The "Four Revolutions" of pharmaceuticals: The Singularity and the birth of Kings on the road to new drug development



The development of new drugs is the cornerstone of the pharmaceutical industry.

Chemical purification and synthesis technology opened the modern pharmaceutical industry;

Target-based pharmaceutical research and biologics began to rise, driving the CRO format;

The birth of translational medicine has promoted the rapid application of research and development results to the clinic.

The emergence of AI will trigger a big explosion in the development of new drugs.

These key technologies have become key nodes in the research and development of new drugs, giving birth to the birth of the "king". Those who were able to master these revolutionary technologies first eventually formed the echelon of the world's leading pharmaceutical companies.

01, chemical synthesis drugs, laying the modern pharmaceutical pattern

The development of pharmaceutical industry has gone through different stages from chemical drugs to biological agents.

Since around 1805, pharmacists have isolated pure chemical components from traditional medicinal plants, such as morphine and cocaine.

By 1895, German dye manufacturers had perfected the purification of individual organic compounds and established basic methods for organic chemical synthesis. A number of chemical synthesis drugs were born, such as anesthetic ether, aspirin and so on.

"Chemical synthesis drugs" opened the modern pharmaceutical research and development, and also gave birth to a group of the earliest modern pharmaceutical companies, Pfizer, Merck, Roche, GSK, Novartis, BMS, AbbVie... They account for almost 70% of the TOP10 global pharmaceutical companies in 2020.

Among them, German-Merck is the world's oldest modern pharmaceutical company,

In 1804, he mastered the technique of isolating and purifying morphine in his laboratory.

The large-scale production and commercial sale of morphine began in 1827, ushering in the commercialization of modern pharmaceuticals.

Uk-gsk (the 9th pharmaceutical company in the world in 2020), began to produce patented drugs in 1842, and became the world's first pharmaceutical factory in 1859.

United States - Pfizer (2020 global pharmaceutical company 7th).

During the American Civil War (1861-1865), due to the soaring demand for painkillers, anti-infection, etc., the drug sales business began to develop rapidly.

In addition, due to its leading chemical production technology, it has become one of the largest chemical companies in the United States by the early 20th century, and has since laid the foundation for its shift to pharmaceutical research and development production.

United States -BMS (2020 global pharmaceutical company 6th).

During the American Civil War (1861-1865), he became a major medical products middleman for the Union Army.

Clinton Pharmaceuticals was purchased in 1887.

In 1890 he introduced his first product Sal Hepatica (a mineral salt laxative).

United States - Eli Lilly, founded in 1876 and began marketing the malaria drug quinine.

In 1883, it produced its first best-selling product, Succus Alteran, for the treatment of syphilis and certain types of rheumatic and skin diseases such as eczema and psoriasis; Revenue from the product has helped fund its expansion of production and research.

Novartis, Switzerland (formed in 1996 by the merger of two Swiss companies Ciba-Geigy and Sandoz Laboratories, the world's second largest pharmaceutical company in 2020).

In 1917, Sandoz began drug research.

In 1943, Swiss chemists Arthur Stoll and Albert Hofmann discovered the psychedelic effects of lysergic acid diethylamine (LSD) in Sandoz's laboratory.

Sandoz began marketing it as a psychiatric drug in the mid-1960s.

Switzerland - Roche (2020 global pharmaceutical company No. 1), founded in 1894, mainly produces a small number of pharmaceutical and chemical products.

In 1896, the business began to focus on: specialty prescription drugs, plant alkaloid drugs and extracted synthetic drugs.

United States - Abbott, (AbbVie spun out in 2012, ranked No. 3 global pharmaceutical companies in 2020).

In 1894, the Abbott alkaloid Company was founded.

In 1916, Chlorazene, the first synthetic antibiotic, was produced.

United States - Merck, (separated from Merck, Germany, the 5th pharmaceutical company in the world in 2020) was founded in 1891.

In 1903, a new pharmaceutical plant was built in New Jersey to replace the original pure import business.

In 1917, during World War I, all German businesses in the United States were confiscated and separated from German Merck.

