AZD-2693 (ION-839): A Comprehensive Report on a Novel Antisense Oligonucleotide for Genetically Targeted MASH Therapy

1. Executive Summary

AZD-2693, also known by its developmental name ION-839, is an investigational antisense oligonucleotide (ASO) therapeutic agent specifically engineered to target the patatin-like phospholipase domain-containing 3 (PNPLA3) protein. Developed through a collaboration between Ionis Pharmaceuticals, the originator of the ASO technology, and AstraZeneca, which is leading further clinical development, AZD-2693 represents a precision medicine approach for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH). The primary focus of AZD-2693 is on individuals homozygous for the PNPLA3 I148M genetic variant, a population at significantly increased risk for MASH development and progression to advanced liver disease.[1]

Phase 1 clinical trials have demonstrated that AZD-2693 is generally well-tolerated and achieves substantial target engagement, evidenced by a marked reduction in hepatic PNPLA3 mRNA and protein levels. These studies also revealed promising pharmacodynamic effects, including a dose-dependent reduction in liver fat content, measured by MRI-Proton Density Fat Fraction (MRI-PDFF), and favorable modulation of inflammatory and lipid biomarkers in homozygous PNPLA3 148M risk allele carriers.[1] The pharmacokinetic profile supports monthly subcutaneous administration. Based on these encouraging early-phase results, AZD-2693 has advanced into a large-scale Phase 2b clinical trial, the FORTUNA study, to rigorously evaluate its efficacy in achieving histological improvement in MASH and its impact on liver fibrosis in the target patient population. The development of AZD-2693 underscores a strategic shift towards genetically informed therapies for complex metabolic disorders like MASH, offering potential for a more personalized and effective treatment option for a defined patient subgroup with high unmet medical need.

2. Introduction to AZD-2693 (ION-839)

Overview of AZD-2693 and its Therapeutic Context

AZD-2693 is an investigational therapeutic agent currently under clinical development. The compound is also widely recognized by its earlier developmental identifier, ION-839.[2] Other synonyms reported include AZD2693, ION 839, ION839, and IONIS-AZ6-2.5-LRx.[3] This agent is being evaluated for its potential in treating MASH, a progressive liver disease characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis, which can ultimately lead to cirrhosis, liver failure, and hepatocellular carcinoma.[1] MASH represents a significant and growing global health burden with a substantial unmet medical need, particularly for effective therapies that can halt or reverse disease progression, especially in genetically predisposed individuals.[1]

Chemical Nature and Drug Classification

AZD-2693 is classified as an antisense oligonucleotide (ASO).[1] Its modality is that of a nucleic acid therapeutic.[3] More specifically, AZD-2693 is an N-acetylgalactosamine (GalNAc)-conjugated ASO.[6] This chemical design, incorporating GalNAc conjugation, is a pivotal modification for ASO therapies targeting hepatic conditions. The GalNAc ligand facilitates high-affinity binding to the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on the surface of hepatocytes. This interaction promotes efficient, receptor-mediated endocytosis of the ASO into liver cells, thereby enhancing its hepatic uptake and concentrating the therapeutic agent at its intended site of action. This targeted delivery mechanism is instrumental in maximizing the drug's efficacy within the liver while potentially minimizing systemic exposure and associated off-target effects, often allowing for lower and less frequent dosing regimens compared to unconjugated ASOs. The transition in nomenclature from ION-839 (Ionis Pharmaceuticals' identifier) to AZD-2693 (AstraZeneca's identifier) typically signifies the progression of the drug's primary development lead from the originating company to the licensing partner, a standard practice within the pharmaceutical industry reflecting the evolving stewardship of the compound's development program.[2]

3. Mechanism of Action

The PNPLA3 Gene and Protein: Role in Liver Pathophysiology

The therapeutic strategy of AZD-2693 is centered on the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and its protein product.[1] PNPLA3, also known as adiponutrin, is intricately involved in lipid metabolism within the liver. A common single nucleotide polymorphism (SNP) in the PNPLA3 gene, rs738409 (C>G), results in an isoleucine to methionine substitution at amino acid position 148 (p.I148M) of the PNPLA3 protein.[1] This I148M variant is the most significant genetic determinant of hepatic steatosis and is strongly associated with an increased risk for the entire spectrum of MASH, including simple steatosis, steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma.[1] The prevailing understanding is that the I148M variant leads to a gain of toxic function or an altered function, rather than a simple loss of function. The mutant PNPLA3-148M protein exhibits a reduced ability to hydrolyze triglycerides and other lipids; it tends to accumulate on the surface of intracellular lipid droplets within hepatocytes, sequestering other proteins and impairing the normal mobilization and trafficking of triglycerides.[8] This impaired lipid handling contributes directly to the accumulation of fat in liver cells (steatosis), a hallmark of MASH.

