Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study.

For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10-2,000 mg) or multiple ascending dose (MAD; dose range 100-1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21-65 years (71% men). LY3509754 had a time to maximum concentration (Tmax) of 1.5-3.5 hours, terminal half-life of 11.4-19.1 hours, and exhibited dose-dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL-17A levels within 12 hours of dosing. Four participants from the 400-mg (n = 1) and 1,000-mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post-last LY3509754 dose), consistent with drug-induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte-rich, moderate-to-severe lobular inflammation. 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.

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).