02, targeted drugs and biologics, CRO value highlights

Research into pharmaceutical processes based on compounds flourished until molecular biology became widespread in the 1960s.

Since then, under the guidance of molecular biology and high-throughput screening, target-based pharmaceutical research and biologics have begun to rise.

The period from the late 1980s to around 2000 saw technological innovation and the introduction of a series of blockbuster drugs.

In 1986, the first therapeutic monoclonal antibody (Orthoclone OKT3) was approved to prevent kidney transplant rejection, but murine monoclonal antibody (now withdrawn);

In 1986, the first anti-tumor biotech drug alpha-interferon (Intron A) came to market, from Merck, Germany;

In 1990, the first personal-source antibody preparation technology was established;

In 1997, Rituxan, the first therapeutic targeted antibody, came to market from Roche.

In 1998, the first tumor therapy targeted antibody Herceptin (Herceptin) came to market, from Roche;

In 1998, Amgen's Neupogen was launched and became the first blockbuster biotech drug (annual sales of more than $1 billion).

In 2001, Novartis' Imatinib (Gleevec) was launched and is considered to be the first targeted drug for tumor therapy

In 2002, the first fully human monoclonal antibody drug Humela (adalimumab) was approved for market, and the annual sales of more than 20 billion US dollars was born.

Target-based pharmaceutical, the requirements for clinical research has also been further highlighted.

In the process of new drug development, clinical research can confirm or reveal the effects of experimental drugs, adverse reactions, etc., is an important way to judge whether a new drug can be used for treatment, and has become the stage with the highest cost of time and money.

During the flourishing period of chemical drugs in the 19th century, the clinical trials of various pharmaceutical manufacturers were in separate affairs without unified supervision. At this time, clinical trials were mainly regulated at the level of ethics and morality.

With the formal establishment of the FDA in 1930, the parallel of ethics and regulations became the industry standard, and the clinical trial teams of various pharmaceutical companies began to standardize. Among them, Merck is at the forefront of clinical trials.

In 1933, Merck's research laboratory was established in Rahway, New Jersey, covering the full range of functions from basic research to clinical trials, which may be an important cornerstone of its new drug development.

In early October 1941, during World War II, four companies - Merck, Pfizer, Squibb and Lederle Laboratories - held a secret meeting with U.S. government experts at the Carnegie Institution to discuss the possibility of growing penicillium and extracting penicillin.

In March 1942, less than five months after the project began, the Medical Research Board first approved Merck's penicillin clinical trials. It provided an important basis for the mass production of penicillin.

Since then, the importance of clinical trials has aroused further attention from various pharmaceutical manufacturers, including Eli Lilly and Pfizer;

In 1934, Lilly opened two new facilities in the McCarty Street building: a replica of Lilly's 1876 laboratory and the new Lilly Research Laboratory, which was "one of the most well-equipped facilities in the world."

In 1950, Pfizer discovered oxytetracycline (the first antibiotic it independently discovered), marking its transition from a fine chemical manufacturer to a research-based pharmaceutical company, and officially launched its research laboratories.

In 1960, Pfizer moved its medical research laboratory operations from New York City to a new facility in Groton, Connecticut.

The soaring cost of research and development and the focus on clinical research have also led to the birth of a new form of the pharmaceutical industry CRO (pharmaceutical research and development contract outsourcing service).

From the early 1980s, with the development of modern biotechnology, target-based drug research and biopharmaceutical began to flourish, so that the overall development costs soared, the average cost of new drug research and development in the United States rose from $138 million in 1975 to $802 million in 2000.

In 1982, Quintiles, the first modern commercial CRO, was founded.

The profits are thinner, but the risks are bigger. In order to manage the drug development process more effectively, and to reduce costs and maximize profits, large pharmaceutical companies and biotechnology companies are beginning to consider contracting clinical research to CRO enterprises, providing a niche market for the development of CROs.

Beginning in the late 1990s, the CRO service market began to grow explosively, rising from 4% in the early 1990s to 50% in the mid-2000s.

