Chronic inflammation in the body’s smallest blood vessels, the microvasculature, may lead to tissue damage due to impaired blood flow. The location of the affected microvessels impacts the clinical manifestation. If inflammation occurs in the microvasculature of the fingers and toes, the patient is often forced to live with debilitating ulcers and severe pain. In many cases, organs such as the kidneys and the lungs may be affected. The cause of chronic inflammation in the microvasculature can vary, but often it is the result of an underlying medical condition. Current pharmaceutical treatments lack precise drug targeting, are often ineffective, and may have safety and tolerability issues.
Microsomal prostaglandin E synthase (mPGES-1) is an enzyme generally present at low levels in the human body. It stimulates production of prostaglandin E2 (PGE2), a potent biological messenger that has a pronounced impact on inflammation. During inflammation the levels of mPGES-1 are upregulated, causing excessive levels of PGE2, which drive the inflammatory symptoms. Harmful inflammatory processes in the microvasculature can lead to severe tissue damage and pain, in worst cases causing gangrene and the need for amputation. In autoimmune diseases such as systemic sclerosis, the chronic inflammation may over time lead to painful co-morbidities and, in some cases, premature death.
Systemic sclerosis, also known as scleroderma, affects around 2.5 million persons globally. A majority of patients are women. In the major markets – the U.S., Germany, France, Italy, Spain, the UK, and Japan – approximately 240,000 people are affected. In Sweden, about 2,000 people are diagnosed with systemic sclerosis. Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are two examples of complex chronic complications that are commonly observed in systemic sclerosis patients. PAH, as an example, arises due to widespread injury in the microvasculature of the lungs and often leads to increased mortality. More acutely, about half of all patients develop painful, difficult-to-heal digital ulcers that significantly impede everyday activities.
Learn more about systemic sclerosis under “further reading” below.
In the early stages of systemic sclerosis, sudden episodes of decreased blood flow may occur in the fingers and toes, leading to discoloration, pain, and impaired fine motor skills. These episodes are known as Raynaud’s phenomenon and are seen in almost all patients with systemic sclerosis. While such episodes can also occur in otherwise healthy individuals, they affect systemic sclerosis patients more often, are more pronounced, and may lead to severe pain on a daily basis. About 95% of all systemic sclerosis patients suffer from Raynaud’s phenomenon, and as the microvascular damage progresses, the lack of proper blood flow may give rise to digital ulcers.
About half of all patients with systemic sclerosis develop ulcerations of the fingers and toes, digital ulcers. These injuries are difficult to heal and cause extreme pain. Unfortunately, the number of approved pharmacological treatments is extremely limited and may carry adverse effects. Due to the location of the ulcers, everyday activities such as taking a walk, opening a car door, putting on gloves or using a computer keyboard become almost impossible. The demand for efficacious and safe treatments that can reduce pain and improve patients’ quality of life is therefore large.
Available treatments of chronic microvascular dysfunction in systemic sclerosis provide insufficient efficacy and may cause adverse effects. To date, there are no approved products for the treatment of digital ulcers in the U.S., and only two in Europe – the prostacyclin analog iloprost and the endothelin receptor antagonist bosentan. However, neither provides optimal efficacy or tolerabilty. The lack of safe and efficacious drugs with a specific effect on digital ulcers has led to the use of drugs intended for the treatment of other indications. The use of these regimens is often constrained by dose-limiting side effects and the efficacy is often limited.
References to key academic papers, patient advocacy organization websites or company documents available for sharing.
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Systemic sclerosis is an autoimmune disease hallmarked by chronic inflammation in the body’s smallest blood vessels.
Half of systemic sclerosis patients develop difficult-to-heal digital ulcers, hampering many everyday activities.
Raynaud’s phenomenon affects most systemic sclerosis patients. It is often the first sign of the disease.
Our lead drug candidate GS-248 is currently under evaluation in a phase 2 study.