Sipagladenant

updated

Sipagladenant (KW-6356) is an unapproved adenosine A2A receptor antagonist and inverse agonist studied for Parkinson's disease. One published phase 2a trial in 168 patients with early, untreated disease showed larger MDS-UPDRS Part III improvements than placebo at both doses, while the 502-patient levodopa add-on trial has no public outcome. No study in any species tested motivation, fatigue or alertness, and its developer authors describe it as non-dopaminergic.

Adenosine A2A receptor antagonist and inverse agonist

  • KW-6356 is sipagladenant (INN): PubChem CID 23144148, C20H19N3O4S, 397.4 g/mol, CAS 858979-50-7.
  • openFDA Drugs@FDA queries for KW-6356 and for sipagladenant returned no application on 9 October 2026.
  • In the phase 2a trial in Japan (168 patients with early, untreated Parkinson's disease, 12 weeks), MDS-UPDRS Part III changed by -5.37 on 3 mg and -4.76 on 6 mg versus -3.14 on placebo; the abstract gives no p-value for the primary comparison.
  • The levodopa add-on phase 2 trial (NCT03703570, enrollment 502) is completed with no posted results, and no published outcome was found.
  • Mean terminal half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg in healthy volunteers.
  • A PubMed search on 9 October 2026 returned 2 records that tested no behavioral outcome; no study in any species tested motivation, fatigue, alertness or performance.

What is sipagladenant, and is it approved?

Sipagladenant is the INN for KW-6356, an investigational adenosine A2A receptor antagonist with no FDA approval record. openFDA queries for KW-6356 and for sipagladenant returned no application on 9 October 2026.

KW-6356 is sipagladenant (INN): PubChem CID 23144148, C20H19N3O4S, 397.4 g/mol, CAS 858979-50-7. Listed synonyms include KW-6356, KW6356 and Sipagladenant [INN]. PubMed returned no records under the name sipagladenant on 9 October 2026; the literature uses the code.

openFDA Drugs@FDA queries for KW-6356 and for sipagladenant returned no application on 9 October 2026. That is a dated, US-scoped search. Status in Japan, where the monotherapy trial ran, and approvals elsewhere are not covered here.

PubChem: sipagladenant (KW-6356) identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 23144148 (sipagladenant, KW-6356).

KW-6356 is sipagladenant (INN): PubChem CID 23144148, C20H19N3O4S, 397.4 g/mol, CAS 858979-50-7. Listed synonyms include KW-6356, KW6356 and Sipagladenant [INN]. PubMed returned no records under the name sipagladenant on 9 October 2026; the literature uses the code.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
FDA record search, 9 October 2026: no matching application

Regulatory record

U.S. Food and Drug Administration, openFDA Drugs@FDA API queries run on 9 October 2026 for KW-6356 and for sipagladenant by brand or generic name.

The queries for KW-6356 and for sipagladenant returned no application. No US approval record was found. This supports only a dated, US-scoped statement; status in Japan, where the monotherapy trial ran, is not covered.

Participants / model
FDA application database, not a clinical population
Treatment
Name searches
Follow-up
Queries run on 9 October 2026
Study design
Dated US approval-record search
Funding
not stated in the source

A search result shows what the database returned on that date. It is not a worldwide status claim.

Read the original source

What did the Parkinson's disease trials find?

One published phase 2a trial in 168 patients with early, untreated Parkinson's disease found larger MDS-UPDRS Part III improvements than placebo at both doses over 12 weeks. The abstract gives no p-value for the primary comparison.

The phase 2a monotherapy trial in Japan randomized 168 patients with early, untreated Parkinson's disease to KW-6356 3 mg/day (n=55), 6 mg/day (n=58) or placebo (n=55) once daily for 12 weeks. Week 12 completion exceeded 90% in each group. The registry lists enrollment as 175.

The least-squares mean change in MDS-UPDRS Part III total score, the primary measure, was -5.37 (95% CI -7.25 to -3.48) on 3 mg, -4.76 (-6.55 to -2.96) on 6 mg and -3.14 (-4.97 to -1.30) on placebo. The KW-6356 changes were larger than placebo at all time points, and the 6 mg point estimate was smaller than the 3 mg one. Secondary MDS-UPDRS scores moved the same way. The most common adverse events were constipation (7.3% on 3 mg, 10.3% on 6 mg) and nasopharyngitis (7.3% and 8.6%).

The abstract gives no p-value for the primary comparison, and sponsor employees were among the authors. This is the only published patient trial in the records found, and the longest exposure in it was 12 weeks.

Phase 2a in Japan: 168 patients, 12 weeks, MDS-UPDRS Part III

Randomized controlled trial

Maeda T et al. Parkinsonism Relat Disord. 2023;117:105907. PMID 37948832.

Least-squares mean change in MDS-UPDRS Part III total score was -5.37 (95% CI -7.25 to -3.48) on 3 mg, -4.76 (-6.55 to -2.96) on 6 mg, and -3.14 (-4.97 to -1.30) on placebo, and the KW-6356 changes were larger than placebo at all time points; the 6 mg point estimate was smaller than the 3 mg one. Secondary MDS-UPDRS scores moved the same way. The most common adverse events were constipation (7.3% on 3 mg, 10.3% on 6 mg) and nasopharyngitis (7.3% and 8.6%). Week 12 completion exceeded 90% in each group.

Participants / model
168 patients with early, untreated Parkinson's disease in Japan: 3 mg/day (n=55), 6 mg/day (n=58) or placebo (n=55)
Treatment
Oral KW-6356 3 or 6 mg once daily, or placebo, as monotherapy
Follow-up
12 weeks
Study design
Randomized placebo-controlled phase 2a trial (NCT02939391; registry enrollment 175)
Funding
not stated in the source

The abstract gives no p-value for the primary comparison. Sponsor employees were among the authors. Primary endpoint was MDS-UPDRS Part III; secondary measures were Parts II, II plus III, and total.

