fremocapavir (VH-499)

Associated long-acting platforms

Unknown

Administration route

Subcutaneous, Intramuscular, Oral

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

Not provided

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Not provided

Manufacturing

Not provided

Specific analytical instrument required for characterization of formulation

Not provided

CINNAMON

Identifier

NCT06039579

Link

https://clinicaltrials.gov/study/NCT06039579

Phase

Phase II

Status

Completed

Sponsor

ViiV Healthcare

More details

The primary purpose of the study is to evaluate the antiviral activity of orally administered VH4004280 and VH4011499 monotherapy over 10 days in human immunodeficiency virus (HIV-1) infected Treatment-Naïve (TN) participants.

Purpose

Proof of Concept Treatment Study of Orally Administered VH4004280 or VH4011499 in HIV-1 Infected Adults

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-10-25

Anticipated Date of Last Follow-up
2025-09-09

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2024-06-24

Actual Completion Date
2024-06-24

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Participants who are overtly healthy (other than HIV-1 infection). * Screening cluster of differentiation-4 (CD4+) T-cell count greater than or equal to (≥)200 cells/microliter (µL). * Documented HIV-1 infection and Screening plasma HIV-1 RNA ≥3000 copies/milliliter (mL). * Treatment-naïve: Defined as no antiretroviral therapy received after the diagnosis of HIV-1 infection. Prior use of oral pre-exposure prophylaxis (PreP) is permitted. Prior use of parenteral PreP is exclusionary. * Has body mass index (BMI) within the range of 18.5-31.0 kilograms per meter square (kg/m\^2). * Participants male at birth must use male condoms and participants female at birth who are of childbearing potential must be using acceptable forms of birth control.

Health status

Study type

Interventional (clinical trial)

Enrollment

44

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Not provided

Studied route(s) of administration

Use case

Treatment

Indication(s)

HIV

Key resources

218547

Identifier

NCT06724640

Link

https://clinicaltrials.gov/study/NCT06724640

Phase

Phase I

Status

Recruiting

Sponsor

ViiV Healthcare

More details

The purpose of this study is to investigate safety and tolerability following single ascending subcutaneous (SC) and intramuscular (IM) doses of VH4011499 in participants without HIV. The study will also describe the pharmacokinetics following single ascending SC and IM doses of VH4011499 in participants without HIV.

Purpose

A Study to Assess the Safety, Tolerability, and Pharmacokinetics of VH4011499 Compared to Placebo in Adults Without HIV

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-12-16

Anticipated Date of Last Follow-up
2025-10-27

Estimated Primary Completion Date
2028-08-16

Estimated Completion Date
2028-08-16

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent. * Participants who are overtly healthy. * Male or female of non-childbearing potential. * Capable of giving signed informed consent. Exclusion Criteria: * History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neurological or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data. * Abnormal blood pressure. * Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected

Health status

Study type

Interventional (clinical trial)

Enrollment

168

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Indication(s)

HIV

Key resources

222420

Identifier

NCT06368986

Link

https://clinicaltrials.gov/study/NCT06368986

Phase

Phase I

Status

Completed

Sponsor

ViiV Healthcare

More details

The purpose of this study is to evaluate effect of food (in fasted and fed conditions) on the bioavailability of CAI VH4011499.

Purpose

A Study to Investigate the Effect of Food on the Bioavailability of a Capsid Inhibitor (CAI) in Male and Female Healthy Participants

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-04-17

Anticipated Date of Last Follow-up
2025-02-13

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2024-10-02

Actual Completion Date
2024-10-02

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Participants who are 18 to 55 years of age. * Participants who are overtly healthy. * One SARs-CoV-2 negative test is required prior to dosing * Body weight within 50-100 kg and body mass index (BMI) within the range 19-32 kg/m2 (inclusive). * Capable of giving signed informed consent. * Participants male at birth must use male condoms, and participants female at birth who are of childbearing potential must be using acceptable forms of birth control.

Health status

Study type

Interventional (clinical trial)

Enrollment

60

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Not provided

Studied LA-formulation(s)

Not provided

Studied route(s) of administration

Not provided

Use case

Not provided

Indication(s)

HIV

Key resources

218306

Identifier

NCT06012136

Link

https://clinicaltrials.gov/study/NCT06012136

Phase

Phase I

Status

Completed

Sponsor

ViiV Healthcare

More details

The primary purpose of the study is to investigate safety and tolerability following single ascending subcutaneous (SC) and intramuscular (IM) doses of capsid inhibitors (VH4004280 and VH4011499) in healthy participants. The study will also describe the pharmacokinetics following single ascending SC and IM doses of capsid inhibitors in healthy participants.

