Sandoz: ergot as the basis of success

Geigy: antirheumatic, Nobel Prize and advertising

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Milestones in pharmaceutical research

The beginnings of the Basel-based chemical industry were characterized by copycat products; that is true both of dyes and of pharmaceuticals. Only gradually did the companies establish their own research departments, which enabled the industry to switch from copying high-volume products to focusing on highly profitable specialties. This move created the basis for the companies’ sustainable success. In this issue of live we focus on the history of pharmaceutical research from the end of the 19th century to the foundation of the Novartis Institutes for BioMedical Research.

Text by Michael Mildner, photos: Novartis

Arthur Stoll (1887–1971) was entrusted with setting up pharmaceutical research at Sandoz in 1917.

Table of contents

Sandoz: ergot as the basis of success

Geigy: antirheumatic, Nobel Prize and advertising

This article was originally published in April 2013.
Published on 01/06/2020

The foundation of the modern pharmaceutical industry was laid in 1884 when Hoechst’s Farbenwerke launched antipyrine for reducing fever. The oldest synthetic analgesic rapidly became the most successful medication of the 19th century in economic terms and inspired countless copies. At the end of the 19th century, both CIBA and Sandoz were among those generating strong sales with legal copies of successful medicines. This development was certainly supported by the fact that patent protection was not introduced in Switzerland until 1907.

From copies to innovation

But after just a few years, companies tended to discontinue making copies and mass-produced articles to concentrate instead on manufacturing patentable specialties, which the Basel-based companies then sold to pharmacies as finished products. It was at this time, around the turn of the century, that CIBA and the Basler Chemische Fabrik, which was founded by Robert Bindschedler, launched their pharmaceutical research activities. Their first products included the antiseptic Vioform® and the antirheumatic Salen. As research departments were set up and the pharmaceutical industry in Basel became increasingly science-based, the exchange with universities gained in significance. Zurich Polytechnic, which was later to become the ETH, played an important role very early on. Practically trained chemists and process engineers repeatedly made major contributions to the development of the Basel-based companies.

CIBA: growth thanks to hormone supplements

The very first company in Basel to undertake its own research activities in the pharmaceutical sector at the end of the 19th century was the Chemische Industrie Basel, or CIBA for short. Up until the beginning of the First World War, CIBA produced three categories of substances: pure substances, standardized extracts from animal and herbal substances, as well as synthetic products. With the production of gonadal extracts and hormone supplements, the company opened up a promising new line of work for itself during the First World War. Eight such medicines were launched between 1918 and 1939. From 1935, CIBA scientists were then capable of manufacturing natural sex hormones by partial synthesis. The seven gonadal extracts and hormone products, as well as the synthetic Percorten®, remained important pillars of sales right up to the 1950s and 1960s.

The Geigy chemist Paul Hermann Mueller (1899–1965, left), who discovered the effectiveness of DDT as an insecticide, received the Nobel Prize in medicine on December 10, 1948, in the Stockholm Concert Hall.

Sandoz: ergot as the basis of success

In scientist Arthur Stoll, who made his PhD at the ETH Zurich, Sandoz found the perfect candidate to set up a pharmaceutical division. His arrival at the company in 1917 is the reason behind the exceptionally successful pharmaceutical department at Sandoz.

Stoll based his program on isolating the active ingredients of natural drugs in their pure form to manufacture medications that could be given in precise doses. Using a new procedure, which Stoll helped develop and which was later patented by Sandoz, he succeeded in isolating a crystalline alkaloid from ergot (Secale cornutum) in 1918. In 1921, the very first drug for stopping postpartum hemorrhage (heavy bleeding after childbirth) was launched under the trade name Gynergen®.

The lack of profitability of the early pharmaceutical department, compared with dyestuffs, almost led to its closure; it was not until 1924 that Arthur Stoll succeeded in making a small profit in his division. The launch of the bestseller Calcium-Sandoz® in 1927 finally put an end to worries about profitability.

Albert Hofmann and LSD

In 1929, Swiss chemist Albert Hofmann joined the natural materials group of the pharmaceutical department of Sandoz. The conditions under which researchers worked at the time were far removed from the highly technical facilities we know today, for example on the Novartis Campus in Basel. The chemistry section of the research department at the time, for instance, consisted of three chemists each with one lab technician – all working in one single lab without ventilation.

In 1935, Hofmann once again started working on the ergot alkaloid. In 1938 he synthesized various amide derivatives of lysergic acid, including – as the 25th substance – the diethylamide LSD-25. Initially it exhibited no pharmacologically interesting characteristics and was therefore not examined further. But in 1943, Hofmann decided to manufacture LSD again. During his lab work, a sudden onset of restlessness and malaise caused him to stop working and go home. After arriving home, he experienced an uninterrupted stream of fantastic visions in intense colors for about two hours. To investigate this unusual experience, he decided to try it again just a few days later, and this test confirmed the hallucinogenic effect of the alkaloid. Hofmann himself summarized his discovery as follows: “LSD came to me.” His trip home from the lab on his bicycle accompanied by strong hallucinations has gone down in history under the name “Bicycle Day.”

