Ulcerative colitis (UC) is a chronic disease that causes inflammation and ulcers (sores) on the inner lining of the large intestine and commonly results in bloody diarrhea. Severe disease can require the surgical removal of parts of the colon.
The disease usually begins gradually and worsens over time. However, it is also an intermittent disease with active periods of disease or "flares" followed by symptom-free remission that can last for weeks or years. This does not seem to be influenced by the severity of disease but patients with more extensive disease (covering more of the colon) are less likely to remain in remission. There is no curative medical therapy at present and the goal of current therapy is to eliminate symptoms initially (induction) and then to keep patients in remission (maintenance) in the long-term.
Symptoms and cause
UC patients typically present with rectal bleeding, diarrhea, an urge to evacuate the bowels but with passage of little stool (tenesmus), and lower abdominal pain which can include painful abdominal cramping with bowel movements. When symptoms first appear, most people with UC have mild to moderate symptoms and around 10% have severe symptoms. In severe disease, signs of toxicity become apparent and in very severe disease, known as fulminant or toxic colitis, or toxic megacolon, death can ensue unless treated promptly.
The pathogenesis of disease is unclear but it is believed to be initiated by the breakdown of the colonic mucosal barrier triggering the release of inflammatory molecules (cytokines), leading to an inappropriate immune response. Evidence suggests a genetic component to the disease and that environmental factors including diet, stress and certain drugs may act as a trigger.
As an inflammatory disease, UC increases risk of developing colon cancer, particularly when a person has UC for at least 8 years and or it affects the entire colon. High risk individuals are advised to have frequent checkups.
Prevalence and diagnosis
UC is estimated to affect between 8 to 246 out of every 100,000 individuals, with between 1 to 20 new cases per 100,000 individuals each year. It can occur at any age but it is more common in people between the ages of 15 and 30 and people over 60. Endoscopies of the large intestine are the most accurate methods for diagnosing UC and ruling out other possible conditions, such as Crohn's disease.
Treatment and unmet needs
Treatment depends largely on how widespread the disease is (level of involvement), severity and symptoms. Drug therapy is the first line of treatment in an attempt to initially induce remission, resolve symptoms and enable mucosal healing of the colon lining, and thereafter to maintain remission for as long as possible (maintenance therapy). Depending on the site of the active disease, medications may be administered by enema to treat the disease directly ie locally either by rectal foams or a suppository.
Current first-line therapy is with a class of anti-inflammatory compounds called aminosalicylates (including 5-ASA drugs such as sulfasalazine and mesalazine) and or corticosteroids (such prednisone) followed by second-line and third-line therapies involving immunosuppressants (such as azathioprine) and biologicals (such as such as infliximab and adalimumab, both anti-TNF-alpha drugs). However, there are safety concerns with long-term steroid use and toxicities associated with immunosuppressants and biologicals which restrict their usage, particularly in the long-term. Moreover, first-line therapy fails in an estimated 50% of patients and despite current treatments, approximately 15% of patients will end up requiring a partial or total colectomy. While surgery can be effective cure for UC, it is considered a last resort because it has significant negative implications for the patient. As a result, there is a pressing need for new treatments that are safe, effective and well tolerated both in the short-term and in the long-term maintenance of UC patients.
TopiVert’s NSKIs, through targeting several important kinases involved in the inflammatory cascade, synergistically inhibit key pathways involved in innate and adaptive immunity. Their specific structural properties have been designed so that NSKIs act locally in the GI tract, with minimal systemic absorption. This can be anticipated to reduce or eliminate the use-limiting side-effects seen with currently available treatments, making NSKIs suitable for long-term treatment.