A Phase II, Randomised, Double-blind, Placebo-controlled Clinical Trial to Assess the Safety and Efficacy of AZD1656 in Diabetic Patients Hospitalised With Suspected or Confirmed COVID-19

The ARCADIA Trial is a randomised, double-blind, placebo-controlled clinical trial to assess the safety and efficacy of AZD1656 in patients with either Type 1 or Type 2 diabetes, hospitalised with COVID-19.

Start Date12 Aug 2020

Sponsor / Collaborator

St George Street Capital Ltd.

NCT05216172 / CompletedPhase 2IIT

AZD1656 in Transplantation With Diabetes tO PromoTe Immune TOleraNce

AZD1656 in Transplantation with Diabetes tO PromoTe Immune TOleraNce: a single site, placebo-controlled, double-blind randomised clinical trial of AZD1656 in renal transplant patients with Type 2 diabetes

Start Date13 Dec 2019

Sponsor / Collaborator

Queen Mary University of London

[+1]

EUCTR2019-001587-30-GB / Unknown statusPhase 2IIT

AZD1656 in Transplantation with Diabetes tO PromoTe Immune TOleraNce - The ADOPTION Study

Start Date26 Jul 2019

Sponsor / Collaborator

Queen Mary University of London

100 Clinical Results associated with AZD-1656

100 Translational Medicine associated with AZD-1656

100 Patents (Medical) associated with AZD-1656

Literatures (Medical) associated with AZD-1656

31 Dec 2022·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists

Q2 · MEDICINE

ReviewOA

Author: Ren, Yixin ; Huang, Yan ; Wan, Li ; Cao, Shuang ; Li, Li

Type 2 diabetes mellitus is a metabolic disorder with complicated pathogenesis, and mono-target therapy often fails to effectively manage the levels of blood glucose. In recent years, the anti-diabetes target glucokinase (GK) has attracted the attention of researchers. It acts as a glucose sensor, triggering counter regulatory responses following a change in glucose levels to aid restoration of normoglycemia. Activation of GK induces glucose metabolism and reduces glucose levels for the treatment of type 2 diabetes. GK agonists (GKA) are a new class of antidiabetic drugs. Among these agents, dorzagliatin is currently being investigated in phase III clinical trials, while PB-201 and AZD-1656 have reached phase II clinical trials. This article describes the mechanism of action of GK in diabetes and of action of GKA at the protein level, and provides a review of the research, trends, and prospects regarding the use of GKA in this setting.

26 Oct 2022·Science Translational MedicineQ1 · MEDICINE

Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats

Q1 · MEDICINE

Article

Author: Maurer, Stefanie ; Oakes, Nicholas D. ; Boucher, Jeremie ; Zarrouki, Bader ; Kroon, Tobias ; Alexandersson, Ida ; Wallenius, Kristina ; Ferm, Annett ; Petersson, Marie ; Hagstedt, Therese

Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.

01 Sep 2022·eClinicalMedicine

A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation

Article

Author: Lockhart, Donna ; Coffey, Pete ; McCafferty, Kieran ; Marelli-Berg, Federica ; Martin, John ; Hollowood, Zoe ; Chorlton, Jamie ; Dyer, Carlene ; Boekman, Pascal

BackgroundA potential immunotherapeutic role for AZD1656 (a glucokinase activator) in the treatment of COVID-19 was hypothesized. The ARCADIA trial investigated the safety and efficacy of AZD1656 in diabetic patients admitted to hospital with COVID-19.MethodsThe ARCADIA trial was a Phase II randomised, double-blind, placebo-controlled clinical trial. Adult diabetic patients, admitted with COVID-19, were recruited at 28 hospitals in the UK, Romania and Czech Republic and randomly assigned (1:1) to receive AZD1656 tablets (100mg twice a day), or matched placebo, for up to 21 days, in addition to usual care. All involved were masked to treatment allocation. The primary endpoint was clinical improvement measured at Day 14. The Full Analysis Set (FAS) included all patients who received at least one dose of assigned treatment. ARCADIA is complete and registered with ClinicalTrials.gov (NCT04516759).FindingsBetween 29 September 2020 to 16 April 2021, 170 patients were screened and 156 patients were randomised, three of whom did not commence treatment. Of the remaining 153, 80 were assigned to AZD1656 and 73 were assigned to placebo and included in the Full Analysis Set (FAS). The primary analysis showed no statistically significant difference between groups (AZD1656: 76·3%; Placebo: 69·9%, p=0·19). There was no difference in the number of adverse events between groups (AZD1656: 35·7%; Placebo: 33·3%). Mortality was lower in the AZD1656 group compared to the placebo group (AZD1656: four (5%); Placebo: nine (12·3%), p=0·090)). At Day 7 there were zero deaths in the AZD1656 group compared to six deaths in the placebo group (p=0·011, post hoc). A difference between groups in time to hospital discharge was also seen (p=0·16). Immunophenotyping data suggested that AZD1656-treated patients had a less pro-inflammatory immune response and a better adaptive immune response than those treated with placebo.InterpretationAlthough the trial did not achieve its primary endpoint, AZD1656 was associated with a decrease in deaths and a reduction in the duration of hospitalisation, as compared to Placebo. Immunophenotyping and immunochemistry indicated an immunomodulatory effect of AZD1656. The trial suggests a beneficial therapeutic effect of AZD1656 and identifies a new therapeutic concept: small molecule activation of endogenous homeostatic immune cells which themselves become the therapeutic agent within the body. Phase 2 trials of this size carry the risk of false positive results and confirmation of these results in a larger clinical trial is now required.FundingUK Research and Innovation (UKRI) 'Innovate UK' programme and Excalibur Medicines Ltd.

