Small Molecule · KW-6356

Sipagladenant

DiscontinuedKyowa Kirin Co., Ltd. (4151)

Oral, once-daily, potent and selective adenosine A2A receptor antagonist/inverse agonist discovered by Kyowa Kirin as the intended next-generation successor to its approved A2A antagonist istradefylline (NOURIANZ/NOURIAST). Distinguishing pharmacology versus istradefylline: higher A2A affinity (human pKi 9.93), a very slow receptor dissociation rate producing insurmountable antagonism (istradefylline's is surmountable), and inverse agonism at constitutively active A2A receptors; high A2A selectivity over A1, A2B and A3 across species. In Japanese Phase 2 studies it improved motor symptoms as monotherapy in early untreated Parkinson's disease and, in a 502-patient Phase 2b as adjunct to levodopa, significantly improved MDS-UPDRS Part III scores (p=0.006 at 3 mg, p=0.049 at 6 mg) and reduced daily OFF time, with no major safety issues. Development was nonetheless discontinued company-wide on 2022-07-15 after Kyowa Kirin's evaluation of the global regulatory landscape, development hurdles and time to market — not for clinical reasons.

Also known as: KW-6356, KW6356, KW 6356, sipagladenant, 858979-50-7, N-[4-(furan-2-yl)-5-(oxane-4-carbonyl)-1,3-thiazol-2-yl]-6-methylpyridine-3-carboxamide

Data current as of

Key facts

Modality
Small molecule
Chemical class
thiazole, carboxamide, pyridine
Chemistry
Achiral
Mechanism
Adenosine A2A receptor Inverse agonist
Highest phase
Discontinued
Lead indication
Parkinson's disease
Developer
Kyowa Kirin Co., Ltd. (4151)
Trials
2 tracked · 8 sites

Mechanism of action#

Potent, selective antagonist and inverse agonist of the adenosine A2A receptor (ADORA2A), a Gs-coupled class-A GPCR enriched on striatopallidal (indirect-pathway) medium spiny neurons. Human A2A pKi 9.93 with high affinity conserved across marmoset, dog, rat and mouse, and high selectivity over the A1, A2B and A3 adenosine receptors in all species. Unlike the first-generation A2A antagonist istradefylline, KW-6356 dissociates very slowly from the receptor and behaves as an insurmountable antagonist, and it suppresses constitutive (agonist-independent) A2A signaling as an inverse agonist; crystallography implicates His250 and Trp246 interactions in the inverse agonism. The therapeutic rationale in Parkinson's disease is non-dopaminergic: blocking A2A tone on the indirect pathway rebalances basal-ganglia output, improving motor function as monotherapy and reducing OFF time as an adjunct to levodopa.

TargetActionAffinity
Adenosine A2A receptorprimaryADORA2AInverse agonistpKi 9.93ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
KW-6356 oral tablet (once daily)
3 mg or 6 mg orally once daily in the Phase 2b adjunct-to-levodopa study (NCT03703570); the early Phase 2 monotherapy study (NCT02939391) tested multiple once-daily dose levels against placebo.
OralOnce daily—

Development timeline#

201720182019202020212022Phase 221 Oct 2020 — readout (met) — Positive Phase 2b topline: KW-6356 adjunct to levodopa met the primary endpoint in 502 Parkinson's disease patients — MDS-UPDRS Part III significantly improved (p=0.006 at 3 mg, p=0.049 at 6 mg QD) and daily OFF time decreased, with no major safety issues.29 Sept 2018 — phase change — Phase 2b study NCT03703570 started: multicenter, randomized, double-blind, placebo-controlled, 26-week study of KW-6356 3 mg and 6 mg once daily as adjunct to levodopa-containing therapy in 502 Parkinson's disease patients in Japan (primary endpoint: change from baseline in MDS-UPDRS Part III).20 Aug 2018 — readout (met) — KW-6356 monotherapy improved motor symptoms vs placebo in early untreated Parkinson's disease (Phase 2, n=175): results presented at IAPRD 2018 and later published in Parkinsonism & Related Disorders (2024).1 Sept 2016 — phase change — Early Phase 2 monotherapy study NCT02939391 started in subjects with early untreated Parkinson's disease (Japan; n=175; multiple once-daily doses vs placebo). ClinicalTrials.gov gives the start date at month precision ('2016-09'); this entry is anchored to the first of the month.Discontinued15 Jul 2022 — phase change — Kyowa Kirin announced discontinuation of the entire KW-6356 clinical development program, explicitly acknowledging the compound was 'potentially effective in relieving motor and non-motor symptoms both as monotherapy and in combination with levodopa-containing therapy' but citing 'a thorough evaluation of the global regulatory landscape, development hurdles, and timelines for potential market entry'. A strategic termination after positive Phase 2 data; no Phase 3 was started.
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedJul 2022
  1. Kyowa Kirin announced discontinuation of the entire KW-6356 clinical development program, explicitly acknowledging the compound was 'potentially effective in relieving motor and non-motor symptoms both as monotherapy and in combination with levodopa-containing therapy' but citing 'a thorough evaluation of the global regulatory landscape, development hurdles, and timelines for potential market entry'. A strategic termination after positive Phase 2 data; no Phase 3 was started.↗
Phase 2Sept 2016 – Oct 2020
  1. metPositive Phase 2b topline: KW-6356 adjunct to levodopa met the primary endpoint in 502 Parkinson's disease patients — MDS-UPDRS Part III significantly improved (p=0.006 at 3 mg, p=0.049 at 6 mg QD) and daily OFF time decreased, with no major safety issues.↗
  2. Phase 2b study NCT03703570 started: multicenter, randomized, double-blind, placebo-controlled, 26-week study of KW-6356 3 mg and 6 mg once daily as adjunct to levodopa-containing therapy in 502 Parkinson's disease patients in Japan (primary endpoint: change from baseline in MDS-UPDRS Part III).
  3. metKW-6356 monotherapy improved motor symptoms vs placebo in early untreated Parkinson's disease (Phase 2, n=175): results presented at IAPRD 2018 and later published in Parkinsonism & Related Disorders (2024).↗
  4. Early Phase 2 monotherapy study NCT02939391 started in subjects with early untreated Parkinson's disease (Japan; n=175; multiple once-daily doses vs placebo). ClinicalTrials.gov gives the start date at month precision ('2016-09'); this entry is anchored to the first of the month.

Sipagladenant for Parkinson's disease#

DiscontinuedDiscontinuedParkinson's disease indication →

KW-6356 (sipagladenant), a next-generation adenosine A2A receptor antagonist/inverse agonist, for Parkinson's disease — Kyowa Kirin's intended successor to its approved A2A antagonist istradefylline, with higher affinity, insurmountable antagonism and inverse agonism, and ambitions for a broader label (monotherapy as well as adjunct use). The Japanese Phase 2 program was positive on both fronts: the early Phase 2 monotherapy study in untreated Parkinson's disease (NCT02939391, n=175) showed improvement in MDS-UPDRS Part III versus placebo (presented at IAPRD 2018 and later published), and the Phase 2b adjunct-to-levodopa study (NCT03703570, n=502, 26 weeks) met its primary endpoint — MDS-UPDRS Part III improved significantly at both 3 mg (p=0.006) and 6 mg (p=0.049) once daily — and reduced mean daily OFF time, with no major safety issues. Despite this, Kyowa Kirin announced on 2022-07-15 that it was discontinuing KW-6356 development entirely, after 'a thorough evaluation of the global regulatory landscape, development hurdles, and timelines for potential market entry' — a strategic, not clinical, termination; no Phase 3 was ever started and the asset has not been out-licensed or revived by any sponsor as of 2026-08-31.

Readouts

  • 2020-10-21ReportedTopline datametNCT03703570

    Positive Phase 2b topline: KW-6356 adjunct to levodopa met the primary endpoint in 502 Parkinson's disease patients — MDS-UPDRS Part III significantly improved (p=0.006 at 3 mg, p=0.049 at 6 mg QD) and daily OFF time decreased, with no major safety issues. ↗

  • 2018-08-20ReportedFull resultsmetNCT02939391

    KW-6356 monotherapy improved motor symptoms vs placebo in early untreated Parkinson's disease (Phase 2, n=175): results presented at IAPRD 2018 and later published in Parkinsonism & Related Disorders (2024). ↗

Clinical trials#

NCT037035706356-004Phase 2Completedn=502

A Study of KW-6356 in Patients With Parkinson's Disease on Treatment With Levodopa-containing Preparations

Started Sept 2018· Primary completion Apr 2020· 1 site across 1 country

Japan

metChange from baseline in MDS-UPDRS Part III score over 26 weeks vs placebo (primary); mean OFF time per day (key secondary)

Met the primary endpoint: KW-6356 significantly decreased MDS-UPDRS Part III total score versus placebo (p=0.006 for 3 mg, p=0.049 for 6 mg once daily) over 26 weeks in 502 Japanese Parkinson's disease patients on levodopa-containing therapy, and decreased mean OFF time/day on the key secondary endpoint. No major safety issues in any group. Announced 2020-10-21; presented at the MDS Virtual Congress.

NCT029393916356-002Phase 2Completedn=175

A Study of KW-6356 in Subjects With Early Parkinson's Disease

Started Sept 2016· Primary completion Dec 2017· 7 sites across 1 country

Japan

metChange from baseline in MDS-UPDRS Part III (motor examination) score, KW-6356 monotherapy vs placebo

Randomized, double-blind, placebo-controlled monotherapy study in early untreated Parkinson's disease (Japan, n=175). Kyowa Kirin reported efficacy on motor symptoms at IAPRD 2018 (2018-08-20 news release), and the randomized controlled trial was subsequently published in Parkinsonism & Related Disorders (2024), reporting improvement in MDS-UPDRS Part III with KW-6356 monotherapy versus placebo. Exact effect sizes are in the publication; the company characterized the compound as potentially effective as monotherapy.

Sources#

  1. Kyowa Hakko Kirin Announces Results of Early Phase 2 Trial of KW-6356 for Parkinson's Disease at IAPRD (2018-08-20) — Kyowa Kirin Co., Ltd. (then Kyowa Hakko Kirin)
  2. Kyowa Kirin Announces Discontinuation for Developing KW-6356 (2022-07-15) — Kyowa Kirin Co., Ltd.
  3. Kyowa Kirin Announces Positive Phase 2b Results for KW-6356 in Patients with Parkinson's Disease (2020-10-21) — Kyowa Kirin Co., Ltd.
  4. NCT02939391 — A Study of KW-6356 in Subjects With Early Parkinson's Disease (Phase 2 monotherapy, n=175, completed 2017-12-08) — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT03703570 — A Study of KW-6356 in Patients With Parkinson's Disease on Treatment With Levodopa-containing Preparations (Phase 2b, n=502, completed 2020-04-15) — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. Ohno Y, et al. In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A2A Receptor Antagonist/Inverse Agonist. Mol Pharmacol. 2023 (human A2A pKi 9.93; slow dissociation; insurmountable antagonism; inverse agonism; A1/A2B/A3 selectivity) — Molecular Pharmacology (ASPET) / PubMed
  7. Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease. Parkinsonism & Related Disorders (2024) — Parkinsonism & Related Disorders (Elsevier)