03, the human genetic code "cracked", pharmaceutical companies into the era of translational medicine

In 2000, the sketch of the human genome was drawn, representing the initial success of the exploration of the human genome, and laying the foundation for precision medicine thereafter.

Since then, on the basis of this technology, the precision efficacy of drugs has been more patient-centered, and it is more aware that many new drugs have a certain disconnect with the clinic in basic research, which has increased the failure rate in the clinical trial stage. The concept of "translational medicine" was introduced at this turning point.

Translational Medicine is known as the last mile of new drug discovery.

The purpose is to combine basic research and solve the practical problems of patients, and its basic feature is multidisciplinary cooperation, in-depth basic research for clinical problems, so that the research results can be applied quickly. From the laboratory to the bedside.

In 1992, Choi, a neurologist at the University of Washington School of Medicine in the United States, first proposed Bench to Bedside, that is, from the laboratory to the clinic, in the journal Science.

Translational medicine first appeared as a new term in 1996 in an article in The Lancet.

In 2003, "Translational medicine" was first formally proposed by the National Institutes of Health (NIH).

Since then, the world's top pharmaceutical companies have begun to set up their own translational medicine teams, with Pfizer taking the lead.

Pfizer first established the Translational Medicine team in 2004, focusing on oncology and immunology. And leading translational medicine is perhaps a microcosm of Pfizer's focus on research and development.

Increasing investment in research and development, by 2000, the proportion of research and development expenses revenue rose to 16.8%.

Other translational medicine teams include the founding of the Translational Medicine Research Center (TMRC) in Singapore in 2009.

In addition to creating their own, some pharmaceutical companies have also created translational medicine centers in conjunction with university research institutes, such as

In 2010, Roche established a "strategic alliance" with the University Hospital in Basel to establish the Center for Translational Medicine Research.

In 2012, Bristol-Myers Squibb entered into a strategic partnership with the Duke Institute for Translational Medicine to strengthen translational medicine.

However, due to the large number of departments and personnel involved in translational medicine, high expenditure or its core problem of slow development, especially in the early stage of clinical trials, only a small proportion of trials have been proved to have economic value, and the contradiction between high input and slow output is difficult to solve.

On the other hand, since 2010, the return on R&D of biopharmaceutical companies has been declining, even at one point only about 1.9%. A new solution needs to be found.

Therefore, with the penetration of AI technology in the field of big health, the pharmaceutical industry is also targeting this technology that saves labor and time costs and may disrupt the industry.

04, AI and agile development, the next stop for new drug research and development

The application of AI in vaccine development and drug research is still in the exploratory stage.

With its support in the new drug development process, including:

Drug discovery: target discovery, compound synthesis, new indication discovery;

Preclinical studies: compound screening, crystal type prediction;

Clinical trials: patient recruitment, clinical trial design

In the global pharmaceutical field, by 2020, the TOP10 pharmaceutical companies Roche, Pfizer, Novartis, Merck, GSK, AbbVie, Johnson & Johnson, Sanofi, BMS, Takeda have carried out AI new drug research and development outsourcing cooperation layout.

The earliest was Merck (Merck), which cooperated with Numerate, an American AI drug development company, to conduct cardiovascular disease target research in 2012.

Pharmaceutical companies partly outsourced AI research and development cooperation, source: Firestone Creation collated according to public information

Just as previous clinical trials, translational medicine and other new drug research and development have undergone changes, the head pharmaceutical companies are also setting up their own AI research and development team, including Pfizer, Roche, Astrazeneca, Eli Lilly, Merck, GSK and so on.

As can be seen from the above data, Novartis and Astrazeneca lead all pharmaceutical companies in both research and development projects and paper publication.

After the establishment of Novartis' AI Innovation Lab in October 2019, cooperation with Microsoft is also in full swing.

Astrazeneca has always been a leader in digital innovation, and at an investor conference in March, its executive vice president of biomedical Research and development, Dr. Mene Pangalos, said that 50% of Astrazeneca's small molecule development projects are now assisted by AI.

The company's in-house REINVENT technology platform enables the creation, selection and validation of candidate molecules through a computer program, while the AiZynth technology platform helps predict the optimal small molecule synthesis route.