AZD-2693 as a PNPLA3-Targeted Antisense Oligonucleotide

AZD-2693 is a liver-targeted ASO specifically designed to interfere with the production of the PNPLA3 protein.[1] As an ASO, AZD-2693 is a short, synthetic strand of nucleic acid that is complementary to a specific sequence within the messenger RNA (mRNA) transcribed from the PNPLA3 gene. Upon administration and uptake into hepatocytes, AZD-2693 binds to the PNPLA3 mRNA through Watson-Crick base pairing.[1] This binding event triggers the activity of RNase H, an intracellular enzyme that recognizes DNA-RNA heteroduplexes and selectively cleaves the RNA strand. The degradation of PNPLA3 mRNA effectively prevents it from being translated into protein by the ribosomes. Consequently, the synthesis of the PNPLA3 protein, including the deleterious I148M variant, is significantly reduced.[1] This direct targeting of PNPLA3 mRNA represents an upstream intervention aimed at mitigating the root genetic cause of increased MASH susceptibility in individuals carrying the I148M variant, as opposed to addressing downstream pathological consequences.

Pharmacological Effect: Inhibition of PNPLA3 Expression

The intended pharmacological effect of AZD-2693 is the specific and potent inhibition of PNPLA3 protein expression in the liver.[2] By reducing the levels of the PNPLA3-148M protein, AZD-2693 aims to alleviate its detrimental effects on hepatocyte lipid metabolism. This, in turn, is expected to lead to a reduction in hepatic steatosis, mitigate associated liver inflammation and cellular injury, and ultimately slow or reverse the progression of liver fibrosis in individuals carrying the PNPLA3 I148M risk allele. The initial focus on PNPLA3 148M homozygous participants in more advanced clinical studies reflects a strategic approach to evaluate the drug in a population with the most pronounced genetic predisposition and likely the highest burden of the pathogenic PNPLA3-148M protein.[1] Demonstrating a clear therapeutic signal in this group would provide robust proof-of-concept for this targeted mechanism. While some Phase 1 cohorts included heterozygous carriers [11], the emphasis on homozygotes aims to maximize the observable effect size.

4. Development and Commercial Rights

Originator: Ionis Pharmaceuticals, Inc.

Ionis Pharmaceuticals, Inc. is the originator of AZD-2693, initially developed under the identifier ION-839.[2] Ionis is a biotechnology company specializing in the discovery and development of RNA-targeted therapeutics, with a strong focus on ASO technology.[4] Their expertise lies in designing and synthesizing ASOs with optimized properties for various therapeutic targets and diseases.

Developer: AstraZeneca PLC

AstraZeneca PLC has licensed ION-839 from Ionis Pharmaceuticals and is now responsible for its continued clinical development and potential future commercialization under the name AZD-2693.[1] This partnership leverages Ionis's specialized capabilities in ASO drug discovery with AstraZeneca's extensive experience and global infrastructure for conducting large-scale clinical trials, navigating regulatory pathways, and bringing novel medicines to market, particularly in the cardiovascular, renal, and metabolism therapeutic areas.[1] Various global research and development units within AstraZeneca, including sites in Cambridge (UK), Gaithersburg (MD, USA), and Gothenburg (Sweden), are involved in the AZD-2693 program.[1] Such collaborations are common in the pharmaceutical industry, combining the innovative power of specialized biotech firms with the development and commercialization strengths of larger pharmaceutical companies to advance promising therapeutic candidates.

5. Therapeutic Rationale and Target Indications

Metabolic Dysfunction-Associated Steatohepatitis (MASH) / Non-alcoholic Steatohepatitis (NASH)

The primary therapeutic indication for AZD-2693 is the treatment of MASH, a condition previously referred to as NASH.[1] Clinical development is specifically focused on patients with non-cirrhotic MASH who exhibit evidence of liver fibrosis.[5] Early Phase 1 studies included patients with fibrosis stages F0-F3 [11], while the ongoing Phase 2b FORTUNA study is enrolling patients with more significant fibrosis, specifically stages F2 or F3.[5] This targeting of patients with established fibrosis (F2-F3) underscores the clinical focus on individuals at a higher risk of progressing to cirrhosis and other severe liver-related complications, a population with a particularly pressing unmet medical need. Regulatory authorities often prioritize endpoints related to fibrosis improvement or MASH resolution without worsening of fibrosis for therapies aimed at this patient group.

Focus on Genetically Predisposed Populations: PNPLA3 I148M Risk Allele Carriers

A defining feature of AZD-2693's development is its specific targeting of individuals who are carriers of the PNPLA3 rs738409 I148M risk allele, with a particular emphasis on those who are homozygous for this variant.[1] The I148M variant is the genetic risk factor with the largest effect size for MASH development, severity, and progression to adverse liver outcomes.[1] This genetically defined targeting strategy positions AZD-2693 as a potential precision medicine for a distinct subpopulation of MASH patients. MASH is a complex and heterogeneous disease driven by multiple factors; by identifying patients based on their PNPLA3 I148M genotype, AZD-2693 aims to provide a tailored therapeutic intervention that directly addresses a key underlying pathogenic mechanism. This approach may lead to enhanced efficacy and a more favorable benefit-risk profile in the selected patient group compared to broader, non-targeted MASH therapies.