Read the original source

Was KW-6356 tested as an add-on to levodopa?

A phase 2 add-on trial in 502 patients is registered and completed, but no results are posted and no outcome was found in PubMed. The supplier's add-on statement is true as a registration only.

NCT03703570, a phase 2 study of KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations, is listed as completed with enrollment 502 and no posted results. PubMed searches on 9 October 2026 for KW-6356 with levodopa or for the NCT number returned 3 records, all preclinical.

Two developer marmoset papers state that adjunct efficacy in patients has been reported but give no data in their abstracts. The supplier's statement that KW-6356 has been studied as an add-on to levodopa is true as a registration. The outcome is not public in the records found, and the developer's current program status is not established here.

Registry: levodopa add-on phase 2 completed, enrollment 502, no results posted

Trial registry record

ClinicalTrials.gov. NCT03703570 (phase 2, KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations), with related sponsor records NCT04342273, NCT04190654, NCT04147910, NCT04070495, NCT03970798 and NCT03830528.

NCT03703570, a phase 2 study of KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations, is listed as completed with enrollment 502 and no posted results. PubMed searches on 9 October 2026 for KW-6356 with levodopa or for the NCT number returned 3 records, all preclinical. Two developer marmoset papers state that adjunct efficacy in patients has been reported but give no data in their abstracts. The sponsor's other registered studies are all completed with no posted results: thorough QT (NCT04342273, enrollment 128), single-dose PK of the drug and its major metabolite (NCT04190654, 26), radiolabeled absorption, metabolism and excretion (NCT04147910, 8), interaction with clarithromycin or rifampicin (NCT04070495, 20), interaction with midazolam, caffeine or rosuvastatin (NCT03970798, 50), and single and multiple doses (NCT03830528, 48).

Participants / model
Patients with Parkinson's disease on levodopa (registry description)
Treatment
KW-6356 (registry)
Follow-up
Not applicable
Study design
Official trial registry
Funding
not stated in the source

The outcome of the add-on trial is not public in the records found. A completed registration is not evidence of efficacy.

Read the original source
MPTP marmosets with L-DOPA: enhanced effect, dyskinesia over 21 days

Animal study

Ohno Y et al. J Pharmacol Sci. 2023;152(3):193-199. PMID 37257947.

In MPTP-treated marmosets, oral KW-6356 1 mg/kg enhanced the anti-parkinsonian effect of L-DOPA at 2.5 to 10 mg/kg, and in L-DOPA-primed animals at 1.25 to 10 mg/kg without enhancing dyskinesia. Over 21 days of co-administration with low-dose L-DOPA (2.5 mg/kg), dyskinesia increased relative to that low dose alone but stayed below the level produced by an optimal L-DOPA dose (10 mg/kg).

Participants / model
MPTP-treated common marmosets, including L-DOPA-primed animals
Treatment
Oral KW-6356 1 mg/kg with L-DOPA
Follow-up
21 days of co-administration
Study design
Preclinical study of anti-parkinsonian activity and dyskinesia
Funding
not stated in the source

Developer authors.

Read the original source

What did the phase 1 studies in healthy volunteers show?

KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. Terminal half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg.

Phase 1 studies in healthy Japanese and White volunteers tested single doses of 1, 3 and 10 mg and multiple doses of 6 mg once daily in Japanese subjects (study 6356-001, no NCT number), and single doses of 21, 42 and 60 mg, multiple doses of 24 mg once daily, and open-label 6 mg once daily in Japanese and White subjects (NCT03830528). KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. PK was linear after single doses up to 60 mg, and safety and PK did not clearly differ between Japanese and White subjects.

A population PK analysis pooled healthy subjects and patients with Parkinson's disease and described KW-6356 and its active metabolite M6 with one-compartment models. Food status, baseline serum albumin and body weight entered the models as covariates, but none had a clinically meaningful effect on KW-6356 or M6 exposure.

The sponsor's other registered studies are all completed with no posted results: thorough QT (NCT04342273, enrollment 128), single-dose PK of the drug and its major metabolite (NCT04190654, 26), radiolabeled absorption, metabolism and excretion (NCT04147910, 8), interaction with clarithromycin or rifampicin (NCT04070495, 20), and interaction with midazolam, caffeine or rosuvastatin (NCT03970798, 50).

Phase 1: single doses to 60 mg, multiple doses to 24 mg for 14 days

Clinical trial

Tayama T et al. Clin Pharmacol Drug Dev. 2023;12(8):801-809. PMID 36683291.

KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. PK was linear after single doses up to 60 mg, and mean terminal elimination half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg. Safety and PK did not clearly differ between Japanese and White subjects.

Participants / model
Healthy Japanese and White volunteers
Treatment
Oral KW-6356: single doses 1, 3 and 10 mg and multiple doses of 6 mg once daily in Japanese subjects (study 6356-001), and single doses of 21, 42 and 60 mg, multiple doses of 24 mg once daily, and open-label 6 mg once daily in Japanese and White subjects (NCT03830528)
Follow-up
Single doses; multiple doses for up to 14 days
Study design
Phase 1 safety, tolerability and PK studies
Funding
not stated in the source

Developer authors. Study 6356-001 has no NCT number.

Read the original source
Population PK: healthy subjects and Parkinson's patients, M6 metabolite

Human study

Tayama T et al. Clin Pharmacol Drug Dev. 2024;13(5):549-559. PMID 38178727.

