
L-649,923. Unfortunately, results were disappointing. Merck Frosst's competitors were experiencing similar set-backs and many had dropped leukotriene antagonist development. At this point it was still unclear whether the initial hypothesis was even correct-namely, that leukotrienes had a central role in asthma.

Merck Frosst decided to press on, and in 1988, almost a decade after research started, was rewarded with MK-571. This compound proved to be nearly 50 times as powerful as existing antagonists and, at last, demonstrated that a leukotriene antagonist could be effective for treating asthma in people.

MK-571 proved itself and proved the hypothesis, but, ultimately, proved disappointing. Tests on laboratory mice found that MK-571 caused peroxysome proliferation of the liver. The risks to humans, however small, were untenable.

Back at the drawing board, the researchers realized that MK-571 comprised two isomers, two components that were mirror-images of each other. Working on the hypothesis that only one of the isomers was causing liver proliferation, Merck Frosst scientists synthesized and tested the isomers in isolation. The hypothesis was proven right, and a number of pure isomers went into clinical trials, including MK-679, later called Venzair. This product appeared to be as effective as MK-571, but disappointingly, some people who took the drug developed minor elevations of liver enzymes and Venzair too became a historical footnote.

The challenge for the team was to find a compound that would not interfere with liver function, would act most effectively on receptors, and would satisfy the extremely rigorous quality standards of Merck Frosst. The ideal compound would also be suitable for once-daily, oral administration.

In the year that followed, hundreds more compounds were synthesized, analyzed, and subjected to preclinical toxicity testing.

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In April 1991 perseverance paid off when the Merck Frosst team produced L-706,631, later to become MK-476 and, finally, montelukast sodium. The "mont" in its name is a tribute to the place it was discovered : Montréal. Montelukast sodium is a very complex organic molecule. It weighs 608.2 g per mole and its chemical formula is C₃₅H₃₅CINNaO₃S. There are 23 steps in its synthesis and the active ingredient in its pure state is a hygroscopic, off-white powder-a long way from the once-daily tablet.

The Pharmaceutical R&D team had to take into account the biological, physical, chemical and mechanical properties of the molecule, as well as its bioavailability-and the tight development timelines. The final challenge for the scientists at Merck Frosst was finding a dosage form that was easy to take, especially for children. The result is a small, easily swallowed tablet for adults and a chewable cherry-flavoured tablet for children.

In 1994, following Phase I pharmacokinetics, pharmacodynamics and safety studies, the efficacy and general tolerability of SINGULAIR^® for the chronic treatment of asthma in adults (15 years of age and older) and in pediatric patients (6 to 14 years of age) were demonstrated in a series of Phase II and Phase III clinical trials.

At last, the goal had been achieved: an oral treatment for asthma that met all quality, efficacy and safety requirements; a highly selective and long-lasting drug that could be given once daily, whose side effects were comparable to those of placebo, in other words, minimal.

On February 23, 1997, Merck & Co., Inc. made a regulatory submission for a new drug to the Food and Drug Administration (FDA) in the U.S.A., for montelukast sodium, now called SINGULAIR^®. It received approval in the U.S. on February 20, 1998 and in Canada on June 17 of the same year.

In 2000, SINGULAIR^® was awarded the Prix Galien Canada 2000 Innovative Product, and the scientists who developed SINGULAIR^® were awarded the Prix Galien Research for their efforts.