Other Potential/Related Indications

While the core development program for AZD-2693 is firmly centered on MASH in PNPLA3 I148M carriers, some broader categorizations of active indications include "Fibrosis" and "Liver Injury" generally.[2] Additionally, certain databases list "Fatty Liver, Alcoholic," "Hepatitis, Alcoholic," and "Liver Cirrhosis" as Phase 2 indications.[3] It is important to note that the PNPLA3 I148M variant is known to influence susceptibility to both alcoholic and non-alcoholic fatty liver diseases. However, the detailed descriptions of AZD-2693's clinical trials, such as the FORTUNA study, consistently specify MASH/NASH as the target condition.[1] The inclusion of alcohol-related liver conditions in some databases might reflect the broad impact of the PNPLA3 gene or a nuance in database categorization, rather than a distinct, active development path for AZD-2693 in alcoholic liver disease at present. The current evidence strongly supports MASH as the primary focus.

6. Preclinical Development and Findings

The progression of AZD-2693 into clinical trials was underpinned by a robust preclinical research program that established its mechanism of action, efficacy in relevant disease models, and initial safety profile.

In Vitro Studies

AZD-2693 was evaluated in sophisticated three-dimensional (3D) cultures of primary human hepatocytes derived from individuals homozygous for the PNPLA3 148M variant.[1] In these physiologically relevant cell culture systems, AZD-2693 demonstrated potent, dose-dependent reduction of both PNPLA3 mRNA and the PNPLA3 protein.[1] The median inhibitory concentration (IC50​) for PNPLA3 mRNA reduction was determined to be approximately 0.5 nM, indicating high potency at the cellular level.[7]

In Vivo Animal Models

The efficacy of AZD-2693 was further assessed in mouse models engineered to express human PNPLA3.[1] Treatment with AZD-2693 led to a potent reduction in PNPLA3 expression within the livers of these mice, confirming target engagement in an in vivo setting.[1] More specific studies utilized a murine tool ASO, analogous to AZD-2693, in homozygous PNPLA3 148M knock-in mice. In these genetically tailored models, which closely mimic the human genetic predisposition to MASH, the tool ASO was shown to effectively reduce liver steatosis, inflammation, and fibrosis.[10] These findings from relevant animal models provided strong proof-of-concept for the therapeutic potential of targeting PNPLA3.

Safety Pharmacology and Toxicology Studies

Comprehensive safety assessments were conducted prior to human trials. AZD-2693 was evaluated in 3-month repeat-dose subcutaneous toxicity studies in preclinical species.[10] The results from these studies revealed findings that are generally consistent with the known class effects of ASO therapeutics. These included observations of histiocytic infiltration (an accumulation of immune cells) in multiple tissues and evidence of ASO accumulation in the liver and spleen, which are common sites of ASO distribution and clearance.[10] Crucially, these effects were not attributed to the pharmacological reduction of PNPLA3 protein itself, but rather to the ASO platform. This distinction is important, as it suggests that the observed toxicities are related to the chemical nature of ASOs rather than an adverse consequence of the intended therapeutic target modulation. Furthermore, preclinical safety pharmacology studies designed to assess effects on major organ systems found no adverse impacts of AZD-2693 on the respiratory, cardiovascular, central, or peripheral nervous systems.[10]

ASO Platform Risks

As with many ASO therapeutics, certain platform-related risks are acknowledged. For AZD-2693 studies, common exclusion criteria include women of child-bearing potential and patients with an increased risk of bleeding.[10] These precautions are often standard for ASO drugs due to potential class-related effects on platelets or coagulation factors, although specific details for AZD-2693 are not fully elaborated in the provided materials beyond this general ASO platform risk.

The preclinical data collectively provided a compelling rationale for advancing AZD-2693 into clinical development. The consistent demonstration of target engagement (PNPLA3 reduction) and beneficial effects on MASH-related pathology (steatosis, inflammation, fibrosis) in both human cell cultures and relevant animal models, coupled with a preclinical safety profile that did not reveal target-specific toxicities, supported its investigation in humans. The involvement of the IL-6/STAT3 signaling pathway in PNPLA3-mediated NAFLD susceptibility, as suggested by studies using human pluripotent stem cell-derived liver cultures [15], offers additional depth to the mechanistic understanding. These studies indicated that the I148M variant might elevate IL-6/STAT3 activity, contributing to NAFLD risk. By reducing PNPLA3 I148M protein, AZD-2693 could potentially modulate this inflammatory pathway, aligning with clinical observations of reduced IL-6 levels in participants treated with AZD-2693.[1]

The following table summarizes key preclinical findings:

