User’s Guide To Jak Inhibitors In Inflammatory Bowel Disease
The use of JAKi is a novel targeted therapeutic approach in the treatment of IBD.
Tofacitinib has shown efficacy in the treatment of moderate to severe UC.
Tofacitinib’s safety profile has generally remained stable and acceptable.
The future of JAKi in the treatment of IBD is promising.
Patient Disposition And Baseline Characteristics
Of 197 patients in TOUCHSTONE, 170 entered the OLE period and received daily ozanimod HCl 1 mg . Of these, 81 patients entered the OLE period at the end of the induction period, seven entered during the maintenance period, and 82 entered at the end of the maintenance period . At the time of this analysis , 99 patients had discontinued the OLE study, with 28% of the patients discontinuing in the first year, and an annual discontinuation rate of 15 18% for existing patients in years 24 . Reasons for discontinuation are shown in . At study closure, of the 71 UC patients eligible to roll over into the phase 3 OLE study, 54 did so as a joint decision of patients and the treating investigators .
*In 2019, the sponsor made the decision to close the phase 2 TOUCHSTONE study after all active patients had completed at least 4 years of follow-up.
Of the 170 patients in the OLE, the mean age of patients at baseline for the double-blind study was 40.4 years, 57.6% of patients were male and 92.4% of patients were white . The mean duration of disease from diagnosis to the baseline of the double-blind study was 5.9 years, and most patients had not received prior anti-tumour necrosis factor therapy.
The mean exposure to ozanimod over the course of the study was 2.8 person-years .
Ozanimod Improves Ulcerative Colitis Symptoms
A phase 3 study involving 645 patients with moderate to severe ulcerative colitis showed treatment with ozanimod improved several critical symptoms, including rectal bleeding and stool frequency.
The True North study evaluated the efficacy of the ozanimod versus placebo on those two symptoms, as well as fecal calprotectin and C-reactive protein during the induction phase, with the researchers assessing how quickly the patients saw improvement.
According to results presented at the virtual Digestive Disease Week meeting, the baseline rectal bleeding scores were 1.7 and 1.6 in the drug and placebo arms, respectively. The mean baseline stool frequency score was 2.4 in both groups.
The researchers noted improvement in rectal bleeding was seen starting at week 2 and SFS at week 5 . At week 10, 52% of patients in the ozanimod arm reported no rectal bleeding compared to 30.1% in the placebo arm . More improvement was also seen in stool frequency .
The mean change in FCP concentration at week 10 was -470.2 Âµg/g with ozanimod and 21.1 Âµg/g with placebo . The mean change in CRP from baseline to weeks 5 and 10 were also greater with ozanimod than placebo .
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Clinically Meaningful Improvements With Ozanimod In Uc Trial
The phase 3 True North trial evaluating the efficacy of ozanimod as an induction and maintenance therapy for adults with moderate to severe ulcerative colitis met both primary and key secondary end points, according to Bristol Myers Squibb.
Ozanimod is a sphingosine 1-phosphate receptor modulator marketed under the brand name ZeposiaÂ®. The product is currently approved for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
The multicenter, double-blind, placebo-controlled True North study included patients with moderate to severe ulcerative colitis who had an inadequate response to prior treatment. In the induction phase, patients were randomized to receive either ozanimod 1mg orally once daily or placebo for 10 weeks. Patients who achieved a clinical response in the induction phase or who were part of an open-label arm were eligible to proceed into the maintenance phase, in which they were re-randomized to receive ozanimod or placebo through week 52.
Results showed that ozanimod met both primary end points achieving statistically significant clinical remission at week 10 in the induction phase and at week 52 in the maintenance phase .
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S1pr Modulators In Ibd
Fingolimod/FTY720 is an S1P-analog, acting as non-selective potent agonist of S1PR1,3,4,5. The first S1PR modulator approved for the treatment of relapsing MS was fingolimod .