A population PK analysis pooled healthy subjects and patients with Parkinson's disease and described KW-6356 and its active metabolite M6 with one-compartment models. Food status, baseline serum albumin and body weight entered the models as covariates, but none had a clinically meaningful effect on KW-6356 or M6 exposure.

Participants / model
Healthy subjects and patients with Parkinson's disease, pooled
Treatment
Oral KW-6356, single and multiple doses
Follow-up
not stated in the source
Study design
Population PK analysis of the parent drug and its active metabolite
Funding
not stated in the source

Developer authors.

Read the original source
Registry: levodopa add-on phase 2 completed, enrollment 502, no results posted

Trial registry record

ClinicalTrials.gov. NCT03703570 (phase 2, KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations), with related sponsor records NCT04342273, NCT04190654, NCT04147910, NCT04070495, NCT03970798 and NCT03830528.

NCT03703570, a phase 2 study of KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations, is listed as completed with enrollment 502 and no posted results. PubMed searches on 9 October 2026 for KW-6356 with levodopa or for the NCT number returned 3 records, all preclinical. Two developer marmoset papers state that adjunct efficacy in patients has been reported but give no data in their abstracts. The sponsor's other registered studies are all completed with no posted results: thorough QT (NCT04342273, enrollment 128), single-dose PK of the drug and its major metabolite (NCT04190654, 26), radiolabeled absorption, metabolism and excretion (NCT04147910, 8), interaction with clarithromycin or rifampicin (NCT04070495, 20), interaction with midazolam, caffeine or rosuvastatin (NCT03970798, 50), and single and multiple doses (NCT03830528, 48).

Participants / model
Patients with Parkinson's disease on levodopa (registry description)
Treatment
KW-6356 (registry)
Follow-up
Not applicable
Study design
Official trial registry
Funding
not stated in the source

The outcome of the add-on trial is not public in the records found. A completed registration is not evidence of efficacy.

Read the original source

What do the marmoset studies show?

In MPTP-treated marmosets, oral KW-6356 reversed motor disability, with a larger effect than istradefylline, and enhanced L-DOPA without increasing dyskinesia at the doses tested. These are developer studies in animals.

In MPTP-treated common marmosets, oral KW-6356 reversed motor disability dose-dependently up to 1 mg/kg, with a significantly larger effect than istradefylline, and repeated dosing induced little dyskinesia in animals primed with L-DOPA. The authors describe KW-6356 as a non-dopaminergic therapy.

In a second marmoset study, oral KW-6356 1 mg/kg enhanced the anti-parkinsonian effect of L-DOPA at 2.5 to 10 mg/kg, and in L-DOPA-primed animals at 1.25 to 10 mg/kg without enhancing dyskinesia. Over 21 days of co-administration with low-dose L-DOPA (2.5 mg/kg), dyskinesia increased relative to that low dose alone but stayed below the level produced by an optimal L-DOPA dose (10 mg/kg).

MPTP marmosets: motor disability reversed, little dyskinesia

Animal study

Ohno Y et al. Eur J Pharmacol. 2023;950:175773. PMID 37146707.

In MPTP-treated common marmosets, oral KW-6356 reversed motor disability dose-dependently up to 1 mg/kg, with a significantly larger effect than istradefylline, and repeated dosing induced little dyskinesia in animals primed with L-DOPA. The authors describe KW-6356 as a non-dopaminergic therapy.

Participants / model
MPTP-treated common marmosets
Treatment
Oral KW-6356, up to 1 mg/kg
Follow-up
Repeated dosing; length not stated in the abstract
Study design
Preclinical study of motor disability and dyskinesia
Funding
not stated in the source

Developer authors. The target is the adenosine A2A receptor, not a dopamine receptor.

Read the original source
MPTP marmosets with L-DOPA: enhanced effect, dyskinesia over 21 days

Animal study

Ohno Y et al. J Pharmacol Sci. 2023;152(3):193-199. PMID 37257947.

In MPTP-treated marmosets, oral KW-6356 1 mg/kg enhanced the anti-parkinsonian effect of L-DOPA at 2.5 to 10 mg/kg, and in L-DOPA-primed animals at 1.25 to 10 mg/kg without enhancing dyskinesia. Over 21 days of co-administration with low-dose L-DOPA (2.5 mg/kg), dyskinesia increased relative to that low dose alone but stayed below the level produced by an optimal L-DOPA dose (10 mg/kg).

Participants / model
MPTP-treated common marmosets, including L-DOPA-primed animals
Treatment
Oral KW-6356 1 mg/kg with L-DOPA
Follow-up
21 days of co-administration
Study design
Preclinical study of anti-parkinsonian activity and dyskinesia
Funding
not stated in the source

Developer authors.

Read the original source

Does KW-6356 raise motivation, fight fatigue or act on dopamine?

No study in any species tested motivation, fatigue, alertness or performance. The developer calls KW-6356 non-dopaminergic, and the contrast with caffeine holds only as a statement about receptor targets.

Sellers describe KW-6356 as giving dopaminergic drive, motivation and anti-fatigue effects with more receptor selectivity than caffeine, plus use in Parkinson's trials as an add-on to levodopa. The add-on point is covered above.

A PubMed search on 9 October 2026 for KW-6356, KW6356 or sipagladenant with fatigue, motivation, effort, caffeine or healthy returned 2 records, the phase 1 PK studies, neither of which measured a behavioral outcome. The whole KW-6356 PubMed literature on that date was 6 records, covering Parkinson's disease patients, MPTP-treated marmosets, in vitro pharmacology and PK. No study in any species tested motivation, fatigue, alertness or performance, and none compared KW-6356 with caffeine on an outcome.