Table 1: Summary of Key Preclinical Findings for AZD-2693

Model System	Key Parameter Investigated	Key Findings	Snippet Reference(s)
3D Cultures of Homozygous PNPLA3 148M Primary Human Hepatocytes	PNPLA3 mRNA and Protein Reduction	Potent, dose-dependent reduction; IC50​ for mRNA reduction ~0.5 nM	1
Mice Expressing Human PNPLA3	PNPLA3 Expression in Liver	Potent reduction of PNPLA3 expression	1
Homozygous PNPLA3 148M Knock-in Mice (Murine Tool ASO)	Liver Steatosis, Inflammation, Fibrosis	Reduction in all three parameters	10
Preclinical Species (3-month SC Toxicity Studies)	General Toxicology	Histiocytic infiltration in multiple tissues, ASO accumulation in liver and spleen (ASO class effects); No effects attributed to PNPLA3 reduction.	10
Preclinical Safety Pharmacology Studies	Respiratory, Cardiovascular, Central & Peripheral Nervous Systems Function	No adverse effects observed	10

7. Clinical Development Program

Overview of Clinical Trials Conducted and Ongoing

The clinical development program for AZD-2693 has systematically progressed from initial human safety and dosing studies (Phase 1) to evaluating its therapeutic potential in patients (Phase 2).[1] The program has been designed to rigorously assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and early efficacy signals of AZD-2693, with a specific focus on individuals carrying the PNPLA3 I148M risk allele.

Phase 1 Clinical Trials

Two primary Phase 1 studies were conducted to establish the foundational clinical profile of AZD-2693: a Single Ascending Dose (SAD) study and a Multiple Ascending Dose (MAD) study.

• Single Ascending Dose (SAD) Study (D7830C00001 / NCT04142424): This randomized, single-blind, placebo-controlled study evaluated single subcutaneous doses of AZD-2693, ranging from 2 mg to 110 mg, in overweight or mildly obese but otherwise healthy volunteers.1 The study also included cohorts of healthy Chinese and Japanese subjects to assess safety and PK in these populations.1 The primary objectives were to assess the safety, tolerability, and pharmacokinetic profile of AZD-2693 after a single administration.16 This study has been completed.16
• Multiple Ascending Dose (MAD) Study (D7830C00002 / NCT04483947): This randomized, double-blind, placebo-controlled, multi-center study investigated the effects of three monthly subcutaneous doses of AZD-2693 (25 mg, 50 mg, and 80 mg) in participants with MASH/NASH, fibrosis stages F0-F3, who were carriers of the PNPLA3 148M risk allele (both homozygous and heterozygous individuals were enrolled in different cohorts).1 The study aimed to evaluate the safety, tolerability, PK, and PD of multiple doses, including changes in liver fat content (measured by MRI-PDFF) and target engagement (PNPLA3 mRNA and protein levels in liver biopsies for the 80 mg cohort).1 This study has also been completed.11
• Pharmacokinetic Profile (Integrated from SAD/MAD): AZD-2693 exhibited a pharmacokinetic profile consistent with other GalNAc-conjugated ASOs. Following subcutaneous administration, maximum plasma concentrations (Cmax​) were generally reached approximately 2 hours post-dose.7 This was followed by a rapid distribution phase and a slower terminal elimination phase, with a half-life (t1/2​) ranging from 14 to 33 days across the investigated dose levels.1 This half-life supports the feasibility of a once-monthly dosing regimen.6 Plasma exposure to AZD-2693 increased approximately proportionally with increasing doses.6
• Pharmacodynamic Effects (Target Engagement & Biomarker Modulation - primarily from MAD): The MAD study provided crucial evidence of target engagement and biological activity.
• PNPLA3 mRNA and Protein Reduction: In participants receiving the 80 mg monthly dose, liver biopsies taken one week after the third dose showed a least-square mean knockdown of hepatic PNPLA3 mRNA by 89% compared to baseline.[1] A corresponding reduction in PNPLA3 protein levels was also observed, confirming robust target engagement at the site of action.[1]
• Reduction in Hepatic Steatosis: Changes in liver fat content were assessed by MRI-PDFF at baseline and at weeks 8 and 12. At week 12, placebo-corrected least-square mean reductions in hepatic steatosis were -7.6% for the 25 mg dose group and -12.2% for the 50 mg dose group.[1] Another source reports up to a 15% placebo-corrected reduction at the 50 mg dose.[6]
• Modulation of Lipid and Inflammatory Markers: Treatment with AZD-2693 resulted in a dose-dependent increase of polyunsaturated fatty acids (PUFAs) in serum triglycerides.[1] Furthermore, dose-dependent decreases compared to placebo were observed in levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), suggesting a potential anti-inflammatory effect.[1]
• Safety and Tolerability Profile (Integrated from SAD/MAD): Across both SAD and MAD Phase 1 studies, AZD-2693 was generally well tolerated.1 In the MAD study, there were no adverse events (AEs) that led to discontinuation of treatment, and no treatment-related serious adverse events (SAEs) were reported.1 One SAE of appendicitis was noted in the SAD study in a participant receiving a 6 mg dose, and one SAE of non-cardiac chest pain occurred in the 80 mg cohort of the MAD study; however, investigators did not consider these events to be related to AZD-2693.7

The successful completion of these early-phase studies, demonstrating a favorable safety profile, predictable pharmacokinetics, strong target engagement, and encouraging effects on MASH-related biomarkers, provided a solid foundation for advancing AZD-2693 into later-stage clinical development.

Phase 2 Clinical Trials

Building on the Phase 1 results, AZD-2693 has progressed into Phase 2 clinical trials to further evaluate its efficacy and safety in the target MASH population.

• The FORTUNA Study (D7830C00004 / NCT05809934 / EudraCT 2022-001629-65): This is a pivotal Phase 2b study titled: "A Randomised, Double-blind, Placebo-Controlled, Multi-centre Phase 2b Study to Evaluate the Efficacy, Safety and Tolerability of AZD2693 in Participants with Non-cirrhotic Non-alcoholic Steatohepatitis (NASH) with Fibrosis Who Are Carriers of the PNPLA3 rs738409 148M Risk Allele".5
• Status: The study is active, with recruitment reported as complete.[3] The estimated primary completion date is July 2025.[14]
• Design: The FORTUNA study is a randomized, double-blind, placebo-controlled, multi-center trial involving approximately 220 adult participants (18-75 years).[5]
• Participants: Eligible participants are those with biopsy-confirmed non-cirrhotic MASH, a NAFLD Activity Score (NAS) of ≥4 (with each component – steatosis, lobular inflammation, and ballooning – having a score of ≥1), and liver fibrosis stage F2 or F3. A key inclusion criterion is being a carrier of the PNPLA3 rs738409 148M risk allele.[5]
• Intervention: Participants are randomized to receive one of two dose levels of AZD-2693 or a placebo, administered via subcutaneous injection once per month for a total treatment duration of 52 weeks.[5]
• Primary Endpoint: The primary efficacy endpoint is the proportion of participants achieving resolution of MASH without worsening of liver fibrosis at 52 weeks. MASH resolution is typically defined histologically (e.g., ballooning score of 0 and inflammation score of 0 or 1).[5]
• Secondary Endpoints: Secondary endpoints include the proportion of participants achieving at least a one-stage improvement in liver fibrosis without worsening of MASH, and changes in the NAFLD Activity Score (NAS).[5] The FORTUNA study is critical for providing more definitive evidence of AZD-2693's ability to induce histological improvement in MASH, which is a key requirement for regulatory approval.
• Study in Hepatic Impairment (D7830C00008 / NCT05919069): A Phase 1, single-dose, non-randomized, open-label, parallel-group study was conducted to investigate the effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of AZD-2693.19
• Status: This study is reported as completed, with a primary completion date of September 2024.[2]
• Participants: The study enrolled male and female participants with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, compared to a control group of participants with normal hepatic function.[19]
• Objective: The primary aim was to characterize the PK profile of a single subcutaneous dose of AZD-2693 in these different hepatic function groups and to assess its safety and tolerability.[19] This study is important for understanding drug disposition in patients with varying degrees of liver function, which is relevant given that MASH can affect liver function.
• Other Relevant Phase 2 Investigations: One database mentions a Phase 2 trial, jRCT2041220155, as recruiting participants for "Hepatitis, Alcoholic | Non-alcoholic Steatohepatitis," with an estimated primary completion in September 2025.3 However, detailed information specifically linking this trial identifier to AZD-2693 and its design parameters was not extensively available in the provided materials, and other trials with similar jRCT number formats relate to different compounds.20 Thus, its direct relevance to the AZD-2693 program requires further clarification.

Integrated Analysis of Safety and Tolerability Across Studies

Collectively, the Phase 1 clinical trial data for AZD-2693 have indicated an acceptable safety and tolerability profile, which has supported its continued development into more advanced Phase 2b studies.[1] The findings from the dedicated hepatic impairment study will further inform the safety profile in populations with compromised liver function. The ongoing FORTUNA study will provide more extensive safety data over a longer treatment duration in a larger MASH patient cohort.

The following table provides an overview of the key clinical trials for AZD-2693:

Table 2: Overview of Key AZD-2693 Clinical Trials

Trial ID (NCT, EudraCT, AstraZeneca ID)	Phase	Title/Brief Description	Key Objectives	Target Population	Intervention(s)	Current Status	Primary Endpoint(s)	Snippet Reference(s)
D7830C00001 / NCT04142424	1	SAD study to assess safety, tolerability, PK of AZD2693	Assess safety, tolerability, PK of single ascending doses	Overweight/mildly obese healthy volunteers (incl. Chinese & Japanese)	AZD-2693 (2-110 mg SC single dose) vs. Placebo	Completed	Safety, tolerability, PK parameters	1
D7830C00002 / NCT04483947	1	MAD study to assess safety, tolerability, PK, PD of AZD2693	Assess safety, tolerability, PK, PD of multiple ascending doses	MASH/NASH patients (fibrosis F0-F3), PNPLA3 148M carriers	AZD-2693 (25 mg, 50 mg, 80 mg SC monthly x3) vs. Placebo	Completed	Safety, tolerability, PK, PD (liver PNPLA3 mRNA, liver fat by MRI-PDFF)	1
D7830C00004 / NCT05809934 / EudraCT 2022-001629-65 (FORTUNA)	2b	Efficacy, safety, tolerability of AZD2693 in non-cirrhotic NASH with fibrosis	Evaluate efficacy (histological improvement), safety, tolerability	Adults (18-75 yrs) with non-cirrhotic NASH (F2-F3 fibrosis, NAS ≥4), PNPLA3 148M carriers (N=220)	AZD-2693 (2 dose levels SC monthly x 52 wks) vs. Placebo	Recruitment Complete	Proportion achieving NASH resolution without worsening of fibrosis at 52 weeks	2
D7830C00008 / NCT05919069	1	Effect of hepatic impairment on PK, safety, tolerability of AZD2693	Characterize PK, safety, tolerability of single dose in hepatic impairment	Mild, moderate, or severe hepatic impairment vs. normal hepatic function	AZD-2693 (single SC dose)	Completed	PK parameters (e.g., AUC, Cmax​), safety, tolerability	2
jRCT2041220155	2	(Details sparse for AZD-2693 linkage)	(Not specified for AZD-2693)	Hepatitis, Alcoholic; Non-alcoholic Steatohepatitis	(Not specified for AZD-2693)	Recruiting	(Not specified for AZD-2693)	3

8. Regulatory Status

Current Regulatory Landscape for AZD-2693

Based on the information available, AZD-2693 (ION-839) has not been explicitly reported to have received specific expedited regulatory designations such as Orphan Drug status, Fast Track designation, Breakthrough Therapy designation, or PRIME (Priority Medicines) scheme eligibility from major regulatory authorities like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[4] One source directly states "Orphan Drug Status: No" for ION-839.[4] The general regulatory field for MASH/NASH therapies is characterized by a high unmet medical need, as highlighted by the fact that, as of late 2020, there were no FDA-approved medicines specifically for this condition.[12]

It is important to distinguish AZD-2693 from other Ionis Pharmaceuticals' products. For instance, olezarsen (marketed as TRYNGOLZA), another ASO developed by Ionis, has received Fast Track, Orphan Drug, and Breakthrough Therapy designations from the FDA for a different indication, familial chylomicronemia syndrome (FCS), and was subsequently approved.[22] This success with olezarsen, while not directly applicable to AZD-2693's regulatory status for MASH, may reflect positively on the underlying ligand-conjugated antisense (LICA) technology platform that is also utilized by AZD-2693. Regulatory agencies' familiarity and comfort with a particular drug platform can sometimes facilitate the review process for other drugs from the same platform, provided each demonstrates its own therapeutic merit and safety for its intended indication.

The absence of specific expedited designations for AZD-2693 in the available materials does not preclude the possibility of such applications in the future, particularly if data from the Phase 2b FORTUNA study are strongly positive. These pathways are typically granted when a drug demonstrates potential to address a serious condition with an unmet medical need and shows promise for substantial improvement over available therapies or, in the case of orphan drugs, targets a rare disease. While MASH is a serious condition with significant unmet needs, the data package for AZD-2693 may still be maturing toward the thresholds required for these special designations, or such information may not yet be publicly disclosed.

9. Discussion and Future Perspectives

Synthesis of Key Preclinical and Clinical Findings

AZD-2693 has emerged as a promising investigational therapy for MASH, distinguished by its precision-medicine approach targeting individuals with the PNPLA3 I148M genotype. The preclinical program provided a strong mechanistic rationale, demonstrating potent reduction of PNPLA3 expression and amelioration of MASH-like features in relevant in vitro and in vivo models.[1] Phase 1 clinical trials successfully translated these findings into humans, confirming robust target engagement with nearly 90% knockdown of hepatic PNPLA3 mRNA, and showed encouraging pharmacodynamic effects, including reductions in liver fat content and improvements in inflammatory biomarkers.[1] Critically, these early studies established an acceptable safety and tolerability profile for AZD-2693, with pharmacokinetics supporting a convenient monthly dosing schedule.[1]

Potential Role of AZD-2693 in the MASH Treatment Paradigm

If the ongoing and future clinical trials confirm its efficacy and long-term safety, AZD-2693 could carve out a significant niche in the MASH treatment landscape as one of the first genetically targeted therapies for this common, yet complex, metabolic liver disease. Its role would likely be most prominent in individuals homozygous for the PNPLA3 I148M allele, who are at the highest risk of disease progression. By addressing a primary genetic driver of MASH, AZD-2693 offers the potential for early intervention to modify the disease course and prevent the development of more severe liver complications, such as cirrhosis and hepatocellular carcinoma. This targeted strategy contrasts with many other MASH therapies in development that employ broader mechanisms of action, potentially offering a more favorable efficacy-to-safety ratio in the selected patient population. The successful development of AZD-2693 would validate the strategy of targeting genetic drivers in common complex diseases and could encourage similar approaches for other MASH-related genetic variants (e.g., TM6SF2, GCKR [24]).

