Chronic obstructive pulmonary disease (COPD) management has evolved with the emergence of advanced pharmacological strategies, notably dual bronchodilation and bifunctional agents. Among these innovations, the selective inhaled phosphodiesterase (PDE)3/4 inhibitor ensifentrine represents a novel therapeutic class that combines bronchodilatory and anti-inflammatory properties within a single molecular entity. Dual bronchodilation, traditionally achieved through the combination of long-acting muscarinic antagonists (LAMAs) and long-acting β₂-agonists, has demonstrated superior efficacy compared with monotherapies, including enhanced pulmonary function, reduced symptom burden, and decreased exacerbation frequency. Ensifentrine, recently approved by the US Food and Drug Administration, exerts bronchodilation via PDE3 inhibition and suppresses inflammation by inhibiting PDE4, offering complementary benefits when combined with LAMAs. Clinical trials, including ENHANCE-1 and ENHANCE-2, have shown that ensifentrine significantly improves FEV₁, reduces exacerbations, and lowers inflammatory biomarkers, with a favorable safety profile. Notably, preclinical and clinical data suggest synergism between ensifentrine and muscarinic antagonists, underpinning the rationale for a combination approach. This has led to the conceptualization of "trifunctional dual bronchodilation," describing a regimen that simultaneously targets distinct bronchodilatory mechanisms and provides robust anti-inflammatory effects. Such a strategy may support corticosteroid stewardship by reducing inhaled corticosteroid use, particularly in patients with low eosinophil counts or corticosteroid resistance. However, limitations remain, including the absence of head-to-head trials against existing triple therapy, high cost, and reliance on nebulized delivery. Future research should evaluate long-term outcomes, optimal placement within treatment algorithms, and potential benefits of dry powder or metered-dose formulations. Overall, ensifentrine, especially in combination with a LAMA, may redefine maintenance therapy in COPD, offering a steroid-sparing alternative grounded in mechanistic synergy and clinical efficacy.

2025-07-14·Journal of Chemical Information and Modeling

Adiabatic-Bias Molecular Dynamics Simulations Reveal the Impact of Mutations on Muscarinic Antagonist Unbinding Kinetics

Article

作者: Coricello, Adriana ; Bottegoni, Giovanni ; Elisi, Gian Marco ; Tehan, Benjamin Gerald ; Chiaravalle, Anna Lisa ; Musgaard, Maria

Ligand-target dissociation rates (k_off) strongly correlate with efficacy and safety profiles, as well as with the therapeutic effect of drugs. As a prototypical example, muscarinic receptor antagonists used as bronchodilators show similar affinity profiles toward the muscarinic M3 receptors (M3R) and M2 receptors (M2R), whereas their kinetic selectivity toward M3R avoids the adverse effects that a prolonged inhibition of M2R would induce at the cardiac level. Previous studies on the dissociation kinetics of human M3R showed that the residence time and binding affinity of muscarinic antagonists are deeply affected by the presence of specific mutations. The aim of our work was to reproduce the rankings of these experimental kinetic rates through an approach based on the application of adiabatic-bias molecular dynamics (ABMD) simulations using Path Collective Variables (PCVs), PCV-ABMD. Employing this methodology, we simulated the translocation of tiotropium, a long-acting bronchodilator targeting M3R, from the orthosteric site to the extracellular vestibule, without considering the whole unbinding process. The estimated times necessary for translocation displayed a strong correlation with the experimental pk_off values. Moreover, a thorough analysis of protein-ligand contacts provided deeper insights into the mechanism of unbinding of muscarinic antagonists. The newly described PCV-ABMD protocol captured relevant metastable states and offered a reliable approach for the prediction of kinetic selectivity in sets of mutants.