News (Medical) associated with AZD-1656

14 Aug 2024

·www.globenewswire.com

Conduit Pharmaceuticals Selects Initial Indications for Lead Clinical Candidate Targeting Autoimmune Disorders

conduit Pharmaceuticals announces plans to initiate Phase 2a trials in both systemic lupus erythematosus and ANCA-associated vasculitis for its lead clinical candidate, AZD1656 AZD1656, a HK-4 glucokinase activator initially developed by AstraZeneca for diabetes, is now being repurposed by Conduit for autoimmune disorders, leveraging its established safety profile and targeted immune-modulating effects Aug. 12, 2024 -- Conduit Pharmaceuticals Inc. (Nasdaq: CDT) (“Conduit” or the “Company”), today announced the selection of initial indications for its lead clinical candidate, HK-4 glucokinase activator AZD1656 licensed from AstraZeneca on August 7, 2024. Conduit intends to initiate Phase 2a clinical trials to evaluate AZD1656 for the treatment of systemic lupus erythematosus (including lupus nephritis) and ANCA-associated vasculitis. This represents a significant milestone in the development of AZD1656, underscoring Conduit’s commitment to address unmet medical needs and its confidence in the asset's potential to impact patient outcomes positively. Carrying out Phase 2a, double-blind, placebo-controlled trials in patients suffering from systemic lupus erythematosus, inclusive of lupus nephritis patients, and patients suffering from ANCA-associated vasculitis, will enable Conduit to assess the potential of AZD1656 across the full spectrum of lupus patients. Simultaneously, we will evaluate the potential of AZD1656 across the broader aspects of autoimmune disorders. Originally developed by AstraZeneca through Phase 2b for diabetes mellitus, AZD1656 is a highly specific glucokinase activator that has undergone extensive safety testing, involving over 1,000 patients, in more than 20 trials. Conduit envisions AZD1656 as a potential cornerstone asset in the autoimmune sector, leveraging its established safety profile and targeted mechanism of action to activate the patient’s immune system and mitigate harmful inflammation. “Having reviewed the extensive data, we are delighted to advance AZD1656 into a new therapeutic area targeting systemic lupus erythematosus and ANCA-associated vasculitis,” said Dr. Freda Lewis-Hall, Chair of the Board of Directors at Conduit. “With its potential to become a first-in-class therapy for autoimmune diseases, AZD1656 represents a significant leap forward in our mission to develop ground-breaking treatments that could transform the landscape of autoimmune care and provide innovative treatments that can truly make a difference to patients.” Lupus affects over 5 million people worldwide, including 1.5 million Americans1. Yet, despite significant progress in the clinical understanding of the disease, treatment still relies heavily on the use of corticosteroids and non-specific immunosuppressants, widely known for their potentially severe side effects with long term use. Given the wide-ranging clinical manifestations of lupus there is a clear unmet need for safer treatments applicable to all patients. The global market size for lupus treatments, including systemic lupus erythematosus (SLE) and other lupus-related conditions, was estimated to be around $2.7 billion in 2024. This market is expected to grow significantly, reaching approximately $4.9 billion by 2030 with a compound annual growth rate (CAGR) of approximately 8.9%2. In addition, the market size of ANCA-associated vasculitis was highest in the U.S. among the seven major markets in 2023, accounting for approximately $620 million, and is expected to experience significant growth by 20323. Conduit is a multi-asset, clinical stage, disease-agnostic life science company delivering an efficient model for compound development. Conduit both acquires and funds the development of Phase 2-ready assets and then seeks an exit through third-party license deals following successful clinical trials. Led by a highly experienced team of pharmaceutical executives including Dr. David Tapolczay and Dr. Freda Lewis-Hall, this novel approach is a departure from the traditional pharma/biotech business model of taking assets through regulatory approval. 1 https://www.pfizer.com/disease-and-conditions/lupus#:~:text=Lupus%20is%20a%20global%20disease,in%20the%20United%20States%20alone.&text=Its%20prevalence%20varies%20significantly%20between%20regions. 2 https://www.marketresearchfuture.com/reports/systemic-lupus-erythematosus-treatment-market-8500 3 https://finance.yahoo.com/news/anca-associated-vasculitis-industry-epidemiology-084800557.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAANkxj8q0WJx_FXr2sjJIlSmylTMmxaJeUARmiWNMn6zifDwMsjRLRxrwchkkTJpnSgmOepq9_4F4VcuFTnK9614lev4EU5ZewxV0sp-_HWjYRNJpQXDsL5LmvJKBUGk93MU9si4jNJXm1dHmn9v7YN7MTrQFHB0yTldyLyE3iDHJ The content above comes from the network. if any infringement, please contact us to modify.

