Ulcerative Colitis Clinical Trials

Overview of Ulcerative Colitis

Inflammatory Bowel Disease (IBD) is a broad term that describes conditions characterized by chronic inflammation of the gastrointestinal tract. This inflammation impairs the ability of affected organs to function properly, leading to symptoms such as fatigue, weight loss, rectal bleeding, persistent diarrhea and abdominal pain. The two most common inflammatory bowel diseases are ulcerative colitis and Crohn’s disease.

Crohn’s disease can affect any part of the gastrointestinal tract, from the anus to the mouth. It usually affects the ileum (the end of the small intestine) where it joins the beginning of the colon. This inflammation sometimes extends throughout the bowel wall.

Ulcerative colitis on the other hand, is limited to the rectum and the colon (large intestine). Here, the inflammation only occurs in the innermost layer of the lining of the intestine. It usually begins in the lower colon and the rectum but sometimes, it may spread to the entire colon.

Causes

Though the exact cause of Ulcerative colitis has not been established, it is generally accepted that it involves an interaction between your genes, immune system and other environmental factors. In people with ulcerative colitis, inflammation occurs because the immune system goes wrong and attacks healthy tissue. The latest research on ulcerative colitis shows that about 20% of affected individuals have a first-degree relative (sibling, child or parent) that also has the disease. No one is really sure what environmental factors trigger Ulcerative colitis but studies have identified several potential risk factors such as smoking, use of antibiotics, use of Nonsteroidal anti-inflammatory drugs, diet and geographic location (more prevalent in industrialized countries).

Current Therapies

There is currently no cure for Ulcerative colitis, but there are many new ulcerative colitis treatments available. The goal of new ulcerative colitis treatments is to reduce the inflammation that triggers the symptoms and signs, thus providing relief, reducing the risks of complications and leading to long-term remission. New ulcerative colitis treatments usually involve drug therapy and sometimes, surgery. Classes of medications used to treat Ulcerative colitis include biologics, immunosuppressants, anti-inflammatories and antibiotics.  

Anti-inflammatories – these are usually the first step used by doctors in the treatment of Ulcerative colitis. These include aminosalicylates (5-ASA) and corticosteroids, such as AstraZeneca‘s Entocort EC, Salix Pharma’s Uceris (budesonide) and Colazal (balsalazide), and Allergan’s mesalamine (Delzicol, Asacol HD others).

Tumor necrosis factor (TNF) – biologics or alpha inhibitors, are a group of medicines that suppress the body’s natural response to tumor necrosis factor (TNF), a protein involved in early inflammatory events. TNF is usually produced by white blood cells. Examples include UCB‘s Cimzia, Janssen‘s Simponi (golimumab), AbbVie‘s Humira (adalimumab) and infliximab (Inflectra, Remicade). Other commonly used biologic therapies are Stelara (ustekinumab), Entyvio (vedolizumab), and Tysabri (natalizumab).

Immune system suppressor medications (immunosuppressants) are used to reduce the immune system’s response that leads to the release of inflammation-inducing chemicals in the intestine. Some examples of immunosuppressants include methotrexate (Xatmep, Trexall, Rheumatrex Dose Pack, Rasuvo, Otrexup), cyclosporine (Sandimmune, Neoral, Gengraf), mercaptopurine (Purixan, Purinethol) and azathioprine (Imuran, Azasan).

Finally, antibiotics are sometimes used with other medications, usually when your care provider is concerned about infections. Metronidazole (Flagyl) and ciprofloxacin (Cipro) are some of the more frequently prescribed antibiotics for Ulcerative colitis.

