LY4100511 for Psoriasis
Recruiting in Palo Alto (17 mi)
+57 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: DICE Therapeutics, Inc., a wholly owned subsidiary of Eli Lilly and Company
Must not be taking: Corticosteroids, Immunosuppressants, Biologics
Disqualifiers: Psoriatic arthritis, Inflammatory conditions, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?The main purpose of this study is to assess the safety and efficacy of LY4100511 in adult participants with moderate-to-severe plaque psoriasis.
Will I have to stop taking my current medications?
Yes, you must stop using topical and/or systemic therapies for psoriasis before starting the study treatment.
How does the drug LY4100511 differ from other psoriasis treatments?
LY4100511, also known as DC-853, is unique because it may target specific immune pathways involved in psoriasis, potentially offering a novel approach compared to traditional treatments that often focus on broad immunosuppression. This could mean fewer side effects and a more targeted action against the disease.
12345Eligibility Criteria
This trial is for adults with moderate-to-severe plaque psoriasis. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be excluded based on other medical conditions or treatments.Inclusion Criteria
I agree to avoid sun exposure and not use tanning devices during the study.
Must have a body mass index (BMI) of 18 to 40 kilogram/square meter (kg/m2) (inclusive)
I have been diagnosed with plaque psoriasis for at least 6 months.
+1 more
Exclusion Criteria
I am being treated with drugs that affect my immune system for psoriatic arthritis.
I have a history of severe psoriasis.
I have a condition like psoriasis or psoriatic arthritis, but not conditions like rheumatoid arthritis or lupus.
+2 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive LY4100511 or placebo orally for the treatment of moderate-to-severe plaque psoriasis
12 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study is testing the safety and effectiveness of a new medication called LY4100511 compared to a placebo in treating plaque psoriasis. This phase 2 trial will help determine the appropriate dose range for future studies.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: LY4100511 Dose 3Experimental Treatment1 Intervention
Participants will receive LY4100511 orally.
Group II: LY4100511 Dose 2Experimental Treatment1 Intervention
Participants will receive LY4100511 orally.
Group III: LY4100511 Dose 1Experimental Treatment1 Intervention
Participants will receive LY4100511 orally.
Group IV: PlaceboPlacebo Group1 Intervention
Placebo administered orally.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
GCP Global Clinical Professionals, LLCSaint Petersburg, FL
Dermatology Trial AssociatesBryant, AR
Clinical Science InstituteSanta Monica, CA
Driven ResearchCoral Gables, FL
More Trial Locations
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Who Is Running the Clinical Trial?
DICE Therapeutics, Inc., a wholly owned subsidiary of Eli Lilly and CompanyLead Sponsor
References
A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice. [2019]There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but not CD11b+ cells. Consistent with this phenotype and the function of slc15a4, induction of IFN-I was virtually absent systemically and via cutaneous gene expression. Induction of other inflammatory cytokines (cytokine storm) was modestly blunted in slc15a4feeble except for inflammasome-associated genes consistent with slc15a4 being required for TLR7-mediated (but not inflammasome-mediated) inflammation downstream of IMQ. Surprisingly, only IFN-I gene expression was suppressed within IMQ-treated skin. Other genes including conserved psoriasiform trademark gene expression were augmented in slc15a4feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.
Clearing of psoriasis by a novel immunosuppressive macrolide. [2019]Accumulating evidence suggests that psoriasis may be a genetically determined immunogenic, inflammatory disorder based on an ongoing autoreactive Th-1 response. Systemic immunosuppressive therapy is highly effective but fraught with longterm side effects. Our research therefore focuses on therapeutic strategies that induce local immunosuppression in the skin by topical, transepidermal delivery of immunosuppressive drugs. SDZ 281-240 is a newly developed macrolide of the ascomycin type. It is immunosuppressive by mechanism of action similar to that of FK506 but has no antiproliferative activity against keratinocytes in vitro. To evaluate whether SDZ 281-240 exhibits antipsoriatic activity when applied topically, we tested 15 patients with severe, recalcitrant psoriasis, using a microplaque assay in randomized, double-blind, placebo-controlled study, comparing the therapeutic efficacy of the macrolide with a potent halogenated corticosteroid and vehicle. All patients showed a significant improvement of psoriatic lesions treated with two concentrations of the macrolide and, as expected, with the corticosteroid but not with placebo. Both concentrations of the macrolide led to clearing of psoriasis after 10 days of treatment and biopsies confirmed a reversal of the histopathological and immunopathological phenotype of psoriasis to that of normal skin. Thus, an immunosuppressive agent that interferes with early T cell activation can be designed to penetrate into psoriatic lesions when applied topically and to be functionally active within the skin to suppress the ongoing psoriatic process.