INDImmunotherapy

08 Aug 2024

·pipelinereview.com

Conduit Pharmaceuticals Enters into Exclusive License Agreement with AstraZeneca for Multiple Assets to Advance Potential First-in-Class Treatments

SAN DIEGO, CA, USA and LONDON, UK I August 08, 2024 I Conduit Pharmaceuticals Inc. (Nasdaq: CDT ) (“Conduit” or the “Company”), today announced that the Company has entered into an agreement with AstraZeneca to exclusively license rights to develop AZD1656 and AZD5658, both HK-4 glucokinase activators, and AZD5904, a myeloperoxidase inhibitor (MPO). AstraZeneca had progressed AZD1656 and AZD5904 through Phase 1 clinical trials. Conduit initially intends to conduct Phase II clinical trials on clinical candidates AZD1656 and AZD5658 in 2024 for applications in autoimmune disorders, a category which affect an estimated 10% of the population 1 . Under the terms of the License Agreement, AstraZeneca will grant Conduit an exclusive license to both AZD1656 and AZD5658 for all human indications, as well as an exclusive license to AZD5904 for use in Idiopathic Male Infertility. As part of the License Agreement, AstraZeneca will be issued shares of common stock in Conduit, and Conduit will also pay AstraZeneca a share of sublicense revenues, including upfront payments, milestones, and royalties received from future partners. AstraZeneca will share pre-clinical and clinical data on the assets and supply Conduit with certain quantities of AZD1656, AZD5904, and AZD5658 from its inventory. The License Agreement also includes provisions for the transfer of know-how related to AZD1656, AZD5658 and AZD5904 from AstraZeneca to Conduit. AstraZeneca has been granted a right of first negotiation to develop, manufacture, and commercialize the licensed compounds if Conduit seeks to assign, license, or grant such rights to a third party. Through the License Agreement, Conduit will analyze existing clinical data and initiate Phase II trials. Conduit believes this will fast-track the development of these compounds and bring innovative new medicines to patients facing substantial unmet needs. “We are delighted to have entered into an agreement with AstraZeneca to secure the rights to develop AZD1656, AZD5658, and AZD5904. The potential of these assets to become important first-in-class medicines for patients is promising. Given the data from AstraZeneca’s clinical trials, we believe there is a strong rationale to initiate Phase II studies in multiple indications to progress to commercialization of these assets,” said Dr. David Tapolczay, Chief Executive Officer of Conduit. Conduit departs from the traditional business model of shepherding assets through an entire commercial lifecycle by acquiring assets that have already undergone pre-clinical and clinical testing. The Company works towards accelerating the assets through Phase II trials and, if successful, intends to seek exits through third-party license opportunities. About Conduit Pharmaceuticals Conduit is a multi-asset, clinical stage, disease-agnostic life science company delivering an efficient model for compound development. Conduit both acquires and funds the development of Phase II-ready assets and then seeks an exit through third-party license deals following successful clinical trials. Led by a highly experienced team of pharmaceutical executives including Dr. David Tapolczay and Dr. Freda Lewis-Hall, this novel approach is a departure from the traditional pharma/biotech business model of taking assets through regulatory approval. 1 https://www-thelancet-com.libproxy1.nus.edu.sg/journals/lancet/article/PIIS0140-6736(23)00457-9/abstract SOURCE: Conduit Pharmaceuticals

