Delving into the Latest Updates on PF-05212377 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

5-HT6 receptor

Mechanism

5-HT6 receptor antagonists(Serotonin 6 (5-HT6) receptor antagonists)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Alzheimer DiseaseCognitive DysfunctionNeuropsychiatric syndrome

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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This study will see how PF-05212377, an experimental drug to treat symptoms from Alzheimer's Disease, distributes in the brain after one dose of PF-05212377 is administered orally to healthy volunteer subjects. The study will also evaluate the safety and tolerability of PF-05212377 in these subjects and will measure the level of PF-05212377 in the blood.

Start Date01 Nov 2013

Sponsor / Collaborator

Pfizer Inc.

NCT01712074

/ TerminatedPhase 2

A Randomized, 18-week, Placebo-controlled, Double-blind, Parallel Group Study Of The Safety And Efficacy Of Pf-05212377 (Sam-760) In Subjects With Mild-to-moderate Alzheimer's Disease With Existing Neuropsychiatric Symptoms On A Stable Daily Dose Of Donepezil

This study will evaluate safety and efficacy of PF-05212377 in subjects with mild-to-moderate Alzheimer's Disease with existing neuropsychiatric symptoms on a stable dose of Donepezil. The 4-week run-in will minimize placebo effect. The 12-week treatment period is considered the minimum length necessary to reliably evaluate the effect PF-05212377 on cognition and and neuropsychiatric symptoms in this population. The 2-week washout will allow to monitor re-emergence of neuropsychiatric and cognitive symptoms.

Start Date01 Nov 2012

Sponsor / Collaborator

Pfizer Inc.

NCT01213355

/ CompletedPhase 1

A Randomized, Double-Blind, Sponsor Unblinded, Placebo Controlled, 5-Way, Crossover Study To Evaluate The Effects Of Single Oral Administrations of PF-05212377 (SAM-760), A 5-HT6 Antagonist, On Scopolamine Induced Deficits In Psychomotor And Cognitive Function In Healthy Young Adults

It is hypothesized that PF-05212377 (SAM-760) will reverse scopolamine induced cognitive impairments in healthy adults subjects.

Start Date01 Apr 2011

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with PF-05212377

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100 Translational Medicine associated with PF-05212377

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100 Patents (Medical) associated with PF-05212377

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3

Literatures (Medical) associated with PF-05212377

01 Feb 2023·Biopharmaceutics & Drug Disposition

Investigating CNS distribution of PF‐05212377, a P‐glycoprotein substrate, by translation of 5‐HT₆ receptor occupancy from non‐human primates to humans

Article

Author: Mancuso, Jessica ; Sawant‐Basak, Aarti ; Huang, Yiyun ; Planeta, Beata ; Carson, Richard E. ; McCarthy, Timothy ; Lockwood, Peter ; Morris, Evan D. ; Fullerton, Terence ; Chen, Laigao ; Nabulsi, Nabeel ; Esterlis, Irina ; Boyden, Tracey ; Zasadny, Kenneth ; Doran, Angela C.

AbstractPF‐05212377 (SAM760) is a potent and selective 5‐HT6 antagonist, previously under development for the treatment of Alzheimer’s disease. In vitro, PF‐05212377 was determined to be a P‐gp/non‐BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF‐05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu/Cpu) of 0.05 in rat and 0.64 in non‐human primates (NHP). Based on pre‐clinical evidence, brain penetration and target engagement of PF‐05212377 was confirmed in NHP using positron emission tomography (PET) measured 5‐HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF‐05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki: 0.32 nM). P‐gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non‐human primates and human; brain penetration of PF‐05212377 in humans was postulated to be similar to that in non‐human primates. In humans, PF‐05212377 demonstrated dose and concentration dependent increases in 5‐HT6 RO; maximal 5‐HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF‐05212377, a P‐gp/non‐BCRP substrate.Clinical trial number: NCT01258751.

