DUBLIN – Gesynta Pharma AB raised SEK190 million (US$20.6 million) in new funding to move GS-248, a selective inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), into a phase IIa trial in systemic sclerosis.

The study is due to get underway toward the year end. “It’s going to be in the second half of the fourth quarter,” Patric Stenberg, CEO of Stockholm-based Gesynta, told BioWorld. “It’s the microvascular dysfunction we’re targeting in patients,” he said. “It’s the major debilitating feature of systemic sclerosis.”

The condition, also called systemic scleroderma, is an autoimmune disorder, which can be limited to the skin or which may also affect internal organs. It is characterized by the occurrence of episodes of Raynaud’s phenomenon, an extreme sensitivity to cold temperatures arising from poor blood flow to the extremities. That is followed by the excessive production and deposition of collagen, which causes fibrosis. Patients can develop painful skin ulcers, which severely limit their ability to conduct everyday activities. About 15% develop pulmonary arterial hypertension (PAH), said Stenberg, which has a 50% fatality rate within three years.

The condition is complex and heterogeneous but immune system dysfunction and blood vessel damage are part of a triad of symptoms, which also includes tissue remodeling arising from fibrosis. GS-248 has a dual mechanism of action, with anti-inflammatory and vasodilatory effects, both of which are relevant to the pathology. It acts on the arachidonic acid metabolism pathway, by inhibiting the conversion of cyclooxygenase-generated prostaglandin H2 (PGH2) to PGE2, a potent mediator of inflammation. The unused PGH2 is then shunted into a prostacyclin synthase pathway, in which it is converted into prostacyclin (PGI2), a short-acting but potent molecule with vasodilatory and antithrombotic effects.

Company co-founder Per-Johan Jakobsson, of the Karolinska Institute, and colleagues, uncovered that second aspect of mPGES-1 inhibition, which opens up the prospect of drugs that have the anti-inflammatory effects of cyclooxygenase 2 (COX-2) inhibitors, without their cardiovascular risks. In contrast with GS-248, COX-2 inhibitors result in decreases in both PGE2 and PGI2. “We are actually generating prostacyclin in situ,” Stenberg said.

The program itself has a complicated backstory. It was originally developed by Biolipox, which gained considerable investor backing 15 years ago for its work with PGES-1 inhibitors. It licensed the program to Boehringer Ingelheim GmbH, of Ingelheim, Germany, around that time, and was then acquired by Uppsala, Sweden-based Orexo AB, to which Boehringer returned the project in 2014. Gesynta, which was founded in 2017, subsequently picked it up from Orexo.

A placebo-controlled phase I study, reported at the Eular 2020 E-Congress in June, demonstrated that oral GS-248 was safe and well-tolerated in healthy volunteers and that its pharmacokinetic profile supported once daily dosing. An ex vivo whole blood assay demonstrated that a single dose of GS-248 completely shut down mPGES-1 activity within 24 hours, while also reducing renal excretion of PGE2 and increasing excretion of PGI2 and thromboxane, another PGH2 metabolite.

Details of the forthcoming phase IIa design are not yet available, as Gesynta is finalizing the protocol with the help of clinical investigators. There are no drugs approved in the U.S. for the microvascular aspects of systemic sclerosis, but two are available in Europe.

Tracleer (Bosentan, Actelion Pharmaceuticals Ltd.), an endothelial receptor antagonist best known as a PAH drug, is also approved in Europe for reducing the development of new digital ulcers in systemic sclerosis. In one placebo-controlled study in 122 patients, it reduced the occurrence of new digital ulcers by 48%; in a second placebo-controlled study in 188 patients, the reduction was 30%. It had no effect on healing existing ulcers, however.

Ilomedine (iloprost), a prostacyclin analogue, has a long history of use and is effective at resolving existing ulcers – rates of 70% and 90% have been reported in clinical studies. “What really works best I would say is Ilomedine,” Stenberg said. However, it requires six hours of intravenous administration several times per week. “It’s pretty cumbersome,” he said. “It’s pretty bad for quality of life.” Attaining a similar level of efficacy with an oral drug would represent a substantial gain, therefore, and enable patients who are now unable to work to become economically active.

With the new infusion of cash in hand, Gesynta can now test the hypothesis that inhibiting mPGES-1 could work. It is the first to employ a member of this drug class in the microvascular injury associated with systemic sclerosis. “There have been failed attempts with oral prostacyclin analogues in this indication,” Stenberg said.

The funding round was led by new investor Hadean Ventures, a life sciences investor focused on the Nordic region, which operates from Oslo and Stockholm. Existing investor Industrifonden and a number of undisclosed private funds also participated. Hadean partner Roger Franklin is joining the Gesynta board in conjunction with the funding round.

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