TAK-279 for Crohn's Disease
Recruiting in Palo Alto (17 mi)
+277 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Takeda
Disqualifiers: Ulcerative colitis, Ostomy, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?Crohn's disease (CD) is a long-lasting condition causing inflammation that can affect any part of the gut. The purpose of this study is to evaluate the efficacy and safety of TAK-279 versus placebo in participants with moderately to severely active Crohn's disease (CD). The main aim of this study is to learn if the 3 different doses of TAK-279 reduce bowel inflammation and ulcers in the bowel compared to the placebo after 12 weeks of treatment. Another aim is to compare any medical problems that participants have when they take TAK-279 or placebo and how well the participants tolerate medical problems. An endoscopy will be used to check the bowel for inflammation.
The participants will be treated with TAK-279 for 52 weeks (1 year).
During the study, participants will visit their study clinic 15 times.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.
What data supports the effectiveness of the drug TAK-279 for Crohn's Disease?
Research shows that TYK2 inhibitors, like TAK-279, can help reduce inflammation in diseases similar to Crohn's Disease by blocking specific pathways that cause inflammation. Studies on similar drugs have shown promising results in treating inflammatory bowel diseases, suggesting TAK-279 might also be effective.
12345Is TAK-279 (a TYK2 inhibitor) generally safe for humans?
Research on TYK2 inhibitors, like TAK-279, suggests they may have fewer side effects compared to other similar drugs, as they are more selective in their action. Studies have shown that these inhibitors can be safe for long-term use in animal models, but more human studies are needed to confirm this.
12367How is the drug TAK-279 different from other treatments for Crohn's Disease?
TAK-279 is a unique treatment for Crohn's Disease because it is a selective TYK2 inhibitor, which means it specifically targets and blocks the TYK2 enzyme involved in inflammation, unlike broader JAK inhibitors that affect multiple enzymes. This selectivity may help reduce side effects while effectively managing inflammation.
12389Eligibility Criteria
This trial is for adults aged 18-75 with Crohn's Disease that's active and moderate to severe. They should have tried other treatments without success or couldn't tolerate them. Participants must follow specific contraception advice.Inclusion Criteria
I have Crohn's disease and treatments so far haven't worked well for me.
Participants must meet the contraception recommendations
My Crohn's disease is moderate to severe, confirmed by tests.
+1 more
Exclusion Criteria
I have a form of colitis or ulcerative colitis.
I currently have an ostomy.
I might need surgery for my Crohn's disease complications during the study.
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Induction
Participants are randomly assigned to receive one of three doses of TAK-279 or placebo for 12 weeks to evaluate efficacy and safety
12 weeks
Approximately 6 visits (in-person)
Treatment
Participants continue to receive TAK-279 or placebo for an additional 40 weeks to assess long-term effects
40 weeks
Approximately 9 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests TAK-279, a potential new treatment for reducing bowel inflammation in Crohn's Disease, against a placebo over one year. It aims to see if different doses of TAK-279 are effective and safe after 12 weeks using endoscopy.
4Treatment groups
Experimental Treatment
Group I: TAK-279 Dose 3Experimental Treatment1 Intervention
Participants will be randomized to receive TAK-279 Dose 3 capsules orally.
Group II: TAK-279 Dose 2Experimental Treatment2 Interventions
Participants will be randomized to receive TAK-279 Dose 2 capsules with TAK-279 placebo-matching capsule orally.
Group III: TAK-279 Dose 1Experimental Treatment2 Interventions
Participants will be randomized to receive TAK-279 Dose 1 capsules with TAK-279 placebo-matching capsule orally.
Group IV: PlaceboExperimental Treatment1 Intervention
Participants will be randomized to receive TAK-279 placebo-matching capsules orally.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
VVCRD Clinical ResearchGarden Grove, CA
GastroIntestinal BioSciencesLos Angeles, CA
United Medical DoctorsMurrieta, CA
I.H.S Health, LLCKissimmee, FL
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
TakedaLead Sponsor
References
Tyrosine Kinase 2 Signalling Drives Pathogenic T cells in Colitis. [2021]Tyrosine kinase 2 [TYK2] is required for the signalling of key cytokines in the pathogenesis of inflammatory bowel disease [IBD]. We assessed the efficacy of a novel selective TYK2 inhibitor [TYK2i] in experimental colitis, using pharmacological and genetic tools.
Selective tyrosine kinase 2 inhibitors in inflammatory bowel disease. [2022]Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms.
