ABI-1179: An Investigational Long-Acting Helicase-Primase Inhibitor for Recurrent Genital Herpes

1. Executive Summary

ABI-1179 is an investigational, orally administered, long-acting small molecule antiviral agent currently under development for the treatment of recurrent genital herpes (RGH). Originated by Gilead Sciences, Inc. and now being advanced by Assembly Biosciences, Inc., ABI-1179 functions as a highly potent inhibitor of the herpes simplex virus (HSV) helicase-primase enzyme complex, a mechanism distinct from current standard-of-care nucleoside analogues.[1]

Preclinical studies have demonstrated ABI-1179's significant in vitro potency against both HSV-1 and HSV-2, including strains resistant to acyclovir. It has shown a higher barrier to resistance compared to acyclovir and a favorable pharmacokinetic profile in animal models, supporting the potential for infrequent dosing.[4] Interim results from the Phase 1a portion of the ongoing Phase 1a/b clinical trial (NCT06698575) in healthy volunteers indicated that ABI-1179 is well-tolerated and exhibits a mean plasma half-life of approximately four days, supporting a once-weekly oral dosing regimen. Notably, target plasma concentrations for antiviral activity were exceeded even at the lowest dose tested (50 mg).[1]

The strategic collaboration between Gilead Sciences, a major pharmaceutical entity with extensive antiviral discovery expertise, and Assembly Biosciences, a biotechnology company focused on viral disease therapeutics, suggests a synergistic approach to developing this promising asset. Gilead's origination and initial patent filings provide a strong foundation, while Assembly Biosciences' dedicated development efforts are rapidly advancing ABI-1179 through early clinical stages.[2] The progression of ABI-1179 directly into Phase 1b clinical studies in patients with RGH, to be run concurrently with another helicase-primase inhibitor candidate (ABI-5366), reflects an accelerated development strategy aimed at addressing the significant unmet medical needs in RGH management.[1] If successful, ABI-1179 could offer a transformative treatment option characterized by improved convenience, potentially enhanced efficacy, and activity against resistant viral strains.

2. Introduction to ABI-1179

Background on Herpes Simplex Virus (HSV) and Recurrent Genital Herpes (RGH)

Recurrent genital herpes (RGH) is a chronic, lifelong viral infection predominantly caused by herpes simplex virus type 2 (HSV-2), although HSV-1 is an increasingly recognized cause. The condition is characterized by periodic outbreaks of painful genital ulcers, which can lead to significant physical discomfort and psychological distress for affected individuals.[4] RGH represents a considerable public health burden, with millions affected globally.[1]

Despite its prevalence, the management of RGH faces substantial unmet medical needs. Current standard-of-care (SOC) antiviral therapies, primarily nucleoside analogues such as acyclovir, valacyclovir, and famciclovir, require daily administration for suppressive therapy or frequent dosing during acute outbreaks. While these agents can reduce the frequency, duration, and severity of recurrences, they are only partially effective in preventing them, and patient adherence to daily regimens can be challenging.[1] Furthermore, the emergence of HSV strains resistant to nucleoside analogues, particularly in immunocompromised populations, poses an additional therapeutic challenge. For several decades, there has been a lack of major therapeutic innovation in this field, underscoring the need for novel antiviral agents with improved efficacy, convenience, and resistance profiles.[1] An analysis of a US claims database for 2023 identified an estimated 148,067 recurrent genital herpes cases within the study sample, with the highest prevalence among females and individuals aged 18-39, highlighting the ongoing impact of this condition.[9]

Introduction of ABI-1179

ABI-1179 is an investigational small molecule drug candidate being developed as a long-acting, orally administered antiviral for the treatment of RGH.[1] Its development program is focused on addressing the limitations of current SOC therapies by offering a potentially more convenient dosing regimen and activity against a broader range of viral strains.

Originator and Developer

ABI-1179 was originated by Gilead Sciences, Inc., a company with a strong legacy in antiviral drug discovery and development. The compound was subsequently contributed by Gilead to Assembly Biosciences, Inc. (NASDAQ: ASMB) under a collaboration agreement.[1] Assembly Biosciences, a biotechnology company specializing in therapeutics for serious viral diseases, is currently responsible for the clinical development of ABI-1179.[1] This collaborative model leverages Gilead's initial discovery and intellectual property with Assembly Biosciences' focused expertise in advancing viral disease candidates through clinical trials. Such partnerships are common in the pharmaceutical industry, allowing larger organizations to maximize the potential of their discovery pipelines while enabling smaller, specialized companies to dedicate resources to promising assets.

