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The use of plants, minerals, and other naturally occurring substances for medicinal purposes dates to ancient times. A trial‐and‐error paradigm was used to identify which plants or extracts resulted in desired effects, and the end products were non‐standardized. In the thirteenth century, drug quality standards were being developed, and in the fourteenth and fifteenth centuries, the first pharmacopeias were being published.¹ Pharmacopoeias list drug effects and directions for their use and laid the foundation for standardized pharmacy practice and drug and drug formulation development. Little changed in the process of drug discovery up until this time as a trial‐and‐error approach for identifying bioactive compounds with medicinal properties was the norm. This is the foundation for the type of drug discovery known as “irrational design,” which resulted in most drug discoveries up until the past century.

At the end of the eighteenth century, digitalis was identified as the active ingredient from the foxglove plant.² Scientists were starting to focus on the relationship between the chemical makeup of a plant's active ingredient and the resulting biologic effect in humans. Numerous drugs were developed for treatment during the 1800s including digitalis, quinine, aspirin, and mercury.³ Modern pharmacology, the study of the properties and reactions of drugs in relation to their therapeutic value, was being developed during this era. The British pharmaceutical company, Beecham, began patenting medicines in 1842 and there were several companies that would go on to manufacture pharmaceuticals in the upcoming century that were founded in the 1800s including Pfizer, Bayer, Solvay S.A., Eli Lilly, Johnson & Johnson, and Hoffmann‐La Roche.⁴

As the twentieth century began, the study of pharmacology and the relatively recent technological innovations of the time provided the foundation for the pharmaceutical industry as it exists today. Drug discovery in the 1930s focused on irrational design, screening natural products and finding active ingredients that could be made synthetically. In 1928, Penicillium mold was identified as being active against the bacteria staphylococcus. Penicillin was being mass produced and commercially available in the 1940s before the end of World War II.² By the end of 1944, Pfizer had perfected a method of production called the deep vat method and was the world's largest penicillin producer. The company was producing enough doses to treat 100 patients each month.⁵

The success of penicillin prompted scientists to research if other soil‐dwelling organisms could work better than penicillin for treating infection, or potentially, for treating infections that penicillin could not. Tuberculosis (TB) was then, and is still today, one of the more prevalent and deadly of bacterial infections. In 1943, a Nobel Prize‐winning scientist found a strain of streptomyces that was effective against TB and later dubbed the drug streptomycin. Merck developed streptomycin commercially and by 1949 began administering the drug around the world treating millions of TB sufferers.⁵

Finding, isolating, testing, and marketing a successful treatment for TB began an explosion in antibiotic research by the pharmaceutical industry. Nearly every major manufacturer had an antibiotic research unit by the 1950s with scientists testing a library of soil‐based organisms for the next cure.⁵ Drugs like vancomycin and erythromycin were developed during this time as scientists worked to find new drugs or ways to tweak the molecular structure of existing drugs. Antibiotic resistance was manifesting itself as a new problem shortly after penicillin was developed, and the need for new antibiotics was high.

While the need for new drugs to treat drug‐resistant bacteria remains high today, the interest in this area of research by the pharmaceutical industry is relatively low. By the 1980s, the industry began pulling out of antibiotic R&D ; by the 1990s, many of the largest companies were out completely or nearly completely out of this space, and by 2017, 15 of the 18 largest pharmaceutical companies had abandoned the antibiotic market.⁵ Pharmaceutical manufacturers would focus their energies from acute treatments to chronic maintenance medications.