Delving into the Latest Updates on Nemiralisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Nemiralisib (USAN/INN), Nemiralisib Succinate, GSK 2269557

+ [4]

Target

PI3Kδ

Action

inhibitors

Mechanism

PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

Immune System DiseasesRespiratory DiseasesCongenital Disorders+ [1]

Active Indication-

Inactive Indication

Activated PI3K-delta SyndromeAsthmaBronchiectasis+ [1]

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

License Organization-

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC26H29ClN6O

InChIKeyGECUEJGEJLAXQA-UHFFFAOYSA-N

CAS Registry1254036-77-5

Nemiralisib is a potent anti-inflammatory agent for the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory lung diseases. The Cytochrome P450 3A4 (CYP3A4) is a major route of clearance for nemiralisib. The co-administration of drug therapies, which modulate CYP3A4, may alter the exposure of nemiralisib. Hence, this clinical drug interaction study with itraconazole (a potent CYP3A4 inhibitor) is required. The study will evaluate the PK, safety and tolerability of nemiralisib when administered alone and when administered concomitantly with repeat doses of itraconazole in healthy males and females. Subjects will receive treatment with nemiralisib alone in Period 1 and itraconazole followed by nemiralisib in Period 2 in single sequence crossover manner. Approximately 20 subjects will be enrolled such that approximately 16 evaluable subjects complete the study. Each subject will participate in the study for approximately 7 weeks including screening visit, 2 treatment periods and a follow up visit.

Start Date17 Jan 2018

Sponsor / Collaborator

GSK Plc

NCT03345407

/ TerminatedPhase 2

A Phase IIb, Randomized (Stratified), Double-Blind (Sponsor Open), Parallel-Group, Placebo-Controlled, Dose-Finding Study of Nemiralisib (GSK2269557) Added to Standard of Care (SoC) Versus SoC Alone in Participants Diagnosed With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)

Nemiralisib is being developed as an anti-inflammatory drug for the treatment of inflammatory airways disease. This study is designed to assess the dose response, efficacy, safety, and pharmacokinetics of nemiralisib across a range of doses [up to 750 micrograms (µg)] compared with placebo. The study consists of a Screening Period, a 12-Week Treatment Period and a 12-Week Post-Treatment Follow-Up Period. Approximately 1,250 subjects with an acute moderate or severe exacerbation of COPD requiring standard of care (SoC) therapy will be randomized in this double-blind study. Subjects will be randomized to receive different doses of nemiralisib or placebo via ELLIPTA® inhaler. The total duration of study participation is approximately 6 months (170 days). ELLIPTA is the registered trademark of GlaxoSmithKline (GSK) group of companies.

Start Date28 Nov 2017

Sponsor / Collaborator

GSK Plc

NCT03315559

/ CompletedPhase 1

An Open-label Study in Healthy Male Subjects, to Determine the Excretion Balance and Pharmacokinetics of [14C]-GSK2269557, Administered as a Single Intravenous Microtracer (Concomitant With an Inhaled Non-radiolabelled Dose) and a Single Oral Dose

GSK2269557 is being developed as an anti-inflammatory agent for the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory lung diseases such as asthma. This study is designed to investigate the recovery, excretion, and pharmacokinetics (PK) of (14 Carbon [C])-GSK2269557 administered as a single intravenous (IV) dose (concomitant with an inhaled non-radiolabelled dose) and as a single oral dose in 6 healthy male subjects. Subjects will receive [14C] radiolabelled GSK2269557 administered as IV infusion, with a nonradiolabelled dose of GSK2269557 via dry powder inhaler (DPI) in treatment period 1 and a single dose of [14C]-GSK2269557, administered as an oral solution in treatment period 2. There will be a washout period of at least 14 days after inhaled and IV dosing before subjects takes part in treatment period 2. The IV microtracer dose of GSK2269557 will be administered concomitant to an inhaled non-radiolabelled dose to ensure that the pharmacokinetics represent a clinically relevant dose. The total study duration will be up to 11 weeks, including a screening visit, 2 treatment periods and a follow-up visit.

Start Date14 Nov 2017

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with Nemiralisib

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100 Translational Medicine associated with Nemiralisib

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100 Patents (Medical) associated with Nemiralisib

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38

Literatures (Medical) associated with Nemiralisib

13 Feb 2025·JOURNAL OF MEDICINAL CHEMISTRY

How to Design an Inhaled Drug: CHF-6523

Article

Author: Perry, Matthew W. D.

Inhalation provides an opportunity to target drugs to the lung, potentially improving efficacy and safety margins for the treatment of respiratory conditions. The discovery of inhaled medicines is a specialized endeavor and has different challenges to medicinal chemistry for oral drugs. The appearance of a successful campaign delivering an inhaled PI3Kδ inhibitor is therefore an opportunity to highlight how a team can address the challenges involved in the identification of such a compound. This Viewpoint seeks to highlight a great example of medicinal chemistry in the inhaled space.