The focus on a "long-acting" therapeutic profile is a central tenet of ABI-1179's development strategy, aiming to directly overcome the compliance and convenience issues associated with the daily dosing regimens of current RGH treatments.[1] This strategic emphasis is consistently highlighted in communications regarding the drug, underscoring its potential to offer a significant practical advantage for patients if clinical development is successful.[1]

Table 1: ABI-1179 - Key Drug Profile

Feature	Description	Reference(s)
Investigational Name	ABI-1179	1
Other Known Designations	Indolinoyl derivative (contextually from patent WO2023/225162)	7
Originator	Gilead Sciences, Inc.	2
Developer	Assembly Biosciences, Inc.	1
Chemical Class	Small molecule; Indolinoyl derivative	3
Mechanism of Action	Herpes Simplex Virus (HSV) helicase-primase inhibitor (HPI)	1
Target Indication	Recurrent Genital Herpes (RGH)	1
Current Development Phase	Phase 1b (as of February 2025 reports)	1

3. Chemical Profile and Mechanism of Action

Known Chemical Class

ABI-1179 is described as a small molecule.[3] Based on its association with patent application WO2023/225162, titled "ANTIVIRAL INDOLINYL COMPOUNDS AND USES THEREOF" filed by Gilead Sciences, ABI-1179 is understood to be an indolinoyl derivative.[7] A specific chemical structure, molecular formula, or molecular weight for ABI-1179 has not been publicly disclosed within the provided research materials. While an evaluation of the aforementioned patent (PMID: 39262042) reportedly presents a "structure proposal" for ABI-1179, the actual structure is not available in the provided documents.[7] Preclinical characterization posters also do not display the chemical structure.[4]

Mechanism of Action as an HSV Helicase-Primase Inhibitor (HPI)

ABI-1179 exerts its antiviral effect by targeting the Herpes Simplex Virus (HSV) helicase-primase (HP) enzyme complex.[1] This complex is critical for viral DNA replication and is composed of three viral proteins: UL5 (the helicase, responsible for unwinding double-stranded viral DNA), UL52 (the primase, responsible for synthesizing short RNA primers required for the initiation of DNA synthesis by the viral DNA polymerase), and UL8 (a processivity factor or helicase accessory protein).[4] By inhibiting the HP complex, ABI-1179 effectively blocks an early and essential step in the viral replication cycle, thereby preventing the production of new viral particles.[4] Preclinical resistance selection studies suggest that ABI-1179 binds at the interface of the UL5 and UL52 proteins.[4]

Comparison with Existing Antiviral Classes

The mechanism of action of HPIs like ABI-1179 is fundamentally different from that of the current standard-of-care nucleoside analogues (e.g., acyclovir, valacyclovir). Nucleoside analogues are prodrugs that require phosphorylation by viral thymidine kinase and subsequently by cellular kinases to their active triphosphate form. This active form then competes with natural deoxynucleoside triphosphates for incorporation into the growing viral DNA chain by the viral DNA polymerase, leading to chain termination and inhibition of DNA synthesis. In contrast, HPIs act upstream of the DNA polymerase, preventing the necessary unwinding and priming of the viral DNA template.[4]

Targeting the HP complex is a clinically validated antiviral strategy. Pritelivir, another HPI, has demonstrated clinical efficacy and serves as a relevant comparator in the development of new agents in this class.[4] The distinct mechanism of HPIs offers the potential for activity against HSV strains that have developed resistance to nucleoside analogues, typically through mutations in the viral thymidine kinase or DNA polymerase genes. This provides a strong rationale for developing HPIs like ABI-1179, as they could offer a therapeutic option for patients with infections refractory to current treatments. The specific binding site of ABI-1179 at the UL5/UL52 interface, if further characterized (e.g., through detailed structural biology, as hinted by the mention of Cryo-EM data, albeit "not shown" [4]), could reveal nuances in its interaction compared to other HPIs. Such differences might translate into variations in potency, the spectrum of activity against viral mutants, and the propensity for resistance development, potentially differentiating ABI-1179 from other compounds in its class.

4. Preclinical Development

The preclinical development program for ABI-1179 has provided a robust foundation for its advancement into clinical trials, demonstrating potent antiviral activity, a favorable pharmacokinetic profile, and a promising resistance profile.

In vitro Antiviral Activity

ABI-1179 has exhibited marked potency in various in vitro assays:

• Inhibition of HSV Helicase-Primase Complex: ABI-1179 is a highly potent inhibitor of the DNA unwinding activity of recombinant HSV-1 and HSV-2 HP complexes. It demonstrates apparent inhibitor constants (Ki,app​) of less than 0.05 nM for both HSV-1 and HSV-2 HP complexes. This potency is substantially greater than that observed for pritelivir, another HPI, which has Ki,app​ values of 5–8 nM.[4] The half-maximal inhibitory concentrations (IC50​) for the DNA unwinding activity were determined to be 0.17±0.05 nM for HSV-1 and 0.16±0.07 nM for HSV-2.[4]
• Cellular Antiviral Activity: In cell-based assays, ABI-1179 showed potent inhibition of viral replication. Against laboratory strains HSV-1 (KOS) and HSV-2 (MS) in ARPE-19 (human retinal epithelial) cells, the half-maximal effective concentrations (EC50​) were 0.95±0.15 nM for HSV-1 and 1.07±0.30 nM for HSV-2. Similar high potency was observed in other physiologically relevant cell lines, including HaCat (human keratinocytes) and NHDF (neonatal human dermal fibroblasts).[4]
• Comparative Potency: ABI-1179 is significantly more potent than acyclovir, the cornerstone of current SOC. In vitro, it was found to be more than 2500-fold more potent than acyclovir against HSV-1 and HSV-2 in ARPE-19 cells, and over 150-fold more potent against HSV-2 in HaCat and NHDF cells.[4]
• Activity against Clinical Isolates: The potent activity of ABI-1179 extends to clinical isolates of both HSV-1 and HSV-2. Against these isolates, ABI-1179 was more than 12-fold more potent than pritelivir and more than 1500-fold more potent than acyclovir.[4]
• Activity against Acyclovir-Resistant Strains: Crucially, all tested HSV isolates with reduced susceptibility to acyclovir remained susceptible to ABI-1179, highlighting its potential utility in cases of nucleoside analogue resistance.[4]

