zamicastat (BIA-5-1058) / Eisai - LARVOL DELTA

Pharmacokinetics, Safety and Tolerability of Concurrent Doses of BIA 5-1058 and Furosemide (clinicaltrials.gov) - P1 | N=44 | Completed | Sponsor: Bial - Portela C S.A.

New P1 trial • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Human metabolism of zamicastat, an oral dopamine β-hydroxylase inhibitor. (PubMed, Drug Metab Dispos) - "Few minor metabolites were identified in circulation. Across species in vitro studies have shown a completely different profile from human metabolism with only trace levels of [14C]-thiocyanic acid observed, precluding the prediction of the extensive zamicastat metabolism observed in humans."

Journal

Metabolism and disposition of zamicastat in rats. (PubMed, Xenobiotica) - "Zamicastat metabolic pathway involved multiple reactions comprising desulfurization, oxidative desulfurization, N-debenzylation followed by further oxidation or N-acetylation, and the unexpected multistep metabolic pathway leading to isocyanic acid/thiocyanic acid.As main conclusion, zamicastat was found to be rapidly absorbed, widely distributed to peripheric tissues and almost completely recovered after 168 h post-dose, mainly via faeces. It is extensively metabolized by multiple reactions with isocyanic acid/thiocyanic acid as the major late metabolite."

Journal • Preclinical • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects. (PubMed, Br J Clin Pharmacol) - "Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Drug-Drug Interaction between Oral Zamicastat and Continuous Epoprostenol Infusion at Steady-State Conditions in Healthy Subjects. (PubMed, J Clin Pharmacol) - "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."

Journal • Cardiovascular

Safety and Efficacy of BIA 5-1058 in PAH (clinicaltrials.gov) - P2 | N=20 | Completed | Sponsor: Bial - Portela C S.A.

New P2 trial • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Dopamine regulates neuroendocrine cell expansion in the developing lung (ENDO 2023) - "Treatment with Metyrosine (Met) and Benserazide (Benz) which inhibits dopamine production, resulted in a striking increase in PNEC number in NEBs as seen by expansion in Ascl1+ cells, without affecting cell proliferation. By contrast, no effect was observed with Zamicastat (Zami) which inhibits norepinephrine production. To examine whether dopamine regulated PNEC differentiation, we used the D1-like receptor antagonist, SCH-23390 and the D2-like receptor antagonist, Haloperidol in lung explant cultures, as before...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • ASCL1

Pharmacokinetics, Safety and Efficacy of BIA 5-1058 in PAH (clinicaltrials.gov) - P2; N=33; Completed; Sponsor: Bial - Portela C S.A.; Trial completion date: Mar 2022 ➔ Oct 2021; Trial primary completion date: Mar 2022 ➔ Oct 2021; Recruiting ➔ Completed

Clinical • Trial completion • Trial completion date • Trial primary completion date • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] PHASE 1 STUDY TO INVESTIGATE THE EFFECT OF P-GLYCOPROTEIN TRANSPORTER INHIBITION MEDIATED BY CARVEDILOL ON THE PHARMACOKINETICS OF ZAMICASTAT (CHEST 2021) - "Co-administration of carvedilol, strong inhibitor of P-gp, had no substantial effect on the rate and extent of exposure of zamicastat and therefore it is expected that such interaction is devoid of therapeutic impact. CLINICAL IMPLICATIONS: P-glycoprotein (P-gp) is a clinically important efflux transporter extensively expressed in various tissues including the gastrointestinal tract, liver, kidney and brain, which has the potential to impact the oral bioavailability, tissue distribution, hepatic and renal elimination of substrates. Zamicastat is a reversible dopamine β-hydroxylase inhibitor, that modulate sympathetic nervous system by reducing norepinephrine biosynthesis in peripheral sympathetic nerves, which was granted Orphan Drug Designation by Food and Drug Administration for the treatment of Pulmonary Arterial Hypertension."

P1 data • PK/PD data • Gastrointestinal Disorder • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] AN INTEGRATED ASSESSMENT OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ZAMICASTAT: A DOPAMINE Β-HYDROXYLASE INHIBITOR IN HEALTHY VOLUNTEERS (CHEST 2021) - "Zamicastat showed a linear dose-PK relationship up to 400mg. The micronization of the API, food and age were found to increase the plasma exposure of Zamicastat. The activity of DβH was inhibited in plasma in a dose-dependent manner."

Clinical • PK/PD data • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Drug-drug interaction study between zamicastat and furosemide in healthy subjects (ERS 2021) - "Zamicastat was safe and well tolerated when administered alone or with furosemide. The dose of furosemide may need to be adjusted to the individual clinical response, if these drugs are concomitantly administered."