2025-07-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Cannabinoid agonist WIN55,212-2 prevents scopolamine-induced impairment of spatial memory in rats

Article

作者: Manuel, Iván ; Llorente-Ovejero, Alberto ; Moreno-Rodríguez, Marta ; Bengoetxea de Tena, Iker ; Rodríguez-Puertas, Rafael ; Martínez-Gardeazabal, Jonatan ; Pereira-Castelo, Gorka

The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a rat model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2, a potent cannabinoid receptor agonist, improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological rat model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine (2 mg/kg), in spatial, recognition and aversive memory tests. Scopolamine induced memory impairment was observed in the three tests and, importantly, the cannabinoid subchronic treatment with low doses of WIN55,212-2 (0.5 mg/kg) prevented this deleterious effect in spatial memory when evaluated in Barnes maze test. Autoradiographic studies indicate that, following the WIN55,212-2 treatment, cannabinoid receptor density increased in the motor and somatosensory cortices. In layers I-V of the motor cortex, the activity of cannabinoid and muscarinic receptors also increased. These results suggest that WIN55,212-2, through the activation of cannabinoid receptors, indirectly elevates the muscarinic tone in key cortical areas for learning and memory, preventing the memory deficits induced by scopolamine specifically in spatial memory. This highlights the importance of the crosstalk between the endocannabinoid and the cholinergic system for learning and memory processes and suggest that cannabinoid agonists might be an alternative for the treatment of cognitive deficits associated with cholinergic dysfunction.

项与 Muscarinic Antagonists(GSK) 相关的新闻（医药）

2025-07-21

·PipelineReview

Genentech Provides Update on Astegolimab in Chronic Obstructive Pulmonary Disease

– The pivotal Phase IIb ALIENTO study met the primary endpoint of a statistically significant reduction in the annualized exacerbation rate (AER) at 52 weeks when astegolimab was given every two weeks – – The Phase III ARNASA study did not meet the primary endpoint of a statistically significant reduction in the AER at 52 weeks – – The safety profile of astegolimab was consistent with previously reported data, with no new safety signals identified – – Analysis of the ALIENTO and ARNASA data will be discussed with regulatory authorities and shared at an upcoming medical meeting – SOUTH SAN FRANCISCO, CA, USA I July 21, 2025 I Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today topline results from the pivotal Phase IIb ALIENTO (n=1,301) and the Phase III ARNASA (n=1,375) trials investigating astegolimab compared to placebo, on top of standard of care maintenance therapy in people with moderate to very severe chronic obstructive pulmonary disease (COPD). The studies included a broad population: both former and current smokers, regardless of blood eosinophil count, who have a history of frequent exacerbations. The pivotal Phase IIb ALIENTO study met its primary endpoint and showed that astegolimab reduced the annualized exacerbation rate (AER) by a statistically significant 15.4% at 52 weeks, when given every two weeks. However, the Phase III ARNASA study did not meet its primary endpoint of a statistically significant reduction in the AER, demonstrating a numerical 14.5% reduction at 52 weeks when astegolimab was given every two weeks. The results were generally consistent across secondary endpoints in both studies. The total number of exacerbations was lower than prospectively anticipated in both trials. The safety profile of astegolimab was consistent with previously reported data, with no new safety signals identified. “While COPD remains the third leading cause of death worldwide, patients and families have limited treatment options for managing this debilitating and complex disease,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “This was the first set of studies in an ‘all-comers’ COPD population, and we will discuss these data with regulatory authorities to evaluate next steps for astegolimab.” Detailed results from ALIENTO and ARNASA will be shared at an upcoming medical meeting. About the ALIENTO and ARNASA studies Astegolimab is an investigational, fully human anti-ST2 monoclonal antibody designed to bind with high affinity to the ST2 receptor, thereby blocking the signaling of IL-33. The astegolimab COPD pivotal program consists of two registrational studies, the Phase IIb ALIENTO (NCT05037929) and Phase III ARNASA (NCT05595642) studies. Both ALIENTO and ARNASA are double-blinded, placebo-controlled, multi-center studies that evaluate the efficacy and safety of astegolimab administered every two or every four weeks in patients with COPD on top of standard of care maintenance therapy. Patients in the studies included former and current smokers, regardless of blood eosinophil count, who have a history of frequent exacerbations. The primary analysis is based on the initial phase of the study, which consisted of 1,301 patients for ALIENTO and 1,375 patients for ARNASA. The primary endpoint is the reduction in the annualized rate of moderate and severe COPD exacerbations (AER) over the 52-week treatment period. AER is the total number of exacerbations (a sudden worsening in airway function and respiratory symptoms) occurring over the relevant treatment period, divided by the total number of patient years. Standard of care maintenance therapy for both studies was one of the following combinations – inhaled corticosteroid (ICS) plus long-acting beta-agonist (LABA); long-acting muscarinic antagonist (LAMA) plus LABA; ICS plus LAMA plus LABA. About Genentech Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com . SOURCE: Genentech