Resistance Profile

The propensity for antiviral resistance development is a critical consideration for long-term therapy:

• ABI-1179 has demonstrated a higher barrier to the development of resistance compared to acyclovir in in vitro passage studies using both HSV-1 and HSV-2 in Vero cells.[4]
• Resistance selection experiments identified specific mutations in the UL5 helicase gene (K356N and S498N for HSV-1) at high drug concentrations (128-fold EC50​). For HSV-2, no variants in the target genes UL5 or UL52 were detected at the highest concentration of ABI-1179 tested (32-fold EC50​) that still allowed for cytopathic effect (CPE).[4] These findings suggest a robust resistance profile.
• The pattern of resistance mutations supports the hypothesis that ABI-1179 binds at the interface of the UL5 and UL52 proteins.[4]
• Phenotypic assessments of specific UL5 helicase variants (e.g., K355 mutations) indicated modest shifts in potency for ABI-1179, which were comparable to or less pronounced than those seen with pritelivir. However, it is noted that certain HSV-2 double and triple mutants can exhibit high-level resistance to both ABI-1179 and pritelivir.[4] Encouragingly, ABI-1179 has shown antiviral activity against some HSV-2 strains that harbor mutations known to confer resistance to other HPIs, suggesting a potentially differentiated interaction with the target or a greater resilience to certain resistance mechanisms.[5]

The superior in vitro potency of ABI-1179 over existing therapies like acyclovir and even other HPIs like pritelivir is a compelling attribute. This high potency could translate into the ability to use lower clinical doses, potentially minimizing dose-related adverse effects and improving the therapeutic index of the drug. Furthermore, the higher barrier to resistance compared to acyclovir, combined with its activity against some HPI-resistant strains, suggests that ABI-1179 could offer a more durable antiviral effect, which is particularly important for a chronic, recurrent infection like RGH.

In vivo Efficacy in Animal Models

In a well-established guinea pig model of recurrent HSV infection, which mimics human RGH, ABI-1179 demonstrated significant in vivo efficacy. When administered via formulated chow at therapeutically relevant concentrations after the establishment of latency, ABI-1179 significantly reduced the development of recurrent herpetic lesions.[4] This finding provides important preclinical proof-of-concept for its potential utility in preventing or reducing recurrences in humans.

Preclinical Pharmacokinetics (ADME)

The pharmacokinetic (PK) properties of ABI-1179 have been investigated in multiple preclinical species:

• ABI-1179 exhibits a favorable oral PK profile in rats, dogs, and cynomolgus monkeys, which supports the potential for once-weekly oral administration in humans.[4]
• In vivo systemic clearance of ABI-1179 was observed to be lower than that predicted from in vitro metabolic studies in these nonclinical species.[4]
• The fraction of unbound drug in plasma is similar between rats and humans. This, along with a restriction factor observed in rats (likely related to tissue distribution or transporter effects), has been used to inform human PK projections.[4]
• Based on preclinical PK/PD modeling, a once-weekly oral dose of 250 mg of ABI-1179 is projected to achieve plasma concentrations sufficient for efficacious antiviral coverage in humans.[4] The consistent PK behavior across different animal species provided a degree of confidence that a desirable long-acting profile could be achieved in humans, a prediction later supported by Phase 1a data.

Preclinical Safety and Toxicology

Early safety assessments have been encouraging:

• ABI-1179 demonstrates a low potential for off-target inhibition of carbonic anhydrases (CAs). Specifically, it does not inhibit CAI (IC50​>100,000 nM) and shows only weak inhibition of CAII (IC50​=6600±750 nM). This profile is more favorable than that of pritelivir, which inhibits CAI with an IC50​ of 451 nM and CAII with an IC50​ of 1800 nM. Significant inhibition of CAs by ABI-1179 is not anticipated at the projected human efficacious dose.[4] This is an important finding, as off-target CA inhibition can be associated with various side effects.

Table 2: Summary of Key Preclinical Data for ABI-1179

Parameter	Finding	Reference(s)
Target	HSV-1 & HSV-2 Helicase-Primase Complex	4
In vitro Potency (HP Complex Ki,app​)	<0.05 nM (HSV-1 & HSV-2)	4
In vitro Antiviral EC50​ (ARPE-19 cells)	∼1 nM (HSV-1 KOS, HSV-2 MS)	4
Comparative Potency (vs. Acyclovir, ARPE-19)	>2500-fold more potent	4
Comparative Potency (vs. Pritelivir, clinical isolates)	>12-fold more potent	4
Activity vs. ACV-Resistant Strains	Yes, susceptible	4
Resistance Barrier	Higher than acyclovir	4
Key in vivo Efficacy	Significant reduction in recurrent lesions (guinea pig model)	4
Key Preclinical PK Supporting Weekly Dosing	Favorable oral PK in rat, dog, monkey	4
Off-Target Carbonic Anhydrase Inhibition	Low potential (No CAI inhibition, weak CAII)	4

5. Clinical Development: Focus on NCT06698575 (ABI-1179-101)

The clinical development of ABI-1179 is centered on the Phase 1a/b trial NCT06698575, also known as study ABI-1179-101. This first-in-human study is designed to evaluate the safety, tolerability, and pharmacokinetics of ABI-1179, and subsequently its antiviral activity in the target patient population.

