Teropavimab (GS-5423): A Comprehensive Clinical and Scientific Monograph on a Novel Broadly Neutralizing Antibody for Long-Acting HIV-1 Therapy

Executive Summary & Key Insights

Teropavimab is an investigational, long-acting, broadly neutralizing antibody (bNAb) at the forefront of a potential paradigm shift in the management of Human Immunodeficiency Virus Type 1 (HIV-1) infection. It is a central component of an innovative, twice-yearly injectable antiretroviral regimen, which combines Teropavimab with a second bNAb, zinlirvimab, and the first-in-class capsid inhibitor, lenacapavir. This tripartite combination, referred to as the LTZ regimen, represents a significant evolution in antiretroviral therapy, aiming to drastically reduce the treatment burden for people living with HIV.

Clinical development has demonstrated the regimen's high efficacy. Primary results from a pivotal Phase 2 study (NCT05729568) established that the twice-yearly LTZ regimen is non-inferior to a continuous daily oral antiretroviral regimen in maintaining virologic suppression over 26 weeks. Suppression rates were nearly identical between the groups, with 96.2% of participants in the LTZ arm and 96.3% in the daily oral therapy arm maintaining an HIV-1 RNA level below 50 copies/mL.[1] The regimen has been generally well-tolerated, with a safety profile characterized predominantly by mild-to-moderate, manageable injection site reactions associated with the subcutaneous administration of lenacapavir. A notable safety finding has been the absence of significant infusion-related reactions to the intravenously administered Teropavimab and zinlirvimab, a positive outcome for biologic-based therapies.[1] In recognition of its potential for substantial improvement over available therapies, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to the investigational combination in January 2025.[3]

Despite its promising clinical profile, the LTZ regimen faces a formidable strategic challenge that may define its ultimate role in HIV care: a mandatory pre-treatment viral sensitivity screening requirement. The clinical program has mandated that participants' virus be susceptible to the neutralizing activity of both Teropavimab and zinlirvimab. This has resulted in a significant screen-failure rate, with clinical trial data indicating that over half of otherwise eligible individuals were excluded due to pre-existing viral resistance or assay failure.[4] This prerequisite poses a substantial logistical and commercial barrier to widespread clinical adoption, potentially limiting the therapy to a select subpopulation of patients.

In conclusion, while the LTZ regimen, with Teropavimab as a cornerstone component, represents a revolutionary scientific achievement and a potential leap forward in simplifying HIV treatment, its future success is not guaranteed. The clinical data strongly support its biological efficacy and safety, but its practical implementation and market penetration will be critically dependent on overcoming the limitations imposed by its patient selection criteria. The trajectory of Teropavimab is thus a compelling case study in modern drug development, where profound clinical innovation must be reconciled with the pragmatic realities of healthcare system integration and patient accessibility.

Molecular Profile and Mechanism of Neutralization

Teropavimab: A Biologic Entity

Teropavimab is a human Immunoglobulin G1 (IgG1​) monoclonal antibody (mAb) under investigation for the treatment of HIV-1 infection.[8] As a protein-based therapy, it is classified as a new molecular entity and represents a significant departure from the small-molecule drugs that have historically dominated the antiretroviral landscape.[9] The drug is identified by several names that trace its developmental lineage. Its primary designation within Gilead Sciences, the principal developer, is GS-5423.[9] It is also referred to as 3BNC117-LS or 3BNC117LS, names which signify its origin from the naturally occurring antibody 3BNC117 and its subsequent engineering for a long-acting ("LS") profile.[9] For systematic identification, it is assigned the DrugBank Accession Number DB18916 and the Chemical Abstracts Service (CAS) number 2417213-72-8.[8]

The development of Teropavimab is a collaborative effort. The foundational antibody, 3BNC117, was originally isolated and characterized at The Rockefeller University.[9] Its clinical and commercial development is now being spearheaded by Gilead Sciences, often in partnership with governmental and academic institutions such as the National Institute of Allergy and Infectious Diseases (NIAID) and the University of Cologne.[9]