Comparison with Other PNPLA3-Targeted Therapies

The therapeutic targeting of PNPLA3 is an active area of research, with several modalities being explored. AZD-2693 (an ASO) faces competition from other investigational agents, notably small interfering RNA (siRNA) therapies and potentially small molecule inhibitors. For instance, ARO-PNPLA3 (developed by Arrowhead Pharmaceuticals), a GalNAc-conjugated siRNA, also targets PNPLA3 mRNA. Phase 1 data for ARO-PNPLA3 in homozygous PNPLA3 148M carriers showed a placebo-corrected reduction in liver fat content of up to 39% at the highest dose tested.[6] This numerically higher reduction in liver fat compared to the up to 15% reported for AZD-2693's 50 mg dose in Phase 1 [6] suggests a competitive landscape. However, it is important to note that direct comparisons based on early-phase data from different trials can be misleading. AZD-2693's near 90% PNPLA3 mRNA knockdown and positive effects on inflammatory markers like hsCRP and IL-6 are also very strong pharmacodynamic signals.[1] Other GalNAc-siRNAs targeting PNPLA3, such as LY3849891 (Eli Lilly/Dicerna) and ALN-PNP (Alnylam/Regeneron), were also in Phase 1 development, although recent data were not available in the reviewed materials.[6] Additionally, Pfizer is developing PF-07853578, an orally available small molecule PNPLA3 modulator, which represents a different therapeutic approach.[6] The ultimate differentiation between these PNPLA3-targeted therapies will depend on the comprehensive results from later-phase trials, particularly histological outcomes, long-term safety, and overall benefit-risk profiles.

Ongoing Research and Future Directions for Clinical Development

The most critical next step for AZD-2693 is the outcome of the Phase 2b FORTUNA study. Positive results demonstrating statistically significant and clinically meaningful improvements in MASH histological endpoints (NASH resolution and/or fibrosis improvement) are essential for progression to Phase 3 trials and eventual regulatory consideration.[5] Beyond the current scope, future research may explore the potential of AZD-2693 in combination with other MASH therapies that have complementary mechanisms of action, given the multifactorial nature of the disease. Long-term extension studies will also be necessary to assess the durability of treatment effects and to monitor for any late-emerging safety signals.

Unmet Needs and Potential Challenges

MASH remains a disease with a substantial unmet medical need, underscored by the limited availability of approved and effective pharmacological treatments.[1] The development of MASH drugs has been fraught with challenges, including the heterogeneity of the patient population, the complexity of defining and measuring clinically relevant endpoints, and the typically long duration and high cost of clinical trials. While AZD-2693's targeted approach may mitigate some of these challenges by focusing on a more homogeneous, genetically defined patient subgroup, the high bar for demonstrating histological improvement remains. The field also continues to seek reliable and validated non-invasive biomarkers that can accurately reflect changes in liver histology and predict long-term clinical outcomes, which would greatly facilitate drug development and patient management.

10. Conclusion

AZD-2693 (ION-839) stands as a scientifically compelling, investigational antisense oligonucleotide therapy, representing a vanguard of precision medicine for metabolic dysfunction-associated steatohepatitis. Its design specifically targets the reduction of PNPLA3 protein expression in individuals carrying the I148M risk allele, particularly homozygotes, thereby addressing a key genetic driver of MASH pathogenesis.

Preclinical studies have robustly validated its mechanism of action, and Phase 1 clinical trials have delivered encouraging results. These early human studies have demonstrated that AZD-2693 is generally well-tolerated, achieves profound target engagement in the liver (evidenced by significant PNPLA3 mRNA knockdown), and elicits positive pharmacodynamic responses, including reductions in hepatic steatosis and favorable modulation of inflammatory markers. The pharmacokinetic profile supports a convenient monthly subcutaneous dosing regimen.

AZD-2693 is currently at a pivotal juncture in its clinical development. The ongoing Phase 2b FORTUNA study is poised to provide critical insights into its efficacy in achieving histological improvements in MASH, a key determinant for future progression to Phase 3 trials and potential regulatory approval. A positive outcome from FORTUNA would not only be a significant milestone for AZD-2693 but also a landmark achievement for genetically targeted therapies in the broader field of hepatology.

In conclusion, AZD-2693 holds considerable promise as a novel therapeutic agent for a genetically defined subset of MASH patients. Its development journey exemplifies the translation of fundamental genetic discoveries into innovative therapeutic strategies, highlighting the potential of antisense technology to address complex diseases with high unmet medical needs. The continued investigation and forthcoming results from later-phase trials will ultimately define the role of AZD-2693 in the evolving treatment landscape for MASH.