Study Design (NCT06698575 / ABI-1179-101)

• Trial Title: "A Study to Assess the Safety, Pharmacokinetics, and Tolerability of ABI-1179 in Healthy Subjects and in Subjects Seropositive for HSV-2 With Recurrent Genital Herpes".[13]
• ClinicalTrials.gov Identifier: NCT06698575.[6]
• Sponsor: Assembly Biosciences, Inc..[13]
• Phase: Phase 1a/b.[1]
• Overall Design: The study is a randomized, blinded (triple blind indicated in one source), placebo-controlled trial.[2] It is structured in two parts:
• Part A (Phase 1a): This part involves single ascending dose (SAD) administration of ABI-1179 or placebo to healthy adult participants. As of February 2025, dosing was reported as complete for three cohorts evaluating oral doses of 50 mg, 100 mg, and 300 mg. Each cohort randomized participants in a 6:2 ratio (ABI-1179 to placebo). A food effect cohort is also planned within Part A but had not yet been conducted at the time of the interim report.[2]
• Part B (Phase 1b): This part will evaluate multiple ascending doses (MAD) of ABI-1179 or placebo in adult participants who are seropositive for HSV-2 and have a history of recurrent genital herpes. It is planned to assess weekly oral administration of ABI-1179 over a 29-day treatment period in up to four cohorts. Participants in Part B will be randomized in a 20:5 ratio (ABI-1179 to placebo) within each cohort, with a pooled analysis of placebo recipients anticipated.[2]
• Planned Enrollment: Approximately 146 participants across both parts of the study.[13]
• Age Range: Eligible participants are aged 18 to 60 years.[13]
• Key Eligibility Criteria:
• Part A (Healthy Volunteers): Participants must have a Body Mass Index (BMI) between ≥18.0 and <32.0 kg/m2, be in good general health as determined by the investigator, and (for females) be non-pregnant and agree to protocol-specified contraception.[13]
• Part B (HSV-2 Seropositive with RGH): Similar BMI and general health requirements (other than HSV infection) apply. Female participants must also be non-pregnant and agree to contraception.[13]
• General Exclusion Criteria (for both parts): Current infection with HIV, HBV, HCV, or acute HAV/HEV; any illness that might confound study results or pose additional risk; history of significant drug-related allergies; history of persistent alcohol or illicit drug abuse within three years prior to screening; and participation in another clinical study with an investigational or marketed drug within 30 days or 5 half-lives before screening.[13]
• Study Locations: The trial is being conducted at 13 locations.[13] It is also listed as recruiting on the Australian New Zealand Clinical Trials Registry (ANZCTR), though specific Australian sites were not detailed at the time of that listing.[15]

Phase 1a Interim Results

Positive interim results from the Phase 1a SAD cohorts in healthy volunteers were announced by Assembly Biosciences on February 20, 2025.[1] These results, based on data from the 50 mg, 100 mg, and 300 mg dose cohorts, were pivotal for the decision to advance to Phase 1b.

• Pharmacokinetics:
• ABI-1179 demonstrated a mean plasma half-life of approximately four days following oral administration. This pharmacokinetic characteristic is highly supportive of the target profile for once-weekly oral dosing.[1]
• The drug exhibited high plasma exposure across all evaluated dose levels.[2]
• Significantly, even at the lowest dose of 50 mg, ABI-1179 plasma concentrations exceeded the target levels established from preclinical pharmacokinetic/pharmacodynamic (PK/PD) modeling. These target concentrations are projected to achieve increased efficacy compared to currently approved therapies.[1] The achievement of these target concentrations at such a low dose is a particularly encouraging finding, suggesting a potentially wide therapeutic window and the feasibility of an effective low-dose weekly regimen. This could translate to an improved safety margin and potentially lower manufacturing costs.
• Safety and Tolerability:
• ABI-1179 was observed to be well-tolerated, with a favorable overall safety profile.[1]
• All treatment-emergent adverse events (TEAEs) reported were mild in intensity. Importantly, all AEs were considered by the study investigators to be unrelated to the study treatment.[1]
• No serious adverse events (SAEs) were reported in any of the dose cohorts.[2]
• A single instance of a self-limited grade 2 alanine transaminase (ALT) elevation was observed in the cohort evaluating the highest dose of 300 mg. This event did not lead to study discontinuation or meet any protocol-defined stopping criteria.[1] While isolated, any hepatic enzyme elevation warrants careful monitoring in subsequent studies involving multiple doses and larger patient populations.
• There were no treatment-related grade 3 or grade 4 laboratory abnormalities, and no clinically significant electrocardiogram (ECG) abnormalities or discernible patterns of AEs or laboratory abnormalities noted.[2]

