AZD8233 / Ionis, AstraZeneca - LARVOL DELTA

Population pharmacokinetics of a novel PCSK9 antisense oligonucleotide. (PubMed, Br J Clin Pharmacol) - P1, P1/2, P2b | "Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher Cmax observed in the Asian population relative to non-Asians."

Journal • PK/PD data • Dyslipidemia

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. (PubMed, Cardiovasc Diabetol) - "Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials...Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials...Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ABCA1 • ACACA • ACSL3 • BMP2 • CD36 • COL1A1 • CPT1A • CTGF • EHHADH • HMGB1 • IFNA1 • IL1B • IL6 • MALT1 • RUNX2 • SCARB1 • SMAD7 • TCF7L2 • TNFA

SOLANO: A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia (clinicaltrials.gov) - P2 | N=411 | Completed | Sponsor: AstraZeneca | Phase classification: P2b ➔ P2

Phase classification • Dyslipidemia

In Vivo Metabolite Profiles of a GalNAc Conjugated Antisense Oligonucleotide AZD8233 Using Liquid Chromatography-High Resolution Mass Spectrometry: a Cross Species Comparison in Animals and Humans. (PubMed, Drug Metab Dispos) - "A biotransformation strategy for ASO drug candidates was established by utilizing tissue, plasma and urine samples collected from toxicology and/or clinical studies and LC-high-resolution mass spectrometry analysis without conducting bespoke radiolabeled ADME studies. The generated biotransformation package was considered adequate by health authorities to progress AZD8233 into a phase 3 programme, proving its applicability to future metabolism studies of ASO candidates in drug development."

Journal • Preclinical

To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants. (clinicaltrials.gov) - P1 | N=3 | Terminated | Sponsor: AstraZeneca | Active, not recruiting ➔ Terminated; A decision has been taken to discontinue the development of AZD8233 (PCSK9-ASO for sc administration) due to low likelihood of demonstrating a benefit significantly above the current standard of care for patients with high-risk hypercholesterolemia.

Trial termination • Chronic Kidney Disease • Nephrology • Renal Disease

Recent Advances in Gene Therapy for Familial Hypercholesterolemia: An Update Review. (PubMed, J Clin Med) - "Various RNA-targeted therapies are in phase 1-3 clinical trials, such as small interfering RNA-based drugs inclisiran, ARO-ANG3, ARO-APOC3, olpasiran, SLN360, and antisense oligonucleotide-based drugs AZD8233, vupanorsen, volanesorsen, IONIS-APO(a)Rx, etc., all of which have demonstrated excellent lipid-lowering effects. With gene editing technologies, such as CRISPR-Cas 9 and meganuclease, completing animal experiments in mice or cynomolgus monkeys and demonstrating lasting lipid-lowering effects, patients with FH are expected to reach a permanent cure in the future. (4) Gene therapy is being widely used for the lipid-lowering treatment of FH patients and has shown excellent therapeutic promise, but the current delivery efficiency, economic burden, immunogenicity and the precision of gene therapy can be further optimized."

Journal • Review • Dyslipidemia • Familial Hypercholesterolemia • Gene Therapies • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders

To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants. (clinicaltrials.gov) - P1 | N=3 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | N=24 ➔ 3 | Trial completion date: Oct 2023 ➔ Nov 2022 | Trial primary completion date: Oct 2023 ➔ Nov 2022

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

HAYATE: A Study of AZD8233 in Participants With Dyslipidemia. (clinicaltrials.gov) - P1/2 | N=87 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Dyslipidemia • Metabolic Disorders • APOA1 • APOB • CLU • CRP • CST3 • KIM1 • LCN2 • OGA • SPP1

Ionis provides update on development program evaluating PCSK9 antisense medicine for the treatment of hypercholesterolemia (PRNewswire) - P2b | N=411 | SOLANO (NCT04964557) | Sponsor: AstraZeneca | "Ionis Pharmaceuticals...announced that topline results from the Phase 2b SOLANO study in patients with hypercholesterolemia demonstrated that 60mg of ION449 (AZD8233) administered monthly achieved a statistically significant 62.3% (p<0.001) reduction in low-density lipoprotein cholesterol (LDL-C) levels after 28 weeks compared to placebo, meeting the study's primary efficacy endpoint. ION449 was generally safe and well tolerated in this study. However, these results did not achieve pre-specified efficacy criteria and AstraZeneca has decided not to advance ION449 (AZD8233) into Phase 3 development for hypercholesterolemia. AstraZeneca is continuing to analyze the results from the SOLANO study to determine its next steps for the program."

