Throwing Light On A Potential New Treatment For Ulcerative Proctitis
On November 17-18, 2020, the Crohns & Colitis Foundation hosted its third annual IBD Innovate: Product Development for Crohns & Colitis conference. This meeting brings together researchers, start-up companies, industry companies, accelerator organizations and more who are committed to accelerating the discovery and development of novel products with the potential to address the unmet needs of patients with IBD. This is the second of three blog posts recapping the presentations from the 2020 IBD Innovate.
It is estimated that over a million people in the United States are affected by ulcerative colitis. When we look at the global picture of IBD, however, its three times more common than Crohns disease. Within those diagnosed with UC, there is a large group of patients who are often underserved because their disease is not severe. When disease is located in the last 15 centimeters of the colon, it’s officially termed ulcerative proctitis. Between 25% and 55% of patients with ulcerative colitis are diagnosed with ulcerative proctitis at diagnosis. Patients with ulcerative colitis that is not advanced or serious enough to need treatment with biologic medications are often not included in clinical trials for these drugs.
During IBD Innovate, Dr. Gil Melmed, Co-Director of the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center, explored the potential for a device to fill a treatment need for people who live with a less severe form of IBD.
Icer Publishes Evidence Report On Targeted Immune Modulator Therapies For Ulcerative Colitis
All assessed therapies provide significant health benefits, but even after rebates, all are priced at levels that exceed common thresholds for cost-effectiveness At the upcoming September 24 virtual meeting, the California Technology Assessment Forum will review the evidence, hear further testimony from stakeholders, and deliberate over these treatments comparative clinical effectiveness, other
Is Combination Therapy For A Lifetime
The optimal duration of combination therapy is an important area of uncertainty, as there are currently very limited prospective data to guide decision-making.54–56 However, Dr Feagan noted that there is a large randomized controlled trial fully recruited in Europe that should help answer this question. Although he speculates that combination therapy will prove to be superior over time, he added that given the risks of thiopurines, his practice is to discontinue azathioprine in his patients who are older than 60 years. Dr Sandborn agreed that his practice is to discontinue thiopurines and switch to monotherapy in patients after they reach 60 to 65 years of age.
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A New Indication Of Success: Fda Approves Ozanimod For Ulcerative Colitis
The novel drug created at Scripps Research has achieved a second FDA approval, this time for ulcerative colitis, as clinical trials continue for Crohns disease.
May 27, 2021
LA JOLLA, CAOzanimod, the drug invented at Scripps Research that won FDA approval last year for relapsing forms of multiple sclerosis, has been approved in the United States for a second high-need medical condition, ulcerative colitis.
The once-daily oral drug, sold by Bristol Myers Squibb under the name Zeposia, can now be prescribed to treat adults with moderate to severe forms of the inflammatory bowel disease. Notably, its the first drug in a novel class of immune-modulating compounds to be approved for ulcerative colitis, which affects about 1 million people in the United States.
For patients with ulcerative colitis, this oral drug offers a better and more convenient option to control disease progression and improve quality of life, says Hugh Rosen, MD, PhD, who invented ozanimod along with fellow Scripps Research professor Edward Roberts, PhD, and their laboratory colleagues. The hope is that this will lead to fewer dangerous complications or serious infections than current treatment options, providing a steadier path for newly diagnosed patients as well as those failing other treatments.
Additional molecules developed by Rosen and Roberts at Scripps Research are currently in phase 2 clinical trials for major depressive disease and anxiety, and phase 1 studies for treatment of autism.
Jak And Tyrosine Kinase Inhibitors
The Janus kinase family comprises of four intracellular tyrosine kinases JAK1, JAK2, JAK3 and non-receptor tyrosine-protein kinase 2 these activate signal transducers and activators of transcription . This JAK-STAT pathway regulates the expression of multiple mediators involved in inflammatory pathways implicated in the pathogenesis of IBD. Tofacitinib, an oral small molecule pan-JAK inhibitor, has shown success in three UC phase 3 .
