Beginnings of research into natural substances at Sandoz

Cyclosporine and immunopharmacology

Research into natural substances at CIBA

A weapon against malaria and a new substance to fight tumors

Science

Of microbes and men

The roots of today’s Natural Products Unit extend back to the companies from which Novartis was founded. At Sandoz, the search for medications from biological sources began around 100 years ago when the Pharmaceutical Department was established in 1917 and Arthur Stoll was appointed its director. CIBA followed in 1934 with the establishment of its own natural products group. Novartis sees in the molecules produced by nature a significant source of new substances that have enormous potential for the development of future medications. The following is a summary of an article written by Frank Petersen, Head of the Natural Products Unit at Novartis, to mark the publication of a book celebrating the 100th birthday of Albert Hofmann, the legendary natural substances chemist and former head of the Natural Products Unit.

Text by Michael Mildner

A preparation labelled by Arthur Stoll from the research group for natural substances with ergotamine tartrate (1920) plus the source substance, ergot, on grains of rye.

Table of contents

Beginnings of research into natural substances at Sandoz

Cyclosporine and immunopharmacology

Research into natural substances at CIBA

A weapon against malaria and a new substance to fight tumors

This article was originally published in April 2014.
Published on 23/06/2020

Thanks to the booming business in dyes, 1916 was an exceptionally successful year for Sandoz. Total sales amounted to 30 million Swiss francs, while earnings reached 9.3 million Swiss francs, three times the entire share capital. To create a counterbalance to the dominance of dyes in the product portfolio, the company pushed for further diversification and in the process decided to establish a research-driven pharmaceuticals sector. In 1917, Professor Arthur Stoll, a Swiss citizen and a natural products chemist, was commissioned by the Board of Directors to set up the new business unit. When Stoll joined Sandoz on October 1, 1917, this marked the emergence of the Pharmaceuticals Division, and thus began the unique success story of this industrial research group.

Packaging for the first pharmaceutical product from Sandoz, Gynergen (picture from the 1930s). The pure active substance ergotamine was first isolated from the sclerotium of the ergot fungus in 1918 and forms the basis for Gynergen, a medication used in childbirth and to reduce postpartum bleeding.

Beginnings of research into natural substances at Sandoz

In order to achieve swift success, Stoll focused on traditional medical remedies that had already proven effective in humans. Specifically, he concentrated on isolating ergot alkaloids.

The ergot fungus (Claviceps purpurea) lives as a parasite on rye and other grasses. The medical use of the aqueous ergot extract as an oxytocic agent to induce childbirth and reduce postpartum bleeding was first described in 1582 in a book on herbs by Adam Lonitzer. Stoll’s idea behind isolating the pharmaceutically relevant principle was based on the conviction that it would be easier to control doses if dealing with the pure compound. In 1918, with the assistance of methods he himself had helped to develop, he was successful in the historic isolation of ergotamine in its pure form. Only three years later, the alkaloid was brought to market under the name Gynergen®, initially for reducing postpartum bleeding. Dur-ing the 1920s the preparation was also used successfully to treat migraines. Gynergen was the first product of the still young Pharmaceuticals Division at Sandoz.

In 1935, the Swiss chemist Albert Hofmann, who joined the natural products group at Sandoz in 1929, resumed work on the ergot alkaloids. He was looking for a new analeptic agent and, in the course of this research, he synthesized lysergic acid diethylamide, or LSD-25, the 25th derivative of the lysergic acid amide series. During the final purification steps, Hofmann by chance experienced the hallucinogenic effects of LSD-25, which he confirmed three days later in an experiment he conducted on himself. The discovery of LSD-25 was the start of psychopharmacology, and during the following decades it led to an understanding of the biochemistry of the neurotransmitters serotonin and dopamine.

Microscopic photograph of the mold Tolypocladium inflatum (active ingredient: Cyclosporine), which was isolated by Sandoz in the 1970s from a soil sample brought back from Norway. Cyclosporine is the basis for Sandimmune, a medication used to fight organ rejection following transplantation.

Cyclosporine and immunopharmacology

Sandoz associate Hans Peter Frey brought back some soil samples from his 1969 summer vacation. From these, the Natural Products Unit isolated a mold that in turn produced a cyclic peptide. As the antifungal activity profile of this natural substance, which was later named cyclosporine, proved disappointing, investigations were stopped. The compound was forwarded to general drug screening, where the surprising immunosuppressive activity of the peptide was discovered. With the decision to develop this new type of peptide for transplantation medicine, Sandoz built upon the era of the ergot alkaloids and entered into a new area of research; Immunobiology.

Cyclosporine came on the market in 1982 as Sandimmune® and revolutionized transplantation medicine. With the administration of cyclosporine and the resulting suppression of immunological defenses, the survival time of transplanted organs increased significantly, while at the same time transplant patients coped much better with infectious diseases. Autoimmune diseases such as serious types of psoriasis, rheumatoid arthritis, Crohn’s disease, systemic lupus and nephrotic syndrome could now be treated more effectively with this cyclic peptide. With the discovery of cyclosporine, Sandoz gained important insights into the molecular relationships of the immune response conveyed by the T cells. In the following years, the company became a scientific leader in research on the specific modulation of the immune response. The consistent examination of substances from molds and bacteria in this area of therapy led to the successful development of the derivatives of rapamycin, ascomycin and mycophenolic acid.

