A Phase 1, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD3366 in Healthy Men and Women of Non-Childbearing Potential Following: Part A: Single Ascending Dose Administration (Including Populations of Japanese and Chinese Subjects) Part B: Single Dose Administration of AZD3366 at One Dose Level or Placebo With Concomitant Repeated Dosing of Ticagrelor and Acetylsalicylic Acid

Part A of this study is a Phase 1, First-in-human (FiH), randomized, single-blind, placebo controlled study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD3366 following single intravenous (IV) ascending doses.
Part B of this study is a randomized, single-blind, parallel group placebo-controlled study to assess the safety, tolerability and PD of a single IV administration of AZD3366 with concomitant loading doses followed by repeated maintenance dosing of ticagrelor and acetylsalicylic acid (ASA).

Start Date15 Oct 2020

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with APT-102

100 Translational Medicine associated with APT-102

100 Patents (Medical) associated with APT-102

Literatures (Medical) associated with APT-102

01 Aug 2023·Cardiovascular drugs and therapyQ3 · MEDICINE

Recombinant Apyrase (AZD3366) Against Myocardial Reperfusion Injury

Q3 · MEDICINE

Article

Author: Ryberg, Erik ; Ye, Regina ; Fjellström, Ola ; Birnbaum, Yochai ; Ye, Yumei ; Carlsson, Leif ; Whatling, Carl ; Chen, Huan

PURPOSE:

Recombinant apyrase (AZD3366) increases adenosine production and ticagrelor inhibits adenosine reuptake. We investigated whether intravenous AZD3366 before reperfusion reduces myocardial infarct size (IS) and whether AZD3366 and ticagrelor have additive effects.

METHODS:

Sprague-Dawley rats underwent 30 min ischemia. At 25 min of ischemia, animals received intravenous AZD3366 or vehicle. Additional animals received intravenous CGS15943 (an adenosine receptor blocker) or intraperitoneal ticagrelor. At 24 h reperfusion, IS was assessed by triphenyltetrazolium chloride. Other rats were subjected to 30 min ischemia followed by 1 h or 24 h reperfusion. Myocardial samples were assessed for adenosine levels, RT-PCR, and immunoblotting.

RESULTS:

AZD3366 and ticagrelor reduced IS. The protective effect was blocked by CGS15943. The effect of AZD3366 + ticagrelor was significantly greater than AZD3366. One hour after infarction, myocardial adenosine levels significantly increased with AZD3366, but not with ticagrelor. In contrast, 24 h after infarction, adenosine levels were equally increased by AZD3366 and ticagrelor, and levels were higher in the AZD3366 + ticagrelor group. One hour after reperfusion, AZD3366 and ticagrelor equally attenuated the increase in interleukin-15 (an early inflammatory marker after ischemic cell death) levels, and their combined effects were additive. AZD3366, but not ticagrelor, significantly attenuated the increase in RIP1, RIP3, and P-MLKL (markers of necroptosis) 1 h after reperfusion. AZD3366, but not ticagrelor, significantly attenuated the increase in IL-6 and GSDMD-N (markers of pyroptosis) 1 h after reperfusion. At 24 h of reperfusion, both agents equally attenuated the increase in these markers, and their effects were additive.

CONCLUSIONS:

AZD3366 attenuated inflammation, necrosis, necroptosis, and pyroptosis and limited IS. The effects of AZD3366 and ticagrelor were additive.

09 Jul 2020·Journal of Crohn's & colitisQ1 · MEDICINE

Modulation of CD39 and Exogenous APT102 Correct Immune Dysfunction in Experimental Colitis and Crohn’s Disease

Q1 · MEDICINE

Article

Author: Longhi, Maria Serena ; Vuerich, Marta ; Harshe, Rasika ; Moss, Alan C ; Wu, Yan ; Mukherjee, Samiran ; Cowan, Peter J ; Csizmadia, Eva ; Xie, Anyan ; Robson, Simon C ; Chen, Ridong ; Robles, René J

Abstract:

Background and Aims:

CD39/ENTPD1 scavenges pro-inflammatory nucleotides, to ultimately generate immunosuppressive adenosine, which has a central role in immune homeostasis. Global deletion of Cd39 increases susceptibility to experimental colitis while single nucleotide polymorphisms within the human CD39 promoter, and aberrant patterns of expression during experimental hypoxia, predispose to Crohn’s disease. We aimed to define the impact of transgenic human CD39 [hTG] overexpression in experimental colitis and to model therapeutic effects using the recombinant apyrase APT102 in vivo. We also determined the in vitro effects of APT102 on phenotypic and functional properties of regulatory T-lymphocytes derived from patients with Crohn’s disease.

