AHB-137: An Investigational Antisense Oligonucleotide for Chronic Hepatitis B

I. Introduction to AHB-137 and Chronic Hepatitis B

Chronic hepatitis B (CHB) infection, caused by the hepatitis B virus (HBV), represents a significant global health challenge, affecting an estimated 290 million individuals worldwide.[1] The long-term persistence of HBV can lead to severe liver complications, including cirrhosis and hepatocellular carcinoma, contributing to substantial morbidity and mortality.[1] Current therapeutic strategies for CHB primarily involve nucleos(t)ide analogues (NAs) and pegylated interferon-alpha (pegIFN-α).[4] While NAs effectively suppress HBV DNA replication, and pegIFN-α can offer a finite treatment course, neither reliably leads to a "functional cure".[5] A functional cure is typically defined as sustained loss of hepatitis B surface antigen (HBsAg) and undetectable serum HBV DNA for at least 24 weeks after completing a finite course of therapy, with or without seroconversion to anti-HBs antibodies.[5] Achieving such a cure is rare with existing treatments, with HBsAg loss rates being notably low.[5] This unmet medical need drives the development of novel therapeutic agents.

AHB-137 is an investigational drug developed by AusperBio Therapeutics Inc. and Ausper Biopharma Co., Ltd. (collectively AusperBio).[1] It is an unconjugated antisense oligonucleotide (ASO) specifically designed to target HBV infection with the goal of achieving a functional cure.[8] AHB-137 emerged from AusperBio's proprietary Med-Oligo™ ASO technology platform, which aims to enhance the therapeutic properties of ASOs.[8] This report provides a comprehensive overview of AHB-137, including its mechanism of action, preclinical findings, extensive clinical development program, regulatory status, and an expert analysis of its potential role in the evolving CHB treatment landscape.

II. The Challenge of Functional Cure in Chronic Hepatitis B

The primary goal in treating chronic hepatitis B has shifted from mere viral suppression to achieving a functional cure. This state is characterized by the sustained loss of HBsAg and undetectable HBV DNA in the serum for at least 24 weeks after the cessation of a finite treatment course, ideally accompanied by the development of anti-HBs antibodies (seroconversion).[5] Achieving a functional cure signifies that the host's immune system can effectively control the virus without ongoing therapy, thereby reducing the long-term risks of liver disease progression, cirrhosis, and hepatocellular carcinoma.

Current standard-of-care treatments, however, fall short of this objective for the vast majority of patients. Nucleos(t)ide analogues (NAs), such as entecavir and tenofovir, are potent inhibitors of HBV DNA replication and are generally taken long-term, often for life.[3] While NAs can significantly reduce viral load and liver inflammation, they rarely lead to HBsAg loss or functional cure; reported rates are typically less than 2-8% even after many years of continuous therapy.[5] Pegylated interferon-alpha (pegIFN-α) offers a finite treatment duration (typically 48 weeks) and works by modulating the immune system.[4] While it can achieve higher rates of HBsAg loss compared to NAs (around 8-14% at 3 to 5 years post-treatment), it is associated with a high rate of side effects, limiting its use.[3]

The persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes is a major barrier to HBV cure.[5] cccDNA serves as a stable transcriptional template for viral RNAs, leading to the production of viral proteins, including HBsAg, and new virions. Integrated HBV DNA in the host genome can also contribute to HBsAg production. Therefore, therapies aiming for a functional cure must not only suppress HBV replication but also reduce HBsAg levels significantly, ideally leading to HBsAg loss and restoration of HBV-specific immune responses.[5] The low rates of HBsAg loss with current therapies underscore the urgent need for novel agents like AHB-137 that can more effectively target viral antigen production and potentially modulate host immunity.