Clinical • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Effect of BIA 5-1058 400 mg on Warfarin Pharmacokinetics (clinicaltrials.gov) - P1; N=26; Completed; Sponsor: Bial - Portela C S.A.

New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Effect of BIA 5-1058 400 mg on the Steady State Pharmacokinetics of Sildenafil (clinicaltrials.gov) - P1; N=20; Completed; Sponsor: Bial - Portela C S.A.

New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Effect of BIA 5-1058 400 mg on the Steady State Pharmacokinetics of Bosentan (clinicaltrials.gov) - P1; N=44; Completed; Sponsor: Bial - Portela C S.A.

New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Effect of Food on BIA 5-1058 (clinicaltrials.gov) - P1; N=57; Completed; Sponsor: Bial - Portela C S.A.

New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Effect of Age-gender on the Pharmacokinetic and Pharmacodynamic Profiles of BIA 5 1058 (clinicaltrials.gov) - P1; N=61; Terminated; Sponsor: Bial - Portela C S.A.

New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

ADME: Absorption, Distribution, Metabolism and Excretion of BIA 5-1058 (clinicaltrials.gov) - P1; N=15; Completed; Sponsor: Bial - Portela C S.A.

New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Drug-Drug Interaction Study Between Zamicastat and Treprostinil in Healthy Subjects (ATS 2021) - "CONCLUSION The dose of zamicastat and treprostinil may need to be adjusted to the individual clinical response, if these drugs are concomitantly administered. Zamicastat was safe and well tolerated when administered alone and concomitantly with treprostinil."

Clinical • Hypertension • Pulmonary Arterial Hypertension • Respiratory Diseases

Pharmacokinetics, Safety and Efficacy of BIA 5-1058 in PAH (clinicaltrials.gov) - P2; N=32; Recruiting; Sponsor: Bial - Portela C S.A.; Trial completion date: Aug 2020 ➔ Mar 2022; Trial primary completion date: Aug 2020 ➔ Mar 2022

Clinical • Trial completion date • Trial primary completion date • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Absorption, Distribution, Metabolism and Excretion of [14C] Labelled BIA 5-1058 (clinicaltrials.gov) - P1; N=7; Completed; Sponsor: Bial - Portela C S.A.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Cardiovascular

Effect of BIA 5-1058 on the Steady State Pharmacokinetics of Treprostinil (clinicaltrials.gov) - P1; N=20; Completed; Sponsor: Bial - Portela C S.A.

Clinical • New P1 trial • Hypertension • Pulmonary Arterial Hypertension • Respiratory Diseases

[VIRTUAL] Sympathetic Down-regulation With Zamicastat Decreases Cardiac Arrhythmias and Improves Survival in a Model of Pulmonary Arterial Hypertension (AHA 2020) - "The improved survival rate in the MCT rat model of PAH with Zamicastat treatment may relate to a decrease in heart rate, a reduction in QTcorrected intervals prolongation, an increase overall HRV and a decrease number of total arrhythmic events."

Atrial Fibrillation • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension

[VIRTUAL] Sympathetic Down-regulation With Zamicastat Reduces Arrhythmogenicity in Isolated Hearts From Rats With Pulmonary Hypertension (AHA 2020) - "These data suggest that treatment with Zamicastat yields a lower proarrhythmic cardiac tissue decreasing the incidence of cardiac arrhythmias."

Atrial Fibrillation • CNS Disorders • Hypertension • Pulmonary Arterial Hypertension

[VIRTUAL] DRUG-DRUG INTERACTION STUDY BETWEEN ZAMICASTAT AND WARFARIN IN HEALTHY SUBJECTS (CHEST 2020) - "Co-administration of single-dose of zamicastat and warfarin did not significantly affect the peak and total exposure of either drugs. Moreover, zamicastat did not significantly altered warfarin PD. Zamicastat was safe and well tolerated when administered alone and concomitantly with warfarin."

Clinical • Hypertension • Pulmonary Arterial Hypertension • CYP2C9

[VIRTUAL] Zamicastat decreases cardiac arrhythmias in a rat model of pulmonary arterial hypertension (ERS 2020) - "Zamicastat shortened JTc intervals but had no effect on Tpeak-Tend intervals. Zamicastat decreased the frequency of arrhythmic beats and the incidence of atrioventricular block, atrioventricular nodal reentrant tachycardia, bundle branch block and the incidence of ventricular fibrillation."

Preclinical • Atrial Fibrillation • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension