Delving into the Latest Updates on Zamicastat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

DBH

Mechanism

DBH inhibitors(Dopamine beta-hydroxylase inhibitors)

Therapeutic Areas

Respiratory DiseasesOther DiseasesCardiovascular Diseases

Active Indication-

Inactive Indication

Chronic heart failureHeart FailureHypertension+ [1]

Originator Organization

BIAL-Portela & Cia SA

Active Organization-

Inactive Organization

BIAL-Portela & Cia SA

Drug Highest PhasePendingPhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC21H21F2N3OS

InChIKeyZSSLCFLHEFXANG-GOSISDBHSA-N

CAS Registry1080028-80-3

AbstractAimsDopamine beta‐hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS).MethodsA single‐centre, prospective, double‐blind, randomized, placebo‐controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days −1 and 10. Plasma and 24 h‐urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DβH activity, were measured.ResultsCompared to placebo, zamicastat showed a − 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (−2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DβH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24‐h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter‐individual variability (CV: 32.6%–36.6%). Steady state was already achieved on Day 6.ConclusionsOur results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

01 Nov 2024·The Journal of Clinical Pharmacology

Drug‐Drug Interaction between Oral Zamicastat and Continuous Epoprostenol Infusion at Steady‐State Conditions in Healthy Subjects

Article

Author: Fonseca, Marlene ; Silva, Nuno ; Magalhães, Luís ; Gama, Helena ; Guimarães, Andreia ; Almeida, Luis ; Henriques, Sara Carolina ; Soares‐da‐Silva, Patrício

AbstractThis study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single‐center, open‐label, two‐period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8‐day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat‐to‐epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC0‐16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%‐125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0‐τ,ss, the zamicastat plus epoprostenol‐to‐zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0‐τ,ss and the zamicastat plus epoprostenol‐to‐zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0‐τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant.

01 Sep 2020·Expert Opinion on Investigational DrugsQ2 · MEDICINE

Dopamine β hydroxylase as a potential drug target to combat hypertension

Q2 · MEDICINE

Review

Author: Kundu, Suman ; Prabhakar, Pankaj ; Dey, Sanjay Kumar ; Saini, Manisha

INTRODUCTIONDespite a large number of commercially available drugs, hypertension and related cardiovascular diseases remain a global problem. It is thus imperative that novel drugs and therapeutic strategies are regularly identified, and alternative targets explored. Dopamine β hydroxylase (DBH), a key player in the catecholamine biosynthetic pathway, may provide a therapeutic opportunity and should be extensively explored as a target for potent anti-hypertensives. Inhibitors of DBH have been successful in combating hypertension, as evidenced by the outcome of clinical trials for etamicastat and zamicastat.AREAS COVEREDWe shed light on the strategies employed to identify inhibitors of the enzyme and outline the advantages that the target might offer. Structural and functional details of the enzyme are described along with specific methodologies for drug discovery that were never utilized for the therapeutic target.EXPERT OPINIONEffective inhibitors of the enzyme may be identified with computer-aided structure-based design. Adoption of new methodologies and the assessment of newly designed inhibitors in DBH-specific animal models will provide new, safe, and cost-effective therapeutic opportunities.