Targeting the HIV-1 Achilles' Heel: The CD4 Binding Site

The therapeutic action of Teropavimab is rooted in its function as an HIV envelope protein gp120 inhibitor.[9] More specifically, it is a broadly neutralizing antibody, a specialized class of antibody capable of neutralizing a wide array of genetically diverse HIV-1 strains.[13] Its mechanism of neutralization is precise and potent: it targets the highly conserved CD4 binding site (CD4bs) on the gp120 subunit of the viral envelope (Env) protein.[4]

The HIV-1 Env protein is a trimer of gp120-gp41 heterodimers that forms the spike-like structures on the virion surface, mediating viral entry into host cells.[13] The process of infection is initiated when the CD4bs on gp120 engages with the CD4 receptor on the surface of human immune cells, primarily T-helper cells.[13] This binding event is an absolute prerequisite for subsequent conformational changes that expose the co-receptor binding site and facilitate fusion of the viral and cellular membranes. By binding directly to this critical CD4bs epitope, Teropavimab acts as a competitive antagonist, physically obstructing the virus from docking with the CD4 receptor. This steric hindrance effectively prevents the first step of viral entry, thereby neutralizing the virus before it can establish infection in a host cell.[13]

The molecular basis for this interaction has been defined at atomic resolution through X-ray crystallography of the parent antibody, 3BNC117, in a complex with the gp120 protein (Protein Data Bank ID: 4JPV).[16] This structural analysis revealed that the antibody's antigen-binding fragment makes extensive contact with the recessed, hydrophobic cavity of the CD4bs.[16] Unusually for antibodies, which typically rely solely on their hypervariable complementarity-determining region (CDR) loops for antigen contact, 3BNC117 also utilizes somatic mutations within its canonical framework regions (FWRs) to enhance binding affinity and flexibility.[16] The targeting of a functionally indispensable and structurally conserved site on the virus is the fundamental reason for Teropavimab's

broad neutralizing activity, allowing it to be effective against a multitude of HIV-1 clades and isolates.[13]

Engineering for Longevity: The "LS" Modification

Teropavimab is a product of sophisticated protein engineering, designed to overcome the pharmacokinetic limitations of natural antibodies for use in a long-acting therapeutic regimen. It is derived from 3BNC117, a potent bNAb isolated from an HIV-1-infected individual who demonstrated exceptional control over the virus.[4] While naturally potent, 3BNC117 has a plasma half-life of approximately three weeks, which is insufficient for the semi-annual dosing interval envisioned for a truly long-acting therapy.

To address this, the antibody was modified with two specific amino acid substitutions in its Fc (Fragment, crystallizable) region: M428L (methionine to leucine at position 428) and N434S (asparagine to serine at position 434).[11] This "LS" modification is a well-characterized strategy to extend antibody half-life. It works by enhancing the antibody's binding affinity to the neonatal Fc receptor (FcRn), a cellular receptor responsible for salvaging IgG antibodies from degradation.[13] Within the acidic environment of endosomes, the LS-modified Fc region binds more tightly to FcRn. This enhanced interaction increases the efficiency of the receptor-mediated recycling process, which returns the antibody to the bloodstream instead of allowing it to be trafficked to lysosomes for catabolism. By optimizing this natural salvage pathway, the LS mutations dramatically prolong the systemic circulation and plasma half-life of Teropavimab, making a six-month dosing interval clinically viable and forming the pharmacokinetic backbone of the LTZ regimen.[11] This progression—from identifying a potent natural antibody, to understanding its precise viral target, to rationally engineering it for a specific clinical application—exemplifies a modern, multi-disciplinary approach to biologic drug design.

The Twice-Yearly Regimen: A Tripartite Combination Therapy

Rationale for Combination: Building a High Barrier to Resistance

Teropavimab is not being developed as a standalone agent but is exclusively investigated as part of a three-drug combination regimen.[10] This strategy is a direct application of a foundational principle in HIV therapy, learned over decades of clinical experience: combination antiretroviral therapy is essential for durable virologic suppression. The high replication rate and inherent error-prone nature of the HIV-1 reverse transcriptase enzyme lead to a high frequency of mutations. When subjected to the selective pressure of a single therapeutic agent, the virus can rapidly evolve and select for mutations that confer resistance, leading to treatment failure.[4]

The LTZ regimen is designed to create a high genetic barrier to the development of such resistance. By combining three distinct therapeutic agents, each with a unique mechanism of action, the regimen presents a multi-faceted attack on the virus. For HIV-1 to escape this tripartite pressure, it would need to acquire multiple, independent mutations simultaneously, an event that is statistically far less probable than escaping a single agent. This approach mirrors the success of standard oral combination ART (cART) but innovatively applies the principle to a fully long-acting, injectable regimen. The FDA's decision to grant Breakthrough Therapy Designation specifically to the combination of lenacapavir with the two bNAbs underscores the regulatory recognition of this multi-pronged strategy's potential for significant clinical benefit.[3]

Synergistic Partners: Zinlirvimab and Lenacapavir

The efficacy of the LTZ regimen relies on the complementary actions of its three components, each targeting a different stage or component of the HIV-1 lifecycle.

• Zinlirvimab (ZAB; GS-2872; 10-1074-LS): Zinlirvimab is the second bNAb in the regimen and serves as a direct partner to Teropavimab. It is also a human IgG1​ monoclonal antibody derived from a potent natural antibody (10-1074) and engineered with the same LS mutations to extend its half-life.[4] Critically, zinlirvimab targets a completely different and non-overlapping epitope on the HIV-1 envelope: the V3 glycan patch.[4] This region, which includes a variable loop (V3) and associated carbohydrate molecules (glycans), is also important for viral function. By targeting a distinct site from Teropavimab's CD4bs target, zinlirvimab provides a second, independent antibody-mediated mechanism to neutralize the virus. This dual-bNAb approach ensures that even if a viral variant develops a mutation to escape Teropavimab, it would still be susceptible to zinlirvimab, and vice versa.
• Lenacapavir (LEN; Sunlenca®): Lenacapavir provides the third, and mechanistically unique, component of the regimen. It is a first-in-class, long-acting HIV-1 capsid inhibitor.[19] The HIV capsid is a conical protein shell that encases the viral genome and essential enzymes. The proper assembly and disassembly (uncoating) of this capsid are critical for multiple steps in the viral lifecycle. Lenacapavir disrupts capsid function at several of these stages, including the transport of the viral pre-integration complex into the host cell nucleus, the assembly of new virions, and the formation of a mature, infectious viral core.[6] Because its mechanism is entirely novel, lenacapavir exhibits no cross-resistance with any existing classes of antiretroviral drugs, such as reverse transcriptase inhibitors or integrase inhibitors.[22] Furthermore, its chemical properties and pharmacokinetic profile allow for slow release from a subcutaneous depot, enabling a six-month dosing interval that is perfectly harmonized with the long half-lives of the LS-modified bNAbs.[24]

Clinical Development and Efficacy Analysis

The Proof-of-Concept Study (Phase 1b: NCT04811040)

The clinical journey of the LTZ regimen began with a foundational Phase 1b study (NCT04811040), a randomized, blinded, proof-of-concept trial designed to provide the first human data on the safety, tolerability, and efficacy of the combination in virologically suppressed adults with HIV-1.[10]