P2b data • Cardiovascular • Dyslipidemia

SOLANO: A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia (clinicaltrials.gov) - P2b | N=411 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Dyslipidemia

To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants. (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Kidney Disease • Nephrology • Renal Disease

To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants. (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: AstraZeneca | Trial completion date: Apr 2023 ➔ Oct 2023 | Initiation date: Nov 2021 ➔ Jul 2022 | Trial primary completion date: Apr 2023 ➔ Oct 2023

Trial completion date • Trial initiation date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

HAYATE: A Study of AZD8233 in Participants With Dyslipidemia. (clinicaltrials.gov) - P1/2 | N=87 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Dyslipidemia • Metabolic Disorders • APOA1 • APOB • CLU • CRP • CST3 • KIM1 • LCN2 • OGA • SPP1

AZD8233 Antisense Oligonucleotide targeting PCSK9 does not prolong QT interval AZD8233 ASO C-QT analysis. (PubMed, Br J Clin Pharmacol) - "Furthermore, the upper 90% ΔΔQTcF confidence interval was estimated to be below 10 ms at all observed concentrations. As the effect on ΔΔQTcF is below the threshold for regulatory concern (10 ms), it can be concluded that AZD8233 does not induce QTcF prolongation at the high clinical exposure scenario."

Journal • Dyslipidemia • Metabolic Disorders

"آسترازينيكا @AstraZeneca تطرح نتائج أولية للتجارب الإكلينيكية المرحلة الثانية للدواء التجريبي لعلاج الكوليسترول 💉AZD8233 💉حقنة واحدة تحت الجلد شهريا 🗓بعد12أسبوع (مايعادل اتمام تلقي ٣ جرعات) ✅⬇️انخفض الكوليسترول "الضار" LDL بنسبة73% https://t.co/MHsLNyO9xe 3️⃣" (@YAYshamsaldeen)

HAYATE: A Study of AZD8233 in Participants With Dyslipidemia. (clinicaltrials.gov) - P1/2 | N=87 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Apr 2022 ➔ Aug 2022 | Trial primary completion date: Apr 2022 ➔ Aug 2022

Trial completion date • Trial primary completion date • Dyslipidemia • Metabolic Disorders • APOA1 • APOB • CLU • CRP • CST3 • KIM1 • LCN2 • OGA • SPP1

SOLANO: A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia (clinicaltrials.gov) - P2b; N=409; Active, not recruiting; Sponsor: AstraZeneca; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Dyslipidemia

To Assess the Pharmacokinetics, Safety, and Tolerability of AZD8233 in Participants With Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and Healthy Participants. (clinicaltrials.gov) - P1; N=28; Not yet recruiting; Sponsor: AstraZeneca

Clinical • New P1 trial • Chronic Kidney Disease • Nephrology • Renal Disease

High-sensitivity workflow for LC-MS-based analysis of GalNAc-conjugated oligonucleotides: a case study. (PubMed, Bioanalysis) - " A high-sensitivity methodology for mass-specific measurement of AZD8233, a GalNAc-conjugated 16-mer oligonucleotide, using LLE-SPE with optimized LC conditions and detection of a low-mass fragment ion was successfully validated in the range of 0.20-100 ng/ml in human plasma. The AZD8233 LC-MS methodology adds valuable insight on the GalNAc linker's in vivo stability to the program and should be broadly applicable to oligonucleotides requiring high sensitivity and mass-selective measurement for quantitative discrimination from metabolites and endogenous interferences."

Clinical • Journal

SOLANO: A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia (clinicaltrials.gov) - P2b; N=376; Recruiting; Sponsor: AstraZeneca; Not yet recruiting ➔ Recruiting

Enrollment open • Dyslipidemia

A Study of AZD8233 in Participants With Dyslipidemia (clinicaltrials.gov) - P2b; N=119; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Trial completion • Dyslipidemia • Metabolic Disorders • APOA1 • APOB

SOLANO: A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia (clinicaltrials.gov) - P2b; N=376; Not yet recruiting; Sponsor: AstraZeneca

Clinical • New P2b trial

A Phase 2b Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants with Hyperlipidaemia (clinicaltrialsregister.eu) - P2; N=376; Ongoing; Sponsor: AstraZeneca AB

Clinical • New P2 trial • Cardiovascular • Dyslipidemia • Hematological Disorders

To Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD8233 After Multiple Dose Administration in Subjects With Dyslipidemia (clinicaltrials.gov) - P1; N=34; Completed; Sponsor: AstraZeneca; Active, not recruiting ➔ Completed

Clinical • Trial completion • Diabetes • Dyslipidemia • Metabolic Disorders • Type 2 Diabetes Mellitus • CLU • CRP • CST3 • KIM1 • LCN2 • OGA • SPP1

HAYATE: A Study of AZD8233 in Participants With Dyslipidemia. (clinicaltrials.gov) - P1/2; N=91; Recruiting; Sponsor: AstraZeneca

New P1/2 trial • Dyslipidemia • Metabolic Disorders • APOA1 • APOB • CLU • CRP • CST3 • KIM1 • LCN2 • OGA • SPP1