On receptor selectivity, a current caffeine citrate label attributes most of caffeine's effects to antagonism of adenosine receptors, both A1 and A2 subtypes. KW-6356 is described as A2A-selective, so the contrast is accurate as a pharmacology statement, although the abstract of the in vitro paper gives no selectivity ratios against other adenosine receptor subtypes.

On dopamine, the developer authors describe KW-6356 as a non-dopaminergic therapy. Its target is the adenosine A2A receptor, not a dopamine receptor, so dopaminergic drive misdescribes it.

PubMed search, 9 October 2026: 2 records, neither measured a behavioral outcome

PubMed search record

PubMed search run on 9 October 2026: (KW-6356 OR KW6356 OR sipagladenant) AND (fatigue OR motivation OR effort OR caffeine OR healthy). 2 records returned.

The search returned 2 records, the phase 1 PK studies, neither of which measured a behavioral outcome. The whole KW-6356 PubMed literature on that date was 6 records, covering Parkinson's disease patients, MPTP-treated marmosets, in vitro pharmacology and PK. No study in any species tested motivation, fatigue, alertness or performance, and none compared KW-6356 with caffeine on an outcome.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source
Caffeine citrate label: adenosine A1 and A2 antagonism

Official label

DailyMed, U.S. National Library of Medicine. Caffeine citrate oral solution, prescribing information, label version effective 29 July 2026. Set ID 5f38c395-0093-4afd-89ec-f96e5dc0934a.

The label attributes most of caffeine's effects to antagonism of adenosine receptors, both A1 and A2 subtypes, shown in receptor binding assays at concentrations close to those reached therapeutically. The label's indication is apnea of prematurity.

Participants / model
Preterm neonates with apnea of prematurity (label population)
Treatment
Caffeine citrate oral solution
Follow-up
Label version effective 29 July 2026
Study design
Official prescribing information
Funding
not stated in the source

Used only for a pharmacology statement. No study compares KW-6356 with caffeine on any outcome.

Read the original source
In vitro: potent, slowly dissociating A2A inverse agonist

Cell study

Ohno Y et al. Mol Pharmacol. 2023;103(6):311-324. PMID 36894319.

KW-6356 is a potent and selective adenosine A2A receptor ligand (negative log of the inhibition constant 9.93 plus or minus 0.01 at the human receptor) with very slow dissociation (rate constant 0.016 plus or minus 0.006 per minute). Functional studies showed insurmountable antagonism and inverse agonism, while istradefylline, which the abstract describes as an approved first-generation A2A antagonist used as an adjunct to levodopa for OFF episodes, showed surmountable antagonism. Cocrystal structures identified the receptor contacts behind the inverse agonism.

Participants / model
Recombinant receptors and cell systems
Treatment
In vitro
Follow-up
Not applicable
Study design
In vitro study of binding affinity, dissociation kinetics, functional antagonism and crystal structure
Funding
not stated in the source

Developer authors. The abstract gives no selectivity ratios against other adenosine receptor subtypes.

Read the original source
MPTP marmosets: motor disability reversed, little dyskinesia

Animal study

Ohno Y et al. Eur J Pharmacol. 2023;950:175773. PMID 37146707.

In MPTP-treated common marmosets, oral KW-6356 reversed motor disability dose-dependently up to 1 mg/kg, with a significantly larger effect than istradefylline, and repeated dosing induced little dyskinesia in animals primed with L-DOPA. The authors describe KW-6356 as a non-dopaminergic therapy.

Participants / model
MPTP-treated common marmosets
Treatment
Oral KW-6356, up to 1 mg/kg
Follow-up
Repeated dosing; length not stated in the abstract
Study design
Preclinical study of motor disability and dyskinesia
Funding
not stated in the source

Developer authors. The target is the adenosine A2A receptor, not a dopamine receptor.

Read the original source

How does sipagladenant work, and what does the body do with it?

KW-6356 is a potent, slowly dissociating adenosine A2A receptor inverse agonist. In healthy volunteers its terminal half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg.

KW-6356 is a potent and selective adenosine A2A receptor ligand (negative log of the inhibition constant 9.93 plus or minus 0.01 at the human receptor) with very slow dissociation (rate constant 0.016 plus or minus 0.006 per minute). Functional studies showed insurmountable antagonism and inverse agonism, while istradefylline, which the abstract describes as an approved first-generation A2A antagonist used as an adjunct to levodopa for OFF episodes, showed surmountable antagonism. Cocrystal structures identified the receptor contacts behind the inverse agonism.

After oral single doses of 1 to 60 mg in healthy volunteers, PK was linear and mean terminal elimination half-life ranged from 18.4 to 43.1 hours. KW-6356 has an active metabolite, M6, and in a population PK analysis food status, baseline serum albumin and body weight had no clinically meaningful effect on exposure to either.

In vitro: potent, slowly dissociating A2A inverse agonist

Cell study

Ohno Y et al. Mol Pharmacol. 2023;103(6):311-324. PMID 36894319.

KW-6356 is a potent and selective adenosine A2A receptor ligand (negative log of the inhibition constant 9.93 plus or minus 0.01 at the human receptor) with very slow dissociation (rate constant 0.016 plus or minus 0.006 per minute). Functional studies showed insurmountable antagonism and inverse agonism, while istradefylline, which the abstract describes as an approved first-generation A2A antagonist used as an adjunct to levodopa for OFF episodes, showed surmountable antagonism. Cocrystal structures identified the receptor contacts behind the inverse agonism.

Participants / model
Recombinant receptors and cell systems
Treatment
In vitro
Follow-up
Not applicable
Study design
In vitro study of binding affinity, dissociation kinetics, functional antagonism and crystal structure
Funding
not stated in the source

Developer authors. The abstract gives no selectivity ratios against other adenosine receptor subtypes.