Phase 1b Design and Objectives

Following the positive Phase 1a interim data, Assembly Bio has initiated preparatory activities to advance ABI-1179 into Part B (Phase 1b) of the ABI-1179-101 study.[2]

• Participant Population: Part B will enroll participants who are seropositive for HSV-2 and have a documented history of recurrent genital herpes.[2]
• Dosing Regimen: The study will evaluate multiple ascending doses of ABI-1179 administered orally once weekly over a 29-day treatment interval. The design allows for up to four dose cohorts, and the potential inclusion of a loading dose may also be explored.[2]
• Key Objectives/Outcome Measures: While formal primary and secondary outcome measures from ClinicalTrials.gov were not available in the provided materials [17], the objectives for Part B are clear from company communications. In addition to continued assessment of safety, tolerability, and pharmacokinetics with multiple dosing, Part B will critically evaluate the antiviral activity of ABI-1179. This will include measuring changes in viral parameters, such as the HSV-2 shedding rate and the quantity of virus obtained from genital swab samples. Furthermore, the study will assess effects on clinical parameters, including the lesion recurrence rate and the duration of lesions.[2]

Current Status and Projected Timelines

• As of February 20, 2025, the Phase 1a interim results were reported as positive, leading to the decision to proceed directly to Phase 1b.[1]
• The Phase 1b study of ABI-1179 will be conducted concurrently with the ongoing Phase 1b evaluation of ABI-5366, which is Assembly Bio's other long-acting HPI candidate. ABI-5366 began dosing in its Phase 1b trial in the fourth quarter of 2024.[1] This parallel development approach is a strategic decision by Assembly Bio. It allows for a more direct comparison of the two candidates, potentially under similar trial conditions (same sites and equivalent eligibility criteria are anticipated), accelerates the overall development timeline for their HPI program, and optimizes the use of resources. It also provides a data-driven basis for selecting the most promising candidate(s) for later-stage, more expensive pivotal trials, or for potentially advancing both if they show distinct, favorable profiles.
• Interim data from the Phase 1b portions of both the ABI-1179 and ABI-5366 studies are anticipated to be reported together in the fall of 2025. This timeline was adjusted to enable the studies to run concurrently.[1]
• The initial projection for ABI-1179 to enter its first-in-human study was by the end of 2024.[5] The study (NCT06698575) is now actively enrolling, with Phase 1a interim data already available as of February 2025. Specific official start and completion dates for NCT06698575 were not found in the provided documentation.[17]

Table 3: Overview of Clinical Trial NCT06698575 (ABI-1179-101)

Feature	Description	Reference(s)
Trial Title	A Study to Assess the Safety, Pharmacokinetics, and Tolerability of ABI-1179 in Healthy Subjects and in Subjects Seropositive for HSV-2 With Recurrent Genital Herpes.	13
ClinicalTrials.gov ID	NCT06698575	6
Sponsor	Assembly Biosciences, Inc.	13
Phase	Phase 1a/b	1
Study Design	Randomized, blinded, placebo-controlled; Part A: SAD in healthy volunteers; Part B: MAD in HSV-2+ RGH patients.	2
Participant Population	Healthy Volunteers (Part A), HSV-2 seropositive patients with recurrent genital herpes (Part B). Approx. 146 total.	13
Key Objectives	Assess safety, tolerability, PK. Part B also antiviral activity (HSV-2 shedding, viral levels) & clinical parameters (lesion recurrence/duration).	6
Doses Evaluated (Phase 1a)	50 mg, 100 mg, 300 mg single oral doses.	2
Key Phase 1a PK Outcomes	Mean half-life ~4 days; high exposure; exceeded target antiviral plasma concentrations at all doses.	1
Key Phase 1a Safety Outcomes	Well-tolerated; AEs mild & unrelated; 1 Gr2 ALT elevation (300mg); no SAEs.	1
Current Status (as of Feb 2025)	Phase 1a interim results positive; advancing to Phase 1b.	1

6. Intellectual Property

The intellectual property landscape for ABI-1179 is anchored by patent application WO2023/225162, titled "ANTIVIRAL INDOLINYL COMPOUNDS AND USES THEREOF".[11] This international patent application was filed by Gilead Sciences, Inc., the originator of ABI-1179.[7] The application, published on November 23, 2023, claims priority from a U.S. provisional application (63/344,510) filed on May 20, 2022.[11] The scope of this patent application generally covers indolinyl compounds that function as inhibitors of viral helicase-primase and their therapeutic use in the treatment of viral infections.[11]

While the specific claims and detailed examples within WO2023/225162, particularly any explicit structural disclosure of ABI-1179 or its direct linkage to this development code, are not accessible from the provided research snippets [21], the context strongly suggests this patent family is central to ABI-1179. An expert evaluation of this patent, referenced by PMID: 39262042, reportedly includes a "structure proposal for indolinoyl derivative ABI-1179".[7] This indicates that the chemical nature of ABI-1179 aligns with the indolinyl compounds described in Gilead's patent application.

The existence of this foundational patent application by Gilead is critical for the future commercial prospects of ABI-1179. It establishes an early priority date, which is essential for determining patentability and the potential term of market exclusivity. The collaboration agreement between Gilead Sciences and Assembly Biosciences would presumably detail the licensing terms, milestone payments, royalty obligations, and territorial rights associated with this intellectual property.

The patent evaluation article further characterizes Gilead's approach in WO2023/225162 as a "me-too approach combining elements from an old Bayer together with a recent Medshine HPI application".[7] This observation implies that while the specific compounds claimed by Gilead, including potentially ABI-1179, are novel, their underlying chemical scaffolds or pharmacophoric elements might draw inspiration from or build upon pre-existing knowledge in the field of helicase-primase inhibitors. If this is the case, the strength and breadth of the patent claims for ABI-1179 would depend on demonstrating significant non-obviousness and inventive step over such prior art, likely through superior properties such as enhanced potency, an improved pharmacokinetic profile (e.g., long half-life), a better safety margin, or a distinct resistance profile.

7. Comparative Landscape and Potential Advantages

ABI-1179 is being developed in a field with established standards of care and emerging competitors. Its potential advantages are best understood by comparing it to current therapies and other investigational agents.

Potential Benefits over Standard-of-Care (SOC) (e.g., Acyclovir and its prodrug Valacyclovir)

Current SOC for RGH primarily involves nucleoside analogues. ABI-1179 offers several potential key advantages:

• Dosing Frequency and Convenience: The most striking potential benefit is the prospect of once-weekly oral dosing. The ~4-day plasma half-life observed in Phase 1a human studies strongly supports this regimen.[1] This contrasts sharply with the daily (for suppression) or multiple-daily (for episodic treatment) dosing required for current SOC agents like acyclovir and valacyclovir. A once-weekly regimen could dramatically improve patient adherence, which is a common challenge with long-term therapies for chronic conditions, and thereby enhance overall treatment effectiveness and quality of life.[1]
• Efficacy against Resistant Strains: ABI-1179 has demonstrated in vitro activity against HSV isolates that are resistant to acyclovir.[4] This is a critical advantage, as acyclovir resistance, while uncommon in the general population, can be a significant problem in immunocompromised patients or those on long-term suppressive therapy.
• Potency: Preclinical data indicate that ABI-1179 is substantially more potent in vitro than acyclovir, with EC50​ values more than 2500-fold lower against HSV-1 and HSV-2 in some cell lines.[4] Higher potency may translate to lower effective doses and potentially a better safety margin.
• Barrier to Resistance: In vitro studies suggest ABI-1179 has a higher barrier to the development of viral resistance compared to acyclovir.[4] A more robust resistance profile would be highly beneficial for long-term management of RGH.
• Projected Efficacy: Pharmacokinetic modeling based on preclinical data projects that ABI-1179 may achieve increased efficacy compared to currently approved therapies.[1] This will need to be confirmed in later-phase clinical trials.

The combination of a significantly more convenient dosing schedule (once-weekly) and activity against resistant viral strains positions ABI-1179 as a potentially transformative therapy rather than merely an incremental improvement. If these advantages are borne out in further clinical studies, ABI-1179 could capture a substantial share of the RGH market, appealing to both treatment-naive patients seeking convenience and treatment-experienced patients who may have suboptimal responses or resistance to current SOC.

Positioning Relative to Other Helicase-Primase Inhibitors (e.g., Pritelivir)

Pritelivir is another HPI that has undergone clinical investigation and serves as an important benchmark. ABI-1179 appears to offer potential differentiation:

• Potency: ABI-1179 has demonstrated higher in vitro potency against the HSV HP complex (Ki,app​<0.05 nM) compared to pritelivir (Ki,app​ 5–8 nM). It was also >12-fold more potent than pritelivir against HSV clinical isolates.[4]
• Off-Target Effects: A key preclinical finding is the lower potential for ABI-1179 to inhibit carbonic anhydrases (CAs) compared to pritelivir. ABI-1179 does not inhibit CAI and shows only weak CAII inhibition, whereas pritelivir inhibits both CAI and CAII at lower concentrations.[4] A more favorable off-target profile, particularly with respect to CA inhibition, could translate to an improved safety and tolerability profile for ABI-1179, especially in the context of long-term suppressive therapy required for RGH.
• Resistance Profile: While both drugs target the HP complex, ABI-1179 has shown activity against some HSV-2 strains harboring mutations known to confer resistance to other HPIs.[5] Furthermore, phenotypic assessment of certain UL5 helicase variants showed modest potency shifts for ABI-1179, which were comparable to or less pronounced than for pritelivir.[4] This suggests a potentially distinct interaction with the target that might offer advantages against certain viral mutants.

