KW-6356

KW-6356 (sipagladenant; CAS 858979-50-7) is a selective, non-xanthine adenosine A2A receptor antagonist and inverse agonist developed by Kyowa Kirin Co., Ltd. (formerly Kyowa Hakko Kirin) as a next-generation successor to istradefylline (NOURIANZ/NOURIAST) for the treatment of motor and non-motor symptoms of Parkinson's disease. The compound exhibits approximately 100-fold greater binding affinity for the human adenosine A2A receptor than istradefylline (pKi 9.93 versus approximately 7.9), with a Kd of 0.13 nM and a Ki of 0.12 nM at the human A2A receptor, and demonstrates greater than 100-fold selectivity over the A1, A2B, and A3 adenosine receptor subtypes [1]. In contrast to istradefylline, which acts as a surmountable antagonist, KW-6356 exhibits two pharmacologically distinct properties: insurmountable antagonism (the capacity to suppress receptor signaling in a manner that cannot be fully overcome by increasing agonist concentration) and inverse agonism (the capacity to reduce constitutive, agonist-independent receptor activity below basal levels). X-ray crystallography of the KW-6356-bound human A2A receptor at 2.30 angstrom resolution (PDB: 8GNE) has revealed that interactions with His250 (position 6.52) and Trp246 (position 6.48) are essential for the inverse agonist activity, while deep orthosteric pocket contacts and stabilization of the extracellular loop conformation contribute to the insurmountable antagonism [1].

The clinical development program evaluated KW-6356 in two pivotal Phase 2 studies in Japanese Parkinson's disease populations. A Phase 2a randomized, double-blind, placebo-controlled monotherapy trial in 168 patients with early, untreated Parkinson's disease demonstrated that once-daily oral KW-6356 at 3 mg and 6 mg produced improvements in MDS-UPDRS Part III motor scores (least-squares mean changes from baseline to week 12 of -5.37 and -4.76, respectively, versus -3.14 for placebo) [2]. A subsequent Phase 2b randomized, double-blind, placebo-controlled adjunct-to-levodopa trial in 503 patients with levodopa-treated Parkinson's disease demonstrated statistically significant improvements in MDS-UPDRS Part III motor scores at both 3 mg (p = 0.006 versus placebo) and 6 mg (p = 0.049 versus placebo), with additional reductions in mean daily OFF time in the key secondary endpoint and improvements on the PD Sleep Scale-2 in post-hoc analysis [3, 4]. Preclinical pharmacology in MPTP-treated common marmosets confirmed dose-dependent reversal of motor disability at oral doses up to 1 mg/kg, with anti-parkinsonian activity significantly greater than that of istradefylline and a low risk of inducing dyskinesia [5, 6].

Pharmacokinetics in healthy volunteers demonstrated linear exposure after single oral doses of 1 to 60 mg, with a mean terminal elimination half-life of 18.4 to 43.1 hours (mean approximately 22.9 hours), a time to peak plasma concentration of 0.75 to 3 hours, and an active metabolite (M6) with comparable A2A antagonist and inverse agonist potency and an elimination half-life of approximately 4.34 hours [7, 8]. Population pharmacokinetic modeling identified food status, baseline serum albumin, and baseline body weight as covariates, but none had clinically meaningful impact on KW-6356 or M6 exposure [8]. The compound was well tolerated in Phase 1 studies at single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days, with no clinically meaningful changes in vital signs, body weight, laboratory parameters, or electrocardiograms [7]. The most common adverse events in the Phase 2a monotherapy trial were constipation (7.3 percent at 3 mg, 6.9 percent at 6 mg) and nasopharyngitis (7.3 percent at 3 mg, 8.6 percent at 6 mg) [2].

Despite positive proof-of-concept results across both monotherapy and adjunct-to-levodopa settings, Kyowa Kirin announced discontinuation of the KW-6356 development program in July 2022, citing evaluation of the global regulatory landscape, development hurdles, and timelines for potential market entry rather than efficacy or safety concerns [9]. The discontinuation followed Lundbeck's earlier decision to return ex-Asia development rights to Kyowa Kirin. No Phase 3 trials were initiated. This monograph documents the chemistry, structural pharmacology, receptor binding and selectivity profile, preclinical and clinical evidence base, pharmacokinetics, safety signal, and a comparative assessment of KW-6356 against five adenosine A2A receptor antagonists on five competency standards.