Read the original source
Phase 1: single doses to 60 mg, multiple doses to 24 mg for 14 days

Clinical trial

Tayama T et al. Clin Pharmacol Drug Dev. 2023;12(8):801-809. PMID 36683291.

KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. PK was linear after single doses up to 60 mg, and mean terminal elimination half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg. Safety and PK did not clearly differ between Japanese and White subjects.

Participants / model
Healthy Japanese and White volunteers
Treatment
Oral KW-6356: single doses 1, 3 and 10 mg and multiple doses of 6 mg once daily in Japanese subjects (study 6356-001), and single doses of 21, 42 and 60 mg, multiple doses of 24 mg once daily, and open-label 6 mg once daily in Japanese and White subjects (NCT03830528)
Follow-up
Single doses; multiple doses for up to 14 days
Study design
Phase 1 safety, tolerability and PK studies
Funding
not stated in the source

Developer authors. Study 6356-001 has no NCT number.

Read the original source
Population PK: healthy subjects and Parkinson's patients, M6 metabolite

Human study

Tayama T et al. Clin Pharmacol Drug Dev. 2024;13(5):549-559. PMID 38178727.

A population PK analysis pooled healthy subjects and patients with Parkinson's disease and described KW-6356 and its active metabolite M6 with one-compartment models. Food status, baseline serum albumin and body weight entered the models as covariates, but none had a clinically meaningful effect on KW-6356 or M6 exposure.

Participants / model
Healthy subjects and patients with Parkinson's disease, pooled
Treatment
Oral KW-6356, single and multiple doses
Follow-up
not stated in the source
Study design
Population PK analysis of the parent drug and its active metabolite
Funding
not stated in the source

Developer authors.

Read the original source

What risks did the studies report?

The most common adverse events in the phase 2a trial were constipation and nasopharyngitis, and phase 1 volunteers tolerated single doses to 60 mg and 14 days at 24 mg. The longest patient exposure was 12 weeks, and interaction study results are not posted.

In the phase 2a trial the most common adverse events were constipation (7.3% on 3 mg, 10.3% on 6 mg) and nasopharyngitis (7.3% and 8.6%). In phase 1 studies, KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days.

The longest patient exposure in the records is 12 weeks. Thorough QT and drug interaction studies (with clarithromycin or rifampicin, and with midazolam, caffeine or rosuvastatin) are registered as completed with no posted results, so no QT or interaction finding is available here.

In marmosets, 21 days of co-administration with low-dose L-DOPA (2.5 mg/kg) increased dyskinesia relative to that low dose alone, although it stayed below the level produced by an optimal L-DOPA dose (10 mg/kg). No safety information exists for the supplier uses.

Phase 2a in Japan: 168 patients, 12 weeks, MDS-UPDRS Part III

Randomized controlled trial

Maeda T et al. Parkinsonism Relat Disord. 2023;117:105907. PMID 37948832.

Least-squares mean change in MDS-UPDRS Part III total score was -5.37 (95% CI -7.25 to -3.48) on 3 mg, -4.76 (-6.55 to -2.96) on 6 mg, and -3.14 (-4.97 to -1.30) on placebo, and the KW-6356 changes were larger than placebo at all time points; the 6 mg point estimate was smaller than the 3 mg one. Secondary MDS-UPDRS scores moved the same way. The most common adverse events were constipation (7.3% on 3 mg, 10.3% on 6 mg) and nasopharyngitis (7.3% and 8.6%). Week 12 completion exceeded 90% in each group.

Participants / model
168 patients with early, untreated Parkinson's disease in Japan: 3 mg/day (n=55), 6 mg/day (n=58) or placebo (n=55)
Treatment
Oral KW-6356 3 or 6 mg once daily, or placebo, as monotherapy
Follow-up
12 weeks
Study design
Randomized placebo-controlled phase 2a trial (NCT02939391; registry enrollment 175)
Funding
not stated in the source

The abstract gives no p-value for the primary comparison. Sponsor employees were among the authors. Primary endpoint was MDS-UPDRS Part III; secondary measures were Parts II, II plus III, and total.

Read the original source
Phase 1: single doses to 60 mg, multiple doses to 24 mg for 14 days

Clinical trial

Tayama T et al. Clin Pharmacol Drug Dev. 2023;12(8):801-809. PMID 36683291.

KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. PK was linear after single doses up to 60 mg, and mean terminal elimination half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg. Safety and PK did not clearly differ between Japanese and White subjects.

Participants / model
Healthy Japanese and White volunteers
Treatment
Oral KW-6356: single doses 1, 3 and 10 mg and multiple doses of 6 mg once daily in Japanese subjects (study 6356-001), and single doses of 21, 42 and 60 mg, multiple doses of 24 mg once daily, and open-label 6 mg once daily in Japanese and White subjects (NCT03830528)
Follow-up
Single doses; multiple doses for up to 14 days
Study design
Phase 1 safety, tolerability and PK studies
Funding
not stated in the source

Developer authors. Study 6356-001 has no NCT number.

Read the original source
MPTP marmosets with L-DOPA: enhanced effect, dyskinesia over 21 days

Animal study

Ohno Y et al. J Pharmacol Sci. 2023;152(3):193-199. PMID 37257947.

In MPTP-treated marmosets, oral KW-6356 1 mg/kg enhanced the anti-parkinsonian effect of L-DOPA at 2.5 to 10 mg/kg, and in L-DOPA-primed animals at 1.25 to 10 mg/kg without enhancing dyskinesia. Over 21 days of co-administration with low-dose L-DOPA (2.5 mg/kg), dyskinesia increased relative to that low dose alone but stayed below the level produced by an optimal L-DOPA dose (10 mg/kg).