Accumulation of FLT3(+) CD11c (+) dendritic cells in psoriatic lesions and the anti-psoriatic effect of a selective FLT3 inhibitor. [2021]Psoriasis is a common chronic T-cell-mediated autoimmune skin disease, and traditional immunotherapies for psoriasis have focused on the direct inhibition of T cells, which often causes toxicity and lacks long-term effectiveness. Safe and effective therapeutic strategies are strongly needed for psoriasis. In this study, we show for the first time a significant accumulation of FLT3(+) CD11c(+) dendritic cells (DCs) in human psoriatic lesions and in the skin of experimental preclinical K14-VEGF transgenic homozygous mice, our animal model, although not an exact match for human psoriasis, displays many characteristics of inflammatory skin inflammation. SKLB4771, a potent and selective FLT3 inhibitor that we designed and synthesised, was used to treat cutaneous inflammation and psoriasis-like symptoms of disease in mice and almost completely cured the psoriasis-like disease without obvious toxicity. Mechanistic studies indicated that SKLB4771 treatment significantly decreased the number and activation of pDCs and mDCs in vitro and in vivo, and subsequent T-cell cascade reactions mediated by Th1/Th17 pathways. These findings show that targeted inhibition of FLT3, and hence direct interference with DCs, may be a novel therapeutic approach for the treatment of psoriasis.
FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes. [2023]Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia. However, the regulatory complexity of cytokine and cellular networks still needs to be investigated. Here, we show that the expression of FXYD3, a member of the FXYD domain-containing regulators of Na+/K+ ATPases family, is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod (IMQ)-induced psoriasis. IL-17A, a cytokine important for the development of psoriatic lesions, contributes to FXYD3 expression in human primary keratinocytes. FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model. Importantly, FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes. This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors. Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation. Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.
Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop regulates Th17 cell differentiation in mouse psoriasis‑like skin inflammation. [2022]IL‑17A, the effector cytokine of T helper (Th) 17 cells, plays a crucial role in the pathogenesis of psoriasis. The Notch1 and PI3K/AKT signaling pathways are implicated in Th17 cell differentiation and IL‑17A production. The present study aimed to evaluate the regulatory effect of the Notch1/hairy and enhancer of split 1 (Hes1)‑PTEN/AKT/IL‑17A feedback loop on Th17 cell differentiation via the PI3K/AKT inhibitor LY294002 in a mouse model of psoriasis. Mice were randomly divided into 3 groups: a control group, a model group [5% imiquimod (IMQ)‑induced group] and an intervention group (5% IMQ‑induced plus LY294002‑treated group). Skin structural characteristics were recorded and evaluated by hematoxylin and eosin staining. The weights of the spleens and inguinal lymph nodes were measured. Th17 cell percentage, as well as the mRNA and protein expression levels of Notch1, Notch1 intracellular domain (NICD1), Hes1, PTEN, AKT, phosphorylated (p)‑AKT, mTOR complex 1 (mTORC1), p‑mTORC1, S6 kinase (S6K)1, S6K2 and IL‑17A were detected in skin samples of the three experimental groups. Additionally, splenic mononuclear cells from model mice were treated by 10 and 50 µM LY294002 to further evaluate its regulatory effect on Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop. Increased Th17 cell percentage, increased expression of Notch1, NICD1, Hes1, AKT, p‑AKT, mTORC1, p‑mTORC1, S6K1, S6K2 and IL‑17A, and decreased PTEN levels were observed in model mice alongside marked psoriasis‑like skin inflammation, splenomegaly and lymphadenopathy. LY294002 treatment significantly alleviated the severity of psoriasis‑like skin inflammation in the intervention mice, attenuated the degree of epidermal hyperplasia and dermal inflammatory cell infiltration, and mitigated splenomegaly and lymphadenopathy. In addition, LY294002 treatment reversed the increased Th17 cell percentage, as well as the increased expression of Notch1, NICD1, Hes1, AKT, p‑AKT, mTORC1, p‑mTORC1, S6K1, S6K2 and IL‑17A, and the decreased expression of PTEN. In vitro study from 5% IMQ‑induced mouse splenic mononuclear cells presented that high dose of LY294002 exerted more obviously regulatory effect on Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop. The current findings suggested that the Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop regulates Th17 cell differentiation within the disease environment of psoriasis. Blocking the Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop may thus be a potential therapeutic method for management of psoriatic inflammation.