Phase 1, Randomised, Open-label, 3-way Crossover Study to Evaluate the Safety, Tolerability, Pharmacokinetics (With Food Effect), and Relative Bioavailability of NTP42:KVA4 Given as a Capsule, Compared With a Liquid, in Healthy Volunteers

This Phase 1 clinical trial will assess the safety, tolerability and pharmacokinetics (PK) of a solid capsule form of NTP42:KVA4 in male and female healthy volunteers. In a randomised, 3-way cross-over study, the Trial will involve 3 dose sessions where all volunteers will receive 3 single doses of NTP42:KVA4. In two of the dose sessions, volunteers will be fasted where, in one, they will be given the NTP42:KVA4 capsule and, in another, they will be given NTP42:KVA4 in oral liquid form. To test the effect of food on drug absorption (PK), the volunteers will also be given the NTP42:KVA4 capsule after eating a full breakfast.

Start Date24 Nov 2023

Sponsor / Collaborator

Atxa Therapeutics Ltd.Startup

[+1]

NCT04919863 / CompletedPhase 1

A Phase I Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of NTP42:KVA4 in Healthy Volunteers

A Phase I clinical trial to assess the safety, tolerability, and pharmacokinetics of NTP42:KVA4 following oral administration in a randomized, double-blind, placebo-controlled trial. The trial will involve of 2 phases, a single ascending dose (SAD) phase and a multiple ascending dose (MAD) phase. The SAD phase will incorporate a food effect arm.

Start Date24 May 2021

Sponsor / Collaborator

Atxa Therapeutics Ltd.Startup

[+1]

100 Clinical Results associated with NTP-42

100 Translational Medicine associated with NTP-42

100 Patents (Medical) associated with NTP-42

Literatures (Medical) associated with NTP-42

01 Dec 2020·European Journal of PharmacologyQ3 · MEDICINE

Efficacy of the thromboxane receptor antagonist NTP42 alone, or in combination with sildenafil, in the sugen/hypoxia-induced model of pulmonary arterial hypertension

Q3 · MEDICINE

Article

Author: Adão, Rui ; Reid, Helen M ; Kinsella, B Therese ; Mendes-Ferreira, Pedro ; Bialesova, Lucia ; Mulvaney, Eamon P ; Brás-Silva, Carmen

NTP42 is a novel antagonist of the thromboxane A₂ receptor (TP) in development for the treatment of pulmonary arterial hypertension (PAH). Recent studies demonstrated that NTP42 and TP antagonism have a role in alleviating PAH pathophysiology. However, the efficacy of NTP42 when used in combination with existing PAH therapies has not yet been investigated. Herein, the Sugen 5416/hypoxia (SuHx)-induced PAH model was employed to evaluate the efficacy of NTP42 when used alone or in dual-therapy with Sildenafil, a PAH standard-of-care. PAH was induced in rats by injection of Sugen 5416 and exposure to hypoxia for 21 days. Thereafter, animals were treated orally twice-daily for 28 days with either vehicle, NTP42 (0.05 mg/kg), Sildenafil (50 mg/kg), or NTP42+Sildenafil (0.05 mg/kg + 50 mg/kg, respectively). While Sildenafil or NTP42 mono-therapy led to non-significant reductions in the SuHx-induced rises in mean pulmonary arterial pressure (mPAP) or right ventricular systolic pressure (RSVP), combined use of NTP42+Sildenafil significantly reduced these increases in mPAP and RVSP. Detailed histologic analyses of pulmonary vessel remodelling, right ventricular hypertrophy and fibrosis demonstrated that while NTP42 and Sildenafil in mono-therapy resulted in significant benefits, NTP42+Sildenafil in dual-therapy showed an even greater benefit over either drug used alone. In summary, combined use of NTP42+Sildenafil in dual-therapy confers an even greater benefit in treating or offsetting key aetiologies underlying PAH. These findings corroborate earlier preclinical findings suggesting that, through antagonism of TP signalling, NTP42 attenuates PAH pathophysiology, positioning it as a novel therapeutic for use alone or in combination therapy regimens.

01 Dec 2020·BMC Pulmonary Medicine

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Article

Author: Bouchard, Annie ; Salvail, Dany ; Reid, Helen M ; Bialesova, Lucia ; Mulvaney, Eamon P ; Kinsella, B Therese

AbstractBackgroundNTP42is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A2is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F2α, a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy ofNTP42in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs.MethodsPAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42(0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT.ResultsFrom haemodynamic assessments, NTP42reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover,NTP42was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.ConclusionsThese findings suggest thatNTP42and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

Frontiers in Pharmacology

Evaluation of NTP42, a novel thromboxane receptor antagonist, in a first-in-human phase I clinical trial

Article

Author: Boyce, Malcolm ; Mulvaney, Eamon P ; Reid, Helen M ; Kinsella, B Therese ; Maginn, Mark ; Yamamoto, Takahiro ; Perkins, C Michael

Background: The thromboxane receptor (TP) antagonist NTP42 is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, NTP42, administered as the oral formulation NTP42:KVA4, was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males.Methods: The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25–243 mg NTP42:KVA4 or placebo; B, food effect study where one SAD group (9 mg) was also given NTP42:KVA4 or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15–135 mg NTP42:KVA4 or placebo once-daily for 7 days.Results: Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to NTP42:KVA4 dose. NTP42 was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T1/2) of 18.7 h, NTP42:KVA4 is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, NTP42 led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation ex vivo, with direct correlation between NTP42 exposure and duration of PD effects.Conclusion: Orally administered NTP42:KVA4 was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of NTP42:KVA4 for cardiopulmonary or other relevant diseases with unmet needs.Clinical Trial Registration:clinicaltrials.gov, identifier NCT04919863.

100 Deals associated with NTP-42

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Phase 2	IE	Atxa Therapeutics Ltd.Startup	30 Jan 2022
Heart Failure	Preclinical	IE	Atxa Therapeutics Ltd.Startup	30 Jan 2022
Neoplasms	Preclinical	IE	Atxa Therapeutics Ltd.Startup	30 Jan 2022
Pulmonary Heart Disease	Preclinical	IE	Atxa Therapeutics Ltd.Startup	30 Jan 2022
Urogenital Diseases	Discovery	IE	Atxa Therapeutics Ltd.Startup	30 Jan 2022

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