Delving into the Latest Updates on Lesogaberan with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ARH 061746, ARH-061746, AZD 3355

+ [1]

Target

GABAB receptor

Action

agonists

Mechanism

GABAB receptor agonists(Gamma-Aminobutyric Acid B Receptor agonists)

Therapeutic Areas

Digestive System DisordersMouth and Tooth DiseasesOtorhinolaryngologic Diseases+ [2]

Active Indication-

Inactive Indication

Gastroesophageal RefluxHeartburnRefractory chronic cough

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

AstraZeneca PLCUniversity Hospital of South Manchester

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC3H9FNO2P

InChIKeyLJNUIEQATDYXJH-GSVOUGTGSA-N

CAS Registry344413-67-8

Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC.

Methods:

A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940.

Findings:

19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887-2.387) and -11.042 (P = 0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P = 0.003) and -7.843 (P = 0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012-1.259), especially taste-related AEs (RR: 6.216, P < 0.05).

Interpretation:

In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough.

Funding:

National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).

01 Jan 2022·ERJ open research

A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough

Article

Author: Smith, Jacky A ; Badri, Huda ; Escott, K Jane ; Wilkinson, Greame ; Whorwell, Peter ; Al-Sheklly, Bashar ; Holt, Alison ; Gibbard, Carmen ; Satia, Imran ; Treadway, Sam ; Dockry, Rachel J ; Canning, Brendan J ; Holt, Kimberley ; McGuiness, Kevin ; Lee, Augustine ; Lee, Theresa ; Denton, Dimitra ; Houghton, Lesley

Objective:

Baclofen is a centrally acting γ-aminobutyric acid type B (GABAB) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABABagonist, but its effects on refractory chronic cough are unknown.

Design:

We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening.

Results:

22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sdage 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8–17.0) years; mean (95% CI) 45 (29–67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study.

Conclusions:

Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABABreceptors in refractory chronic cough.

01 Dec 2021·Pulmonary pharmacology & therapeuticsQ3 · MEDICINE

Effect of centrally and peripherally acting GABAB agonism on the healthy human cough reflex

Q3 · MEDICINE

Article

Author: Satia, Imran ; Badri, Huda ; Escott, Jane ; Dockry, Rachel J ; LGibbard, Carmen ; Wilkinson, Greame ; Holt, Kimberley ; Holt, Alison ; Denton, Dimitra ; Smith, Jacky A ; Canning, Brendan J

BACKGROUND:

Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABA_B receptors in both the peripheral and central nervous systems inhibit cough.

OBJECTIVE:

To compare the effect of central and peripherally acting GABA_B agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers.

METHODS:

We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50).

RESULTS:

Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 μM (95%CI 24.4-91.7) vs 37.6 μM (95%CI 19.2-73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 μM (95%CI 37.2-151.8), p = 0.002).

CONCLUSION:

This data suggests the anti-tussive actions of GABA_B agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.

100 Deals associated with Lesogaberan

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Lesogaberan	-	DB11920

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Refractory chronic cough	Phase 2	United Kingdom	University Hospital of South Manchester	16 Apr 2015
Heartburn	Phase 2	United States	AstraZeneca PLC	01 Oct 2009
Gastroesophageal Reflux	Phase 2	Australia	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	Belgium	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	France	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	Germany	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	Hungary	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	Netherlands	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	Norway	AstraZeneca PLC	01 Nov 2006
Gastroesophageal Reflux	Phase 2	Romania	AstraZeneca PLC	01 Nov 2006

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01005251 (Pubmed \| Gut)	Phase 2	Gastroesophageal Reflux	661	Lesogaberan 60 mg	jqxucehewb(dgrdaxbqxg) = xfcnbrxztc rtcrofjklk (hjmkykgejv )	Negative	01 Sep 2013
				Lesogaberan 120 mg	jqxucehewb(dgrdaxbqxg) = hjktznqeve rtcrofjklk (hjmkykgejv )
NCT00703534 (C27, CTgov)	Phase 2	Gastroesophageal Reflux \| Heartburn	478	Gelusil®+AZD3355 (AZD3355)	wdnzepugue(fgcyjcleek) = eaerctepnv fetqwxelic (xqufwadcbl, eonmixweqn - myzpgqguqj) View more	-	20 Jun 2011
				Placebo+Gelusil® (Placebo)	wdnzepugue(fgcyjcleek) = ucerdszgae fetqwxelic (xqufwadcbl, tzyxrecoit - wdkfrkwlef) View more
NCT01043185 (CTgov)	Phase 2	Gastroesophageal Reflux	27	AZD3355 (AZD3355 30 mg)	nulhiwitgl(noffcwxzbr) = lxdiafqykc bdbjityzju (poljiafklh, tybktomtbh - gvpyaqfvko) View more	-	14 Jun 2011
				AZD3355 (AZD3355 90 mg)	nulhiwitgl(noffcwxzbr) = tavspclplt bdbjityzju (poljiafklh, ybetqkidjm - soxhnhnlkv) View more
NCT00743444 (CTgov)	Phase 2	Gastroesophageal Reflux	27	AZD3355 (AZD3355)	tmlgldjzkh(roegrqwipy) = qugqhipxnx khkfgmhlaq (ukoeuycxqa, lxrnshwkhx - crkujcqfzr) View more	-	10 Jun 2011
				placebo (Placebo)	tmlgldjzkh(roegrqwipy) = ygjkmjwxwk khkfgmhlaq (ukoeuycxqa, mgptenripz - gwxggzvbam) View more
NCT01005251 (CTgov)	Phase 2	Gastroesophageal Reflux \| Heartburn	661	Placebo	xcyextlcap = vrrhermzij xezarmknbz (aurobvegin, nzjxtqnlgl - kajyphbkge) View more	-	25 Apr 2011