临床结果临床2期临床3期

2025-07-21

·GlobeNewswire-Health Care

[Ad hoc announcement pursuant to Art. 53 LR] Roche provides update on astegolimab in chronic obstructive pulmonary disease

The pivotal phase IIb ALIENTO study met the primary endpoint of a statistically significant reduction in the annualised exacerbation rate (AER) at 52 weeks when astegolimab was given every two weeksThe phase III ARNASA study did not meet the primary endpoint of a statistically significant reduction in the AER at 52 weeksThe safety profile of astegolimab was consistent with previously reported data, with no new safety signals identifiedAnalysis of the ALIENTO and ARNASA data will be discussed with regulatory authorities and shared at an upcoming medical meeting Basel, 21 July 2025 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today topline results from the pivotal phase IIb ALIENTO (n=1,301) and the phase III ARNASA (n=1,375) trials investigating astegolimab compared to placebo, on top of standard of care maintenance therapy in people with moderate to very severe chronic obstructive pulmonary disease (COPD). The studies included a broad population: both former and current smokers, regardless of blood eosinophil count, who have a history of frequent exacerbations. The pivotal phase IIb ALIENTO study met its primary endpoint and showed that astegolimab reduced the annualised exacerbation rate (AER) by a statistically significant 15.4% at 52 weeks, when given every two weeks. However, the phase III ARNASA study did not meet its primary endpoint of a statistically significant reduction in the AER, demonstrating a numerical 14.5% reduction, at 52 weeks when astegolimab was given every two weeks. The results were generally consistent across secondary endpoints in both studies. The total number of exacerbations was lower than prospectively anticipated in both trials. The safety profile of astegolimab was consistent with previously reported data, with no new safety signals identified. "While COPD remains the third leading cause of death worldwide, patients and families have limited treatment options for managing this debilitating and complex disease," said Levi Garraway, MD, PhD, Roche’s Chief Medical Officer and Head of Global Product Development. "This was the first set of studies in an ‘all-comers’ COPD population, and we will discuss these data with regulatory authorities to evaluate next steps for astegolimab.” Detailed results from ALIENTO and ARNASA will be shared at an upcoming medical meeting. About the ALIENTO and ARNASA studies1,2Astegolimab is an investigational, fully human anti-ST2 monoclonal antibody designed to bind with high affinity to the ST2 receptor, thereby blocking the signalling of IL-33.3 The astegolimab COPD pivotal programme consists of two registrational studies, the phase IIb ALIENTO (NCT05037929) and phase III ARNASA (NCT05595642) studies. Both ALIENTO and ARNASA are double-blinded, placebo-controlled, multicentre studies that evaluate the efficacy and safety of astegolimab administered every two or every four weeks in patients with COPD on top of standard of care maintenance therapy. Patients in the studies included former and current smokers, regardless of blood eosinophil count, who have a history of frequent exacerbations. The primary analysis is based on the initial phase of the study, which consisted of 1,301 patients for ALIENTO and 1,375 patients for ARNASA. The primary endpoint is the reduction in the annualised rate of moderate and severe COPD exacerbations (AER) over the 52-week treatment period. AER is the total number of exacerbations (a sudden worsening in airway function and respiratory symptoms) occurring over the relevant treatment period, divided by the total number of patient years. Standard of care maintenance therapy for both studies was one of the following combinations – inhaled corticosteroid (ICS) plus long-acting beta-agonist (LABA); long-acting muscarinic antagonist (LAMA) plus LABA; ICS plus LAMA plus LABA. About Roche Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. For over 125 years, sustainability has been an integral part of Roche’s business. As a science-driven company, our greatest contribution to society is developing innovative medicines and diagnostics that help people live healthier lives. Roche is committed to the Science Based Targets initiative and the Sustainable Markets Initiative to achieve net zero by 2045. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com. All trademarks used or mentioned in this release are protected by law.References[1] A Study to Evaluate Astegolimab in Participants With Chronic Obstructive Pulmonary Disease (ARNASA). [Internet; cited March 2025]. Available from: https://clinicaltrials.gov/study/NCT05595642. [2] A Study to Evaluate the Efficacy and Safety of Astegolimab in Participants With Chronic Obstructive Pulmonary Disease. [Internet; cited March 2025]. Available from: https://clinicaltrials.gov/study/NCT05037929.[3] Kelsen SG, Agache O, Soong W, Israel E, Chupp GL, Cheung DS, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial. Journal of Allergy and Clinical Immunology. 2021 Sep;148(3):790–8. Roche Global Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com Hans Trees, PhDPhone: +41 79 407 72 58 Sileia UrechPhone: +41 79 935 81 48 Nathalie AltermattPhone: +41 79 771 05 25 Lorena CorfasPhone: +41 79 568 24 95 Simon GoldsboroughPhone: +44 797 32 72 915 Karsten KleinePhone: +41 79 461 86 83 Kirti PandeyPhone: +49 172 6367262 Yvette PetillonPhone: +41 79 961 92 50 Dr Rebekka SchnellPhone: +41 79 205 27 03 Roche Investor Relations Dr Bruno EschliPhone: +41 61 68-75284e-mail: bruno.eschli@roche.com Dr Sabine BorngräberPhone: +41 61 68-88027e-mail: sabine.borngraeber@roche.com Dr Birgit MasjostPhone: +41 61 68-84814e-mail: birgit.masjost@roche.com Investor Relations North America Loren KalmPhone: +1 650 225 3217e-mail: kalm.loren@gene.com Attachment Media Investor Release Astegolimab ALIENTO ARNASA English