Participants / model
MPTP-treated common marmosets, including L-DOPA-primed animals
Treatment
Oral KW-6356 1 mg/kg with L-DOPA
Follow-up
21 days of co-administration
Study design
Preclinical study of anti-parkinsonian activity and dyskinesia
Funding
not stated in the source

Developer authors.

Read the original source
Registry: levodopa add-on phase 2 completed, enrollment 502, no results posted

Trial registry record

ClinicalTrials.gov. NCT03703570 (phase 2, KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations), with related sponsor records NCT04342273, NCT04190654, NCT04147910, NCT04070495, NCT03970798 and NCT03830528.

NCT03703570, a phase 2 study of KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations, is listed as completed with enrollment 502 and no posted results. PubMed searches on 9 October 2026 for KW-6356 with levodopa or for the NCT number returned 3 records, all preclinical. Two developer marmoset papers state that adjunct efficacy in patients has been reported but give no data in their abstracts. The sponsor's other registered studies are all completed with no posted results: thorough QT (NCT04342273, enrollment 128), single-dose PK of the drug and its major metabolite (NCT04190654, 26), radiolabeled absorption, metabolism and excretion (NCT04147910, 8), interaction with clarithromycin or rifampicin (NCT04070495, 20), interaction with midazolam, caffeine or rosuvastatin (NCT03970798, 50), and single and multiple doses (NCT03830528, 48).

Participants / model
Patients with Parkinson's disease on levodopa (registry description)
Treatment
KW-6356 (registry)
Follow-up
Not applicable
Study design
Official trial registry
Funding
not stated in the source

The outcome of the add-on trial is not public in the records found. A completed registration is not evidence of efficacy.

Read the original source

Why does sipagladenant sit in C tier?

KW-6356 has a well-characterized A2A profile, a phase 1 program and one published phase 2a trial in 168 patients, but its larger add-on trial is unreported and no approval was found. The grade does not cover the supplier's motivation and anti-fatigue claim.

The C reflects a selective A2A inverse agonist with a well-characterized in vitro profile, a phase 1 program up to 60 mg single and 24 mg daily doses, and one published phase 2a monotherapy trial in which both doses moved MDS-UPDRS Part III more than placebo and the higher dose did not show the larger point estimate.

The larger levodopa add-on trial (enrollment 502) is completed but unreported, no approval was found, and the longest patient exposure in the records is 12 weeks. On the supplier's claims, the add-on trial exists only as a registration with no public outcome, dopaminergic drive misdescribes a drug its developer calls non-dopaminergic, and motivation and anti-fatigue effects have not been tested in any species.

In vitro: potent, slowly dissociating A2A inverse agonist

Cell study

Ohno Y et al. Mol Pharmacol. 2023;103(6):311-324. PMID 36894319.

KW-6356 is a potent and selective adenosine A2A receptor ligand (negative log of the inhibition constant 9.93 plus or minus 0.01 at the human receptor) with very slow dissociation (rate constant 0.016 plus or minus 0.006 per minute). Functional studies showed insurmountable antagonism and inverse agonism, while istradefylline, which the abstract describes as an approved first-generation A2A antagonist used as an adjunct to levodopa for OFF episodes, showed surmountable antagonism. Cocrystal structures identified the receptor contacts behind the inverse agonism.

Participants / model
Recombinant receptors and cell systems
Treatment
In vitro
Follow-up
Not applicable
Study design
In vitro study of binding affinity, dissociation kinetics, functional antagonism and crystal structure
Funding
not stated in the source

Developer authors. The abstract gives no selectivity ratios against other adenosine receptor subtypes.

Read the original source
Phase 1: single doses to 60 mg, multiple doses to 24 mg for 14 days

Clinical trial

Tayama T et al. Clin Pharmacol Drug Dev. 2023;12(8):801-809. PMID 36683291.

KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. PK was linear after single doses up to 60 mg, and mean terminal elimination half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg. Safety and PK did not clearly differ between Japanese and White subjects.

Participants / model
Healthy Japanese and White volunteers
Treatment
Oral KW-6356: single doses 1, 3 and 10 mg and multiple doses of 6 mg once daily in Japanese subjects (study 6356-001), and single doses of 21, 42 and 60 mg, multiple doses of 24 mg once daily, and open-label 6 mg once daily in Japanese and White subjects (NCT03830528)
Follow-up
Single doses; multiple doses for up to 14 days
Study design
Phase 1 safety, tolerability and PK studies
Funding
not stated in the source

Developer authors. Study 6356-001 has no NCT number.

Read the original source
Phase 2a in Japan: 168 patients, 12 weeks, MDS-UPDRS Part III

Randomized controlled trial

Maeda T et al. Parkinsonism Relat Disord. 2023;117:105907. PMID 37948832.

Least-squares mean change in MDS-UPDRS Part III total score was -5.37 (95% CI -7.25 to -3.48) on 3 mg, -4.76 (-6.55 to -2.96) on 6 mg, and -3.14 (-4.97 to -1.30) on placebo, and the KW-6356 changes were larger than placebo at all time points; the 6 mg point estimate was smaller than the 3 mg one. Secondary MDS-UPDRS scores moved the same way. The most common adverse events were constipation (7.3% on 3 mg, 10.3% on 6 mg) and nasopharyngitis (7.3% and 8.6%). Week 12 completion exceeded 90% in each group.

Participants / model
168 patients with early, untreated Parkinson's disease in Japan: 3 mg/day (n=55), 6 mg/day (n=58) or placebo (n=55)
Treatment
Oral KW-6356 3 or 6 mg once daily, or placebo, as monotherapy
Follow-up
12 weeks
Study design
Randomized placebo-controlled phase 2a trial (NCT02939391; registry enrollment 175)
Funding
not stated in the source

The abstract gives no p-value for the primary comparison. Sponsor employees were among the authors. Primary endpoint was MDS-UPDRS Part III; secondary measures were Parts II, II plus III, and total.

