Background/Purpose: LY2775240 is a potent and selective phosphodiesterase (PDE4) inhibitor being investigated as a potential treatment for inflammatory disorders, such as psoriasis. PDE4 is expressed primarily in immune cells, and enzymatically degrades cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 leads to increased cytoplasmic cAMP and reduced pro-inflammatory immune responses. Pharmacodynamic (PD) effect measured as inhibition of PDE4 activity can be assessed with an ex vivo whole blood assay where the stimulant is the bacterial endotoxin lipopolysaccharide (LPS) and the readout is secretion of the cytokine TNF alpha.

Methods: In the first part of a Phase 1 (First-in-Human), single-center, randomized, 2-part study evaluating safety, tolerability and pharmacokinetics of LY2775240 in healthy subjects; subjects received LY2775240 or placebo (8:2) in a blinded manner. LY2775240 at 0.1, 0.5, 1.5, 5, 10, 20, 30, or 40 mg was given orally as a single dose. Ex vivo PDE4 inhibition assays were conducted at pre-dose, 4, 12, and 24 hours. The second part was an open-label, 2-period, crossover design in healthy subjects (n=11) that included a single dose of either LY2775240 (20 mg) or apremilast (30 mg) in each period. Ex vivo PDE4 inhibition assays were conducted at pre-dose, 1, 4, 8, 12, and 24 hours. TruCulture (Myriad RBM) assay tubes containing LPS with a 24-hour incubation at 37°C were used for the ex vivo PD assay, with TNF alpha levels measured by MSD assay at Covance (Durham NC).

Results: LY2775240 was safe and well tolerated in this Phase 1 study. The most common AEs were nausea, diarrhea and headache, consistent with those reported with other drugs in the PDE4 inhibitor class. No SAEs were reported. LY2775240 PK was well characterized over the dose range studied, and the half-life supports a once-a-day dosing regimen. In the first part, the ex vivo PD assay showed dose dependent decreases of TNF alpha across the dose range studied. The 20 mg dose of LY2775240 led to near maximal inhibition in this assay and was selected for comparison with the clinical dose (30 mg) of apremilast. LY2775240 maintained >50% inhibition of TNF alpha induction over the 24-hour duration, while apremilast achieved peak inhibition of 50% at 4 hours, while returning to ~10% inhibition within 12 hours post dose.

Conclusion: The 20 mg dose of LY2775240 demonstrated an increased and sustained inhibition of PDE4 activity over 24 hours when compared to the clinical dose of apremilast.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-i-evaluation-of-the-pde4-inhibitor-ly2775240-head-to-head-comparison-with-apremilast-using-an-ex-vivo-pharmacodynamic-assay/