Although Hofmann never received a Nobel Prize because of the controversial LSD, he was one of the most respected researchers worldwide. In 2007, at the age of 101, Hofmann was voted the greatest living legend by British daily newspaper, The Guardian. There is virtually no other discovery of the 20th century that has had a more significant influence on science, society and culture than the mysterious, incomparably potent substance which in doses of just a few micrograms causes a dramatic change of consciousness. The discovery of LSD-25 was the beginning of psychopharmacology and in the following decades was to lead to the understanding of the biochemistry of the neurotransmitters serotonin and dopamine.

The first blockbuster in the company’s history.

Geigy: antirheumatic, Nobel Prize and advertising

Although company founder Johann Rudolf Geigy-Gemuseus started trading with “materials, chemicals, dyes and drugs of all kinds” back in 1758, the company was the last of the Novartis predecessor companies to become involved in pharmaceutical research in 1938.

One year later, in 1939, the research department of Geigy was able to celebrate a major success, even though this was not in the pharmaceutical sector. Swiss researcher Paul Hermann Mueller discovered the effectiveness of DDT (dichlorodiphenyltrichloroethane) as an insecticide and received the Nobel Prize in medicine for his discovery in 1948. It was the first time that this prize had been awarded to someone who was not a medical specialist.

It was also in 1939 that Geigy was to make another discovery, a painful one: The launch of the mothproofing agent Mitin® was a failure due to a poor commercial strategy. After this episode, Geigy paid particular attention to its advertising. The innovative advertising concept devised by René Rudin with its top-quality design and world-famous Geigy style was to play a major role in the successful sale of pharmaceutical products in the following decades.

From 1953 to 1964, Geigy led the antirheumatic market with Butazolidin® (phenylbutazone). When a more effective competitor product came onto the market in 1964, Geigy intensified research into a novel and well-tolerated anti-inflammatory agent. The development was very nearly stopped in the test phase, however, because of tolerability issues; the turning point came when the group leader tested the active substance diclofenac on himself without any complications. This paved the way for the blockbuster Voltaren®. The drug was launched in 1974 after the merger of CIBA and Geigy.

From Ciba-Geigy and Sandoz to Novartis

The collaboration with numerous biotechnological companies, a trend that emerged in the US from the mid-1970s onwards, brought valuable insights for the Basel-based pharmaceutical companies. Important successes were achieved not only in biotechnology, however, but also in the area of natural substance chemistry. One milestone was certainly the discovery of Sandimmun® (ciclosporin). This substance, extracted from mushrooms, is capable of suppressing cells that play a key role in our immune systems in a highly specific way and thus preventing organ rejection in transplantation medicine. Sandoz launched Sandimmun in 1982; the drug is not only used in transplantation medicine, but also in the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis.

The success of American researchers who for the very first time in the history of medicine were able to identify defective genetic material resulting from translocation of genes as a cause of cancer encouraged Ciba-Geigy to start its own research program at the end of the 1980s. The scientists examined chemically synthesized substances that can specifically block the effect of the genetic defect. After two years, Ciba-Geigy had developed a substance in 1993 that blocks the specific protein that triggers chronic myeloid leukemia (CML). And Glivec® was born – a drug that can stop the proliferation of white blood cells without having a detrimental effect on normal cells and thus disturbing the body’s balance.

Just before the merger with Sandoz to form Novartis, in mid-1996, Ciba-Geigy launched valsartan under the trade name Diovan®. The novel chemical structure made it possible to continuously lower blood pressure. The drug was also well tolerated and played a role in reducing cardiovascular-related deaths following a heart attack. Even today, cardiovascular diseases such as hypertension are a rapidly increasing medical problem affecting over one billion people worldwide and are responsible for the majority of deaths in industrial countries. The Diovan product family became an important mainstay of sales for Novartis and achieved sales of over 6 billion US dollars in 2010.

A new chapter in the history of research

With the reorganization of its global research network and the foundation of the Novartis Institutes for BioMedical Research (NIBR) in 2002, Novartis began another important chapter in its research history. Today, more than 6000 scientists worldwide are currently committed to changing medical practice with innovative research strategies. The international research network with its three Campus sites Basel, Cambridge (US) and Shanghai (China) is instrumental for the ability of Novartis, which wields more than 138 research products in its pipeline, to play a leading role in the pharmaceutical industry.

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