Filgotinib, an oral, once daily administered JAK 1 selective inhibitor, has been studied in moderately to severely active CD. In the phase 2 FITZROY study, significantly more patients achieved clinical remission on filgotinib compared with the placebo after 10 weeks of treatment . There was no significant difference in terms of severe adverse events between the groups at 20 weeks. Currently, phase 3 trials are underway investigating long term efficacy and safety in CD patients . The SELECTION phase 2B/3 study investigating filgotinib in patients with moderately to severely active UC showed that a significantly higher rate of patients in the treatment arm achieved a combined endpoint of endoscopic, rectal bleeding and stool frequency remission compared with placebo . The 200mg filgotinib dosage met all key endpoints including endoscopic, histologic and 6-month corticosteroid free remission. There was no increase in adverse event compared with placebo.
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Positioning Therapies In Uc
With the availability of several classes of biologics and targeted therapies with demonstrated efficacy in UC, positioning different agents in the treatment course of patients can be challenging.57 Although clinical practice guidelines effectively synthesize the evidence regarding efficacy and safety of these therapies, they offer limited guidance on choosing the optimal first- and second-line therapies for individual patients. Commenting on this, Dr Sandborn noted that All the tightening of the guideline process and adding other stakeholders doesnt solve the underlying problem, which is a lack of data to help distinguish what is similarly effective and what drugs you should use in what order. Such decisions require consideration of the advantages and limitations of each therapy in the context of patients values, preferences, and clinical circumstances. Beyond efficacy, key factors that may inform clinical decision-making include the rapidity of action, safety, safety in pregnancy, route of administration, effect on extraintestinal manifestations , and cost/access .58,59
Icer Publishes Final Report And Policy Recommendations For Targeted Immune Modulator Therapies For Ulcerative Colitis
Independent appraisal committee votes that evidence is adequate to demonstrate clinical superiority of vedolizumab over adalimumab Due to competition introduced with biosimilars, the price for infliximab has dropped substantially in recent years although prices are still marginally above traditional cost-effectiveness thresholds, the majority of independent appraisal committee members votes that infliximab and
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New Treatments And Physiological Insights But Mortality Gap Remains
byDiana Swift, Contributing Writer, MedPage Today December 1, 2020
The outlook for patients with ulcerative colitis is improving, with better treatments reducing the need for colectomy as well as the risk of cancer, and new scientific insights into the nature of the disease are rapidly emerging.
Here’s a look at some of the promising research from 2020.
Battle of the Biologics
In January, an concluded that infliximab is the most effective biologic therapy for biologically naive patients with moderate to severely active UC.
A total of 16 trials published through September 2019 ranked this tumor necrosis factor antibody highest for the induction of clinical remission, for an odds ratio of 4.07 versus placebo and a surface under the cumulative ranking curve of 0.95, according to the analysis by Siddharth Singh, MD, MS, of the University of California San Diego Health, and colleagues.
The analysis also found infliximab best for endoscopic improvement, with a surface under the cumulative ranking curve of 0.95.
Low Secondary Bile Acids and Inflammation
In February, Sidhartha R. Sinha, MD, of Stanford University School of Medicine in California, and colleagues performed metabolomic, microbiome, metagenomic, and transcriptomic profiling of stool from ileal pouches in colectomy-treated UC patients versus controls with familial adenomatous polyposis .
Siblings Better Stool Donors Than Parents
Adding Immunomodulators to Biologics
New Anemia Not a UC Risk
UC at ACG 2020
Ulcerative Colitis: Bacteria Findings Raise Hopes For New Treatment
Sufferers found to have low levels of gut microbes that convert bile acids into other substances
Hopes of developing a new treatment for ulcerative colitis have been raised by research suggesting the condition may be linked to low levels of certain bacteria in the gut.
Ulcerative colitis is a long-term condition in which the colon becomes inflamed. According to the NHS, it is thought to be an autoimmune disease and affects one in every 420 people in the UK. Sufferers need to empty their bowels frequently, develop ulcers in their colon and have recurring bouts of diarrhoea with blood and pus in the faeces.
While a number of medicines can help manage the condition, ulcerative colitis can only be cured by removing the colon. However, about half of those who have this surgery go on to have inflammation in the area of the small intestine that is reconstructed into a pouch to serve as a rectum. Such inflammation is treated with antibiotics.