Purpose

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Single Suspension Injection of Investigational Capsid Inhibitors Compared to Placebo in Healthy Adults

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-08-24

Anticipated Date of Last Follow-up
2026-08-02

Estimated Primary Completion Date
2026-09-02

Estimated Completion Date
2026-09-02

Actual Primary Completion Date
2026-06-09

Actual Completion Date
2026-06-09

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Participants who are overtly healthy. * Participants who are negative on a single test for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (approved molecular polymerase chain reaction (PCR), point of care test), performed on the day of admission (Day -1). A negative result is required prior to the administration of study intervention on Day 1. * Male or female participants of non-childbearing potential. * Capable of giving signed informed consent. Exclusion Criteria: * History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neurological or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs.

Health status

Study type

Interventional (clinical trial)

Enrollment

85

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Indication(s)

HIV

Key resources

218490

Identifier

NCT05393271

Link

https://clinicaltrials.gov/study/NCT05393271

Phase

Phase I

Status

Completed

Sponsor

ViiV Healthcare

More details

This FTIH study aims to evaluate the safety, tolerability and PK of the novel investigational Human immunodeficiency virus (HIV)-1 capsid inhibitor VH4011499 in healthy adults. The study will be conducted in 3 parts: Part 1 will investigate single ascending doses (SAD) and Part 2 will investigate multiple ascending doses (MAD). Part 3 will investigate single dose of a new formulation of VH4011499. The transition from SAD to MAD will be based on the assessment of the Safety and Dose Escalation Committee.

Purpose

First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4011499 in Healthy Participants

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2022-10-03

Anticipated Date of Last Follow-up
2025-03-31

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2023-04-24

Actual Completion Date
2023-04-24

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: * Participants who are overtly healthy. * Participants must have two consecutive Severe Acute Respiratory Syndrome Coronavirus 2 (SARs-CoV-2) Polymerase chain reaction (PCR) negative results prior to dosing. * Participants must have body weight \> 50 kilograms (kg) and body mass index (BMI) within the range 19-32 kilograms per meter square (kg/m^2). * Male or female participants (either of non-childbearing potential or of child-bearing potential and using acceptable contraception). * Capable of giving signed informed consent.

Health status

Study type

Interventional (clinical trial)

Enrollment

73

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

This is a double-blind (sponsor unblinded) study.

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Not provided

Studied route(s) of administration

Use case

Treatment

Indication(s)

HIV

Key resources

CINERGY

Identifier

NCT07816250

Link

https://clinicaltrials.gov/study/NCT07816250

Phase

Phase II

Status

Not yet recruiting

Sponsor

ViiV Healthcare

More details

The purpose of this Phase 2b study is to evaluate the efficacy and therapeutic window of chronically dosed VH4011499 paired with an integrase strand transfer inhibitor (INSTI). This study will explore 4 different regimens of VH4011499 when paired with cabotegravir (CAB) as an initial two-drug regimen.

Purpose

A Phase 2b Study Evaluating VH4011499 Capsid Inhibitor Long-Acting Injectable Plus Cabotegravir in Treatment Naïve Adults (CINERGY)

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Not provided

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
2026-10-19

Actual Start Date
Not provided

Anticipated Date of Last Follow-up
2026-09-06

Estimated Primary Completion Date
2032-06-10

Estimated Completion Date
2032-06-11

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Inclusion Criteria: * Participant must be at least 18 years of age (or older, if required for adults by local regulations). * Screening CD4+ T-cell count ≥ 200 cells/µL. * Documented HIV-1 infection and screening plasma HIV-1 RNA ≥ 1 000 and ≤ 100 000 copies/mL. * Treatment-naïve. Prior use of oral pre-exposure prophylaxis (PrEP) or oral post-exposure prophylaxis (PEP) that is not INSTI or CAI based is permitted. * Body weight ≥ 50.0 kg (110 lbs) for participants assigned male at birth and ≥ 45.0 kg (99 lbs) for participants assigned female at birth. * Agrees to adequate birth control if a participant of childbearing potential Exclusion Criteria: * Participants with acute HIV-1 infection * Prior exposure to any HIV-1 capsid inhibitor or any HIV-1 INSTI for any reason is prohibited. *

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

200

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Not provided

Use case

Treatment

Indication(s)

HIV

Key resources

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

Not provided

Residual solvents used

Not provided

Compound patent families

Publications

Umumararungu T, Nyandwi JB, Katandula J, et al. Current status of the small molecule anti-HIV drugs in the pipeline or recently approved. Bioorg Med Chem. 2024;111:117860. doi:10.1016/j.bmc.2024.117860

Link: https://pubmed.ncbi.nlm.nih.gov/39094527/

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.

N. Thakkar et al. Injectable HIV-1 Capsid Inhibitor VH4011499 (VH-499) Formulation Supports Ultra-Long-Acting Dosing. Presented at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI). February 2026.

Background: The HIV-1 capsid inhibitor VH4011499 (VH-499) is currently in development as a long-acting antiretroviral agent for HIV-1. In a proof-ofconcept study, oral VH-499 demonstrated rapid and potent antiviral activity in people with HIV-1 and was well tolerated. Here we present safety and pharmacokinetics (PK) findings from a first-time-in-human study assessing the ultra-long-acting (ULA) potential of an injectable VH-499 formulation. Methods: In this double-blind (sponsor-unblinded) ongoing phase 1 study (NCT06724640), we randomized participants without HIV-1 to receive single ascending intramuscular (IM) or subcutaneous (SC) doses of VH-499 (100, 200, or 400 mg evaluated herein) or placebo. Safety and PK data were collected post-dose. Single-dose PK parameters using available data were evaluated by non-compartmental analyses. Results: Overall, 48 participants received VH-499 or placebo as an IM or SC injection (6 groups total, n=8 each). Median age was 36 years, 94% of participants were male, and 40% identified as non-White. Most adverse events (AEs) had a maximum grade of 1 or 2 in severity across all treatment groups. VH-499–related AEs were primarily injection site reactions (ISRs), most frequently injection site pain (27/36; 75%). Median overall ISR event duration ranged from 1 to 3 days across all groups. Frequency of VH-499–related ISRswas higher in SC vs IM groups (83%-100% vs 33%-83%). No participants withdrew for safety reasons. No serious AEs were reported. Based on preliminary PK analysis, median time to maximum VH-499 concentration (tmax) was approximately 7 to 18 days post-dose for IM; tmax was approximately 112 days post-dose for SC due to slower absorption (Figure). Maximum VH-499 concentrations were lower after SC administration compared with IM at all doses. Given the relatively flat VH-499 PK profile for both IM and SC routes, no terminal half-life could be identified based on available data, and longer-term PK data are required. Conclusions: Both IM and SC single-dose injections of VH-499 were well tolerated and demonstrated slower absorption through SC administration in people without HIV-1. These results suggest that the long-acting injectable VH-499 formulation has the potential to support ULA (ie, ≥4 months) dosing intervals, and either healthcare provider or self-administration could be feasible. Model-informed drug development approaches using emerging PK and safety data from this study will help to optimize the design of the future development of VH-499.

Thakkar N, Griesel R, Pierce A, et al. Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV. Infect Dis Ther. Published online April 2, 2025. doi:10.1007/s40121-025-01129-y

Introduction: This first-time-in-human study describes the pharmacokinetics, drug-drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor.

Methods: This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV administered orally as single ascending doses as powder-in-bottle (PiB; part 1) and tablet (part 3) formulations and as multiple ascending doses as PiB formulation dosed once daily for 14 days (part 2). Midazolam was used to evaluate the effect of VH-499 on cytochrome P450 3A (CYP3A) activity (part 2).

Results: Overall, 73 participants were included (VH-499, n = 56; placebo, n = 17). VH-499 plasma exposures were less than dose-proportional, with median time to maximum observed concentration of 8.0-12.0 h for the PiB formulation and 24.0 h for the tablet formulation. Geometric mean terminal half-life was 51.2-66.5 h (2-3 days). The tablet formulation resulted in 45-63% lower exposures compared with PiB. Concomitant midazolam administration after single and multiple VH-499 doses did not lead to clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-499 is not expected to inhibit or induce CYP3A4. VH-499 was well tolerated. Adverse event (AE) frequency was comparable between placebo and VH-499 groups. VH-499-related AEs were predominantly grade 1. No serious AEs across VH-499 groups, AEs leading to withdrawal from drug/study, or deaths occurred. There were no trends in vital signs, electrocardiograms, or laboratory hematology parameters and no clinically relevant changes in chemistry parameters.

Conclusion: First-time-in-human data further characterize the pharmacokinetics of orally administered VH-499 and provide support for development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment and prevention.

Clinical trial registration: ClinicalTrials.gov, NCT05393271.

Additional documents

No documents were uploaded

Useful links

• ViiV's pipeline

• Clinical Pharmacokinetics and Safety of Orally Administered VH4011499 (VH-499), a Novel HIV-1 Capsid Inhibitor, in Adults Without HIV - Thakkar et al. - Poster WEPEB105-IAS2024-Munich

• Clinical pharmacokinetics and safety of orally administered VH4004280 (VH-280), a novel HIV-1 capsid inhibitor, in healthy volunteers. Griesel R, et al. Poster THPEB093 - IAS2024

• Proof-of-Concept Trial of Oral VH4011499 (VH-499), a New HIV-1 Capsid Inhibitor. Griesel et al - presentation at CROI2025-SanFrancisco

• Pre-clinical profiles of HIV-1 capsid inhibitors VH4004280 (VH-280) and VH4011499 (VH-499). Wang et al, Poster WEPEA027-IAS2024- Munich

• dezecapavir chemical properties

• Proof of concept study of orally administered VH4004280 or VH4011499 in HIV-1 infected adults

• Proof-of-Concept Trial of Oral VH4011499 (VH-499), a New HIV-1 Capsid Inhibitor