Various preclinical studies have demonstrated its efficacy at ameliorating colitis in animal models of IBD. Treatment of IL-10 knockout mice for 4 weeks efficiently reduced the number of CD4+ T cells in the colonic lamina propria and decreased the production of IFN- in the colon . Similar data were reported with other colitis models, such as dextran sulfate sodium , trinitrobenzene sulfonic acid, and T cell transfer into immunocompromised mice . The clinical use of fingolimod in IBD has not been tested, and other, more selective, S1PR modulators are being developed for clinical use in IBD .
KRP-203 is a S1PR1,4,5 agonist and partial agonist of S1PR3. The safety, tolerance, and efficacy of KRP203 were tested in 27 patients with active moderate UC, in a multicenter, double-blind, placebo-controlled study . KRP203 demonstrated adequate tolerance and safety. While KRP203 was shown to be minimally effective with regards to the clinically relevant threshold , a 14% in the KRP203 group achieved clinical remission in comparison a 0% in the placebo group . Based on the results of this small study, further development of KRP-203 for ulcerative colitis was terminated .
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Jak Inhibitors For The Treatment Of Ibd
Typically, IBD is associated with chronic inflammation, defined by a dysregulated response of the innate and adaptive immune systems . Chronic inflammation in Crohns disease is characterized by a response of helper T cells type 1 and helper T cells type 17 , with inadequate activity of regulatory T cells , whereas UC has generally been considered a type 2 T helper cell cytokine profile . In both diseases, many of the cytokines produced by these T cells signal through JAK receptors therefore, JAK proteins have an important place in the signaling of inflammation in IBD .
Key cytokines in the pathogenesis of IBD belong to Type I and Type II cytokines receptors . These cytokines all signal through the JAK/STAT pathway. In contrast, the cytokines TNF, IL-1, and IL-17, which are the major drivers of IBD, do not use the JAK-STAT pathway in their signaling pathways . However, these cytokines induce the expression of a wide range of downstream pro-inflammatory cytokines, that in turn depend on JAK/STAT signaling .
Interleukin-12 and IL-23 also play an important role in IBD, and JAK2 and tyrosine kinases type 2 are involved in the signaling of these cytokines by activating STAT3 and STAT4, promoting inflammatory reactions through their ability to induce Th1 and Th17 polarization, respectively, and production of IFN-, IL-21, and IL-22 .
Conflict Of Interest Statement
WS reports research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, Abbvie, Janssen, Takeda, Lilly, Celgene/Receptos consulting fees from Abbvie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Conatus, Cosmo, Escalier Biosciences, Ferring, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis Nutrition Science Partners, Oppilan Pharma, Otsuka, Paul Hastings, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Ritter Pharmaceuticals, Robarts Clinical Trials , Salix, Shire, Seres Therapeutics, Sigmoid Biotechnologies, Takeda, Tigenix, Tillotts Pharma, UCB Pharma, Vivelix and stock options from Ritter Pharmaceuticals, Oppilan Pharma, Escalier Biosciences, Gossamer Bio, Precision IBD, Progenity. AJ-R is consultant and part of the speaker bureau for Prometheus Laboratories and employee of Prometheus Laboratories. DP has been a speaker bureau ABBVIE.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Positioning Of Small Molecules In The Therapeutic Algorithm Of Ibd
The choice of IBD treatment must be personalized according to the activity, severity, phenotype, preferences of the patients, comorbidities, history of the therapies used previously, and surgery .
The current treatment for IBD is based on aminosalicylates, steroids, immunosuppressants, and biologic therapies . The 5-ASA compounds are used as first line in mild-to-moderate UC, and in some cases of IBD-associated arthritis . These drugs have an excellent safety profile. Immunosuppressants can be added during maintenance therapy in cases of moderate severity, or in combination with biologic therapy in moderate-to-severe cases due to their synergism or to decrease the immunogenicity of the biologic . In recent years, measuring drug and antibody levels has allowed optimization of biological therapies and assisted in avoiding misuse of biologics by under dosing or drug failure . The calcineurin inhibitors have a limited role in the treatment due their narrow therapeutic window and side effects. Thus, they are mostly being used as a bridge to another maintenance drug in cases of acute severe colitis refractory to corticosteroid. However, in this last case infliximab seems to be a better option, due to less toxicity in comparison with cyclosporine .
