by Åsa Malmberg, Uppsala University

Anders Hallberg follows the work in the lab with interest. To his right is Marcus Söderström. Credit: Mikael Wallerstedt

During the 1990s, medicinal chemist Anders Hallberg was working in his lab at the Department of Medicinal Chemistry. He was exploring a hormonal system in the body that regulates blood pressure, among other things, by designing different molecules. Thirty years later, one of these molecules has been developed into a drug candidate to treat a severe and incurable disease, idiopathic pulmonary fibrosis, and is now being tested on patients in multiple countries.

"As we have seen in clinical trials, what our substance does is improve lung capacity in patients. On average, a couple of people die each day in Sweden from this rare disease," says Hallberg, emeritus professor at the Department of Medicinal Chemistry and former Vice-Chancellor of Uppsala University.

When developing and designing these different molecules, there was initially no aim to target any specific disease. The focus for Hallberg and his colleagues was primarily to better understand a hormonal system in the body called the renin-angiotensin system (RAS). It regulates blood pressure and fluid balance but is also involved in a variety of other functions in the body. The research group wanted to see if they could switch functions in the RAS on and off with the help of specially designed small molecules.

Molecules activating only the AT2 receptor

In particular, they were interested in being able to steer and activate the angiotensin II type 2 receptor (AT2 receptor), which is one of two receptors in the RAS. Its function was largely unknown, but Hallberg had inklings that it could do good things in the body when it was switched on. So he wanted to produce molecules that activated only the AT2 receptor but not the other receptor, the AT1 receptor, as this would instead lead to problems such as an unwanted rise in blood pressure.

"Early in our research, the AT2 receptor was considered to belong to what is now commonly called the protective arm of RAS and seemed to be expressed somewhat more in the course of certain diseases. So we wanted to produce selective drug-like molecules that only activated the AT2 receptor to help determine what effect it had," says Hallberg.

Began to tailor-make substances

Hallberg collaborated with Lars Fändriks from Sahlgrenska Academy in Gothenburg, and they began to tailor-make substances that could potentially be suitable for this purpose. They created a large number of these substances, and one of the small molecules in particular, which was named C21, proved to be especially promising.

In addition to being able to activate the AT2 receptor, the molecule was designed so it could be delivered in tablet form and absorbed from the gastrointestinal tract, and to be relatively long-lived in humans. All of these properties are important for a future drug.

However, the road from basic research to a market-ready drug was and is very long. Two important steps towards that goal were taken in the early 2000s when Hallberg, with Fändriks and others, founded the company Vicore Pharma and patented C21 and other similar molecules. What drove them to start the company was the opportunity to help seriously ill patients have a better life.

"As scientists, we are just looking for new knowledge. But if it turns out that we have a molecule that really works, it's our duty to help it get to market. So we had to start the company where further drug development could be done while we continued our basic research at the university," he says.

May be a key to treating lung diseases

When Hallberg became Vice-Chancellor of Uppsala University in 2006, his research was pretty much put on hold. The new role demanded his full attention. He also temporarily left his engagement with Vicore Pharma. But the company continued to work on C21.

Over the past few years, nearly 200 scientific articles have been published on C21 and its effects on various systems in the body. The researchers at Vicore Pharma found that the substance may be a key to treating lung diseases that have previously not been treatable.

"It's been recently discovered that the AT2 receptor is found in the lung's alveoli, the lung's air sacs, and it seems to be central to the proper functioning of the alveoli," explains Hallberg.

One disease that C21 appears to be effective against is idiopathic pulmonary fibrosis. This disease causes scar tissue in the lungs and eventually makes them so stiff that, over time, it becomes impossible to breathe. There is currently no cure.

Successful trials on patients

As a drug candidate, C21 has now been named buloxibutid. The first clinical trials in which patients have been able to test the drug have proved successful. Buloxibutid is the very first drug candidate to activate the AT2 receptor and to be evaluated in humans.

A larger study of 270 patients from 14 countries, including the United States, has now been initiated. The French pharmaceutical group Sanofi invested heavily in Vicore Pharma just before this study started. In total, they have purchased shares to a value of SEK 102 million. The study is estimated to cost about half a billion SEK to carry out.

"Of course it's going to be extremely interesting to see if buloxibutid will be shown to have as positive an effect in a large placebo-controlled study as in the smaller study that has been done so far," says Hallberg.

Provided by Uppsala University