Methods:

Colitis was induced by administration of dextran sulfate sodium in wild-type [WT] or hTG mice, and, in another model, by adoptive transfer of CD45RBhigh cells with or without WT or hTG regulatory T cells [Treg]. In additional experiments, mice were treated with APT102. The effects of APT102 on phenotype and function of Treg and type-1 regulatory T [Tr1] cells were also evaluated, after purification from peripheral blood and lamina propria of Crohn’s disease patients [n = 38].

Results:

Overexpression of human CD39 attenuated experimental colitis and protected from the deleterious effects of systemic hypoxia, pharmacologically induced by deferoxamine. Administration of APT102 in vivo enhanced the beneficial effects of endogenous Cd39 boosted by the administration of the aryl hydrocarbon receptor [AhR] ligand unconjugated bilirubin [UCB]. Importantly, supplemental APT102 restored responsiveness to AhR stimulation by UCB in Treg and Tr1 cells, obtained from Crohn’s disease patients.

Conclusions:

hCD39 overexpression ameliorated experimental colitis and prevented hypoxia-related damage in vivo. Exogenous administration of APT102 boosted AhR-mediated regulatory effects in vivo while enhancing Treg functions in Crohn’s disease in vitro.

01 Jan 2020·Korean journal of radiologyQ3 · MEDICINE

Human Recombinant Apyrase Therapy Protects Against Myocardial Ischemia/Reperfusion Injury and Preserves Left Ventricular Systolic Function in Rats, as Evaluated by 7T Cardiovascular Magnetic Resonance Imaging

Q3 · MEDICINE

Article

Author: Chen, Ridong ; Chen, Wei ; Xu, Ziqian ; Zhang, Ruzhi ; Wang, Lei ; Gao, Fabao ; Zheng, Jie

OBJECTIVE:

The occurrence of intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO) in myocardial infarction (MI), known as severe ischemia/reperfusion injury (IRI), has been associated with adverse remodeling. APT102, a soluble human recombinant ecto-nucleoside triphosphate diphosphohydrolase-1, can hydrolyze extracellular nucleotides to attenuate their prothrombotic and proinflammatory effects. The purpose of this study was to temporally evaluate the therapeutic effect of APT102 on IRI in rats and to elucidate the evolution of IRI in the acute stage using cardiovascular magnetic resonance imaging (CMRI).

MATERIALS AND METHODS:

Fifty-four rats with MI, induced by ligation of the origin of the left anterior descending coronary artery for 60 minutes, were randomly divided into the APT102 (n = 27) or control (n = 27) group. Intravenous infusion of APT102 (0.3 mg/kg) or placebo was administered 15 minutes before reperfusion, and then 24 hours, 48 hours, 72 hours, and on day 4 after reperfusion. CMRI was performed at 24 hours, 48 hours, 72 hours, and on day 5 post-reperfusion using a 7T system and the hearts were collected for histopathological examination. Cardiac function was quantified using cine imaging and IMH/edema using T2 mapping, and infarct/MVO using late gadolinium enhancement.

RESULTS:

The extent of infarction (p < 0.001), edema (p < 0.001), IMH (p = 0.013), and MVO (p = 0.049) was less severe in the APT102 group than in the control group. IMH size at 48 hours was significantly greater than that at 24 hours, 72 hours, and 5 days after reperfusion (all p < 0.001). The left ventricular ejection fraction (LVEF) was significantly greater in the APT102 group than in the control group (p = 0.006). There was a negative correlation between LVEF and IMH (r = -0.294, p = 0.010) and a positive correlation between IMH and MVO (r = 0.392, p < 0.001).

CONCLUSION:

APT102 can significantly alleviate damage to the ischemic myocardium and microvasculature. IMH size peaked at 48 hours post reperfusion and IMH is a downstream consequence of MVO. IMH may be a potential therapeutic target to prevent adverse remodeling in MI.