Therapeutic potential of a synthetic dual JAK1/TYK2 inhibitor in inflammatory bowel disease. [2023]Inflammatory bowel disease (IBD) is a chronic and incurable disease with an increasing incidence rate and low mortality rate. Selectively inhibiting JAK1 and TYK2 has been proposed as a strategy to enhance the efficacy of such inhibitors while minimizing the potential side effects on other JAK isoforms. Our previous studies identified small molecule 18 as a JAK1/TYK2 inhibitor with high selectivity and a new structure. Specifically, the IC50 of 18 at the kinase level reached 39 nM and 21 nM for JAK1 and TYK2, respectively, with 10-fold selectivity over both JAK2 and JAK3. In in vitro studies, 18 dose-dependently inhibited cytokine-induced STAT phosphorylation downstream of the JAK1 and TYK2 signaling pathway. In pharmacokinetic experiments, 18 demonstrated an oral bioavailability of 59.82%, making it a promising candidate for further in vivo studies. Using two mouse models of acute ulcerative colitis (UC) induced by the administration of dextran sulfate sodium (DSS) or oxazolone (OXA), 18 dose-dependently showed a better therapeutic effect than the positive control drug tofacitinib. Additionally, after long-term administration for 32 days, 18 displayed low toxicity to mice and a high safety profile. Taken together, these findings suggest that 18 is a JAK1/TYK2 dual inhibitor with therapeutic effects superior to those of tofacitinib in the treatment of IBD. Moreover, 18 is also a suitable clinical candidate for further investigation in diseases with strong involvement from interferon and/or IL-12/IL-23 in their pathogenesis. This study confirmed the therapeutic effect and long-term safety of inhibiting JAK1 and TYK2 to treat IBD.
Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors. [2023]Janus kinases (JAKs) are central components in cytokine signaling pathways. A number of small molecule JAK inhibitors have been approved to treat a wide range of inflammatory and autoimmune diseases. Due to safety concerns of pan-JAK inhibition, the thrust of current research is toward the discovery of isoform-selective JAK inhibitors. Selective inhibition of tyrosine kinase 2 (TYK2) has the potential to balance efficacy and safety. Substantial efforts have been made to develop selective TYK2 inhibitors: Deucravacitinib (BMS-986165) is a representative allosteric inhibitor that has been approved by the FDA, and ropsacitinib (PF-06826647) is an active site-directed inhibitor currently being evaluated in clinical trials. Herein, we outline the key roles of TYK2 in diseases, review the advances of selective TYK2 inhibitors, and finally discuss future perspectives and challenges in the development of TYK2 inhibitors.
Identification of a Novel 2,8-Diazaspiro[4.5]decan-1-one Derivative as a Potent and Selective Dual TYK2/JAK1 Inhibitor for the Treatment of Inflammatory Bowel Disease. [2022]In this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration of the structure-activity relationship through the introduction of spirocyclic scaffolds based on the reported selective TYK2 inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on TYK2/JAK1 kinases with IC50 values of 6 and 37 nM, respectively, and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more potent anti-inflammatory efficacy than tofacitinib in acute ulcerative colitis models. Moreover, the excellent anti-inflammatory effect of compound 48 was mediated by regulating the expression of related TYK2/JAK1-regulated genes, as well as the formation of Th1, Th2, and Th17 cells. Taken together, these findings suggest that compound 48 is a selective dual TYK2/JAK inhibitor, deserving to be developed as a clinical candidate.
Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise. [2023]Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.
Efficacy of JAK inhibitors in Crohn's Disease. [2021]Inhibition of Janus kinases [JAKs] in Crohn's disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.
Discovery of 3-(4-(2-((1H-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease. [2021]TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.
Novel TYK2 Inhibitors with an N-(Methyl-d 3)pyridazine-3-carboxamide Skeleton for the Treatment of Autoimmune Diseases. [2023]Tyrosine kinase 2 (TYK2) mediates the interleukin-23 (IL-23), IL-12, and type I interferon (IFN)-driven signal responses that are critical in autoimmune diseases. Here, a series of novel derivatives with an N-(methyl-d 3)pyridazine-3-carboxamide skeleton that bind to the TYK2 pseudokinase domain were designed, synthesized, and evaluated. Among them, compound 30 demonstrated more excellent inhibitory potency against STAT3 phosphorylation than the positive control deucravacitinib. In addition to JAK isoform selectivity, compound 30 exhibited good in vivo and in vitro pharmacokinetic properties. Furthermore, compound 30 was orally highly effective in both IL-23-driven acanthosis and anti-CD40-induced colitis models. Together, these findings support compound 30 as a promising candidate for therapeutic applications in autoimmune diseases.