8. Future Outlook and Significance

Potential Impact on RGH Management

Should ABI-1179 successfully navigate clinical development and gain regulatory approval, it holds the potential to significantly alter the management landscape for recurrent genital herpes. The prospect of a highly potent, orally administered antiviral with a once-weekly dosing regimen would represent a major advancement in convenience and could substantially improve patient adherence to long-term suppressive therapy.[1] This improved adherence, coupled with its high potency and activity against acyclovir-resistant strains, could lead to better control of recurrences, reduced viral shedding, and an enhanced quality of life for individuals living with RGH.[1] The market for RGH treatments has seen limited innovation for decades, creating a substantial opportunity for a therapy that offers clear advantages over existing options.[1]

Development Pathway and Challenges

The immediate next step for ABI-1179 is the successful completion of the Phase 1b portion of the NCT06698575 trial. This phase will provide crucial data on the drug's safety, tolerability, pharmacokinetics with multiple dosing, and, importantly, its antiviral activity (e.g., reduction in HSV-2 shedding and lesion frequency/duration) in patients with RGH. Interim data from this phase are anticipated in the fall of 2025.[1]

Positive results from Phase 1b would pave the way for larger, more definitive Phase 2 and Phase 3 trials designed to establish robust clinical efficacy and further characterize the long-term safety profile. Challenges in this pathway include demonstrating a clinically meaningful benefit over placebo and, potentially, active comparators. The single, self-limited Grade 2 ALT elevation observed in one participant at the highest dose in Phase 1a, while not halting development, underscores the need for continued careful monitoring of hepatic safety in all subsequent studies, particularly with prolonged exposure.[1]

The competitive landscape includes other HPIs, such as pritelivir and Assembly Biosciences' own ABI-5366, as well as potentially other novel antiviral mechanisms that may emerge. The concurrent development of ABI-1179 and ABI-5366 by Assembly Biosciences is a notable strategic approach.[1] Running their Phase 1b trials in parallel, with an anticipated joint interim data readout, allows the company to directly compare these two assets under similar conditions. This strategy accelerates the decision-making process for prioritizing which candidate(s) to advance into more resource-intensive late-stage development, thereby optimizing resources and de-risking their overall HPI program. The data expected in fall 2025 will be a critical inflection point for Assembly Bio's HSV portfolio.

Beyond clinical development, manufacturing scale-up to support commercial demand and establishing a cost of goods that allows for viable pricing will be important considerations. Given that current SOC therapies for RGH are largely generic and inexpensive, ABI-1179 will need to demonstrate substantial clinical benefits—particularly in terms of quality of life improvements, superior recurrence prevention, and efficacy in managing treatment-resistant cases—to justify premium pricing and gain widespread payer acceptance and market adoption.

The success of ABI-1179 could also have broader implications. It could validate the long-acting HPI strategy not only for HSV but potentially as a platform concept for managing other chronic viral infections where adherence to daily oral therapies is a significant barrier to effective treatment. While the specific viral targets and drug mechanisms would differ, the principle of combining a potent antiviral mechanism with a pharmacokinetic profile optimized for infrequent dosing could be a valuable paradigm for future antiviral drug development.

9. Conclusions

ABI-1179 is an investigational helicase-primase inhibitor that has demonstrated considerable promise in early-stage development for the treatment of recurrent genital herpes. Its high in vitro potency against HSV, including acyclovir-resistant strains, a higher barrier to resistance than acyclovir, and a favorable preclinical safety profile provide a strong rationale for its clinical evaluation. The interim results from the Phase 1a clinical trial are particularly encouraging, highlighting a pharmacokinetic profile supportive of once-weekly oral dosing and good tolerability in healthy volunteers.

The strategic collaboration between Gilead Sciences and Assembly Biosciences, coupled with Assembly Bio's focused and accelerated clinical development plan (including the concurrent advancement of ABI-1179 and ABI-5366), positions these candidates to potentially address long-standing unmet needs in RGH management. Key differentiating factors for ABI-1179 include its potential for a significantly more convenient dosing regimen than current standards of care and its activity against resistant viruses.

Future clinical data from the ongoing Phase 1b study (NCT06698575), expected in fall 2025, will be critical in further defining the safety, pharmacokinetic, and antiviral activity profile of ABI-1179 in patients with RGH. Successful outcomes in this and subsequent larger trials could lead to a paradigm shift in how RGH is treated, offering patients a more effective and convenient therapeutic option. However, continued diligent assessment of safety, particularly hepatic safety, and demonstration of clear clinical superiority will be essential for its ultimate success and adoption. The development of ABI-1179 represents a significant step forward in the pursuit of innovative therapies for chronic viral diseases.

Works cited

1. Assembly Biosciences Reports Positive Interim Phase 1a Results from Clinical Trial Evaluating Long-Acting Helicase-Primase Inhibitor ABI-1179 in Development for Recurrent Genital Herpes, accessed May 23, 2025, https://www.stocktitan.net/news/ASMB/assembly-biosciences-reports-positive-interim-phase-1a-results-from-bn0upsavfqj2.html
2. Assembly Biosciences Reports Positive Interim Phase 1a Results from Clinical Trial Evaluating Long-Acting Helicase-Primase Inhibitor ABI-1179 in Development for Recurrent Genital Herpes - GlobeNewswire, accessed May 23, 2025, https://www.globenewswire.com/news-release/2025/02/20/3029571/16259/en/Assembly-Biosciences-Reports-Positive-Interim-Phase-1a-Results-from-Clinical-Trial-Evaluating-Long-Acting-Helicase-Primase-Inhibitor-ABI-1179-in-Development-for-Recurrent-Genital-H.html
3. ABI 1179 - AdisInsight - Springer, accessed May 23, 2025, https://adisinsight.springer.com/drugs/800076861
4. www.assemblybio.com, accessed May 23, 2025, https://www.assemblybio.com/wp-content/uploads/2025/04/ASMB_ICAR_2025_Poster_ABI-1179_Preclin-Characterization.pdf
5. Assembly Biosciences Presents New Preclinical Data Highlighting Investigational Helicase-Primase Inhibitors at International Herpesvirus Workshop - BioSpace, accessed May 23, 2025, https://www.biospace.com/assembly-biosciences-presents-new-preclinical-data-highlighting-investigational-helicase-primase-inhibitors-at-international-herpesvirus-workshop
6. Assembly Biosciences Reports Positive Interim Phase 1a Results from Clinical Trial Evaluating Long-Acting Helicase-Primase Inhibitor ABI-1179 in Development for Recurrent Genital Herpes, accessed May 23, 2025, https://investor.assemblybio.com/news-releases/news-release-details/assembly-biosciences-reports-positive-interim-phase-1a-results-0
7. Helicase-primase inhibitors for the treatment of herpes simplex virus ..., accessed May 23, 2025, https://pubmed.ncbi.nlm.nih.gov/39262042/
8. Assembly Biosciences Reports Positive Interim Phase 1a Results from Clinical Trial Evaluating Long-Acting Helicase-Primase Inhibitor ABI-1179 in Development for - University of Liverpool, accessed May 23, 2025, https://www.liverpool.ac.uk/centre-of-excellence-for-long-acting-therapeutics/global-news/stories/title,1510635,en.html
9. Assembly Biosciences Presents New Data Highlighting Long-Acting Herpes Simplex Virus Candidate ABI-5366 and Genital Herpes Prevalence and Treatment Patterns at the 2025 ESCMID Congress, accessed May 23, 2025, https://www.assemblybio.com/news/assembly-biosciences-presents-new-data-highlighting-long-acting-herpes-simplex-virus-candidate-abi-5366-and-genital-herpes-prevalence-and-treatment-patterns-at-the-2025-escmid-congress/
10. Assembly Biosciences Advances ABI-1179 to Phase 1b in Clinical Study for Recurrent Genital Herpes with Promising Interim Results | Nasdaq, accessed May 23, 2025, https://www.nasdaq.com/articles/assembly-biosciences-advances-abi-1179-phase-1b-clinical-study-recurrent-genital-herpes
11. WO/2023/225162 ANTIVIRAL INDOLINYL COMPOUNDS AND USES THEREOF - Patentscope, accessed May 23, 2025, https://patentscope.wipo.int/search/en/WO2023225162
12. Valaciclovir: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed May 23, 2025, https://go.drugbank.com/drugs/DB00577
13. A Study to Assess the Safety, Pharmacokinetics, and Tolerability of ..., accessed May 23, 2025, https://ctv.veeva.com/study/a-study-to-assess-the-safety-pharmacokinetics-and-tolerability-of-abi-1179-in-healthy-subjects-and
14. ASSEMBLY BIOSCIENCES, INC. Form 8-K Current Event Report Filed 2025-02-20, accessed May 23, 2025, http://pdf.secdatabase.com/776/0000950170-25-024134.pdf
15. ANZCTR search results - Australian Clinical Trials, accessed May 23, 2025, https://www.australianclinicaltrials.gov.au/anzctr-search-results?search_text=&condition_category=all&condition_code=all&recruitment_status=Recruitingðics_approval=all&page=479
16. Form 8-K for Assembly Biosciences INC filed 02/20/2025, accessed May 23, 2025, https://investor.assemblybio.com/static-files/7ca00150-f7d4-4e1b-8643-32dcd956b4e0
17. clinicaltrials.gov, accessed May 23, 2025, https://clinicaltrials.gov/study/NCT06698575
18. accessed January 1, 1970, https://www.clinicaltrials.gov/study/NCT06698575?intr=ABI-1179&rank=1
19. BOPI 04/2025 - agepi.md, accessed May 23, 2025, https://agepi.gov.md/sites/default/files/bopi/BOPI_04_2025.pdf
20. Patentes - RPI - Instituto Nacional da Propriedade Industrial, accessed May 23, 2025, https://revistas.inpi.gov.br/pdf/Patentes2826.pdf
21. patentscope.wipo.int, accessed May 23, 2025, https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023225162
22. accessed January 1, 1970, https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023225162&_cid=P20-LXR0WH-77649-1
23. Structure of helicase-primase inhibitor (HPI) amenamevir, pritelivir and IM-250., accessed May 23, 2025, https://www.researchgate.net/figure/Structure-of-helicase-primase-inhibitor-HPI-amenamevir-pritelivir-and-IM-250_fig1_362679961
24. Helicase–primase inhibitors for the treatment of herpes simplex virus infections – patent evaluation of WO2023/225162 from Gilead Sciences Inc | Request PDF - ResearchGate, accessed May 23, 2025, https://www.researchgate.net/publication/383976439_Helicase-primase_inhibitors_for_the_treatment_of_herpes_simplex_virus_infections_-_patent_evaluation_of_WO2023225162_from_Gilead_Sciences_Inc