Arthur Stoll, founder of research into natural substances at Sandoz, around 1920.

Research into natural substances at CIBA

In 1934, Professor Emil Schlitter was hired by CIBA to set up an independent research group for natural substances. In the years that followed, Schlitter processed indole alkaloids from the plant Vallesia glabra and cardiac glycosides from Adenium somalense, a plant used in Eastern Africa to produce poison for arrowheads. During World War II, CIBA’s trading partners in India reported on a medicinal plant that was useful in helping relieve Mahatma Gandhi’s sleeping disorders. According to ayurvedic writings, the roots of the “pagla-ka-dawa” or snakeroot (Rauwolfia serpentina) have a soothing effect and are used to treat anxiety and excitement. In 1946, Schlitter started a project to isolate the active principle, and in 1952 he was able to extract the pure form of a new alkaloid, which was named reserpine. With the marketing of reserpine as Serpasil® in the following year, modern human therapy gained one of its first sedatives. From the late 1950s, an ETH research group worked together with CIBA’s Natural Products Unit on the development of natural substances with iron-chelating properties. As part of this research program, CIBA developed the industrial production of desferrioxamine B and in 1963 launched the active ingredient as Desferal®. Using Desferal therapy, the shortened life expectancy of patients with thalassemia and hemochromatosis was increased to that of healthy people; to this day, Novartis has a market share of 100 percent in the treatment of these illnesses.

A further project in natural substances at CIBA was started at around the same time. From 1957, the natural products team at the company Lepetit conducted research into a highly active unknown antibiotic. To drive the development of the antibacterial substance (called rifamycin), both companies decided to pursue this project jointly. Professor Jakob Nüesch, who would later become president of the ETH Zurich, started to uncover the novel mechanisms of rifamycin, and in 1967 CIBA brought a semisynthetic derivative of rifamycin to market as Rimactane®. Due to its high level of activity against mycobacteria, Rimactane has to this day been a key antibiotic in the global fight against tuberculosis and leprosy.

CIBA has been researching antibiotics for more than 25 years. When in the mid-1980s the view spread globally that the classes of antibiotics already available were totally adequate to fight bacterial infections, the search for new antibacterial natural substances was cut back or even stopped. CIBA also followed this trend and realigned its work with natural substances. In the following years, drug discovery based on natural substances was integrated into the emerging area of high-throughput screening.

Albert Hofmann with a molecular model of LSD, 1940.

A weapon against malaria and a new substance to fight tumors

The initiative for a new development project surprisingly came from China. In 1989, Chinese authorities approached Ciba-Geigy and suggested the joint development of a new medication for P. falciparum malaria, the most dangerous form of malarial disease. The candidate for development was to be a combination preparation made up of a synthetic active ingredient and a derivative of the plant metabolite of artemisinin, which is extracted from the Chinese medicinal plant Artemisia annua. In 1994, Ciba signed a cooperation agreement with various Chinese institutions that set out the joint development of the new medication. After extensive clinical studies, the new malaria medication was approved under the trade name Coartem®/Riamet®, which in 2001 was added to the World Health Organization’s Model List of Essential Medicines.

In recent years as well, Novartis has repeatedly introduced natural substances and their chemical derivatives into clinical research with the goal of developing new forms of therapy.

At the present time, for instance, an antibiotic for treating intestinal infections with the bacteria Chlostridium difficile is being investigated, and work with a new type of natural substance is focusing on the possible treatment of inflammatory skin diseases. In the identification of innovative approaches for the therapy of hepatitis C, a natural substance took an international research team from Novartis and the University of Kyoto down a totally surprising path. A family of proteins that is a prerequisite for the effectiveness of cyclosporine is also needed by the hepatitis virus if it is to replicate. Cyclosporine and its non-immunosuppressive derivatives prevent the recruitment of these proteins and hence the replication of these virus particles. Novartis is presently conducting various clinical studies to see if the mechanism also shows a therapeutic effect in patients.

Research work on everolimus conducted by the Friedrich Miescher Institute in Basel and the Novartis oncology research department suggested that this substance, for which Novartis received approval in 2003 as an immunosuppressive, could also be effective in cancer therapy. These investigations drew upon earlier results of the Canadian company Ayerst that had published papers about the antitumor effect of this class of substances but in 1982 stopped researching it for six years. The clinical investigations initiated by Novartis confirmed the efficacy of everolimus, which in 2011 and 2012 received the first approvals as Afinitor® for the treatment of renal cell carcinoma and pancreatic cancer as well as advanced breast cancer.

Molecules from plants and microorganisms are still being studied today for the development of new therapies. Their special chemical structures are leading to the discovery and chemical investigation of new classes of substances. Uncovering their mechanisms has opened insights into the prime movers of diseases and their possible medications. Novartis has recently strengthened this area of research in a targeted manner. Through the integration of the latest technologies and approaches from molecular genetics as well as analytical and preparative chemistry, this area of research will be able to contribute its enormous potential for innovation to the search for future active ingredients.

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