1

News (Medical) associated with Zamicastat

25 Aug 2021

·www.globenewswire.com

Pulmonary Arterial Hypertension Pipeline Insight Research

Los Angeles, USA, Aug. 24, 2021 (GLOBE NEWSWIRE) -- Pulmonary Arterial Hypertension Pipeline Insight Research Report Around 55+ key companies are developing therapies for Pulmonary Arterial Hypertension, among which the drug of Liquidia Technologies is in the advanced stage (Pre Registration) DelveInsight’s “Pulmonary Arterial Hypertension (PAH) Pipeline Insight” report provides comprehensive insights about 55+ companies and 55+ pipeline drugs in the Pulmonary Arterial Hypertension pipeline landscapes. It comprises Pulmonary Arterial Hypertension pipeline drug profiles, including clinical and non-clinical stage products. It also includes the Pulmonary Arterial Hypertension therapeutics assessment by product type, stage, route of administration, and molecule type and further highlights the inactive Pulmonary Arterial Hypertension pipeline products. Some of the key takeaways from the Pulmonary Arterial Hypertension Pipeline Report Get an overview of pipeline landscape @ Pulmonary Arterial Hypertension Clinical Trials Analysis Pulmonary Arterial Hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure in the arteries of the lungs for no apparent reason. Pulmonary Arterial Hypertension Emerging Drugs Sotatercept is a first-in-class therapeutic fusion protein composed of the extracellular domain of human activin receptor type IIA, fused to the Fc domain of human immunoglobulin G1 (IgG1). The United States Food and Drug Administration (FDA) has granted Orphan Drug designation and Breakthrough Therapy designation to sotatercept for the treatment of PAH; the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) designation to sotatercept for the treatment of PAH. Sotatercept is in Phase III clinical trials for the treatment of PAH. LIQ861 is an investigational, inhaled dry powder formulation of treprostinil designed using the Company’s novel PRINT technology and engineered to enhance deep-lung delivery of treprostinil in PAH patients using a convenient, palm-sized dry powder inhaler. Liquidia resubmits New Drug Application for LIQ861 under the 505(b)(2) regulatory pathway for the treatment of pulmonary arterial hypertension (PAH). Gossamer Bio is developing Seralutinib (GB002) for the treatment of Pulmonary Arterial Hypertension. It is currently in the Phase II stage of development (NCT04456998). It acts as an inhibitor of Platelet-derived growth factor receptors, CSF1R, c-KIT. Bial is developing Zamicastat for the treatment of Pulmonary Arterial Hypertension. It is currently in the Phase II stage of development (NCT04316143). It acts as an inhibitor of Dopamine beta-hydroxylase. For further information, refer to the detailed report @ Pulmonary Arterial Hypertension Pipeline Therapeutics Scope of Pulmonary Arterial Hypertension Pipeline Drug Insight · Pulmonary Arterial Hypertension Therapies Late-stage (Phase III) · Pulmonary Arterial Hypertension Therapies Mid-stage (Phase II)· Pulmonary Arterial Hypertension Therapies Early-stage (Phase I) · Pulmonary Arterial Hypertension Preclinical stage and Discovery candidates · Discontinued and Inactive candidates · Epoprostenol receptor agonists· Activin inhibitors· Platelet-derived growth factor receptor antagonists· Dopamine beta-hydroxylase inhibitors· Vasoactive intestinal peptide type II receptor agonists· Angiogenesis inhibitors; Bcr-abl tyrosine kinase inhibitors · Cyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors· Galectin 3 inhibitors · Peptides· Monoclonal antibodies· Small molecules · Proteins· Gene therapy · Parenteral · Oral· Intravenous· Subcutaneous · Monotherapy· Combination· Mono/Combination Key Questions regarding Current Pulmonary Arterial Hypertension Treatment Landscape and Emerging Therapies Answered in the Pipeline Report Table of Contents Get a customized pipeline report @ Pulmonary Arterial Hypertension Drugs Pipeline Report Other Reports About DelveInsightDelveInsight is a leading Business Consultant, and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing comprehensive end-to-end solutions to improve their performance. It also provides Healthcare Consulting services comprising credible market analysis that will help accelerate the business growth and overcome challenges with a practical approach.

Gene TherapyAntibodyOrphan DrugBreakthrough TherapyFirst in Class

100 Deals associated with Zamicastat

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Phase 2	UA	BIAL-Portela & Cia SA	03 Jun 2019
Pulmonary Arterial Hypertension	Phase 2	PT	BIAL-Portela & Cia SA	03 Jun 2019
Pulmonary Arterial Hypertension	Phase 2	DE	BIAL-Portela & Cia SA	03 Jun 2019
Pulmonary Arterial Hypertension	Phase 2	IT	BIAL-Portela & Cia SA	03 Jun 2019
Pulmonary Arterial Hypertension	Phase 2	ES	BIAL-Portela & Cia SA	03 Jun 2019
Pulmonary Arterial Hypertension	Phase 2	AT	BIAL-Portela & Cia SA	03 Jun 2019
Pulmonary Arterial Hypertension	Phase 2	GB	BIAL-Portela & Cia SA	03 Jun 2019
Heart Failure	Phase 2	GB	BIAL-Portela & Cia SA	09 Apr 2018
Chronic heart failure	Phase 2	NL	BIAL-Portela & Cia SA	01 Mar 2011
Hypertension	Phase 2	NL	BIAL-Portela & Cia SA	01 Mar 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04316143 (CTgov)	Phase 2	Pulmonary Arterial Hypertension	33	Oral zamicastat (50 mg Zamicastat)	wwxjfqrbba(afacfzkidl) = umkjxehaax pulckxzjij (eplhvoglsd, ykhqmdfwum - skbnnooltm) View more	-	15 Oct 2024
				Oral zamicastat (100 mg Zamicastat Once Daily)	wwxjfqrbba(afacfzkidl) = azwxvsitpm pulckxzjij (eplhvoglsd, jtcqelgvvx - xvhmayxxxr) View more
BIA-51058-111 (ERS2021)	Not Applicable	-	44	Zamicastat 400 mg	(ehhkocigsh) = sadrrnthvj lhmwasmlva (lujzjeyrqo, 94 - 108) View more	-	05 Sep 2021
				Furosemide 40 mg	(ehhkocigsh) = oveasaawif lhmwasmlva (lujzjeyrqo, 64 - 87) View more
ATS2021	Not Applicable	-	-	Zamicastat 200 mg	(gbnaflqumz) = tetdrztstd ddpsolvmbr (ftgpinjmuv, 112 - 140) View more	-	03 May 2021
				Treprostinil 1 mg b.i.d	(gbnaflqumz) = cixgbuugto ddpsolvmbr (ftgpinjmuv, 73 - 100) View more
ERS2020	Not Applicable	-	20	Zamicastat 400 mg	(qsoeklmpgq) = imtuyxqwyp igehgitfag (dphzkpehax, 79 - 111) View more	-	07 Sep 2020
				Sildenafil 20 mg	(qsoeklmpgq) = iwzjskwopk igehgitfag (dphzkpehax, 89 - 107) View more