Drug Pipeline

Right now, there are a couple of new ulcerative colitis treatment therapies being explored through clinical trials. Some of them include – glucocorticosteroids, aminosalicylates and TNF-alpha inhibitors. Common mechanisms and targets include:

• Dihydroorotate dehydrogenase (DHODH) inhibitors: these provide an immunomodulatory effect selective towards activated immune cells.
• Human interleukin IL-23, IL-22, (IL)-12 and IL-36 inhibitors. These are proteins that are involved in the immune system’s inflammation response.
• Selective S1P receptor modulators. These receptors have been demonstrated to be involved in the modulation of several biological responses including autoimmune diseases.
• Janus kinase (JAK) 3 inhibitors. The JAK pathways are believed to play an important role in inflammatory processes as they are involved in signaling for over 50 growth factors and cytokines, many of which drive immune-mediated conditions

Clinical Trials – Development by Phase

As of February 2020, there are 371 clinical trials for ulcerative colitis (not yet recruiting/active/active, no longer recruiting) listed on clinicaltrials.gov. Of these new ulcerative colitis treatment trials, 26 are in Canada, 35 in the United States and the remaining are spread across the globe. When broken down by phase, there are 29 trials in phase I, phase II has 76 trials, 56 phase III trials and the remaining are in phase IV or are other types of studies, including observational studies or behavioral modification, those using various devices and dietary supplements.

The ulcerative colitis new drugs market contains a mixture of both small and big biotech and pharma companies. But, Pfizer and Janssen both dominate the market with 5 drugs each. Janssen has its new ulcerative colitis drugs in all phases (I-III), while Pfizer’s 5 drugs are in phases I and II only. The other companies in the new ulcerative colitis treatments market include AbbVie with three drugs in phase II, II and III, and Roche in collaboration with Genentech with three drugs in phases I-III.

Below, we’ll analyze selected new drug for ulcerative colitis in the clinical trials pipeline and will briefly discuss how each drug works and where it is in clinical trials. 

Genentech/Roche  

Genentech/Roche has three new ulcerative colitis treatments in development: RO7049665, Etrolizumab (RG7413) and UTTR1147A/ RG7880

• RO7049665’s phase I trial is currently underway to evaluate its tolerability and safety when subcutaneously administered in patients with active ulcerative colitis.
• Etrolizumab (RG7413) is a monoclonal antibody designed to stop alphaEbeta7 (αEβ7) and alpha4beta7 (α4β7) from working – two proteins involved in the immune system’s response. A phase I trial is evaluating etrolizumab in pediatric patients of 4 to <18 years of age with moderate to severe ulcerative colitis (UC). While phase I and II clinical trials, which evaluated patients with moderate to severe ulcerative colitis, were successfully completed. Currently, there are 5 trials being carried out in the U.S and 1 non-U.S. based trial for patients with UC. All these studies are currently recruiting participants.
• UTTR1147A/ RG7880 is a recombinant human protein which targets Interleukin-22 (IL-22). Phase I and two phase II trials are currently underway for both Crohn’s disease and ulcerative colitis.

AbbVie  

AbbVie also has three drugs in development for ulcerative colitis.

• Upadacitinib (ABT-494) is a JAK1 selective inhibitor. There are seven active phase II and III trials underway for Crohn’s disease and ulcerative colitis.
• Risankizumab (ABBV-066) is an anti-IL-23 antibody. Several phase II and III trials are currently underway and Results show that open-label subcutaneous risankizumab maintained remission until week 52 in most patients who were in clinical remission at week 26.
• ABBV-323 is an antagonist to CD40. Proof of concept data is expected this year. Right now, a phase II trial is currently recruiting 60 patients with moderate to severe ulcerative colitis who failed prior therapy. 

Pfizer

Pfizer has five drugs in development for both Crohn’s disease and ulcerative colitis.

• PF-06480605 is an antibody that blocks tumor necrosis factor (TNF). A phase IIA trial met tolerability and safety endpoints. Another phase IIB trial is currently recruiting participants with moderate to severe ulcerative colitis.
• PF-06700841 and PF-06651600: PF-06700841 is a JAK 1 and TYK2 inhibitor while PF-06651600 is a small oral molecule that hinders Janus kinase (JAK) 3. Two phase II trials are underway evaluating the combination of these drugs together; one for moderate-to-severe ulcerative colitis and the other for moderate-to-severe Crohn’s disease.
• IB-PF-06687234 and PF-06687234; A phase I trial is currently evaluating the tolerability, safety, and PK of [124I] IB-PF-06687234 and PF-06687234 (given simultaneously) in participants with moderate to severe UC. Also, another phase II trial is underway to determine if PF-06687234 is safe and effective as an add-on therapy to infliximab in participants with active ulcerative colitis who are not in remission.