New SM offers an alternative to the current therapeutic arsenal, especially in cases of steroid-resistance and cases of nonresponse and/or are intolerance to conventional therapies.
Differences Between Small Molecules And Monoclonal Antibodies
Monoclonal antibodies are large molecules with high molecular weights . The mAb structure consists of four polypeptide chains, two identical heavy chains, and two identical light chains. Each mAb molecule has an antigen-binding region or variable region, and a constant region or Fc . The size and structure of the mAb determines the drug pharmacokinetic, target location, the drugdrug interaction, the antigenicity, and the route of administration. The mAbs are eliminated from the circulation by catabolism, which depends on the rates of proteolysis , recycling rates , and receptor-mediated antibody endocytosis rates . Due to the large size of mAb the renal clearance is insignificant . Because of the protein composition of mAbs, the immune system can recognize them as immunogenic foreign antigens, which may lead to the development of specific anti-drug antibodies that nullify their therapeutic effect . This results in increased drug clearance and ultimately may contribute to treatment failure and/or hypersensitivity reactions . The addition of immunomodulators can decrease anti-drug antibody formation but increases the risks associated with inmunosupression .
Table 1. Comparison of properties of SM drugs and mAbs .
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Ozanimod Is An Efficacious Oral Therapy After 5
A post hoc analysis of data from the phase 3 True North trial assessed the efficacy of 10 weeks of ozanimod induction therapy, with or without concomitant corticosteroid treatment.1,2 The patients had received prior treatment with 5-aminosalicylic acid, but not with immunomodulators or biologic therapies. Bruce Sands, MD, presented the results.1 Among 464 enrolled patients, 101 received placebo and 205 received ozanimod in cohort 1, while 158 received open-label ozanimod in cohort 2.
Among all patients in the analysis, clinical remission at week 10 was reported in 23.4% of cohort 1, 30.4% of cohort 2, and 8.9% of the placebo arm . A clinical response occurred in 53.7% of cohort 1, 62.7% of cohort 2, and 30.7% of the placebo arm . Endoscopic improvement was reported in 35.6% of cohort 1, 38% of cohort 2, and 14.9% of the placebo arm . Mucosal healing occurred in 18% of cohort 1, 14.6% of cohort 2, and 5.0% of the placebo arm .
At week 10, in cohort 1, the rate of clinical remission was 19.0% with ozanimod vs 5.0% with placebo among the patients receiving concomitant corticosteroids. Among patients who were not receiving corticosteroids, clinical remission was reported in 24.5% of the ozanimod arm vs 9.9% of the placebo arm . The rate of clinical response was 59.5% with ozanimod vs 30.0% with placebo in patients who concomitantly used corticosteroids , and 52.1% vs 30.9% in those who did not.
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Nma Of The Safety Of Jak Inhibitors In Rcts
3.8.1 Adverse events
No statistically significant differences were observed with respect to the rate of AEs among the evaluated treatments, except between tofacitinib 3 mg and tofacitinib 0.5 mg . In terms of AEs, the ranking probability based on SUCRA indicated that placebo was likely to be the safest treatment .
3.8.2 AEs leading to study drug discontinuation
Pooled RRs and 95% CIs for the WDAEs of the different interventions from the NMA are shown in Figure G and Table F. The difference between the intervention groups was not statistically significant. For the outcome of WDAEs, placebo performed best and upadacitinib 7.5 mg was the worst .
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Other Jak Inhibitors In Development For Uc
Filgotinib, an oral JAK1-selective inhibitor, has been shown to induce clinical remission in patients with moderate-to-severe Crohns disease.30 The SELECTION trial is a Phase 2b/3 in patients with moderate-to-severe UC. An interim futility analysis was performed after 350 patients completed the induction period in the Phase 2b. The independent Data Monitoring Committee conducting the analysis recommended to proceed the study into Phase 3.31
PF-06651600 and PF-06700841 are being developed by Pfizer. A double-blind, placebo-controlled, parallel group, randomised trial including patients with moderate-to-severe UC is ongoing and will compare the efficacy and safety of these compounds and placebo . Phase 2 trials are also ongoing with SHR0302 and itacitinib .
