Background/Purpose: HDAC6 is a pleiotropic enzyme which removes of acetyl groups from non-histone proteins. HDAC6 inhibition represses inflammatory responses such as cytokines, chemokines and cell adhesion molecules by repressing NADPH Oxidase activity in macrophage as well as enhance Treg function by enhancing transcriptional activity of FOXP3 which induces several immunomodulatory proteins such as CTLA4. Thus, HDAC6 was proposed as a therapeutic target to provide significant therapeutic benefit to patients with severe immune disorders. CKD-506 is an oral hydroxamate HDAC6 selective inhibitor without genotoxicity. CKD-506 has shown strong therapeutic efficacy in adjuvant-induced arthritis (AIA) rheumatoid arthritis model. Furthermore, CKD-506 showed strong synergistic therapeutic efficacy in combination with methotrexate (MTX). In RA patients’ PBMC and fibroblast like synoviocytes (FLS), CKD-506 suppressed inflammatory cytokines such as TNFa, CXCL10 and CCL2 and induced the anti-inflammatory cytokines such as IL-10, strongly implying that CKD-506 may be efficacious in RA patients.

Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CKD-506 in single ascending dose (SAD) and multiple ascending dose (MAD) in healthy volunteers.

Methods: This first-in-human study consisted of two randomized, double-blind, placebo-controlled parts: Part A, 7 SAD cohorts (50 – 1000 mg) and in Part B, 5 MAD cohorts with 14 days treatment (200, 400, 600 mg and 800 mg QD and 400 mg BID). Adverse events (AEs), clinical labs, vital signs and electrocardiogram (ECGs) were evaluated. Plasma PK concentration were assessed by LC-MS/MS. PD was assessed by measuring the acetylated a-tubulin and histone H3 using flow cytometry.

Results: CKD-506 was safe and well-tolerated following single and multiple doses for 14 days without significant changes in vital sign, ECG and laboratory measurements. All treatment-emergent adverse events (TEAEs) were mild in severity and the most common AEs were headache, hot flush, rash, pruritus and abdominal discomfort. Following single doses of CKD-506, CKD-506 was rapidly absorbed with median time to maximum observed concentration (t_max) between 0.5-1 hour. Following multiple doses of CKD-506, exposure reached steady state on day 6 for all QD dosing and day 12 for the 400 mg BID dosing. A minimal accumulation was observed with mean accumulation ratio (R_ac) ranged from 1.05 to 1.30. The mean changes-from-baseline for acetylated a-tubulin and histone H3 generally displayed a dose-dependent increase in CD3⁺ T cells and monocytes on day 1 and day 14. The maximum levels of acetylated a-tubulin was observed between 1-4 hours post-dose on day 1 and 14 with returned to near basal levels by 24 hours.

Conclusion: CKD-506 was generally safe and well-tolerated following single and multiple doses in healthy volunteers. Plasma exposure was relatively dose proportional. The levels of acetylated a-tubulin increased dose dependently. These results support further clinical development of CKD-506 with once daily dosing regimen for the treatment of RA and other inflammatory and autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-ckd-506-a-novel-histone-deacetylase-6-hdac6-inhibitor-in-healthy-volunteers/