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-

Login to view timeline

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 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.

01 Jan 2024·Journal of Cardiac Failure

Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results

Article

Author: Erlinge, David ; Lam, Carolyn S P ; Schou, Morten ; Wijngaarden, Jan VAN ; Voors, Adriaan A ; Lindstedt, Eva-Lotte ; Shah, Sanjiv J ; Nelander, Karin ; Gustavsson, Andreas ; Lund, Lars H ; Svedlund, Sara ; Saraste, Antti ; Grove, Erik L ; Aziz, Ahmed ; Pirazzi, Carlo ; Gabrielsen, Anders ; Garkaviy, Pavlo ; Barasa, Anders ; Gan, Li-Ming

BACKGROUNDInflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models.METHODS AND RESULTSIn this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1).CONCLUSIONSAZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831.LAY SUMMARYFew treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise.

100 Deals associated with Mitiperstat

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Heart failure with normal ejection fraction	Phase 3	PL	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	TW	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	CA	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	JP	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	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	BG	AstraZeneca PLC	30 Jun 2021
Heart failure with normal ejection fraction	Phase 3	TR	AstraZeneca PLC	30 Jun 2021

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03756285 (SATELLITE, CTgov)	Phase 2	Heart failure with normal ejection fraction	41	AZD4831 (AZD4831)	umyorashlx(kbychdpily) = pmaqoardvh hztdhmgtyc (xivkeoafej, zkzxvcshlf - fbjmesyihr) View more	-	19 Jul 2021
				Placebo (Placebo)	umyorashlx(kbychdpily) = joccqfqqzy hztdhmgtyc (xivkeoafej, celqhgludc - pubcaxthhh) View more