News (Medical) associated with APT-102

28 Jul 2023

·www.fiercebiotech.com

AstraZeneca axes assets, inks Pfizer gene therapy deal and loses key R&D exec in Friday news flurry

Mene Pangalos, Ph.D., is set to step down as EVP of biopharmaceuticals R&D early next year. It’s all change at AstraZeneca. In a Friday morning full of announcements, the Anglo-Swedish drugmaker not only revealed its second-quarter earnings results but also disclosed the elimination of several pipeline programs, the purchase of a portfolio of preclinical gene therapies from Pfizer and the upcoming departure of a key, long-serving R&D executive. On the pipeline side, the most advanced casualty is AZD4573, a CDK9 inhibitor that AstraZeneca took as far as phase 2 as a treatment for hematological malignancies. The company designed the drug to suppress MCL-1 and induce apoptosis in hematologic cancer cells and advanced it into phase 1/2 and phase 2 clinical trials as a monotherapy and combination treatment in 2021. Now, AstraZeneca has discontinued the studies as part of its second-quarter pipeline update (PDF). The company attributed the decision to stop work in indications including peripheral T-cell lymphoma to its “strategic portfolio prioritization.” The second quarter clearout also affected a phase 1 hematologic cancer program. AstraZeneca kicked AZD0466 to the curb, stopping a pair of phase 1/2 blood cancer clinical trials, after assessing the benefit-risk profile. AZD0466 is a BCL-22/XL inhibitor that was supposed to solve the shortcomings of another asset, AZD4320. Dose-limiting cardiovascular toxicity, coupled to physicochemical properties, torpedoed AZD4320 before it reached the clinic. But AstraZeneca identified a path forward, teaming with Starpharma to create an AZD4320-dendrimer conjugate, later codenamed AZD0466, with an improved therapeutic index. While AZD0466 and AZD4573 are leaving the pipeline at the same time, Susan Galbraith, Ph.D., EVP of oncology R&D at AstraZeneca, said the hematology pipeline remains “very robust.” The two scrapped oncology assets are “both molecules that address a cell death mechanism for hematology,” Galbraith told Fierce Biotech on an earnings call with journalists this morning. “The therapeutic index for these is relatively narrow and overall the benefit-risk was not viewed to be one that we felt was able to go forward into subsequent trials.” AstraZeneca is also ending development of AZD3366 in cardiovascular disease. The drug candidate, a recombinant form of human apyrase enzyme, showed anti-thrombotic, anti-inflammatory and tissue-protective properties in preclinical studies but has fallen at the first hurdle in the clinic. News of the pipeline updates emerged alongside details of other changes at the company. Mene Pangalos, Ph.D., is set to step down as EVP of biopharmaceuticals R&D early next year after five years in the role and 14 years at AstraZeneca. The Big Pharma has already found Pangalos’ replacement. Sharon Barr, who has headed up R&D at AstraZeneca’s rare disease unit Alexion since 2013, will fill the post vacated by Pangalos. On the call with the media, Pangalos said he has no job lined up for when he leaves AstraZeneca. Rather, the executive said he plans to “spend more time with my wife, my girls, see my family in Greece.” The idea is to step back and enjoy “a different pace of life,” he added. Barr is departing Alexion just as the rare disease group is getting an expanded preclinical pipeline. In yet another announcement this morning, AstraZeneca revealed that Alexion has agreed a deal worth “up to $1 billion” for “a portfolio of preclinical gene therapy programs and enabling technologies from Pfizer.” The deal, which will see employees move to Alexion, includes a number of novel adeno-associated virus capsids, a delivery technology that Pfizer has pulled back from as part of its recent early-stage R&D pivot.