Read the original source
Registry: levodopa add-on phase 2 completed, enrollment 502, no results posted

Trial registry record

ClinicalTrials.gov. NCT03703570 (phase 2, KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations), with related sponsor records NCT04342273, NCT04190654, NCT04147910, NCT04070495, NCT03970798 and NCT03830528.

NCT03703570, a phase 2 study of KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations, is listed as completed with enrollment 502 and no posted results. PubMed searches on 9 October 2026 for KW-6356 with levodopa or for the NCT number returned 3 records, all preclinical. Two developer marmoset papers state that adjunct efficacy in patients has been reported but give no data in their abstracts. The sponsor's other registered studies are all completed with no posted results: thorough QT (NCT04342273, enrollment 128), single-dose PK of the drug and its major metabolite (NCT04190654, 26), radiolabeled absorption, metabolism and excretion (NCT04147910, 8), interaction with clarithromycin or rifampicin (NCT04070495, 20), interaction with midazolam, caffeine or rosuvastatin (NCT03970798, 50), and single and multiple doses (NCT03830528, 48).

Participants / model
Patients with Parkinson's disease on levodopa (registry description)
Treatment
KW-6356 (registry)
Follow-up
Not applicable
Study design
Official trial registry
Funding
not stated in the source

The outcome of the add-on trial is not public in the records found. A completed registration is not evidence of efficacy.

Read the original source
PubMed search, 9 October 2026: 2 records, neither measured a behavioral outcome

PubMed search record

PubMed search run on 9 October 2026: (KW-6356 OR KW6356 OR sipagladenant) AND (fatigue OR motivation OR effort OR caffeine OR healthy). 2 records returned.

The search returned 2 records, the phase 1 PK studies, neither of which measured a behavioral outcome. The whole KW-6356 PubMed literature on that date was 6 records, covering Parkinson's disease patients, MPTP-treated marmosets, in vitro pharmacology and PK. No study in any species tested motivation, fatigue, alertness or performance, and none compared KW-6356 with caffeine on an outcome.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

Studies and sources

PubChem: sipagladenant (KW-6356) identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 23144148 (sipagladenant, KW-6356).

KW-6356 is sipagladenant (INN): PubChem CID 23144148, C20H19N3O4S, 397.4 g/mol, CAS 858979-50-7. Listed synonyms include KW-6356, KW6356 and Sipagladenant [INN]. PubMed returned no records under the name sipagladenant on 9 October 2026; the literature uses the code.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
In vitro: potent, slowly dissociating A2A inverse agonist

Cell study

Ohno Y et al. Mol Pharmacol. 2023;103(6):311-324. PMID 36894319.

KW-6356 is a potent and selective adenosine A2A receptor ligand (negative log of the inhibition constant 9.93 plus or minus 0.01 at the human receptor) with very slow dissociation (rate constant 0.016 plus or minus 0.006 per minute). Functional studies showed insurmountable antagonism and inverse agonism, while istradefylline, which the abstract describes as an approved first-generation A2A antagonist used as an adjunct to levodopa for OFF episodes, showed surmountable antagonism. Cocrystal structures identified the receptor contacts behind the inverse agonism.

Participants / model
Recombinant receptors and cell systems
Treatment
In vitro
Follow-up
Not applicable
Study design
In vitro study of binding affinity, dissociation kinetics, functional antagonism and crystal structure
Funding
not stated in the source

Developer authors. The abstract gives no selectivity ratios against other adenosine receptor subtypes.

Read the original source
Caffeine citrate label: adenosine A1 and A2 antagonism

Official label

DailyMed, U.S. National Library of Medicine. Caffeine citrate oral solution, prescribing information, label version effective 29 July 2026. Set ID 5f38c395-0093-4afd-89ec-f96e5dc0934a.

The label attributes most of caffeine's effects to antagonism of adenosine receptors, both A1 and A2 subtypes, shown in receptor binding assays at concentrations close to those reached therapeutically. The label's indication is apnea of prematurity.

Participants / model
Preterm neonates with apnea of prematurity (label population)
Treatment
Caffeine citrate oral solution
Follow-up
Label version effective 29 July 2026
Study design
Official prescribing information
Funding
not stated in the source

Used only for a pharmacology statement. No study compares KW-6356 with caffeine on any outcome.

Read the original source
Phase 2a in Japan: 168 patients, 12 weeks, MDS-UPDRS Part III

Randomized controlled trial

Maeda T et al. Parkinsonism Relat Disord. 2023;117:105907. PMID 37948832.

Least-squares mean change in MDS-UPDRS Part III total score was -5.37 (95% CI -7.25 to -3.48) on 3 mg, -4.76 (-6.55 to -2.96) on 6 mg, and -3.14 (-4.97 to -1.30) on placebo, and the KW-6356 changes were larger than placebo at all time points; the 6 mg point estimate was smaller than the 3 mg one. Secondary MDS-UPDRS scores moved the same way. The most common adverse events were constipation (7.3% on 3 mg, 10.3% on 6 mg) and nasopharyngitis (7.3% and 8.6%). Week 12 completion exceeded 90% in each group.

Participants / model
168 patients with early, untreated Parkinson's disease in Japan: 3 mg/day (n=55), 6 mg/day (n=58) or placebo (n=55)
Treatment
Oral KW-6356 3 or 6 mg once daily, or placebo, as monotherapy
Follow-up
12 weeks
Study design
Randomized placebo-controlled phase 2a trial (NCT02939391; registry enrollment 175)
Funding
not stated in the source

The abstract gives no p-value for the primary comparison. Sponsor employees were among the authors. Primary endpoint was MDS-UPDRS Part III; secondary measures were Parts II, II plus III, and total.

