Analysis: Vincent Barry and his team initially developed clofazimine as a treatment for TB before using it against leprosy

By Robert Redmond and Paul Evans, UCD

The availability of and access to effective and safe medicines is one of modern society's biggest accomplishments. Production and distribution, along with understanding of how these medicines work, has led to enormous improvements in the quality and length of people’s lives. In the last 100 to 150 years, it has been estimated that life-expectancy in many parts of the world has almost doubled.

Of course, challenges in public health do still exist. Not every person on the planet, for instance, has access to healthcare of this type. There are conditions that need more effective medicines than those currently available and then the current pandemic demonstrates that we cannot be complacent as new medical emergencies appear. However, medicines to improve the symptoms of, or indeed cure, many of the common conditions we as a human race suffer from have been invented, produced, formulated and are available.

Since 1977, the World Health Organisation (WHO) has published and periodically updated an Essential Medicine List. The 21st version of this list contains 460 distinct medicines and represents what the WHO considers are the most effective and safe medicines to meet the health needs of a nation.

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From Down to Earth, the WHO have added new cancer treatment drugs to their Essential Medicine List

Most of these medicines are compounds that have carbon atoms at their core. The route to finding the ideal carbon-based compound to interact with something in the body that is not working as it should has been likened to finding the right "key" for a particular "lock." The process of searching for an ideal "key" typically requires large numbers of differently composed carbon-based compounds to be prepared in the laboratory.

The discovery and subsequent efforts to bring these medicines to the world's population is time-consuming and costly and usually take place with companies who have the financial wherewithal to do so. Estimates of the overall costs associated with bringing a completely new medicine to the market range from approximately $1 billion to $2.5 billion.

This makes the little-known story of a drug on this Essential Medicine List discovered by a small team of Irish scientists all the more amazing. This drug, called clofazimine, is used as part of a multidrug treatment that has proven to cure the serious bacterial infection that causes leprosy.

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From RTÉ Radio 1's Leap Of Faith, Michael Comyn talks to Ken Gibson from Leprosy Mission Ireland about the fight to eradicate this ancient illness

Clofazimine and its anti-bacterial action was uncovered by Dr. Vincent Barry and his team in Trinity College Dublin in the 1950s. Barry began his college education in the Royal College of Science for Ireland after winning a scholarship to study Organic Chemistry (the study of the chemistry of carbon-based compounds). Subsequently, he transferred to UCD and graduated with first-class honours in 1928. He then worked in University College Galway (now NUI Galway) as an assistant to Professor Thomas Dillon with whom he co-authored a chemistry textbook in Irish

Barry returned to Dublin in 1943 where he began to investigate treatments for tuberculosis (TB), a serious bacterial infection (related to leprosy) that was an enormous Irish and global health burden at the time. The research was funded by the Medical Research Council of Ireland (a forerunner for the Health Research Board) and Barry originally set up his laboratory in Merrion Street, Dublin where UCD’s chemistry department was once housed.

In 1950, Barry’s growing research team moved to a larger laboratory situated in TCD, and in 1954 clofazimine was first synthesised. Although the chemical structure of clofazimine is rather complex, it proved simple to prepare from cheap starting materials using established chemical reactions. Barry’s research team kept moving forward and together they proved that clofazimine was as effective at treating TB as the anti-bacterial agents available at the time. Ultimately, clofazimine was never used as a medicine for the treatment of TB, partly due to improvements in the medical management of this disease.

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From RTÉ Archives, George Devlin reports for RTÉ News on the 1990 closure of the Dublin lab where the anti-leprosy drug was first developed

However, it is clear that his team were only too aware of the terrible burden leprosy placed on society following their interaction with The Leprosy Mission, a charity founded in Ireland and based in Lincoln Place next to TCD and Barry's visits to leper colonies in India and Zimbabwe. Due to similarities between the bacteria causing TB and those leading to leprosy (they both belong to the same bacterial family), researchers around the globe made the connection and investigated clofazimine’s anti-leprosy effects.

A 1962 report by medical doctors Stanley G. Browne and Lykle Hogerzeil brought to light the useful anti-leprosy properties of the drug. These clinical trials were conducted in the Leprosy Research Unit at Uzuakoli in East Nigeria where Brown was senior leprologist and some of the most important research on treatments for leprosy was carried out.

In order to supply the drug to the world, clofazimine was initially manufactured by J. R. Geigy SA, a Swiss-based chemical/dye stuff company. They also funded many of the subsequent clinical trials involving clofazimine for the treatment of leprosy. That company is now part of Novartis, one of the largest chemical manufacturers in the world.

From Novartis, how the company are helping to treat the disease

We now know that leprosy is caused by a rod-shaped bacterium named Mycobacterium leprae. Unlike many species of bacteria, this organism multiplies very slowly and has an incubation period of about five years so symptoms take a while to present themselves, by which time the infection has taken hold. The worst effects of infection are noticeable on the skin and eyes, but the disease also affects the peripheral nerves and the upper respiratory tract, among other parts of the body. If the disease is allowed to progress - either due to poor patient adherence to the lengthy treatment (up to one year or longer due to the slow growth of the bacterium), or if no treatment is given at all, irreversible damage can occur.

Thankfully, the disease is now curable with a multidrug therapy regime. This effective combination of drugs consists of three compounds: dapsone, rifampicin and Barry’s clofazimine. Historically, this medicine has been provided free of cost by the WHO and Novartis and the synergistic effect of the three drugs included has saved millions of people from disfigurement, isolation and death. Apparently, Barry was directly involved in the negotiations between Geigy and the Indian government which led to the drug being freely available there.

It may surprise people to know that it is still not fully understood how clofazimine works. However, evidence suggests that the drug binds to Mycobaterium leprae’s DNA and in doing so inhibits its ability to grow. It also exhibits anti-inflammatory effects and as such is useful to control the development of inflamed subcutaneous lumps – a symptom of the more serious type of leprosy.

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From RTÉ Archives, Charlie Bird reports for RTÉ News in 1981 on the Irish scientists who will receive the UNESCO Science Award for their work into the treatment of leprosy

Although clofazimine’s legacy is already secure, it is still continuing to make medical headlines almost 70 years after its discovery. Researchers at the Hong Kong University have recently learned that clofazimine can inhibit coronaviruses, including SARS-CoV-2, when used in combination with the anti-viral agent remdesivir. This research is still in it is infancy but, based on these results, it may be an ideal candidate for future treatment of Covid-19 infections.

As the direct result of the skills of a small group of Irish scientists, clofazimine's impact will continue well into the future. Some members of Barry’s research team, which included Frank Winder, J. G. Belton, Michael L. Conalty, Joan M. Denneny, Deirdre W. Edward, John (Séan) F. O’Sullivan, Dermot Twomey and Stanley McElhinney, were awarded the UNESCO Science Prize in 1980 for their discovery.

Robert Redmond is a PhD candidate with the SSPC, the SFI Research Centre for Pharmaceuticals at UCD. Prof Paul Evans is a Funded Investigator with the SSPC and a lecturer in the Department of Chemistry in UCD. The authors thank Prof Brian Mc Murry and Prof Mary J Meegan from Trinity College Dublin for their advice on this piece.

The views expressed here are those of the author and do not represent or reflect the views of RTÉ