III. AHB-137: Mechanism of Action and Preclinical Profile

A. Mechanism of Action of AHB-137 for HBV

AHB-137 is an unconjugated antisense oligonucleotide (ASO) designed to specifically target chronic hepatitis B virus infection.[8] ASOs are short, synthetic strands of nucleic acids that bind to specific messenger RNA (mRNA) sequences through Watson-Crick base pairing. This binding can lead to the degradation of the target mRNA by cellular enzymes like RNase H, or otherwise interfere with mRNA processing or translation, ultimately reducing the production of the encoded protein.[11] In the case of AHB-137, it is engineered to block all HBV RNA transcripts.[12] By targeting these transcripts, AHB-137 aims to effectively suppress viral replication and the expression of all viral antigens, including HBsAg.[11]

Several sources refer to AHB-137 as a "novel dual-mechanism ASO".[8] Beyond the direct reduction of viral RNAs and proteins, it is suggested that AHB-137 treatment could also boost immune responses.[12] This immunomodulatory effect might be a consequence of reducing the high viral antigen load (particularly HBsAg), which is thought to contribute to immune exhaustion and tolerance in CHB patients. By lowering HBsAg levels, AHB-137 may help restore the functionality of the host's HBV-specific immune cells.

It is important to note that some sources [17] describe a compound named "AHB 137" (with a space) as a selective inhibitor of diacylglycerol lipase alpha (DAGLα), involved in endocannabinoid synthesis. This mechanism is distinct from and unrelated to the ASO mechanism described for AusperBio's AHB-137 targeting HBV. The context of all other provided materials clearly indicates that AusperBio's AHB-137 is an ASO for HBV treatment.[8]

B. The Med-Oligo™ ASO Technology Platform

AHB-137 was developed using AusperBio's proprietary Med-Oligo™ ASO technology platform.[1] This platform is reported to incorporate novel insights into ASO design, leading to chemical modifications that substantially enhance the potency and safety profile of ASO therapeutics compared to earlier generation ASOs.[8] The platform is described as modular and, when combined with efficient targeted delivery conjugation technologies, can empower ASO therapeutics to treat a broad range of diseases, including viral infections (like HBV), metabolic conditions, genetic disorders, and immune diseases.[8] The successful development of AHB-137 would serve as a significant validation of this platform technology.

C. Summary of Preclinical Findings

Compelling preclinical data for AHB-137 were highlighted at the European Association for the Study of the Liver (EASL™) Congress in 2023.[2] Two posters presented at this conference (SAT-173, Abstract #2944; SAT-178, Abstract #3039) detailed data from IND-enabling studies.[19] These presentations showcased AHB-137's substantially enhanced in vitro and in vivo antiviral activity against HBV. Furthermore, the preclinical studies demonstrated a favorable pharmacokinetic profile and a good safety profile for AHB-137.[19] These robust preclinical results were crucial in supporting the progression of AHB-137 into clinical trials and securing regulatory approvals for human studies, such as the Investigational New Drug (IND) application clearance from the U.S. Food and Drug Administration (FDA).[1]

IV. Clinical Development Program of AHB-137

A. Overview of Clinical Phases and Global Strategy

AHB-137 is undergoing a rapid and comprehensive clinical development program, underscored by a global strategy aimed at establishing it as a functional cure for CHB.[8] AusperBio, with operational bases in both the USA and China, is leveraging international resources to advance AHB-137.[8] The program has successfully completed a global Phase 1b trial and is currently progressing through multiple Phase 2 studies, predominantly in China, with plans for Phase II trials outside mainland China as well.[10] This dual-hemisphere approach allows AusperBio to access diverse patient populations and navigate different regulatory landscapes, potentially accelerating the overall development timeline. China, with its large HBV patient population, is a particularly important region for CHB drug development. The company's commitment is further evidenced by significant funding, such as a $50 million Series B+ financing round, earmarked to support these ongoing and planned clinical activities.[10]

B. Phase I/Ib Clinical Trials

The initial human studies for AHB-137 focused on establishing its safety, tolerability, and pharmacokinetic (PK) profile, alongside obtaining preliminary signals of antiviral efficacy.

Key trials in this phase include:

• NCT05717686: This global Phase 1b trial was a multiregional, randomized, double-blind, placebo-controlled study conducted at sites outside of China, including the USA, New Zealand, and Taiwan.[1] It was designed to assess the safety, tolerability, PK, and initial efficacy of AHB-137 administered via subcutaneous injection in both healthy volunteers (HVs) and CHB patients after single and multiple doses.[21] The study comprised four parts: Part A (single ascending dose - SAD - in HVs), Part B (multiple dose - MD - in HVs), Part C (open-label MD in CHB patients), and Part D (double-blind MD in CHB patients versus placebo).[21]
• NCT06115993 (ChinaDrugTrials.org.cn #CTR20232098): This was a Phase 1/2a trial conducted in China.[11] The Phase 1 component involved dose-escalation and dose-expansion cohorts in Chinese healthy volunteers and CHB subjects to evaluate safety, tolerability, PK, and preliminary efficacy.[2]

Findings from these Phase 1 trials were presented at the EASL Congress in 2024 (Abstracts LB249 and LB256).[2] The data indicated that AHB-137 was well-tolerated and demonstrated a favorable safety profile, along with promising preliminary antiviral activity.[2] These positive early-phase results were foundational for progressing to larger efficacy-focused Phase II studies.

C. Phase IIa Clinical Trial (AB-10-8002 / part of NCT06115993)

The Phase IIa portion of the NCT06115993 study (designated AB-10-8002) provided the first robust efficacy signals in CHB patients.[11] Conducted in China, this trial enrolled adults (18-65 years) with HBeAg-negative CHB who were on stable NA therapy.[11] Participants received weekly subcutaneous injections of AHB-137 at doses of either 225 mg or 300 mg for 24 weeks, following two loading doses.[11]

Interim 12-week results were presented at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting® in 2024 (Abstract 5011), showing rapid reductions in HBsAg levels.[11] At the end of the 24-week treatment period (EOT), the study reported:

• HBsAg loss (defined as HBsAg <0.05 IU/mL): Achieved by 57% of patients in the 225 mg arm and 63% in the 300 mg arm.[12]
• Anti-HBs Seroconversion: Observed in up to 75% of participants who achieved HBsAg loss.[12]

AHB-137 was well tolerated in this study, with no serious adverse events reported. The most common treatment-related side effects included injection site reactions, fever, and laboratory abnormalities, which were generally mild to moderate.[11] The remarkably high rates of HBsAg loss and, particularly, seroconversion observed in this Phase IIa study were highly encouraging. Such significant biomarker improvements at this stage of development are strong positive indicators and likely played a pivotal role in securing the Breakthrough Therapy Designation from China's NMPA [14] and bolstering investor confidence.[10]

D. Phase IIb Clinical Trial (AB-10-8003 / CTR20242026 / NCT06550128 / EASL Congress 2025 Presentation)

Building on the promising Phase IIa results, a larger Phase IIb study (AB-10-8003; also identified by CTR20242026 and NCT06550128) was initiated to further evaluate the efficacy and safety of AHB-137.[8] This multicenter, randomized trial was conducted in China, enrolling 64 HBeAg-negative CHB patients who were already receiving stable NA therapy.[8]

Study Design:

Participants were randomized 1:1 into two treatment arms, each with 32 patients, stratified by baseline HBsAg levels (≤1000 IU/mL or >1000 IU/mL at screening) 12:

• Arm A: Received weekly subcutaneous injections of 300 mg AHB-137 for 24 weeks.
• Arm B: Received weekly placebo injections for the first 8 weeks, followed by weekly 300 mg AHB-137 for 16 weeks. The primary endpoint was the proportion of participants achieving HBsAg <0.05 IU/mL (the lower limit of quantification, LLOQ) AND HBV DNA <LLOQ (defined as 10 IU/mL) at the End of Treatment (EOT).[8] Dosing was completed, and the study was unblinded prior to the interim data presentation.[13]

Key Efficacy Outcomes (Interim EOT data presented at EASL Congress 2025):

The interim EOT data from this Phase IIb study demonstrated substantial antiviral activity, as summarized in Table 1.

Table 1: Key Phase IIb Efficacy Results for AHB-137 (AB-10-8003 / EASL 2025)

Efficacy Outcome	Arm A (24-wk AHB-137, N=32)	Arm B (16-wk AHB-137 after 8-wk Placebo, N=32)
Primary Endpoint Achievement (HBsAg <0.05 IU/mL & HBV DNA <10 IU/mL at EOT)	75% (24/32)	66% (21/32)
HBsAg Loss (<0.05 IU/mL) at EOT	75% (24/32)	66% (21/32)
HBsAg <10 IU/mL at EOT	97% (31/32)	Data not specified
HBsAg <100 IU/mL at EOT	100% (32/32)	Data not specified
Anti-HBs Seroconversion (anti-HBs ≥10 mIU/mL at EOT in HBsAg losers)	54% (13/24 HBsAg losers)	33% (7/21 HBsAg losers)
HBsAg Loss by Week 12 (among those achieving HBsAg loss at EOT)	83% (20/24)	81% (17/21)
HBsAg Loss at EOT (Baseline HBsAg >1000 IU/mL)	72.7% (8/11)	50.0% (6/12)

Source: [8]

Key observations from the efficacy data include:

• A high percentage of patients in both arms achieved the primary endpoint. The 24-week treatment duration in Arm A resulted in a numerically higher proportion of patients meeting this endpoint compared to the 16-week AHB-137 treatment in Arm B.[8]
• HBsAg loss was rapid, with over 80% of those who ultimately lost HBsAg achieving this milestone within the first 12 weeks of AHB-137 treatment in both arms.[8] This rapid decline is a notable feature, potentially reducing treatment burden and having a more profound impact on viral reservoirs or host immune responses by quickly diminishing the viral antigen load.
• Anti-HBs seroconversion rates were substantial, particularly in the 24-week arm, where over half of the patients who lost HBsAg also developed protective antibodies.[8] This outcome is crucial, as seroconversion is strongly associated with sustained immune control after treatment cessation. The difference in seroconversion rates between the 24-week and 16-week arms (54% vs. 33%) suggests that a longer duration of AHB-137 exposure may be beneficial for inducing a more robust and potentially durable immune response.
• Significant HBsAg reduction was observed even in patients with high baseline HBsAg levels (>1000 IU/mL).[12]
• All four participants who had detectable HBV DNA (>10 IU/mL) at baseline achieved HBV DNA <LLOQ during AHB-137 treatment, although most patients were already on NA therapy and likely had suppressed HBV DNA at the start of the study.[12]

Safety and Tolerability Profile (Interim EOT data from EASL 2025):

AHB-137 demonstrated a favorable safety and tolerability profile in the Phase IIb study, consistent with earlier trials. Table 2 summarizes the key safety findings.

Table 2: Summary of Adverse Events in Phase IIb (AB-10-8003 / EASL 2025)

Adverse Event Category	Arm A (24-wk AHB-137)	Arm B (16-wk AHB-137)
Treatment-Related Adverse Events (TRAEs)	Primarily Grade 1 or 2	Primarily Grade 1 or 2
Common TRAEs	Injection site reactions, laboratory abnormalities	Injection site reactions, laboratory abnormalities
Grade 3 and above AEs	Laboratory abnormalities, injection site reactions (mostly transient, recovered without intervention)	Laboratory abnormalities, injection site reactions (mostly transient, recovered without intervention)
Grade 4 TRAEs	2 participants	Data not specified
Treatment-Related Serious Adverse Events (SAEs)	None	None
Deaths	None	None
Drug Discontinuations due to AEs	None	None

Source: [8]

Adverse events were predominantly mild (Grade 1) or moderate (Grade 2).[12] No treatment-related serious adverse events, deaths, or discontinuations due to adverse events were reported.[12] Grade 3 or higher AEs primarily consisted of laboratory abnormalities and injection site reactions, which were mostly transient and resolved without specific intervention.[12] Two participants experienced Grade 4 TRAEs, reported as laboratory abnormalities or injection site reactions.[12] The overall safety profile supports continued development.

The robust efficacy, particularly the high HBsAg loss and seroconversion rates combined with a favorable safety profile from this Phase IIb study, positions AHB-137 as a highly promising candidate for the functional cure of CHB. These results, especially if long-term follow-up demonstrates durability of response, could establish AHB-137 as a cornerstone therapy, potentially used in combination with other agents in the future, aligning with AusperBio's broader HBV cure strategy.[24]

E. Other Ongoing/Planned Phase II Studies

AusperBio is further exploring the potential of AHB-137 in different CHB patient populations through additional Phase II studies. This systematic investigation aims to define the optimal use and full therapeutic breadth of AHB-137. Table 3 provides an overview of these key trials.

Table 3: Overview of Other Key Phase II Trials for AHB-137

NCT ID	Phase	Status (as of latest report)	Patient Population	Key Design Features/Objectives	Region
NCT06829329 (AB-10-8008)	2	Recruiting (Feb 2025) 25	Approx. 60 treatment-naive CHB participants with low viral load (HBV DNA 20-2000 IU/mL, HBsAg 100-10000 IU/mL) 25	Randomized, AHB-137 vs. Placebo; 16-week treatment, 24-week follow-up. Evaluate efficacy and safety. 25	China 25
NCT06993480	2	Not yet recruiting (May 2025) 26	CHB participants	Evaluate antiviral activity and immune response of AHB-137 injection. 26	China (implied by sponsor Ausper Biopharma Co., Ltd.) 26

The NCT06829329 trial is particularly noteworthy as it investigates AHB-137 in treatment-naive patients with low viral load.[25] This patient segment is often managed with a "watchful waiting" approach under current guidelines. A finite, effective therapy like AHB-137 could be transformative for these individuals if it can induce a functional cure, potentially obviating the need for long-term NA therapy. Success in this population could define an important niche for AHB-137 and demonstrate its efficacy even without prior NA-induced viral suppression.

V. Regulatory Status and Milestones

A. U.S. Food and Drug Administration (FDA)

In a significant step for its global development program, AusperBio announced in August 2023 that the U.S. FDA had granted clearance for the Investigational New Drug (IND) application for AHB-137.[1] This clearance permitted the initiation of clinical trials in CHB patients in the United States, specifically for the multiregional Phase 1b study NCT05717686.[1] FDA IND clearance is a critical regulatory milestone, signifying that the agency has reviewed the preclinical data package, manufacturing information, and clinical trial protocols and deemed them acceptable for human testing.

B. China National Medical Products Administration (NMPA)

AHB-137 has received Breakthrough Therapy Designation (BTD) from the Center for Drug Evaluation (CDE) of China's NMPA.[14] This designation was granted based on the promising clinical evidence from the Phase 1/2a trial conducted in China (NCT06115993 / CTR20232098) and the global Phase 1 trial (NCT05717686).[14] The NMPA's BTD program is designed to accelerate the development and review of investigational therapies that show potential for substantial improvement over available treatments for serious or life-threatening diseases.[14] While BTD does not alter the standards for final approval, it provides benefits such as more intensive CDE guidance and communication, and eligibility for expedited review, which can significantly shorten the drug development timeline in China.[14] This designation underscores the potential of AHB-137 to address the urgent unmet needs in CHB treatment.

C. European Medicines Agency (EMA)

Based on the provided information, there are no specific designations, such as PRIME (PRIority MEdicines), from the European Medicines Agency (EMA) mentioned for AHB-137.[22] While AHB-137 was discussed at EASL Congress 2025, a major European liver conference [22], details regarding its regulatory status with the EMA are not available in the supplied materials.

D. Key Conference Presentations

AusperBio has strategically utilized major international liver disease conferences to disseminate the evolving data on AHB-137, building a compelling narrative from preclinical research to mid-stage clinical efficacy. This approach ensures visibility within the scientific and medical communities and facilitates peer review.

• EASL Congress:
• 2023: Presentation of preclinical data, including AHB-137's antiviral activity, pharmacokinetic properties, and safety profile (Posters SAT-173, SAT-178).[2]
• 2024: Disclosure of Phase 1 clinical trial results, covering safety, tolerability, pharmacokinetics, and preliminary efficacy from both global and China-based studies (Late-breaking posters LB249, LB256).[2]
• 2025: Unveiling of interim end-of-treatment clinical data from the Phase IIb study (AB-10-8003), focusing on HBsAg loss, seroconversion rates, and safety (Late-breaking poster LBP-014).[8]
• AASLD Liver Meeting®:
• 2024: Presentation of Phase IIa data (AB-10-8002), highlighting HBsAg loss and seroconversion rates (Late-breaking oral presentation, Abstract 5011).[8]

This consistent presentation of progressively more mature and positive data at premier scientific venues has likely contributed to the positive regulatory feedback (like the NMPA BTD) and investor confidence, as seen with the successful Series B+ financing round announced in May 2025, shortly after the EASL 2025 data release.[10] Such milestones are key value inflection points for biotechnology companies, de-risking the asset and supporting further development.

VI. Expert Analysis and Future Outlook

A. Interpretation of Clinical Efficacy and Safety Data

The clinical data for AHB-137, particularly from the Phase IIb trial (AB-10-8003), are highly encouraging for the treatment of HBeAg-negative CHB patients already on NA therapy. The achievement of the primary endpoint (HBsAg <0.05 IU/mL and HBV DNA <10 IU/mL at EOT) by 75% of patients in the 24-week AHB-137 arm and 66% in the 16-week AHB-137 arm is a substantial improvement over what is achievable with current standard-of-care treatments.[8]

Key strengths of AHB-137's clinical profile include:

1. Rapid and Deep HBsAg Reduction: Over 80% of responders achieved HBsAg loss within 12 weeks of initiating AHB-137.[8] Furthermore, in the 24-week arm, 97% of all participants achieved HBsAg levels <10 IU/mL, and 100% achieved <100 IU/mL by EOT.[12] Such profound reductions are rarely seen with existing therapies and are critical for enabling immune reconstitution.
2. High Seroconversion Rates: The anti-HBs seroconversion rates of 54% (24-week arm) and 33% (16-week arm) among those who achieved HBsAg loss are particularly noteworthy.[8] Seroconversion is a hallmark of immune control and is strongly correlated with a durable off-treatment response, a key component of a functional cure. These rates suggest AHB-137 may have a significant immunomodulatory effect, potentially linked to its "dual mechanism" of action that includes boosting immune responses alongside direct viral transcript inhibition.[12]
3. Favorable Safety Profile: AHB-137 has been consistently well-tolerated across studies, with most adverse events being mild to moderate and transient, primarily injection site reactions and manageable laboratory abnormalities.[8] The absence of treatment-related SAEs or discontinuations due to AEs in the Phase IIb study is a positive indicator.[12]

However, some considerations remain. The presented data are interim EOT results; the long-term durability of HBsAg loss and seroconversion after treatment discontinuation is paramount and will be determined from ongoing follow-up phases. The two Grade 4 TRAEs noted in the Phase IIb poster (though characterized as laboratory abnormalities/ISRs) warrant continued careful monitoring and more detailed reporting in future publications.[12]

B. Potential of AHB-137 as a Functional Cure for CHB

Compared to the standard of care, where functional cure rates with NAs are less than 2-8% [6] and HBsAg loss with pegIFN is around 8-14% after several years post-treatment [5], the EOT HBsAg loss and seroconversion rates achieved with AHB-137 in a finite treatment duration of 16 or 24 weeks are substantially superior. If these responses prove to be durable off-treatment, AHB-137 could represent a transformative therapy for a significant proportion of CHB patients.

The field of HBV therapeutics is dynamic, with other investigational agents also showing promise. For instance, bepirovirsen, another ASO, has demonstrated potential for functional cure when combined with NAs in Phase III development.[6] RNA interference (RNAi) therapies, such as imdusiran in combination with interferon, have also reported functional cure rates up to 50% in specific patient subsets (HBeAg-negative, baseline HBsAg <1000 IU/mL).[29] AHB-137's monotherapy (as an add-on to existing NA therapy) data, particularly the seroconversion rates in the 24-week arm, appear highly competitive within this evolving landscape. The ability to achieve these outcomes without the need for interferon, which carries a significant side effect burden [3], would be a major advantage.

C. Significance of the Med-Oligo™ Platform

The promising clinical results of AHB-137 serve as a strong validation for AusperBio's proprietary Med-Oligo™ ASO technology platform. This platform is credited with enhancing the potency and improving the safety profile of ASOs.[8] If AHB-137 successfully navigates late-stage development and gains regulatory approval, it would not only provide a new treatment for CHB but also bolster confidence in the Med-Oligo™ platform's potential to generate other ASO-based therapeutics for HBV and a range of other diseases, as envisioned by the company.[8]

D. AusperBio's Strategic Positioning and Future Development Pathway

AusperBio has adopted a comprehensive global development strategy for AHB-137, focusing on achieving a functional cure for CHB.[8] The company's vision extends to positioning AHB-137 as a "cornerstone" or "backbone" therapy for future combination regimens aimed at HBV cure.[8] This is a forward-thinking approach, as achieving functional cure in diverse CHB patient populations may ultimately require therapies that target the virus and modulate the immune system through multiple mechanisms. A potent HBsAg-reducing agent like AHB-137, which also appears to promote seroconversion, would be an ideal component in such combinations.

Immediate next steps for AusperBio will include the completion of ongoing Phase II trials, meticulous collection and analysis of long-term follow-up data to assess the durability of virologic and serologic responses off-treatment, and subsequent design and execution of pivotal Phase III trials. Concurrently, scaling up commercial manufacturing partnerships will be essential.[10] Further exploration in other CHB populations, such as HBeAg-positive patients and those in different geographical regions or with varying disease characteristics, will also be important.

E. Unanswered Questions and Areas for Further Investigation

Despite the promising data, several questions remain and will be areas for future research:

• Durability of Response: The most critical question is the long-term sustainability of HBsAg loss and anti-HBs seroconversion after discontinuation of AHB-137.
• Efficacy in Other Populations: Efficacy and safety data in HBeAg-positive CHB patients, who often have higher viral loads and different immune profiles, are needed.
• Immune Mechanisms: A more detailed understanding of the immune mechanisms by which AHB-137 promotes seroconversion and immune control would be valuable.
• Treatment Optimization: The optimal duration of treatment, potential for retreatment in case of relapse, and patient selection criteria need further definition.
• Long-Term Safety: Comprehensive safety data from larger patient cohorts and longer follow-up periods will be essential, including more detailed characterization of any Grade 3/4 adverse events.
• Impact on cccDNA: Studies assessing the direct or indirect impact of AHB-137 on the cccDNA pool and its transcriptional activity would provide further insights into its curative potential.
• Comparative Efficacy: Eventually, how AHB-137 compares to or combines with other emerging HBV therapies will shape its place in treatment algorithms.

VII. Conclusion

AHB-137, an unconjugated antisense oligonucleotide developed by AusperBio using its proprietary Med-Oligo™ platform, has emerged as a highly promising investigational therapy for chronic hepatitis B. The interim results from its Phase IIb clinical trial (AB-10-8003) have demonstrated impressive rates of HBsAg loss and, significantly, anti-HBs seroconversion in HBeAg-negative CHB patients on existing NA therapy, particularly with a 24-week treatment regimen. These efficacy outcomes, coupled with a generally favorable safety and tolerability profile, mark a substantial advancement over the functional cure rates achievable with current standard-of-care treatments.

The rapid HBsAg decline and the high proportion of patients achieving seroconversion suggest that AHB-137 not only potently suppresses viral antigen production but may also facilitate a beneficial restoration of host immune control over HBV. If these positive end-of-treatment results translate into durable off-treatment responses, AHB-137 holds the potential to become a key component of finite therapeutic regimens aimed at achieving functional cure for a significant number of individuals living with CHB, addressing a major global unmet medical need. The continued successful development of AHB-137 would also validate the Med-Oligo™ ASO technology platform for future therapeutic innovations. While the current data are exceptionally encouraging, the successful completion of pivotal Phase III trials and the demonstration of long-term sustained efficacy and safety will be crucial for definitively establishing AHB-137's role in transforming the management of chronic hepatitis B.

VIII. References

[1]

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