Janssen

Janssen has five drugs in development for ulcerative colitis

• Guselkumab is an interleukin-23 blocker. Already approved as Tremfya by the FDA for the treatment of moderate-to-severe plaque psoriasis in adults, there are now 3 new clinical trials underway to determine its efficacy for both UC and CD. They are: QUASAR, GALAXI, and VEGA, 
• JNJ-67864238 (PTG-200) is a potential first-in-class oral IL-23R antagonist. A phase I trial was completed in Australia and demonstrated that PTG-200 was well-tolerated, with no dose-limiting toxicities or serious adverse events. Now, PRISM – a phase IIB trial, is ongoing  and is focused on patients with moderately to severely active CD.
• JNJ-64304500 (NN-8555/IPH-2301/ JNJ-4500) is an Anti-NKG2D antibody in licensed in May of 2015 by Novo Nordisk . TRIDENT, a phase IIB trial started in 2016 and is still currently recruiting patients with moderate to severe CD.
• Ustekinumab, already approved by the FDA as Stelara, is a monoclonal antibody that inhibits the action of inflammatory cytokines human interleukin IL-23 and (IL)-12. A number of phase I-III studies are currently evaluating ustekinumab in combination with other therapies and as a monotherapy too for maintenance and induction in patients with both ulcerative colitis and Crohn’s disease.
• Golimumab too has already been approved by the FDA as Simponi and right now, phase I and phase III trials focused on pediatrics with ulcerative colitis are underway.

Lifestyle Advice

Now, though there’s currently no cure for ulcerative colitis, there are a few things patients living with UC can do to help reduce their risk of complications and to keep symptoms under control. We’ll discuss some of these options below

Dietary Advice

Some changes you can make to your diet to help control your condition include:

Increase your vitamin C Intake: People who eat diets rich in vitamin C have noticed that their UC remission periods are more prolonged. Some vitamin C-rich foods include berries, spinach, bell peppers and parsley.

Eat More Low-Fat Foods: the results are not quite definitive, but research suggests that eating a diet that’s low-fat may delay flares. 

Take Food Supplements – ask your GP or gastroenterologist if you need food supplements, as you might not be getting enough vitamins and minerals in your diet

Drink Lots Of Water – as you lose a lot of fluid through diarrhea, it’s very easy to become dehydrated. Drink lots of water but avoid alcohol and caffeine, as these will make your diarrhea worse.

Eat smaller meals – rather than eating 3 main meals daily, it may be better to eat 6 or 5 smaller meals as it may help keep your symptoms under control

Keep a food diary – documenting what you eat can be helpful as you’ll be able to identify the foods you that make your symptoms worse and those that improve your symptoms.

Stress Relief

Although stress does not cause ulcerative colitis, successfully managing stress levels may reduce the frequency of symptoms.

The following advice may help:

Practise Relaxation Techniques – yoga, meditation and breathing exercises are good ways of getting yourself to relax

Exercise –has been proven to boost your mood and reduce stress; ask your care team or GP for advice on appropriate exercise plans

Communication – because of its symptoms, living with ulcerative colitis can be both isolating and frustrating; talking to others living with the condition may help

Ulcerative Colitis Natural Treatment

Some natural remedies have been shown to help manage ulcerative colitis include:

Turmeric: This spice is chock-full of curcumin, an antioxidant that has been shown to reduce inflammation.

Psyllium seed/husk: This can help regulate bowel movements that may prevent constipation and alleviate symptoms.

Probiotics: Taking probiotic supplements or eating foods with probiotics can help boost your gut’s health thereby helping your body ward off inflammation and symptoms of UC.

Bromelain: also sold as supplements, these enzymes are naturally occurring pineapples and may reduce flares and ease symptoms of UC.

Boswellia: Found in tree barks, research suggests that boswellia can reduce the occurrence of inflammation.

Current Outlook

Over the last few years, there’s been significant progress in the understanding of both ulcerative colitis and Crohn’s disease. A greater understanding of the underlying mechanisms that cause Inflammatory Bowel Disease has already led to the development of new treatments, and lots of newer treatments are being tested in clinical trials. One day (hopefully soon) we’ll find a cure for both diseases.