BMS-986165 is a potent oral TYK2 allosteric inhibitor that has been studied in psoriasis with promising results.32 This molecule blocks IL-12, IL-23, and type I interferon, and has been successfully applied in preclinical models of IBD.33 Phase 2 trials in UC and CD are ongoing .
Ozanimod Yields Clinical Response Remission In Ulcerative Colitis Patients
Serious infections occurred in less than 2% of patients treated with the medication during the duration of the 52-week trial.
Results from both an induction and maintenance therapy trial show ozanimod can be an effective treatment for patients with inflammatory bowel disease .
A team, led by William J. Sandborn, MD, University of California San Diego, compared ozanimod with placebo in achieving both clinical remission and clinical response in patients with moderate to severely active ulcerative colitis.
Ozanimod is a selective sphingosine-1-phosphate receptor modulator currently being studied for the treatment of patients with IBD.
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Fda Approves Ozanimod For Adults With Ulcerative Colitis
The treatment is also being studied for safety and efficacy in patients with Crohns disease.
The US Food and Drug Administration has approved ozanimod 0.92 mg, an oral agent that selectively targets sphingosine-1-phosphate receptor subtypes 1 and 5, for adult patients with moderately to severely active ulcerative colitis.
The approval, awarded to Bristol Myers Squibb, was based on the data from a placebo-controlled phase 3 trial dubbed True North. In the study, researchers evaluated ozanimod as a single, daily oral therapy for both adults and pediatric patients at least 12 years old with moderately to severely active ulcerative colitis.
Despite the availability of approved therapies, there is still unmet need and an opportunity to deliver additional treatment options to help patients better manage their disease, said Adam Lenkowsky, general manager and head, U.S., Cardiovascular, Immunology and Oncology, Bristol Myers Squibb, in a statement. Were thrilled that our pursuit of transformative science in immunology may benefit patients in their ulcerative colitis treatment by introducing a new option that has a different mechanism of action than available therapies. Zeposia combines disease control through lasting remission and demonstrated safety in a once-daily pill.
What Is New And Conclusion
In this NMA, among 18 interventions tested as induction treatments in patients with UC, filgotinib 100 mg, peficitinib 75 mg QD/75 mg BID/150 mg and tofacitinib 3 mg formed a cluster with the best performance with respect to efficacy. AEs and WDAEs did not differ between JAK inhibitors and placebo groups. These results are not generalizable to other patient populations and require confirmation in larger patient populations and real-world settings. Long-term studies are needed to determine the relative efficacy and safety of JAK inhibitors in a larger number of patients with UC.
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Whats In The Pipeline
Pipeline drugs are currently being developed and tested but aren’t FDA-approved for any use. Every one of these drugs must go through three phases of clinical trials before it can be brought to the FDA for approval.
Several JAK inhibitors are making their way through the pipeline, undergoing clinical trials that aim to determine their safety and effectiveness in treating a variety of autoimmune conditions.
Future Directions For The S1p Pathway
Ponesimod, Ceralifimod, Siponimod AUY954, SEW2871, AUY954, W061, CS-0777, and GSK2018682 are currently being investigated for use in other autoimmune/immune-mediated disorders . The pathways involved in the synthesis, degradation, and the mechanism of transport of these molecules represent an attractive new area of research .
There are two isoforms of sphingosine kinase , SphK1 and SphK2. TNF induces SphK1 activation, leading to cyclooxygensase-2 expression and production of prostaglandin E2 that may contribute to mucosal inflammation . Moreover, SphK1 expression was found to be elevated in both colonic epithelial cells and inflammatory cells in patients with UC patients correlating with COX2 overexpression . Data from mice indicate that the SphK1/S1P pathway participates in the development and maintenance of intestinal inflammation . Thus, inhibition of this enzyme could represent a potential new target.
This enzyme, expressed in the gastrointestinal tract, catalyzes dephosphorylation of S1P to sphingosine, resulting in regulation of S1P levels. Elevated sphingosine phosphatase expression has been demonstrated in colitis and contributes to its pathogenesis by disrupting barrier integrity, indicating that its inhibition may have beneficial effects in IBD .
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