• Design & Dosing: The study enrolled participants who were on a stable daily oral ART regimen and switched them to the investigational LTZ regimen. Dosing for the bNAbs was weight-based to ensure adequate exposure across participants of different sizes. On day one, participants received a single intravenous (IV) infusion of Teropavimab at a dose of 30 mg/kg, a subcutaneous (SC) injection of Lenacapavir at 927 mg (following an oral loading dose), and were randomized to one of two doses of IV Zinlirvimab: either 10 mg/kg or 30 mg/kg.[6] A total of 21 participants were assigned to the primary cohort, with 20 receiving the complete study regimen.[26]
• Patient Population: The study population was carefully selected to maximize the chances of success in this initial trial. Key inclusion criteria required participants to be virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 18 months, have a robust immune system (CD4+ T-cell count ≥500 cells/μL), and, most importantly, have pre-existing proviral HIV DNA that was confirmed to be phenotypically sensitive to both Teropavimab and Zinlirvimab via the PhenoSense mAb Assay.[10] The median age of the 21 participants in the primary cohort was 44 years, and the population was predominantly male (86%).[26]
• Efficacy Results: While the primary endpoint was safety, the key secondary efficacy measure was the maintenance of virologic suppression after switching from oral ART. The regimen demonstrated high efficacy. At the Week 26 timepoint, 90% of participants (18 of 20) who received the full regimen remained virologically suppressed. There was one case of confirmed virologic rebound at Week 16 in a participant from the 10 mg/kg zinlirvimab group; this individual was successfully re-suppressed upon restarting their baseline oral ART. A second participant, in the 30 mg/kg zinlirvimab group, withdrew from the study at Week 12 while still virologically suppressed.[26]
• Pilot Cohort: A particularly insightful component of this study was a small, embedded pilot cohort that enrolled 10 participants whose virus was sensitive to only one of the two bNAbs.[20] This cohort was designed to explore whether the regimen could be effective in a broader, less-selected population. The results were striking and highly informative for future development. Overall, 8 of the 10 participants remained suppressed at Week 26. However, efficacy was strongly dependent on the zinlirvimab dose. All six participants (100%) who received the higher 30 mg/kg dose of zinlirvimab maintained suppression, whereas only two of the four participants (50%) in the lower 10 mg/kg dose group did so.[7] This efficient study design provided a clear and early signal that higher bNAb concentrations are crucial for maintaining suppression in individuals with reduced baseline sensitivity, a finding that directly de-risked and guided the dosing strategy for the subsequent Phase 2 trial.

The Head-to-Head Comparison (Phase 2: NCT05729568)

Building on the success of the proof-of-concept study, Gilead Sciences initiated a larger Phase 2, randomized, open-label trial (NCT05729568).[3] This study was designed to rigorously evaluate the LTZ regimen by directly comparing it against the current standard of care—a continuous, stable baseline oral regimen (SBR). The trial is ongoing and is estimated to reach completion in December 2029.[31]

• Design & Dosing: A key evolution in this phase was the transition from a complex, weight-based dosing strategy to a simplified, fixed-dose regimen, a critical step toward commercial and clinical viability. The investigational arm (n=53) received subcutaneous Lenacapavir 927 mg, intravenous Teropavimab 2550 mg, and intravenous Zinlirvimab 2550 mg, all administered once every 6 months. The control arm (n=27) simply continued their existing daily oral ART.[1] The 2550 mg fixed doses for the bNAbs were selected based on pharmacokinetic modeling, which predicted that this dose would produce exposures comparable to the highly successful 30 mg/kg weight-based dose from the Phase 1b trial.[4]
• Patient Population: The study enrolled 80 virologically suppressed adults. Similar to the primary cohort of the Phase 1b trial, participants were required to have HIV-1 that was highly susceptible to both Teropavimab and Zinlirvimab, defined as a 90% inhibitory concentration (IC90​) of ≤ 2 μg/mL.[2] The baseline characteristics for the LTZ versus SBR arms were generally well-matched, with a median age of 46 versus 57 years, 15% female participants in both arms, and 40% versus 30% Black participants, respectively.[1]
• Primary Results (CROI 2025): The primary results from the first 26 weeks of the study were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in 2025.[2] The primary endpoint was the proportion of participants experiencing virologic failure, defined as having an HIV-1 RNA level ≥50 copies/mL at Week 26. The data confirmed the regimen's high efficacy and demonstrated its non-inferiority to daily oral therapy.

The following table summarizes the key design elements of the two pivotal clinical trials, illustrating the program's progression from initial proof-of-concept to a direct comparative evaluation.

Parameter	Phase 1b (NCT04811040)	Phase 2 (NCT05729568)
Study Phase	1b, Proof-of-Concept	2, Randomized, Open-Label
# Participants	21 (Primary Cohort) + 11 (Pilot)	80 (53 LTZ, 27 SBR)
Comparator	Single Arm (Switch Study)	Stable Baseline Oral Regimen (SBR)
Dosing Strategy	Weight-Based (IV): Teropavimab 30 mg/kg, Zinlirvimab 10 or 30 mg/kg	Fixed-Dose (IV): Teropavimab 2550 mg, Zinlirvimab 2550 mg
Primary Endpoint	Incidence of Serious Adverse Events	Proportion with HIV-1 RNA ≥50 copies/mL at Week 26
Key Efficacy Result	90% maintained virologic suppression at Week 26	96.2% (LTZ) vs 96.3% (SBR) maintained suppression at Week 26

Efficacy Outcomes: Non-Inferiority to Daily Oral Therapy

The primary analysis of the Phase 2 trial at Week 26 yielded a clear and positive result. The twice-yearly LTZ regimen was highly effective at maintaining viral control, with 96.2% (51 out of 53) of participants in the investigational arm maintaining virologic suppression. This outcome was statistically equivalent to the 96.3% (26 out of 27) suppression rate observed in the control arm, where participants continued their daily oral SBR.[1] This finding successfully met the study's primary objective, establishing that the novel, long-acting regimen is non-inferior to the current standard of care.

• Virologic Failure Analysis: The study reported a single case of confirmed virologic failure (1.9%) in the LTZ arm. A detailed analysis of this participant's virus provided valuable information about potential resistance pathways and reinforced the rationale for the triple-drug combination. Genotypic and phenotypic testing revealed the emergence of the Q67H resistance-associated mutation in the HIV capsid, which confers resistance to Lenacapavir. The virus also showed a loss of phenotypic susceptibility to Zinlirvimab. Importantly, however, the virus remained fully susceptible to Teropavimab.[1] This case powerfully illustrates the protective value of a multi-mechanistic regimen; even with the failure of two components, the third agent remained active, potentially preventing complete loss of virologic control and preserving future treatment options.
• CD4+ Cell Counts: As a marker of overall immune health, CD4+ T-cell counts were monitored throughout the study. Participants in both treatment arms experienced an increase in their CD4+ cell counts from baseline to Week 26. While the mean increase was numerically higher in the SBR group (+69 cells/μL) compared to the LTZ group (+23 cells/μL), the difference was not statistically significant, indicating that the switch to the long-acting regimen did not have a detrimental effect on immune status.[1]

Safety, Tolerability, and Immunogenicity

Consolidated Safety Profile: A Tale of Two Administration Routes

Across both the Phase 1b and Phase 2 clinical trials, the LTZ regimen has demonstrated a favorable and manageable safety profile.[2] The adverse events observed can be largely categorized based on the route of administration of the different components.

• Lenacapavir-Associated Events: The most frequently reported treatment-emergent adverse events (TEAEs) are consistently linked to the subcutaneous injection of Lenacapavir. These injection site reactions (ISRs) are a known effect of the drug's formulation, which creates a subcutaneous depot for slow release. Common ISRs include localized pain, erythema (redness), induration (hardening of the tissue), and the formation of small, palpable nodules under the skin.[2] In the Phase 1b study, ISRs were reported in 85% of participants who received subcutaneous lenacapavir, with the majority (60%) being mild (Grade 1) in severity.[27] The Phase 2 data showed a similar pattern, with nodules being the most common ISR (reported in under 40% of participants), followed by pain and erythema (reported in under 20%).[2] These reactions were generally short-lived and did not impact treatment tolerability or lead to discontinuations.[2]
• bNAb-Associated Events: A key positive safety finding from the clinical program, particularly emphasized in the Phase 2 results, was the complete absence of infusion-related reactions to the intravenously administered Teropavimab and Zinlirvimab.[1] Such reactions can be a concern with biologic therapies and their absence in this program is a significant advantage, suggesting good tolerability of the antibody components.
• Serious Adverse Events (SAEs): The LTZ regimen has not been associated with any treatment-related SAEs or deaths. Across the trials, no participants in the LTZ arms have discontinued the study drugs due to adverse events.[2] In the Phase 1b trial, two Grade 3 AEs were reported—one case of injection site cellulitis and one of injection site erythema—both of which were related to the lenacapavir injection and resolved completely.[26]

Immunogenicity and Anti-Drug Antibodies (ADAs)

As with all protein-based therapeutics, there is a potential for the host immune system to recognize the drug as foreign and generate an immune response, leading to the formation of anti-drug antibodies (ADAs). ADAs can have clinical consequences, including altered pharmacokinetics, reduced efficacy, or safety issues.

In the Phase 2 trial, the development of ADAs was monitored closely. By the Week 26 timepoint, treatment-emergent ADAs were detected in a minority of participants. Specifically, 11.3% (6 of 53) of participants developed ADAs against Teropavimab, and 17.0% (9 of 53) developed ADAs against Zinlirvimab.[1] Despite their detection, the presence of these ADAs did not appear to have any discernible clinical impact. The analysis showed that pharmacokinetic profiles, safety outcomes, and efficacy rates were comparable between participants who developed ADAs and those who did not.[1] This finding suggests that, at least within the first six months of treatment, the immunogenicity of Teropavimab and Zinlirvimab is low and does not compromise the performance of the regimen.

The table below provides a direct, head-to-head comparison of the primary efficacy and key safety outcomes from the Phase 2 trial, contextualizing the performance of the novel twice-yearly regimen against the current gold standard of daily oral therapy.

Outcome (at Week 26)	LTZ Regimen (n=53)	Stable Baseline Regimen (SBR) (n=27)
EFFICACY
HIV-1 RNA <50 copies/mL, n (%)	51 (96.2%)	26 (96.3%)
HIV-1 RNA ≥50 copies/mL, n (%)	1 (1.9%)	0
Mean Change in CD4+ Count (cells/μL)	+23	+69
SAFETY & TOLERABILITY
Any TEAE (excluding ISRs), n (%)	36 (67.9%)	17 (63.0%)
Treatment-Related TEAE (excluding ISRs), n (%)	6 (11.3%)	0
Serious TEAEs, n (%)	0	1 (3.7%)*
TEAEs Leading to Discontinuation, n (%)	0	1 (3.7%)*
Injection Site Reactions (any grade), n (%)	~40% (nodule), <20% (pain/erythema)	N/A
Infusion-Related Reactions, n (%)	0	N/A
Note: The single SAE in the SBR arm was metastatic pancreatic cancer, not considered related to study drug.1

Strategic Analysis and Future Outlook

The Long-Acting Treatment Landscape: A Paradigm Shift in Dosing Frequency

The primary strategic value and disruptive potential of the Teropavimab-containing LTZ regimen lie in its unprecedented twice-yearly dosing schedule. This represents a monumental advance in reducing the burden of treatment for people living with HIV, far surpassing any currently available option.[38]

• Comparative Analysis vs. Cabenuva: The current market leader and pioneer in long-acting HIV treatment is Cabenuva, a co-packaged injectable formulation of cabotegravir (an integrase inhibitor) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor).[39] Cabenuva is administered via two separate intramuscular injections every one or two months.[39] While this was a groundbreaking improvement over daily oral pills, it still requires patients to attend 6 to 12 clinic visits per year for administration. The LTZ regimen, if approved, would reduce this requirement to just two visits per year. This decrease in frequency offers a profound improvement in convenience, enhances patient privacy by minimizing interactions with the healthcare system, and has the potential to significantly improve quality of life and long-term adherence to therapy.[2]

Clinical Implementation: The Sensitivity Screening Hurdle

The most significant and defining challenge to the widespread clinical implementation and commercial success of the LTZ regimen is the mandatory pre-treatment screening for viral sensitivity. The entire clinical development program has been predicated on enrolling participants whose virus is susceptible to the neutralizing effects of both Teropavimab and Zinlirvimab, as determined by a specialized and complex proviral DNA phenotypic assay (the PhenoSense mAb Assay).[10]

This screening requirement has proven to be a critical bottleneck in patient recruitment and, by extension, would be a major barrier in real-world clinical practice. Data from the screening process for the clinical trials are stark: over 50% of otherwise eligible, virologically suppressed individuals had to be excluded.[4] The reasons for screen failure were twofold: either the participant's latent proviral DNA showed phenotypic resistance to one or both of the bNAbs, or the assay itself failed to produce a result.

This has profound strategic implications. It suggests that the LTZ regimen, in its current form, would only be a suitable option for less than half of the intended patient population. Furthermore, the screening assay itself is a major logistical hurdle. It is a specialized test that is not widely available, adding a significant layer of cost, complexity, and delay to the process of initiating treatment.[6] This creates a paradox: the regimen offers unparalleled convenience post-initiation but is preceded by a highly inconvenient and restrictive selection process. The commercial viability of the regimen will therefore depend not only on its clinical performance but on the ability of healthcare systems to integrate this novel "screen-then-treat" paradigm.

Developmental and Regulatory Path Forward

Despite the screening challenge, the LTZ regimen is progressing steadily through clinical development, buoyed by strong efficacy and safety data.

• Development Status: The regimen is currently in Phase 2 of clinical development.[21] The positive, non-inferiority results from the NCT05729568 trial provide a strong foundation for advancing to larger, global Phase 3 registrational trials, which will be required for regulatory approval.
• Regulatory Designation: In a significant endorsement of the regimen's potential, the U.S. FDA granted Breakthrough Therapy Designation to the investigational combination of lenacapavir with Teropavimab and Zinlirvimab in January 2025.[3] This designation is reserved for drugs intended to treat a serious condition where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. It is designed to expedite the development and review process.
• Component Status: While the three-drug combination is investigational, its anchor component, Lenacapavir, has a well-established regulatory track record. It is already approved as Sunlenca® for the treatment of multi-drug resistant HIV and was recently approved as Yeztugo® for HIV pre-exposure prophylaxis (PrEP) in both the United States and the European Union.[42] This existing approval provides confidence in the manufacturing, quality control, and long-term safety profile of at least one-third of the regimen.

Unanswered Questions and Future Directions

The development of Teropavimab and the LTZ regimen is a dynamic field, and several key questions remain to be addressed in future research and development.

• Long-Term Durability and Resistance: The 26-week data are highly encouraging, but longer-term follow-up from the ongoing Phase 2 trial and data from future Phase 3 trials will be essential to confirm durable efficacy beyond six months and to comprehensively characterize the long-term risk of virologic failure and the emergence of resistance.
• Solving the Screening Bottleneck: Addressing the patient selection barrier is the single most critical task for the program's future. Several strategies could be pursued. One avenue is the development of next-generation bNAbs with even greater breadth of activity, which could reduce the proportion of patients with pre-existing resistance. Another is to further explore the signal from the Phase 1b pilot study, which suggested that a high-dose regimen might be effective even in individuals with sensitivity to only one of the two bNAbs. A third, and equally important, area is the development of more accessible, scalable, and cost-effective diagnostic assays for screening.
• Administration and Formulation: The current regimen requires both intravenous infusions for the bNAbs and a subcutaneous injection for lenacapavir. This dual-route administration, while infrequent, still requires specialized clinical infrastructure. A major goal for future development will likely be the creation of co-formulations that could allow for a single, fully subcutaneous administration of all three components, which would further simplify treatment and broaden the settings in which it could be administered.
• Role in HIV Cure Strategies: Beyond its role in long-term suppressive therapy, Teropavimab and other bNAbs are being actively investigated for their potential contribution to HIV cure strategies.[21] In addition to their direct antiviral activity, bNAbs can engage the host's immune system through their Fc region, potentially mediating the killing of HIV-infected cells (a process known as antibody-dependent cellular cytotoxicity, or ADCC). This immunomodulatory function makes them attractive candidates for "shock and kill" or other strategies aimed at reducing or eliminating the latent viral reservoir.[6] The ongoing exploration of Teropavimab in this context may open up entirely new therapeutic applications in the future.

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