临床结果临床2期临床3期

2025-06-27

·Pharmaceutical Technology

Viatris gains China approval for Yupelri to treat COPD

Yupelri is approved in China for the maintenance treatment of chronic obstructive pulmonary disease. Credit: NMK-Studio / Shutterstock. Theravance Biopharma’s partner Viatris has received China’s National Medical Products Administration (NMPA) approval for Yupelri (revefenacin) inhalation solution for maintenance treatment of chronic obstructive pulmonary disease (COPD). Yupelri is the first once-daily nebulised long-acting muscarinic antagonist (LAMA) approved in China for COPD treatment. The approval will initiate a one-time payment of $7.5m to Theravance Biopharma from Viatris, anticipated to be disbursed in the third quarter (Q3) of 2025. Additionally, Theravance Biopharma will gain $37.5m in sales-related milestones and is entitled to receive escalating royalties ranging from 14% to 20% on net sales within China. Viatris will handle all development and commercialisation aspects of Yupelri in the country. The NMPA approval supports Theravance Biopharma’s financial growth strategy through $131m in cash reserves, along with an influx of $225m from its latest transaction involving Trelegy royalty divestiture to GSK. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence Furthermore, the company retains entitlements amounting to 35% of US-generated profits from Yupelri sales and could potentially accrue up to an additional $150m through imminent Trelegy milestone payments from Royalty Pharma. In the US, Theravance Biopharma received orphan drug designation (ODD) for ampreloxetine, a norepinephrine reuptake inhibitor under development for treating symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA). The advantages of ampreloxetine therapy observed in MSA patients from Study 0170 encompassed an elevation in norepinephrine levels, a positive effect on blood pressure, significant and lasting symptom enhancement, and no indication of exacerbation of supine hypertension. Pending positive results from its ongoing Phase III CYPRESS study, which is evaluating ampreloxetine’s efficacy over 20 weeks, the company plans a new drug application (NDA) submission seeking full approval for this indication. Pharmaceutical Technology Excellence Awards - Have you nominated? Nominations are now open for the prestigious Pharmaceutical Technology Excellence Awards - one of the industry's most recognised programmes celebrating innovation, leadership, and impact . This is your chance to showcase your achievements, highlight industry advancements , and gain global recognition . Don't miss the opportunity to be honoured among the best - submit your nomination today! Nominate Now

临床3期申请上市上市批准孤儿药

100 项与 Muscarinic Antagonists(GSK) 相关的药物交易

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