23 Sep 2024·Journal of Chemical Information and Modeling

Prediction of Inhibitory Activity against the MATE1 Transporter via Combined Fingerprint- and Physics-Based Machine Learning Models

Article

Author: Sasaki, Shunta ; Bender, Andreas ; Iijima, Takeshi ; Kageyama, Michiharu ; Asano, Satoshi ; Handa, Koichi

Renal secretion plays an important role in excretion of drug from the kidney. Two major transporters known to be highly involved in renal secretion are MATE1/2 K and OCT2, the former of which is highly related to drug-drug interactions. Among published in silico models for MATE inhibitors, a previous model obtained a ROC-AUC value of 0.78 using high throughput percentage inhibition data [J. Med. Chem. 2013, 56(3), 781-795] which we aimed to improve upon here using a combined fingerprint and physics-based approach. To this end, we collected 225 publicly available compounds with pIC50 values against MATE1. Subsequently, on the one hand, we performed a physics-based approach using an Alpha-Fold protein structure, from which we obtained MM-GB/SA scores for those compounds. On the other hand, we built Random Forest (RF) and message passing neural network models using extended-connectivity fingerprints with radius 4 (ECFP4) and chemical structures as graphs, respectively, which also included MM-GB/SA scores as input variables. In a five-fold cross-validation with a separate test set, we found that the best predictivity for the hold-out test was observed in the RF model (including ECFP4 and MM-GB/SA data) with an ROC-AUC of 0.833 ± 0.036; while that of the MM-GB/SA regression model was 0.742. However, the MM-GB/SA model did not show a dependency of the performance on the particular chemical space being predicted. Additionally, via structural interaction fingerprint analysis, we identified interacting residues with inhibitor as identical for those with noninhibitors, including substrates, such as Gln49, Trp274, Tyr277, Tyr299, Ile303, and Tyr306. The similar binding modes are consistent with the observed similar IC50 value inhibitor when using different substrates experimentally, and practically, this can release the experimental scientists from bothering of selecting substrates for MATE1. Hence, we were able to build highly predictive classification models for MATE1 inhibitory activity with both ECFP4 and MM-GB/SA score as input features, which is fit-for-purpose for use in the drug discovery process.

01 Apr 2024·Clinical therapeutics

Efficacy of Nemiralisib in Chronic Obstructive Pulmonary Disease: A Systematic Review

Review

Author: Liang, Linbao ; Yang, Hongkuan ; Pan, Junjie ; He, Shuifeng

PURPOSE:

Chronic obstructive pulmonary disease (COPD) is a major public health concern. Exacerbation of COPD leads to poor health and frequent episodes of increased systemic and airway inflammation. Immunomodulatory drugs have garnered extensive attention because they may reduce the rate of COPD exacerbation. This review aimed to evaluate the efficacy and safety of nemiralisib in COPD patients.

METHODS:

Medical databases, including the Cochrane Library, EMBASE, and PubMed, were queried from inception to June 2023 to identify randomized controlled trials (RCTs) on the efficacy of nemiralisib in COPD patients. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Cochrane Collaboration tool was used to assess the risk of bias of the included RCTs. Two authors independently conducted literature screening and data extraction. Key information from the included studies was extracted, tabulated, and compared using a data extraction table. Moreover, the key characteristics, quality, potential bias, and endpoint outcomes of the included studies were summarized. A meta-analysis was conducted when the study outcomes were sufficiently comparable, and the required data were available for extraction.

FINDINGS:

Initially, 48 references were identified, leading to the inclusion of four trials. No significant difference was found between the nemiralisib and placebo groups in St George's Respiratory Questionnaire score, modified Medical Research Council Dyspnea Scale score, COPD Assessment Test score, time to next on-treatment exacerbation, proportion of patients achieving exacerbation recovery, time to exacerbation recovery, and rescue medication use. Contrastingly, the results demonstrated that nemiralisib may lower oral corticosteroid use during acute exacerbation of COPD. Meanwhile, the efficacy of nemiralisib on the exacerbation rate, as well as several parameters associated with lung function, including forced expiratory volume in 1 second, specific airway conductance, specific imaging airway wall thickness, distal specific imaging airway volume measured at functional residual capacity, specific imaging airway resistance, low attenuation score, and internal airflow lobar distribution in the lower pulmonary region, were conflicting. Attributed to the limited number of included RCTs and insufficient extracted data, it was not feasible to conduct a comprehensive meta-analysis.