License out/inPhase 1Phase 2

08 Aug 2024

·firstwordpharma.com

Conduit bets on three of AstraZeneca’s potential first-in-class assets

Looking to strengthen its pipeline, Conduit Pharmaceuticals forged an exclusive licensing agreement with AstraZeneca to acquire multiple assets with first-in-class potential from the latter, including two HK-4 glucokinase activators, codenamed AZD1656 and AZD5658, and a myeloperoxidase inhibitor AZD5904.As part of the deal announced Thursday, Conduit will secure exclusive rights to both AZD1656 and AZD5658 across all autoimmune indications, and to AZD5904 for idiopathic male infertility. Additionally, Conduit will receive relevant preclinical and clinical data, certain quantities of the experimental drugs, and knowledge transfer from AstraZeneca.Meanwhile, AstraZeneca stands to receive an undisclosed number of common stock shares in Conduit, in addition to a slice of sublicense revenues, comprising upfront and milestones payments plus any royalties from future partners. Moreover, AstraZeneca holds the first negotiation rights to develop, produce, and commercialise the licensed compounds if Conduit chooses to transfer or license the rights to another party.With AstraZeneca having advanced AZD1656 and AZD5904 through early-stage trials, Conduit will take charge of the drugs’ mid-stage programmes in autoimmune disorders. “Given the data from AstraZeneca’s clinical trials, we believe there is a strong rationale to initiate Phase II studies in multiple indications” commented David Tapolczay, chief executive of Conduit.Founded in 2019, Conduit specialises in acquiring assets that are already in preclinical and clinical stages. The company advances these candidates through Phase II trials and, if successful, aims for an exit via third-party licenses.

License out/inPhase 2Phase 1

100 Deals associated with AZD-1656

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Kidney Failure, Chronic	Phase 2	GB	AstraZeneca PLC	13 Dec 2019
Transplant complication	Phase 2	GB	AstraZeneca PLC	13 Dec 2019
COVID-19	Discovery	RO	St George Street Capital Ltd.	12 Aug 2020
COVID-19	Discovery	GB	St George Street Capital Ltd.	12 Aug 2020
COVID-19	Discovery	CZ	St George Street Capital Ltd.	12 Aug 2020
Hyperglycemia	Discovery	US	AstraZeneca PLC	01 Sep 2010
Diabetes Mellitus, Type 2	Discovery	US	AstraZeneca PLC	01 Jan 2009
Diabetes Mellitus, Type 1	Discovery	US	AstraZeneca PLC	01 Dec 2008
Hypoglycemia	Discovery	US	AstraZeneca PLC	01 Nov 2008

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04516759 (ARCADIA, Pubmed) Manual	Phase 2	COVID-19 \| Diabetes Mellitus	153	AZD-1656	(lducieblpr) = xjaqrskwel zrocjpmolq (mhnbkhkpqr ) View more	Negative	18 Aug 2022
				Placebo	(lducieblpr) = audzpvwqok zrocjpmolq (mhnbkhkpqr ) View more
NCT04516759 (ARCADIA, CTgov)	Phase 2	COVID-19	170	AZD1656 (AZD1656 (Plus Usual Hospital Care))	atkdfcixnz(rheqzjtwhl) = ufflnwhtgd ywkaxoejls (nfabhnepvv, fpcntlqhdx - sbulmqfgxw) View more	-	25 Apr 2022
				Placebo (Matched Placebo (Plus Usual Hospital Care))	atkdfcixnz(rheqzjtwhl) = vnupoknqfy ywkaxoejls (nfabhnepvv, ryeisfvrys - ghstcekkar) View more
NCT01152385 (Pubmed \| Diabetes Obes Metab)	Phase 2	Diabetes Mellitus, Type 2	224	AZD1656 40-200 mg	(hommksjbsa) = gmheanhppb ucnmtpiywg (kmsbkgaeli, ( - 0.65, 0.20))	-	01 Oct 2013
				Placebo	(hommksjbsa) = vgccxhiovd ucnmtpiywg (kmsbkgaeli )
NCT00856908 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	20	AZD1656 (Experimental)	giljqrxoxw(eplwlcxrau) = sdtenwxdav iqnmnjxqgo (ixllperyfu, dvfizpiyvz - qxokdylwir) View more	-	26 Nov 2012
				placebo (Placebo Comparator)	giljqrxoxw(eplwlcxrau) = hnwmltgoum iqnmnjxqgo (ixllperyfu, byuyjxdmdn - ozwgdomxeg) View more
NCT01020123 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	530	AZD1656+metformin (Higher Dose)	djadbboujb(fkeuxdggcj) = oznxokbgzs ccuzhhjgyp (nnctiylzrv, nuwnakwsfm - ejiuhapoct) View more	-	26 Nov 2012
				AZD1656+metformin (Lower Dose)	djadbboujb(fkeuxdggcj) = ronjarfchl ccuzhhjgyp (nnctiylzrv, jfddqcnoga - pofshbglmq) View more

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