Now researchers say patients who have had this surgery for ulcerative colitis have lower levels of certain acids in their faeces, and fewer of the bacteria that produce them, than those who have had the surgery for other reasons.
The team say the results shed light on why the latter have a far lower risk of inflammation in their pouch. They say it also offers insights into ulcerative colitis itself, with experiments in mice suggesting inflammatory bowel diseases could be treated by introducing these missing acids into the colon.
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Icer Releases Draft Evidence Report On Ulcerative Colitis Therapies
Public comment period now open until July 29, 2020 Requests to make oral comment during public meeting also being accepted BOSTON, May 26, 2020 The Institute for Clinical and Economic Review today released a Draft Evidence Report assessing the comparative clinical effectiveness and value of treatments for ulcerative colitis . This preliminary draft marks the midpoint
New Treatments And Medications For Ulcerative Colitis
When you have ulcerative colitis , the goal of treatment is to stop your immune system from attacking the lining of your intestine. This will bring down the inflammation causing your symptoms and put you into remission.
Your doctor can choose from several different types of to help you achieve these goals.
In the past few years, the number of drugs used to treat has increased. Researchers are studying other new and possibly improved treatments in clinical trials.
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What About Network Meta
Principles of network meta-analysis.9
After the quality of the evidence is assessed, recommendations are developed and graded to differentiate those based on strong evidence from those based on weak evidence.5 This information is intended to provide the user with an estimate of the groups confidence that following the recommendation will produce the desired health outcome.7 As with levels of evidence, many classification schemes have been developed for grading recommendations. The GRADE approach is commonly used to grade the strength of recommendations and has been adopted as the standard by many guideline developers and organizations, including the AGA and the ACG.4,11,12 The GRADE approach typically scores the strength of recommendations as either strong or weak, also known as conditional or discretionary.2,6 While the GRADE approach acknowledges that expertise is required to interpret any form of evidence, it considers that opinion is an interpretation ofrather than a form ofevidence.6
Once recommendations are developed and graded, the guidelines are then made available for public policy evaluation. This step is critical, Dr Feagan pointed out, because there is no point in having guidelines if they cant be implemented. Lastly, the guidelines are submitted for peer review and published.
Incorporating Combination Therapy Into Practice
The TNF- antagonists are relatively immunogenic, and combination therapy is essential, if tolerated, to prevent immunogenicity and loss of efficacy. Analyses of data from large pivotal trials have demonstrated reduced antibody formation, higher serum concentrations of TNF- antagonists, and greater clinical benefit when immunosuppressive therapies are combined with these agents.48–50 Most notably, the landmark prospective UC-SUCCESS trial clearly demonstrated the superiority of combination infliximab/ thiopurine therapy compared with either agent as monotherapy.31 Accordingly, the ACG and AGA guidelines agree that TNF- antagonists should be combined with immunosuppressives during induction.11,16
Outcome with combination therapy compared with monotherapy for vedolizumab and ustekinumab in patients with inflammatory bowel disease.53
Combination therapy is essential with anti-TNF therapies, but in my opinion, there is not enough evidence to suggest that combination therapy is necessary to optimize efficacy with ustekinumab or vedolizumab.
William J. Sandborn, MD
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Active Uc Of Any Extent Not Responding To Aminosalicylates
In mild-to-moderate UC of any extent, aminosalicylates such as mesalamine are the preferred initial treatment . In patients with disease activity limited to the rectum, topical therapy alone might suffice, but combination therapy is more effective and is also recommended for left-sided and extensive UC . Table 2 gives an overview on current treatment options.
Table 2.
Medical therapy for UC
Fig. 1.
Active ulcerative colitis of any extent not responding to 5-aminosalicylates . MMX, multimatrix AZA, azathioprine 6-MP, 6-mercaptopurine.