Gene TherapyPhase 2Executive ChangePhase 1

28 Jul 2023

·firstwordpharma.com

AstraZeneca records robust Q2 sales and shrugs off COVID-19 revenue decline

Headline results for the second quarter: Revenue: $11.4 billion (forecasts of $10.97 billion), up 6% Profit: $1.8 billion, versus $360 million in the prior yearNote: All changes are versus the prior-year period unless otherwise statedWhat the company said:Commenting on performance for the year to date, AstraZeneca noted that each of its non-COVID-19 therapy areas saw double-digit revenue growth, with eight medicines delivering more than $1 billion of revenue in the first half of 2024. CEO Pascal Soriot said: “our pipeline momentum continues with eight positive pivotal trials for our oncology medicines so far this year, and we are encouraged by the positive data from TROPION-Lung01, the first pivotal trial of datopotamab deruxtecan. We look forward to sharing the data with the medical community at an upcoming medical congress and are proceeding to file the data with the FDA.”Other results: Oncology product sales: $4.4 billion, up 18% Tagrisso: $1.5 billion, up 7% Imfinzi: $1.1 billion, up 55% Lynparza: $717 million, up 7% Calquence: $653 million, up 34% Enhertu: $67 million, with the company also recording $255 million in alliance revenue from the product from partner Daiichi Sankyo Cardiovascular, renal and metabolic disease product sales: $2.7 billion, up 14% Farxiga: $1.5 billion, up 36% Brilinta: $331 million, down 5% Rare disease product sales: $2 billion, up 8% Soliris: $814 million, down 21% Ultomiris: $613 million, up 64% Respiratory and immunology product sales: $1.5 billion, up 7% Symbicort: $600 million, down 2% Fasenra: $406 million, up 15% Pulmicort: $124 million, up 7% Emerging market sales: $3.1 billion, up 12%, with sales in China flat at $1.4 billion AstraZeneca reported no sales of its COVID-19 vaccine versus $445 million in the second quarter of 2022.Looking ahead:AstraZeneca reaffirmed that it expects revenue this year to increase by a low-to-mid single-digit percentage on a constant exchange rate basis, while stripping out COVID-19 medicines is forecast to lead to a low double-digit percentage rise. The company indicated that sales in China are expected to return to growth and increase by a low to mid single-digit percentage. Meanwhile, core earnings per share are seen increasing by a high single-digit to low double-digit percentage.What analysts said:Morgan Stanley analysts noted: "the majority of the product sales beat was driven by Imfinzi (+17% ahead), which has been given a new lease of life in combination with Imjudo in liver, lung and biliary tract cancers, and strong demand for Farxiga (+11% ahead) in heart failure and kidney disease." They also noted that Enhertu beat consensus expectations by 11%, with global sales of $661m (versus $508m in 1Q23) reflecting rapid adoption in HER2-low breast cancer in the US and strong uptake in breast and gastric cancer in ex-US markets.Pipeline updates:AstraZeneca separately announced on Friday that it has acquired a portfolio of preclinical gene therapy assets from Pfizer. The company confirmed that its clinical development programme for brazikumab in inflammatory bowel diseases has been discontinued following a review of the drug’s development timeline and a Phase III trial evaluating Fasenra in bullous pemphigoid was discontinued for futility (efficacy). Phase II development of the CDK9 inhibitor AZD4573 in haematological malignancies has been discontinued and AZD0186 (oral GLP-1 in type 2 diabetes), AZD0466 (haematological malignancies) and AZD3366 (cardiovascular disease) have all been discontinued in Phase I.Phase III data for Enhertu (DESTINY-Breast06) in HER2-low breast cancer, Tagrisso (LAURA) in non-small cell lung cancer (NSCLC), and Imfinzi (NILE) in bladder cancer are expected in the first half of 2024, with AstraZeneca having previously guided to readout in the second half of this year

VaccinePhase 3Phase 2Gene TherapymRNA

100 Deals associated with APT-102

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Phase 1	US	AstraZeneca PLC	15 Oct 2020
Thrombosis	Preclinical	US	APT Therapeutics, Inc.	30 Jan 2022

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ESC2022	Not Applicable	ST Elevation Myocardial Infarction	16	AZD3366	tdahdakfoe(gpuuvwisen) = gljqfqvgto fopxevzacc (ccxcwrruni ) View more	-	28 Aug 2022
				Vehicle	tdahdakfoe(gpuuvwisen) = jtaehmxgrm fopxevzacc (ccxcwrruni ) View more
ESC2020	Not Applicable	-	20	Ticagrelor	drptocycya(hilabtbpmy) = osjizkswek idzagrnrro (dthgyhpojr ) View more	-	01 Sep 2020
				AZD3366 1mg/kg	drptocycya(hilabtbpmy) = gzywfaygjv idzagrnrro (dthgyhpojr ) View more

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Leverages most recent intelligence information, enabling fullest potential.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

APT-102

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation