The Father of Statins passes away: The Legacy of Dr. Akiro Endo

The scientific community mourns the loss of Dr.Akiro Endo, whose death was announced by the Tokyo University of Agriculture and Technology where Dr.Endo was a professor emeritus. Dr.Endo’s groundbreaking research has been compared to the discovery of penicillin and led to the development of statins, a class of drugs that revolutionized the treatment of high cholesterol.

From Rural Roots to Scientific Renown

Born in 1933 to a farming family in northern Japan, young Akiro Endo’s passion for science was ignited by his grandfather’s interest in medicine. Akiro Endo was fascinated with mushrooms and other Molds and dreamt of becoming a scientist. Akiro Endo pursued a career in science, and graduated from Tohoku University in 1957 with a degree in agricultural studies. Akiro Endo was inspired by Alexander Fleming’s discovery of penicillin and deeply impressed that antibiotics saved many lives. Akiro Endo joined the Japanese company Sankyo, was assigned to one of the applied microbiology groups where he worked on developing and isolating enzymes, their purification, elucidation of properties

A Journey through Cholesterol Biosynthesis

At this point Akiro Endo became interested in Cholesterol biosynthesis and wished to work with Dr. Konrad Bloch in United States. Dr. Bloch was awarded Nobel prize for his research on Cholesterol bio synthesis in 1964. The research of Konrad E. Bloch, Feodor Lynen, John Cornforth, and George Popják had worked out the complex pathway by which cholesterol was synthesized in the body, involving 30 enzymatic reactions. Cholesterol synthesis takes place in the body in four stages. (1) condensation of three acetate units to form a six-carbon intermediate, mevalonate; (2) conversion of mevalonate to activated isoprene units; (3) polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene; (4) cyclization of squalene to form the steroid nucleus, with a further series of changes to produce cholesterol. The third reaction in the first stages is the rate-limiting step. Reduction of HMG-CoA to mevalonate is the major point of regulation on the pathway to cholesterol.

But Dr.Endo could not join to work with Dr. Konrad Bloch, and joined Albert Einstein College of Medicine in New York City and worked on role of phospholipids in an enzyme system for 2 years, from 1966 to 1968. During his time in America, Dr Endo observed that coronary heart disease was a leading cause of death, with over 10 million people affected by hypercholesterolemia, a precursor to coronary heart disease. Dr.Endo returned to Japan in 1968 and rejoined Sankyo who gave him opportunity to work on project of his choice.

The Quest for a Cholesterol-Lowering Drug 

In the human body, the liver produces more cholesterol than is taken in from food. Many companies were searching for molecules that would block one of the 30 steps in the synthesis of cholesterol from acetyl-coenzyme A in the human body. Antibiotics were known to inhibit many different kinds of enzymes, but no metabolites that inhibited enzymes involved in cholesterol synthesis had been isolated previously. Studies suggested that the inhibition of HMG-CoA reductase would be an effective means of lowering plasma cholesterol in humans. Dr.Akiro Endo speculated that fungi like molds and mushrooms would produce antibiotics that inhibited HMG-CoA reductase. Dr.Endo and his team began their project using culture broths of thousands of fungi in April 1971.

Discovery of Compactin: The First Statin

After scanning through thousands of culture broths, Dr. Endo and his team identified a particularly active strain of the blue-green mold Penicillium citrinum with potent inhibitory activity. By July 1973, they successfully isolated three metabolites from this culture that demonstrated significant inhibitory effects on cholesterol synthesis both in vitro and in vivo. The most active among the three was ML-236B, also known as Compactin. Dr. Endo’s team noted that Compactin bore a structural similarity to HMG-CoA, the substrate of the enzyme HMG-CoA reductase, the rate-controlling enzyme in cholesterol synthesis. This structural similarity made Compactin an extremely potent competitive inhibitor, very specific to HMG-CoA reductase. In 1976 Dr.Akiro Endo and team published two papers reporting the discovery and characterization of Compactin, the first statin

Merck isolates Lovastatin

The Pharmaceutical giant Merck who was also on the quest for a cholesterol reducing drug, learnt about Dr.Akriro Endo and his team’s work on Compactin and its role in inhibition of Cholesterol synthesis in the human body. In 1976, Dr. Roy Vagelos, then President of Merck Research Laboratories, entered into a confidentiality agreement with Sankyo. This agreement granted Merck access to Compactin samples and the confidential experimental data from Dr. Endo’s research. Merck embarked on its own journey into statins under the guidance of Alfred Albert. By February 1979, Merck team isolated another new statin, structurally akin to Compactin, from the fungus Aspergillus terreus. This novel compound was initially named mevinolin and would later be known to the world as Lovastatin.

Early Clinical studies and set backs

Buoyed by the early efficacy studies of Compactin, Sankyo initiated a Phase 1 clinical study in 1978. However in August 1980, Sankyo discontinued the clinical development of Compactin, due to concerns that the drug induced lymphoma in dogs in the clinical studies. But the dogs were receiving extremely high doses of Compactin, about 200 times the dosage that would be used in patients. Merck also started its preliminary clinical studies of Lovastatin in April 1980 but after 5 months, the studies were discontinued because of rumours that the closely related compound Compactin, caused certain cancers in dogs.

Overcoming Challenges: FDA approves Merck’s Lovastatin, First Commercial Statin

However, by July 1982, a series of studies revealed that treatments with Lovastatin and Compactin were significantly lowering LDL cholesterol levels with minimal side effects in patients suffering from severe hypercholesterolemia and were unresponsive to existing medications. These encouraging results prompted Merck to commence extensive clinical trials and toxicity assessments of Lovastatin in 1984. The trials confirmed that Lovastatin effectively decreased cholesterol levels without causing tumors. Based on these findings, Merck submitted a New Drug Application to the USFDA in November 1986. Subsequently, in September 1987, the FDA approved Lovastatin, marking its entry as the first commercially available statin.

Conclusions

Since the commercialization of the first statin, the pharmaceutical market has witnessed the introduction of several statin drugs, including two semi-synthetic statins—simvastatin and pravastatin—and four synthetic statins—fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. Today, statins rank among the most widely sold class of drugs globally, with an estimated 200 million people benefiting from the medication. The world truly owe it to Dr.Akiro and his team for a live that is lived under vastly improved conditions for countless individuals.

Acknowledgements:

• Endo A. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(5):484-93. doi: 10.2183/pjab.86.484. PMID: 20467214; PMCID: PMC3108295.
• Akira Endo, researcher who found cholesterol-fighting statins, dies at 90; The Washington Post