Except in case of isolated proctitis, where topical corticosteroids alone may be considered, treatment with oral corticosteroids should be initiated in patients who do not respond adequately to 5-ASA . In case of isolated proctitis, topical corticosteroids alone might be considered. The introduction of corticosteroids should be a shared decision-making process that includes patients preference of therapy and tolerance to 5-ASA. It is, however, recommended to start corticosteroids in patients with sustained rectal bleeding for 2 weeks, persistent abdominal symptoms after 6 weeks of adequate therapy with 5-ASA or if symptoms deteriorate . In selected cases, a prolonged therapy with up to 16 weeks might still be able to achieve remission.
Recommendations Provided For Treatment Of Ulcerative Colitis
In a new clinical guideline from the American Gastroenterological Association, recently published in Gastroenterology, treatment recommendations are presented for patients with moderate-to-severe ulcerative colitis .
Joseph D. Feuerstein, M.D., from the Beth Israel Deaconess Medical Center in Boston, and colleagues developed guidelines for medical management of adult outpatients with moderate-to-severe UC.
The authors recommend using infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or ustekinumab over no treatment in adult outpatients with moderate-to-severe UC for induction and maintenance of remission. Infliximab or vedolizumab are recommended over adalimumab for induction of remission in adult outpatients with moderate-to-severe UC who are naive to biologic agents tofacitinib should only be used in the setting of a clinical or registry study. Ustekinumab or tofacitinib are suggested rather than vedolizumab or adalimumab for induction of remission in adult outpatients with moderate-to-severe UC who have previously been exposed to infliximab, particularly those with primary nonresponse. Thiopurine monotherapy is not recommended for induction of remission in adult outpatients with active moderate-to-severe UC. For maintenance of remission, thiopurine monotherapy is recommended over no treatment for adult outpatients with moderate-to-severe UC in remission.
One author disclosed financial ties to the pharmaceutical industry.
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Fda Approves Ozanimod For Ulcerative Colitis
Megan Brooks
May 28, 2021
The US Food and Drug Administration has approved ozanimod for adults with moderately to severely active ulcerative colitis , the company has announced.
Ozanimod , an oral medication taken once daily, is the first sphingosine-1-phosphate receptor modulator approved for UC.
In March 2020, the FDA approved ozanimod for adults with relapsing forms of multiple sclerosis, as reported by Medscape Medical News.
The approval of ozanimod for UC is based on data from True North, a phase 3 placebo-controlled trial that evaluated the drug as induction therapy over 10 weeks in 645 adults with moderately to severely active UC, followed by maintenance therapy over 42 weeks.
All participants in the trial had failed to respond adequately to or were intolerant of oral aminosalicylates, corticosteroids, immunomodulators, or a biologic 30% had previously experienced treatment failure or were intolerant of tumor necrosis factor blockers. Prior to and during induction, patients were treated with oral aminosalicylates and/or corticosteroids.
During induction at week 10, the trial met its primary endpoint significantly more patients who took ozanimod achieved clinical remission than patients who took placebo .
Ozanimod was also superior to placebo on the secondary endpoints of clinical response , endoscopic improvement , and endoscopic-histologic mucosal improvement .
Complete prescribing information and medication guide are available online.
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Tofacitinib: New Drug Approved For The Treatment Of Patients With Ulcerative Colitis
Ulcerative colitis is a chronic inflammatory disease that affects the colonic mucosa. There is no curative treatment. Instead, patients must take medication to control the inflammation over the course of their lives. There are some patients whose condition cannot be sufficiently controlled by the drugs currently available. For them, the new treatment with tofacitinib could be an alternative.
In 2017, the European Medicines Agency approved tofacitinib for the treatment of ulcerative colitis in adult patients who presented an intolerance, insufficient response or loss of response to conventional treatment or biological medical products , which are also commonly administered to treat ulcerative colitis.
Tofacitinibs mechanism of action is different to all other currently approved molecules: it inhibits a route of inflammation known as JAK . Inhibiting this route of action represents a new approach in the treatment of ulcerative colitis.
This treatment has many advantages in terms of its administration: it is administered orally, and this encourages patients to accept and follow the treatment. Furthermore, it has a fast onset of action, the effect of the drug only lasts for a few hours in the body, there is no risk of producing antibodies against it and it is used in monotherapy, in other words, there is no need to combine it with other drugs.
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