LY3509754 / Eli Lilly - LARVOL DELTA

Silencing SLC52A2 promotes tertiary lymphoid structure formation and inhibits IL-17 pathway to ameliorate melanoma progression. (PubMed, Apoptosis) - "Experimentally, SLC52A2 knockdown reduced IL-17A/IL-17RA protein levels, and IL-17 receptor antagonist LY3509754 exhibited the anti-tumor role in vitro. Collectively, SLC52A2 drives melanoma progression by inhibiting TLS-mediated anti-tumor immunity and activating the IL-17 pathway, positioning SLC52A2 as a promising therapeutic target for melanoma."

Journal • Melanoma • Oncology • Solid Tumor • CD20 • CD4 • CD68 • CD8 • GZMB • IFNG • IL17A • IL17RA

Mechanistically resolved prediction of compound hepatotoxicity using primary human liver spheroids-Application to recent real-world cases. (PubMed, Drug Metab Dispos) - "Cholestatic liability was identified using bile acid coexposure with accurate classification of chlorpromazine and bosentan and confirmation of bile salt export pump downregulation. Importantly, the model also recapitulated hepatotoxicity signals observed in recent clinical development, including for Bruton's tyrosine kinase inhibitors (tolebrutinib and evobrutinib), oral glucagon-like peptide-1 receptor agonists (danuglipron vs orforglipron), synergistic toxicity on azelaprag-tirzepatide coexposure and enhanced sensitivity to the IL-17A inhibitor LY3509754 on coculture with nonparenchymal liver cells...The model maintains stable CYP expression and metabolic activity, captures the impact of nonparenchymal cells on hepatic clearance, and detects mitochondrial, cholestatic, and interaction-driven toxicity, including recent real-world clinical cases. These findings support 3-dimensional human liver spheroids as translational new approach methodologies for integrating..."

Journal • Real-world evidence • Hepatology • Liver Failure • Metabolic Disorders • IL17A

Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors. (PubMed, J Med Chem) - "IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754."

Journal • Preclinical • Ankylosing Spondylitis • Dermatology • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Psoriasis • Psoriatic Arthritis • Rheumatology • Seronegative Spondyloarthropathies • IL17A

Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study. (PubMed, Clin Pharmacol Ther) - P1 | "We theorize that the DILI relates to an off-target effect rather than IL-17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated."

Journal • P1 data • PK/PD data • Dermatology • Hepatology • Immunology • Inflammation • Liver Failure • Psoriasis • IL17A

A Study of LY3509754 in Healthy Non-Japanese and Japanese Participants (clinicaltrials.gov) - P1 | N=104 | Terminated | Sponsor: Eli Lilly and Company | Suspended ➔ Terminated; Terminated due to safety findings

Trial termination

A Study of LY3509754 in Healthy Non-Japanese and Japanese Participants (clinicaltrials.gov) - P1 | N=105 | Suspended | Sponsor: Eli Lilly and Company | Trial completion date: Feb 2022 ➔ Sep 2022 | Trial primary completion date: Feb 2022 ➔ Sep 2022

Trial completion date • Trial primary completion date

A Safety Study of LY3462817 and LY3509754 in Participants With Psoriasis (clinicaltrials.gov) - P1 | N=30 | Terminated | Sponsor: Eli Lilly and Company | N=94 ➔ 30 | Active, not recruiting ➔ Terminated; Terminated due to liver findings

Enrollment change • Trial termination • Dermatology • Immunology • Psoriasis

A Safety Study of LY3462817 and LY3509754 in Participants With Psoriasis (clinicaltrials.gov) - P1 | N=94 | Active, not recruiting | Sponsor: Eli Lilly and Company | Suspended ➔ Active, not recruiting

Enrollment closed • Dermatology • Immunology • Psoriasis

A Safety Study of LY3462817 and LY3509754 in Participants With Psoriasis (clinicaltrials.gov) - P1; N=94; Suspended; Sponsor: Eli Lilly and Company; Trial completion date: Jul 2022 ➔ Mar 2022; Trial primary completion date: Jul 2022 ➔ Mar 2022

Clinical • Trial completion date • Trial primary completion date • Dermatology • Immunology • Psoriasis

A Study of LY3509754 in Healthy Non-Japanese and Japanese Participants (clinicaltrials.gov) - P1; N=105; Suspended; Sponsor: Eli Lilly and Company; Trial completion date: Oct 2021 ➔ Feb 2022; Active, not recruiting ➔ Suspended; Trial primary completion date: Oct 2021 ➔ Feb 2022

Clinical • Trial completion date • Trial primary completion date • Trial suspension

A Safety Study of LY3462817 and LY3509754 in Participants With Psoriasis (clinicaltrials.gov) - P1; N=94; Suspended; Sponsor: Eli Lilly and Company; Trial completion date: Apr 2022 ➔ Jul 2022; Trial primary completion date: Apr 2022 ➔ Jul 2022

Clinical • Trial completion date • Trial primary completion date • Dermatology • Immunology • Psoriasis