S42909, a proprietary new chemical entity, is an inhibitor of β-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. S42909 has demonstrated vascular anti-inflammatory properties by preventing leukocyte endothelial cell adhesion, and vascular protection by reducing the expression of the endothelial cell dysfunction marker plasminogen activator inhibitor-1 (PAI-1) and decreasing matrix metalloproteinase-2 (MMP-2) activity. It is initially proposed for development for the oral treatment of venous leg ulcers.
During its preclinical development, S42909 has demonstrated promising pharmacological properties on wound healing, indicating that the compound may represent a potentially significant clinical advance in the treatment of venous lower limb ulcers by correcting the microcirculatory disorders associated with venous disease. Moreover, improvement of microcirculation should contribute to a better oxygenation of the damaged tissue, thus favouring ulcer healing.
Venous disease is quite common and represents a major cause for seeking medical advice. In the case of venous disease, the veins become weak or damaged, the blood venous circulation is impaired and the blood pressure inside the veins increases. Different studies demonstrated that a large part of the general population suffers from lower limb venous symptoms, including, for example: swelling of the legs or ankles (edema), pain in the legs while standing, leg cramps, aching, throbbing, or a feeling of heaviness in the legs, itchy legs, weak legs, thickening of the skin on the legs or ankles.
When the venous disease becomes severe, open lesions or ulcers can occur on the skin of the leg between the knee and the ankle. Venous leg ulcers are the most common type of leg ulcers, accounting for 60-90% of them.
Venous leg ulcers are open, often painful sores in the skin. In addition to the lower limb venous symptoms described above, symptoms of venous leg ulcers may also include: discoloration and darkening of the skin around the ulcer, hardened skin around the ulcer, red, flaky, scaly and itchy skin on the legs, swollen and enlarged veins of the legs and an unpleasant and foul-smelling discharge from the ulcer.
Epidemiological surveys suggest that 15% to 20% of the general population have early symptoms, warning of the disease onset, but without any visible or detectable sign of chronic venous disease.
It is agreed that 1% of the population will develop at least one episode of venous leg ulcer during their life with a higher prevalence in the elderly, ranging from 1.65 to 1.74% in adults aged 65 years and older.
Risk Factors and Causes
Risk factors for the development of venous leg ulcers include, for example: older age, female sex, obesity, leg trauma, deep vein thrombosis (DVT), phlebitis, varicose veins, congestive heart failure, family history of venous leg ulcers, high number of pregnancies, jobs involving long periods of standing, poor mobility.
General practitioners (GPs) are usually the primary care givers who examine patients presenting for the first time with a venous leg ulcer. In most cases, GPs will refer patients to specialists for the confirmation of the diagnosis. Depending on the causes of venous disease and existing patient co-morbidities and considering the interdisciplinary nature of venous disease, patients can be referred to numerous specialists. These primarily include specialists in phlebology, angiology, dermatology, cardiology, endocrinology, surgery, vascular surgery, internal medicine and podiatry (in the United States). A multidisciplinary approach is often required, and specialties involved will depend on local availability, the complexity of the wound and the patient’s needs.
The diagnosis of a venous leg ulcer is largely based on clinical symptoms and on clinical examination of the affected leg, although additional tests may be required, such as a Doppler study and a duplex ultrasonography.
- A Doppler study will confirm the venous disease and rule out peripheral arterial disease (a condition affecting the arteries) as a possible cause of the clinical symptoms. This involves measuring the blood pressure in the arteries at the ankles and comparing it to the blood pressure in the arms (ankle-brachial index).
- A duplex ultrasonography (duplex scan) is a painless method which looks at the veins and arteries (if needed) of the legs and feet to see how the blood circulates through them.
Treatment of Venous Leg Ulcers
Treatment of venous leg ulcers includes cleaning and dressing the ulcer, compression therapy, local treatments and surgical management.
Treatment usually involves: cleaning and dressing the wound; and 2) using compression, such as compression bandages or stockings to improve the flow of blood in the legs. Antibiotics may also be used if the ulcer becomes infected, but they do not help ulcers to heal.
Unless the underlying cause of the ulcer is addressed, there’s a high risk of a venous leg ulcer coming back after treatment.
The healing rate of venous leg ulcers is variable according to the size and duration of the ulcer and compliance to treatment.
With appropriate treatment, most venous leg ulcers heal within three to four months. However, after a first venous leg ulcer, another one could develop within months or years.
About 10% of ulcers are resistant to treatment and will not have healed after one year. There is also a high incidence of recurrence of ulcerations and 37% and 48% of ulcers will occur again after 3 and 5 years, respectively, after wound healing.