Read the original source
Registry: levodopa add-on phase 2 completed, enrollment 502, no results posted

Trial registry record

ClinicalTrials.gov. NCT03703570 (phase 2, KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations), with related sponsor records NCT04342273, NCT04190654, NCT04147910, NCT04070495, NCT03970798 and NCT03830528.

NCT03703570, a phase 2 study of KW-6356 in Parkinson's disease patients treated with levodopa-containing preparations, is listed as completed with enrollment 502 and no posted results. PubMed searches on 9 October 2026 for KW-6356 with levodopa or for the NCT number returned 3 records, all preclinical. Two developer marmoset papers state that adjunct efficacy in patients has been reported but give no data in their abstracts. The sponsor's other registered studies are all completed with no posted results: thorough QT (NCT04342273, enrollment 128), single-dose PK of the drug and its major metabolite (NCT04190654, 26), radiolabeled absorption, metabolism and excretion (NCT04147910, 8), interaction with clarithromycin or rifampicin (NCT04070495, 20), interaction with midazolam, caffeine or rosuvastatin (NCT03970798, 50), and single and multiple doses (NCT03830528, 48).

Participants / model
Patients with Parkinson's disease on levodopa (registry description)
Treatment
KW-6356 (registry)
Follow-up
Not applicable
Study design
Official trial registry
Funding
not stated in the source

The outcome of the add-on trial is not public in the records found. A completed registration is not evidence of efficacy.

Read the original source
MPTP marmosets: motor disability reversed, little dyskinesia

Animal study

Ohno Y et al. Eur J Pharmacol. 2023;950:175773. PMID 37146707.

In MPTP-treated common marmosets, oral KW-6356 reversed motor disability dose-dependently up to 1 mg/kg, with a significantly larger effect than istradefylline, and repeated dosing induced little dyskinesia in animals primed with L-DOPA. The authors describe KW-6356 as a non-dopaminergic therapy.

Participants / model
MPTP-treated common marmosets
Treatment
Oral KW-6356, up to 1 mg/kg
Follow-up
Repeated dosing; length not stated in the abstract
Study design
Preclinical study of motor disability and dyskinesia
Funding
not stated in the source

Developer authors. The target is the adenosine A2A receptor, not a dopamine receptor.

Read the original source
MPTP marmosets with L-DOPA: enhanced effect, dyskinesia over 21 days

Animal study

Ohno Y et al. J Pharmacol Sci. 2023;152(3):193-199. PMID 37257947.

In MPTP-treated marmosets, oral KW-6356 1 mg/kg enhanced the anti-parkinsonian effect of L-DOPA at 2.5 to 10 mg/kg, and in L-DOPA-primed animals at 1.25 to 10 mg/kg without enhancing dyskinesia. Over 21 days of co-administration with low-dose L-DOPA (2.5 mg/kg), dyskinesia increased relative to that low dose alone but stayed below the level produced by an optimal L-DOPA dose (10 mg/kg).

Participants / model
MPTP-treated common marmosets, including L-DOPA-primed animals
Treatment
Oral KW-6356 1 mg/kg with L-DOPA
Follow-up
21 days of co-administration
Study design
Preclinical study of anti-parkinsonian activity and dyskinesia
Funding
not stated in the source

Developer authors.

Read the original source
Phase 1: single doses to 60 mg, multiple doses to 24 mg for 14 days

Clinical trial

Tayama T et al. Clin Pharmacol Drug Dev. 2023;12(8):801-809. PMID 36683291.

KW-6356 was well tolerated after single doses up to 60 mg and multiple doses up to 24 mg once daily for 14 days. PK was linear after single doses up to 60 mg, and mean terminal elimination half-life ranged from 18.4 to 43.1 hours across single doses of 1 to 60 mg. Safety and PK did not clearly differ between Japanese and White subjects.

Participants / model
Healthy Japanese and White volunteers
Treatment
Oral KW-6356: single doses 1, 3 and 10 mg and multiple doses of 6 mg once daily in Japanese subjects (study 6356-001), and single doses of 21, 42 and 60 mg, multiple doses of 24 mg once daily, and open-label 6 mg once daily in Japanese and White subjects (NCT03830528)
Follow-up
Single doses; multiple doses for up to 14 days
Study design
Phase 1 safety, tolerability and PK studies
Funding
not stated in the source

Developer authors. Study 6356-001 has no NCT number.

Read the original source
Population PK: healthy subjects and Parkinson's patients, M6 metabolite

Human study

Tayama T et al. Clin Pharmacol Drug Dev. 2024;13(5):549-559. PMID 38178727.

A population PK analysis pooled healthy subjects and patients with Parkinson's disease and described KW-6356 and its active metabolite M6 with one-compartment models. Food status, baseline serum albumin and body weight entered the models as covariates, but none had a clinically meaningful effect on KW-6356 or M6 exposure.

Participants / model
Healthy subjects and patients with Parkinson's disease, pooled
Treatment
Oral KW-6356, single and multiple doses
Follow-up
not stated in the source
Study design
Population PK analysis of the parent drug and its active metabolite
Funding
not stated in the source

Developer authors.

Read the original source

Why is Sipagladenant in C tier?

C fits a well-characterized A2A inverse agonist with a phase 1 program and one published phase 2a monotherapy trial in 168 patients, in which both doses moved MDS-UPDRS Part III more than placebo and the higher dose did not show the larger point estimate. The larger levodopa add-on trial is completed but unreported, no approval was found, and the longest patient exposure is 12 weeks. The grade does not cover the supplier's motivation and anti-fatigue claim.