IMPLICATIONS:

Because of insufficient data, this systematic review could not make any definitive statement regarding the efficacy of nemiralisib in COPD patients. In terms of safety, nemiralisib was generally well tolerated. Further trials are required to explore the efficacy of this drug.

1

News (Medical) associated with Nemiralisib

06 Feb 2019

·www.biospace.com

GSK Cuts Six Respiratory Assets as It Continues to Focus on Oncology Treatments

Courtesy of Willy Barton/Getty Images GlaxoSmithKline has been in the midst of a significant reshaping to focus on pharmaceuticals, particularly a renewed interest in oncology treatments. As a result, the company has made some cuts to its pipeline, including six quietly announced this morning in the company’s year-end report. Willy Barton / Shutterstock.com GlaxoSmithKline has been in the midst of a significant reshaping to focus on pharmaceuticals, particularly a renewed interest in oncology treatments. As a result, the company has made some cuts to its pipeline, including six quietly announced this morning in the company’s year-end report. In a slide-show of graphics used during a conference call with analysts and media members, the company revealed it had terminated eight programs, mostly in its respiratory line. In the small section marked “terminated,” GSK said it shed two treatments for chronic obstructive pulmonary disease, GSK1325756 (danirixin) and GSK2269557 (nemiralisib). It also cut GSK2245035, a TLR7 agonist used for treating asthma and the TRPV4 antagonist GSK2798745, under development for acute respiratory distress syndrome and cough. Additionally, the company cut the combination treatment of GSK2398852 + GSK2315698 (anti-SAP) in transthyretin cardiomyopathy (ATTR-CM) and GSK3008348, an aVb6 antagonist for the treatment of idiopathic pulmonary fibrosis. The respiratory asset cuts are not much of a surprise, as the company has increasingly focused its resources on oncology treatments. In October, Alex Hoos, head of oncology at GSK, indicated that the company was shifting away from its respiratory base due to increased competition and loss of patent exclusivity. In an interview with S&P Global Market Intelligence , Hoos said the company could narrow its drug development focus to aim at products that will generate growth. The Hoos announcement followed the long-term plan for R&D unveiled over the summer by GSK Chief Science Officer and head of R&D, Hal Barron. The company said it will focus on the development of medicines that target mechanisms of action with strong human genetic validations. Those targets have a higher probability of success, which means a shift to a genetics-driven portfolio, the company said. Since taking over the helm of GSK, Chief Executive Officer Emma Walmsley has been driving the company toward its new focus and has reshaped her executive leadership and made several significant deals to support the plan. Among the deals made by GSK, was the December 2018 decision to put down $5.1 billion to acquire Tesaro and its PARP inhibitor, Zejula, which is used as maintenance treatment for ovarian cancer. Barron has touted the belief in PARP inhibitors that “that have been underappreciated in terms of the impact they can have on cancer patients.” More recently, GSK struck a deal with Merck KGaA, Darmstadt, Germany to collaborate on the development and potential commercialization of M7824 , an immunotherapy for difficult to treat cancers. M7824 is an investigational bifunctional fusion protein immunotherapy that has the potential to be a treatment for difficult-to-treat cancers including non-small cell lung and biliary tract cancers. Barron said the alliance with Merck KGaA is an “opportunity to further accelerate our oncology strategy.” In its announcement today, GSK noted that in its oncology pipeline, it has 16 oncology assets in clinical development with a potential for three launches by 2020. In July of 2018, the company only had eight oncology assets in clinical development. The doubling of the number of assets over the past eight months demonstrated the company’s discipline in building its oncology program. Over the course of the next year, the U.K.-based company said it will strengthen its oncology pipeline as it anticipates several key data readouts this year, including one with Zejula as first-line maintenance therapy in ovarian cancer. GSK is also anticipating a respiratory readout this year, its CAPTAIN study of Trelegy, which it expects will support regulatory submission.