Works cited

1. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials - PubMed, accessed May 8, 2025, https://pubmed.ncbi.nlm.nih.gov/39798707/
2. AZD-2693 - Drug Targets, Indications, Patents - Synapse, accessed May 8, 2025, https://synapse.patsnap.com/drug/1ce3f13fa23e452eac9cbc73cb54ff72
3. AZD-2693 Drug Profile - Ozmosi, accessed May 8, 2025, https://pryzm.ozmosi.com/product/20842
4. ION 839 - AdisInsight - Springer, accessed May 8, 2025, https://adisinsight.springer.com/drugs/800056403
5. Azd2693 Sodium – Application in Therapy and Current Clinical ..., accessed May 8, 2025, https://clinicaltrials.eu/inn/azd2693-sodium/
6. Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and ..., accessed May 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11907219/
7. www.postersessiononline.eu, accessed May 8, 2025, https://www.postersessiononline.eu/173580348_eu/congresos/EASL2024/aula/-LBP_31_EASL2024.pdf
8. AZD2693, a PNPLA3 antisense oligonucleotide, for the treatment of MASH in 148M homozygous participants: Two randomized phase I trials | Request PDF - ResearchGate, accessed May 8, 2025, https://www.researchgate.net/publication/387888641_AZD2693_a_PNPLA3_antisense_oligonucleotide_for_the_treatment_of_MASH_in_148M_homozygous_participants_two_randomized_phase_I_trials
9. A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank | Request PDF - ResearchGate, accessed May 8, 2025, https://www.researchgate.net/publication/339783258_A_common_variant_in_PNPLA3_is_associated_with_age_at_diagnosis_of_NAFLD_in_patients_from_a_multi-ethnic_biobank
10. AZD2693 - AstraZeneca Open Innovation, accessed May 8, 2025, https://openinnovation.astrazeneca.com/clinical-research/clinical-molecules/azd2693.html
11. A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients - AstraZeneca Clinical Trials, accessed May 8, 2025, https://www.astrazenecaclinicaltrials.com/study/D7830C00002/
12. Ionis announces third investigational antisense medicine to treat nonalcoholic steatohepatitis (NASH) enters development, accessed May 8, 2025, https://ir.ionis.com/news-releases/news-release-details/ionis-announces-third-investigational-antisense-medicine-treat
13. Pipeline - AstraZeneca, accessed May 8, 2025, https://www.astrazeneca.com/our-therapy-areas/pipeline.html
14. A study to evaluate AZD2693 in participants who are carriers of the ..., accessed May 8, 2025, https://www.astrazenecaclinicaltrials.com/study/D7830C00004/
15. IL6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease | Request PDF - ResearchGate, accessed May 8, 2025, https://www.researchgate.net/publication/363105839_IL6STAT3_axis_dictates_the_PNPLA3-mediated_susceptibility_to_non-alcoholic_fatty_liver_disease
16. A Study to Understand the Safety, Tolerability, and Activity of Drug in Body Over a Period of Time of AZD2693, in Subjects of Non-Childbearing Potential in Overweight but Otherwise Healthy Subjects, and Healthy Chinese and Japanese Subjects - AstraZeneca Clinical Trials, accessed May 8, 2025, https://www.astrazenecaclinicaltrials.com/study/D7830C00001/
17. fortuna - EU Clinical Trials Register, accessed May 8, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2022-001629-65/IT
18. A Study to Evaluate AZD2693 in Participants Who Are Carri... - Clinical Trial Discovery, accessed May 8, 2025, https://clinicaltrial.be/en/details/264609?per_page=100&only_recruiting=0&only_eligible=0
19. A Phase I Study to Investigate the Effect of Hepatic Impairment on ..., accessed May 8, 2025, https://www.astrazenecaclinicaltrials.com/study/D7830C00008/
20. A Study to Assess the Efficacy and Safety of Ruxolitinib Cream in Children and Adolescents (6 to <18 Years Old) With Moderate Atopic Dermatitis (TRuE-AD5) - ClinicalTrials.Veeva, accessed May 8, 2025, https://ctv.veeva.com/study/a-study-to-assess-the-efficacy-and-safety-of-ruxolitinib-cream-in-children-and-adolescents-6-to18
21. A study to assess the efficacy and safety of ruxolitinib cream in children with Atopic Dermatitis (TRuE-AD3), Trial ID INCB%2018424-305, accessed May 8, 2025, https://www.incyteclinicaltrials.com/trials/INCB%2018424-305
22. Ionis Pharmaceuticals to pursue approval of FCS drug after Phase III win, accessed May 8, 2025, https://www.clinicaltrialsarena.com/news/ionis-pharmaceuticals-persue-approval-olezarsen-win/
23. FDA approves Ionis' TRYNGOLZA for FCS treatment - Pharmaceutical Technology, accessed May 8, 2025, https://www.pharmaceutical-technology.com/news/fda-ionis-tryngolza-fcs/
24. Design and rationale for a global novel non-invasive screening observational study using genetics and non-invasive methodologies to identify at-risk MASLD participants: The ALIGN study - PMC - PubMed Central, accessed May 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11800087/