The hunt for a better cure for inflammation

PHARMA In 2020, Gesynta raised SEK 190 million in one of the year’s largest private biotech investments in the Nordic region. Now the company is one step closer to a new drug for systemic sclerosis. The future promises several innovative treatments for a number of inflammatory diseases, including cardiovascular disease and cancer.

However, the story can be said to have begun when Per-Johan Jakobsson worked as a postdoctoral fellow at Merck Frosst in Montreal, Canada, where he discovered a new protein family called MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) at the end of the 1990s. Once back home at KI, he continued research into mapping the protein family. His research led to the discovery of the enzyme microsomal prostaglandin E synthase 1 (mPGES-1).

“Many people previously thought the enzyme existed. We took on the challenging task of setting up the experiment that would confirm its existence. Since then, we’ve done a lot more work on this and today have a thorough understanding of it,” says Per-Johan Jakobsson, professor of translational inflammation research.

Substances that drive inflammation

The mPGES-1 enzyme plays a key role in the body’s ability to create inflammation as it helps to form the substance that drives the inflammation itself: prostaglandin E2. Prostaglandins are a group of hormone-like substances that are targets for some of our most common anti-inflammatory painkillers, such as Voltaren and Ipren.

These have many applications but do not work for all inflammatory diseases and they have a number of side effects. There has therefore long been a search for a more effective method of inhibiting inflammation, and mPGES-1 could hold the key to this.

Once back at KI, Per-Johan continued his postdoc with Bengt Samuelsson, who received the Nobel Prize for his work with prostaglandins in 1982. Together with Professor Rolf Morgenstern, they patented ways to inhibit mPGES-1 and founded NovaSaid in 2004 with the goal of finding a new drug.

“Several substances were also developed there that are now vital to prostaglandins research. But we never managed to create our own drug substance,” says Jakobsson.

However, the research was followed by others who succeeded in developing more promising substances, including Orexo and AstraZeneca.

Gesynta was founded in 2017 with the aim of developing new drugs that reduce inflammation and increase blood flow at the same time. First up is a drug for patients suffering from the autoimmune disease systemic sclerosis. Inflammation in these patients affects the smallest blood vessels – microvessels – which reduces circulation in the body’s tissues.

This in turn leads to serious complications in, for example, the kidneys, lungs and fingers, with acute suffering and sometimes even death as a result. Synthesis’ most advanced inhibitors of mPGES-1, GS-248, reduce inflammation and increase blood flow in small vessels. Due to the founders’ extensive knowledge and new substances, development has been rapid.

“Our first Phase I study had excellent results and we were able to show that GS-248 is not only safe, but also inhibits subjects’ mPGES-1. We’re now moving on to the next phase in a large international study to investigate what anti-inflammatory and vascular protective effects this inhibition has for patients with systemic sclerosis,” says Patric Stenberg, Gesynta CEO.

Support from KI Innovations

NovaSaid and Gesynta have been supported by KI Innovations with financing both the patent application and other early-stage activities. Most recently, Gesynta was part of the incubator programme Drive.

“This gave us support in the form of innovation checks, advice, and access to the broad network that surrounds the incubator,” says Stenberg.

The drug for systemic sclerosis is the start of finding other and more effective anti-inflammatory drugs for chronic inflammatory diseases. In addition, pre-clinical research has shown success in the treatment of cancer.

“We have shown that an inhibition of the enzyme mPGES-1 also resulted in reduced tumor growth in mice,” says Jakobsson.

mPGES-1 research now has support from the Swedish Research Council and the Cancer Foundation.

“It’s incredibly important that KI has an innovation player such as KI Innovations with a system for supporting innovations that emerge from research. It’s especially important for us as researchers who don’t want to run companies, but would rather continue with our research,” says Jakobsson.

Prostaglandin: a KI story

Prostaglandin research has largely been conducted at Karolinska Institutet. As early as 1935, Professor Ulf von Euler became the first person to isolate the hormone following its discovery in 1930.

In 1982, KI’s Sune K. Bergström and Bengt I. Samuelsson received the Nobel Prize for their research on prostaglandins together with American John R. Vane.

Today, Samuelsson is Professor Emeritus and one of those who worked close to him is Professor Per-Johan Jakobsson, whose research has now resulted in the establishment of Gesynta..

Founders: Gunilla Ekström, Charlotte Edenius, Urban Paulsson, Ralf Morgenstern, Per-Johan Jakobsson, and Patric Stenberg. Established: 2017.