Delving into the Latest Updates on Mitiperstat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

MPO

Mechanism

MPO inhibitors(Myeloperoxidase inhibitors)

Therapeutic Areas

Cardiovascular DiseasesDigestive System DisordersRespiratory Diseases+ [1]

Active Indication

Heart failure with normal ejection fractionPulmonary Disease, Chronic ObstructiveFibrosis+ [2]

Inactive Indication-

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

AstraZeneca PLC

Inactive Organization-

Drug Highest PhasePhase 2/3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC15H15ClN4OS

InChIKeyBHKKSKOHRFHHIN-MRVPVSSYSA-N

CAS Registry1933460-19-5

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits.

01 Nov 2024·Clinical Drug Investigation

Pharmacokinetics and Tolerability of the Novel Myeloperoxidase Inhibitor Mitiperstat in Healthy Japanese and Chinese Volunteers

Article

Author: Heijer, Maria ; Bhattacharya, Chandrali ; Ericsson, Hans ; Collén, Anna ; Holden, Julie ; Sunnåker, Mikael ; Garkaviy, Pavlo ; Han, David ; Aurell, Malin ; Trebski, Monika ; Nelander, Karin

BACKGROUND AND OBJECTIVEMitiperstat (AZD4831) is a novel irreversible oral myeloperoxidase inhibitor in clinical development for heart failure with preserved ejection fraction, metabolic dysfunction-associated steatohepatitis and chronic obstructive pulmonary disease. This study evaluated the pharmacokinetics, safety and tolerability of multiple ascending doses of mitiperstat in healthy male Japanese and Chinese volunteers.METHODSThree cohorts of eight Japanese participants were randomized to receive once-daily oral doses of mitiperstat 2.5, 5 or 10 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo, per cohort). One cohort of eight Chinese participants was randomized to receive mitiperstat 5 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo).RESULTSMitiperstat was rapidly absorbed, with a time to maximum plasma concentration of 1-2 h. Exposure was dose proportional over the investigated dose range, as assessed by area under the concentration-time curve and maximum and trough plasma concentrations. Steady state was reached within 10 days, and accumulation was observed, consistent with the observed long elimination half-life of mitiperstat (50.2-57.8 h). Except for a few events of maculopapular rash, mitiperstat up to 5 mg was well tolerated in participants of Japanese or Chinese origin.CONCLUSIONSThe pharmacokinetics of mitiperstat were similar among Japanese and Chinese participants. These characteristics were similar to those in a previous multiple ascending-dose study in healthy primarily white and Black/African American volunteers. Therefore, the pharmacokinetics of mitiperstat do not affect dosing regimens in these different populations.TRIAL REGISTRATIONNCT04232345 (03/01/2020).

01 Apr 2024·Pharmacology Research & Perspectives

The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses

Article

Author: Ericsson, Hans ; Rekić, Dinko ; Ebrahimi, Ahmad ; Sundell, Jesper ; Dota, Corina ; Sunnåker, Mikael ; Parkinson, Joanna ; Nelander, Karin

AbstractMitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non‐alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT‐interval prolongation with mitiperstat using concentration–QT (C‐QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372). Time‐matched pharmacokinetic and digital electrocardiogram data were collected at the baseline (pre‐dose) and at 11 time‐points up to 48 h post‐dose. C‐QT analysis was prespecified as an exploratory objective. The prespecified linear mixed effects model used baseline‐adjusted QT interval corrected for the heart rate by Fridericia's formula (ΔQTcF) as a dependent variable and plasma mitiperstat concentration as an independent variable. Initial exploratory analyses indicated that all model assumptions were met (no effect on heart rate; appropriate use of QTcF; no hysteresis; linear concentration–response relationship). Model‐predicted mean baseline‐corrected and placebo‐adjusted ΔΔQTcF was +0.73 ms (90% confidence interval [CI]: −1.73, +3.19) at the highest anticipated clinical exposure (0.093 μmol/L) during treatment with mitiperstat 5 mg once daily. The upper 90% CI was below the established threshold of regulatory concern. The 16‐fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT‐interval prolongation at expected therapeutic concentrations.

100 Deals associated with Mitiperstat

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart failure with normal ejection fraction	Phase 3	TW	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	BR	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	US	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	DK	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	RU	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	NL	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	SE	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	HU	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	FR	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	TR	AstraZeneca PLC	30 Jun 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04232345 (Pubmed \| Clin Drug Investig)	Phase 1	-	32	Mitiperstat 2.5 mg	newhngrhyq(kpltyksfjz) = a few events of maculopapular rash iwzcudbvol (idogdgjtoc ) View more	Positive	04 Nov 2024
				Mitiperstat 5 mg
NCT03756285 (SATELLITE, CTgov)	Phase 2	Heart failure with normal ejection fraction	41	AZD4831 (AZD4831)	ouphooekke(hxlnrcrnvu) = mrjtrkvdrf cdjzppjwxq (ypmjgghmgg, frbbwhmclv - hvsayervto) View more	-	19 Jul 2021
				Placebo (Placebo)	ouphooekke(hxlnrcrnvu) = kwhxbxmxge cdjzppjwxq (ypmjgghmgg, fqdhemoptf - bnetznqswr) View more