ImmunotherapyExecutive ChangeAcquisition

100 Deals associated with Nemiralisib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11267	-	-	DB16253

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 3	United States	GSK Plc	13 Oct 2016
Asthma	Phase 3	Japan	GSK Plc	13 Oct 2016
Asthma	Phase 3	Argentina	GSK Plc	13 Oct 2016
Asthma	Phase 3	Australia	GSK Plc	13 Oct 2016
Asthma	Phase 3	Canada	GSK Plc	13 Oct 2016
Asthma	Phase 3	Germany	GSK Plc	13 Oct 2016
Asthma	Phase 3	Italy	GSK Plc	13 Oct 2016
Asthma	Phase 3	Netherlands	GSK Plc	13 Oct 2016
Asthma	Phase 3	Poland	GSK Plc	13 Oct 2016
Asthma	Phase 3	Romania	GSK Plc	13 Oct 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02294734 (Pubmed \| Int J Chron Obstruct Pulmon Dis) Manual	Phase 2	Pulmonary Disease, Chronic Obstructive	104	nemiralisib	gkgymegwrh(jvxfosogux) = ejxaohmiae ckulmttsxw (gkkezyyvsd ) View more	Positive	03 Jun 2021
				Placebo	gkgymegwrh(jvxfosogux) = qyvzsfhxuj ckulmttsxw (gkkezyyvsd )
NCT03345407 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	943	placebo+Albuterol (salbutamol) (Placebo)	paowkybkms(awhdqhkacn) = qnhkosrnhh asuxbacerm (bvvcymwvtq, drnsxuqqdf - dauizlpeku) View more	-	10 Feb 2020
				Nemiralisib (Nemiralisib 12.5 mcg)	paowkybkms(awhdqhkacn) = gwkgqbcygv asuxbacerm (bvvcymwvtq, vrkideeyhq - uqzypcsmmb) View more
NCT02522299 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	44	DISKUS (Placebo Via DISKUS)	yjkjqznumc = wtxntsshzk csnnzbgnrz (hirohrdstu, cflasiblnk - vstuktrwmg) View more	-	25 Nov 2019
				Placebo (Placebo Via ELLIPTA)	yjkjqznumc = knaupcjnjl csnnzbgnrz (hirohrdstu, nozqiqczwi - aqhghgnftd) View more
NCT03398421 (CTgov)	Phase 1	Pulmonary Disease, Chronic Obstructive	20	Nemiralisib (Nemiralisib 100 mcg)	bliftuatll(zdknagncup) = sumtertqqf gmnvokfbeu (hgbtaqiogs, 29.8) View more	-	03 Jun 2019
				Itraconazole+Nemiralisib (Itraconazole 200 mg and 100mcg Nemiralisib on Day 5)	nszsbclnag(pjmcqabpvy) = rhtuxdylha ytzbewwwdl (tnkivcgtlg, 27.5) View more
NCT03315559 (CTgov)	Phase 1	Pulmonary Disease, Chronic Obstructive	6	GSK2269557 (Nemi IH + 14C-Nemi IV)	neystkljhy(bbxlrrhxtx) = ulselyufdk vbomqwcgle (tkfuikkvpg, 8.17885) View more	-	20 Mar 2019
				[14C\]-GSK2269557 (14C-Nemi Oral)	qhggxrhfst(sqhvclxdid) = wrvlahytkj oxsfllktun (yszbwimyjp, NA) View more
NCT03189589 (CTgov)	Phase 1	Pulmonary Disease, Chronic Obstructive	12	GSK2269557 (GSK2269557 500 mcg)	jbimyqfuji(tjxsfnxwxl) = lqztcevijz hbwlxpyzhs (pcsrfberlu, 0.00) View more	-	14 Jan 2019
				GSK2269557 (GSK2269557 750 mcg)	jbimyqfuji(tjxsfnxwxl) = ekgvzaymtm hbwlxpyzhs (pcsrfberlu, 0.00) View more
NCT02567708 (Pubmed \| J Pharmacol Exp Ther)	Phase 2	Persistent asthma	50	Inhaled Nemiralisib (1000 µg)	yursjuhwkw(qrbzbnoion) = nemiralisib: 35%; placebo: 9% vuqqlqaccp (uywawsfgjh )	Negative	01 Dec 2018
				Placebo
NCT02567708 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive \| Asthma	50	placebo (Placebo)	evimtiatvl(wdmndixdvl) = olukmxsyni gihteergai (inkgxslbrp, ezxpmemftu - nntfciejzx) View more	-	01 Aug 2018
				GSK2269557 (GSK2269557 1000 µg)	evimtiatvl(wdmndixdvl) = jtyxwvtyvq gihteergai (inkgxslbrp, jecoqjnwqg - mqzjtnisib) View more
NCT02130635 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	64	PLACEBO (Part A: Placebo)	rpqmxndlgq = tdgrauwwjs coyhvgwqfu (nfyvdgtcjt, frhqhwztqs - fmjejccyuz) View more	-	12 Jul 2017
				PLACEBO (Part B: Placebo)	xyrsgyhhsv(gwtysnyofs) = urxtlkdjbk ylhqweobso (rhynnjbudd, asznsjvzcj - czrsvgjbjm) View more
NCT02294734 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	126	placebo (Placebo)	hjankasufx(slhamjguag) = cpcmymjerw ogrdjtuebb (txhykqnzpk, tvuifkwevz - llnnfxwils) View more	-	09 Mar 2017
				GSK2269557 (GSK2269557 1000 mcg)	hjankasufx(slhamjguag) = xobgwubvbq ogrdjtuebb (txhykqnzpk, jqvtlpxrpl - sntnvskydj) View more