This column deals with treatment strategies for rare genetic diseases. I would like to discuss the recycling of existing drugs. In technical terms, it is called “drug repositioning” or “drug repurposing.” In Korean, the term is also translated as “drug reinvention” or “drug recycling.” None of them are perfect, but I will use the term "drug repositioning" here.

It refers to the utilization of previously developed and used drugs to treat new diseases (or indications). In other words, the new indication is expanded, added, or changed. It is an innovative way to reduce costs and time compared to developing a completely new drug.

In other words, developing new uses (indications) for already approved drugs or drugs in development is an attractive strategy for discovering new disease treatments. In fact, in recent years, about 40 percent of the drugs approved as orphan drugs by the U.S. Food and Drug Administration have been developed using a "drug repositioning" strategy.

Why is this strategy gaining traction as a new drug development strategy? First and foremost, it is because of lower development costs, faster time to market, and higher success rates. The traditional drug development method requires basic research, preclinical research, and clinical research (phase 1-2-3), which usually takes 10-15 years to develop a new drug, and the success rate is less than 10 percent.

On the other hand, the "drug repositioning" strategy saves the cost and time of conducting new clinical trials because the safety and efficacy information of already approved drugs is already available. In addition, the use of a well-known drug reduces the risk of a new development phase. Phase 1 clinical trials, which include basic research and safety studies, are often omitted, shortening the timeframe by three to 12 years and increasing the success rate by 30 to 75 percent.

In particular, there is a huge unmet need in the treatment of rare diseases, with drugs developed for less than 5 percent of all rare diseases. Therefore, in order to rapidly develop safe medicines for the treatment of rare diseases, drug repositioning strategies that make existing drugs available for new uses (indications) are important.

Currently, there is an increasing number of studies utilizing drug repositioning, and many are underway. That is due to advances in computer technology and bioinformatics. The use of computer modeling and bioinformatics has helped to predict and discover new benefits of existing drugs.

However, there is a need to carefully database the side effects and adverse effects of drugs in clinical use. Therefore, post-marketing testing of drugs and registration of patients receiving orphan drugs are very important. Governments and drug agencies are working to support drug repositioning research and reduce legal obstacles. The pharmaceutical industry is also increasingly interested in repositioning and is working to identify potential new uses for existing drugs.

The history of drug repositioning can be traced back to aspirin.

Aspirin is well known for its ability to reduce fever, pain, and inflammation. Initially, it was widely used as a fever and pain reliever. However, in the 1950s, aspirin's antiplatelet effects were discovered. It was found to inhibit platelet aggregation, which helps prevent blood clots from forming. This led to the idea that aspirin could be used to prevent heart disease, and in the 1970s it became clearer that aspirin could be used to prevent thrombotic disease.

What about rare diseases, then? For example, we use erectile dysfunction drug sildenafil to treat pulmonary arterial hypertension in newborns, antihypertensive drugs to prevent aortic dissection in the rare disease Marfan syndrome, and the antitussive expectorant ambroxol in combination with enzyme replacement therapy to relieve neurologic symptoms in patients with neurologic Gaucher disease.

Also, the drug thalidomide was developed in Germany in the 1950s as a sedative and was considered safe enough to be used without a doctor's prescription. It was used to treat morning sickness in pregnant women. It was later removed from the market when thalidomide caused serious side effects, including babies being born with arm and leg deformities.

However, thalidomide's side effect of inhibiting new blood vessels has been recognized and used in limited cases to treat Hansen's disease, multiple myeloma, and cancer. In this case, the word "drug repurposing" can be translated as "drug recycling".

On the contrary, there are examples of drugs developed based on the pathophysiology of rare diseases not highly prevalent being used to treat very common conditions.

Examples include the use of antibody therapies in patients with severe hypercholesterolemia caused by hyperfunctional mutations in the PCSK9 gene, a rare disease, and the use of antibody therapies in patients with severe hypercholesterolemia caused by various causes of hypercholesterolemia, and the rare condition of nephrogenic diabetes, in which a gene mutation called SGLT2 reduces the ability of the renal tubules to reabsorb glucose, resulting in normal glucose levels in the blood but not glucose excretion in the urine.

For example, SGLT2 inhibitors were developed based on the pathophysiology of nephrogenic diabetes and used to treat type 2 diabetes, or GLP-1 receptor stimulating drugs were initially developed for diabetes and found to reduce appetite and weight during diabetes treatment, but were then tested in obese patients and approved for obesity treatment.

In this way, researchers are trying to expand or change the indications of already approved drugs through various clinical trials. Orphan drugs used to treat rare diseases can become so-called "blockbusters" for common conditions.

Of course, the opposite is also true as mentioned above. Drugs that have already been withdrawn from the market due to side effects can be recalled, and drugs that have failed for a specific indication in clinical trials can be developed into new treatments by focusing on other mechanisms. In other words, there is a need to rekindle the flame.

For the “repositioning of drugs”' strategy to be successful, careful observation by clinicians and insight by researchers to find the junction between drug mechanisms and pathogenesis are crucial.

Professor Yoo graduated from Seoul National University College of Medicine and trained at the Center for Jewish Genetics at Mount Sinai Hospital in the United States from 1989 to 1992 before becoming a board certified medical geneticist. He served as director of the Medical Genetics Clinic at Asan Medical Center and director of its Pediatric Hospital, and is currently a professor of the Department of Pediatrics and Adolescents at CHA Bundang Medical Center. He has served as president of the Korean Society of Pediatric Endocrinology, chairman of the Korean Society of Medical Genetics, director of the Center for Genomic Research on Congenital Malformations and Genetic Diseases at the Ministry of Health and Welfare, and chairman of the Planning Committee for the Conquest of Rare and Difficult Diseases Project at the Promotion Institute.