01 Dec 2018·Alzheimer's Research & Therapy

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

Article

Author: Binneman, Brendon ; Kupiec, James ; Miceli, Jeffrey ; Bell, Joanne ; Fullerton, Terence ; Mancuso, Jessica ; Delnomdedieu, Marielle ; David, William ; Lockwood, Peter

BACKGROUNDSymptomatic benefits have been reported for 5-HT₆ receptor antagonists in Alzheimer's disease (AD) trials. SAM-760 is a potent and selective 5-HT₆ receptor antagonist that has demonstrated central 5-HT₆ receptor saturation in humans at a dose of 30 mg.METHODSThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10-24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.RESULTSAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).CONCLUSIONSSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT₆ receptor antagonists.TRIAL REGISTRATIONClinicaltrials.gov, NCT01712074 . Registered 19 October 2012.

01 Jul 2018·Drug Metabolism and DispositionQ2 · MEDICINE

Metabolism of a 5HT6 Antagonist, 2-Methyl-1-(Phenylsulfonyl)-4-(Piperazin-1-yl)-1H-Benzo[d]imidazole (SAM-760): Impact of Sulfonamide Metabolism on Diminution of a Ketoconazole-Mediated Clinical Drug-Drug Interaction

Q2 · MEDICINE

Article

Author: Doran, Angela ; Obach, R Scott ; Sawant-Basak, Aarti ; Comery, Thomas A ; Lockwood, Peter ; Tse, Susanna ; Schildknegt, Klaas ; Gao, Hongying ; Mancuso, Jessica

SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT₆ antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean C_max and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [¹⁴C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [¹⁴C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.

100 Deals associated with PF-05212377

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16044

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	GB	Pfizer Inc.	01 Nov 2012
Alzheimer Disease	Phase 2	DE	Pfizer Inc.	01 Nov 2012
Alzheimer Disease	Phase 2	US	Pfizer Inc.	01 Nov 2012
Alzheimer Disease	Phase 2	CL	Pfizer Inc.	01 Nov 2012
Neuropsychiatric syndrome	Phase 2	CL	Pfizer Inc.	01 Nov 2012
Neuropsychiatric syndrome	Phase 2	US	Pfizer Inc.	01 Nov 2012
Neuropsychiatric syndrome	Phase 2	ES	Pfizer Inc.	01 Nov 2012
Alzheimer Disease	Phase 1	CA	Pfizer Inc.	01 Nov 2012
Alzheimer Disease	Phase 1	FR	Pfizer Inc.	01 Nov 2012
Alzheimer Disease	Phase 1	ES	Pfizer Inc.	01 Nov 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01258751 (Pubmed \| Biopharm Drug Dispos)	Phase 1	-	12	PF-05212377	bbhmlmogcw(lzbsodebgm) = uqtoikucoa cftungmyxp (gdjskscndt ) View more	-	24 Feb 2023
NCT01712074 (Pubmed) Manual	Phase 2	Alzheimer Disease \| Neuropsychiatric syndrome	186	donepezil+PF-05212377	(lopfanqksk): difference = 0.70, P-Value = 0.43 View more	Negative	05 Apr 2018
NCT01712074 (Pubmed) Manual	Phase 2	Alzheimer Disease \| Neuropsychiatric syndrome	186	donepezil+Placebo	(lopfanqksk): difference = 0.70, P-Value = 0.43 View more	Negative	05 Apr 2018
NCT01712074 (CTgov)	Phase 2	Alzheimer Disease \| Neuropsychiatric syndrome	186	Placebo	owxbafbngf(jcqxjmfiei) = rwogygcejo bxlpizaula (oxvbqgfhez, apnkwqixnt - ykkooinigo) View more	-	20 Mar 2017
AAIC2016	Not Applicable	Alzheimer Disease	342	PF-05212377 30 mg	(cvumqfijha) = whsfzqihbo ezqmfhmgnz (wucfhzsiax ) View more	Negative	01 Jul 2016
AAIC2011	Not Applicable	Alzheimer Disease 5 hydroxytrypamine receptors[5-HT6R]	-	SAM-760	aeaiprycav(npupnnbhdb) = The most frequently reported treatment emergent AEs was headache jbsfgsamyd (zgmvysswyh ) View more	-	01 Jul 2011
AAIC2011	Not Applicable	Alzheimer Disease 5 hydroxytrypamine receptors[5-HT6R]	-	Placebo		-	01 Jul 2011