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

04 Jun 2024·Journal of the American Heart Association

Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo‐Controlled Study

Article

Author: Åstrand, Magnus ; Egnell, Ann-Charlotte ; Fjellström, Ola ; Whatling, Carl ; Gabrielsen, Anders ; Daniels, Samuel J ; Kardassis, Dimitris

Background:

ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y 12 receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long‐acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease.

Methods and Results:

We conducted this phase 1, first‐in‐human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose‐dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP‐stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters.

Conclusions:

AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters.

Registration:

URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04588727.

07 May 2024·European heart journal

Recombinant human soluble domain of CD39L3 and ticagrelor: cardioprotective effects in experimental myocardial infarction

Article

Author: Sutelman, Pablo ; Hidalgo, Alberto ; Radike, Monika ; Badimon, Lina ; Vilahur, Gemma ; Gabrielsen, Anders ; Ben-Aicha, Soumaya ; Hovdal, Daniel ; Gutiérrez, Manuel ; Casaní, Laura ; Carlsson, Leif ; Fjellström, Ola ; Ongstad, Emily L

Abstract:

Background and Aims:

The ecto–nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI).

Methods:

Ticagrelor-treated pigs underwent balloon-induced MI (90 min) and, before reperfusion, received intravenously either vehicle, 1 mg/kg AZD3366 or 3 mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed.

Results:

Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3 mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3 mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3 mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time.

Conclusions:

Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.

01 Aug 2023·Cardiovascular drugs and therapyQ3 · MEDICINE

Recombinant Apyrase (AZD3366) Against Myocardial Reperfusion Injury

Q3 · MEDICINE

Article

Author: Ryberg, Erik ; Ye, Regina ; Birnbaum, Yochai ; Fjellström, Ola ; 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.

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

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Phase 1	United States	AstraZeneca PLC	15 Oct 2020
Thrombosis	Preclinical	United States	APT Therapeutics, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ESC2020	Not Applicable	-	20	Ticagrelor	xjvtkptvek(lcxafgxfbv) = tsahwhqsxv hrnspshhmx (oieljmcgnq ) View more	-	01 Sep 2020
				AZD3366 1mg/kg	xjvtkptvek(lcxafgxfbv) = rprhpnzggs hrnspshhmx (oieljmcgnq ) View more

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