lepetegravir + lenacapavir pacfosacil (GS-1720+GS-4182)

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Undisclosed

Tentative equipment list for manufacturing

Undisclosed

Manufacturing

Undisclosed

Specific analytical instrument required for characterization of formulation

Undisclosed

WONDERS1

Identifier

NCT06544733

Link

https://clinicaltrials.gov/study/NCT06544733

Phase

Phase II/III

Status

Suspended

Sponsor

Gilead Sciences

More details

The goal of this clinical study is to learn more about the experimental drugs GS-1720 and GS-4182; to compare the combination of GS-1720 and GS-4182 with the current standard-of-care treatment bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, BVY), to see if the combination of GS-1720 and GS-4182 is safe and if it works for treating human immunodeficiency virus type 1 (HIV-1) infection. This study has two phases: Phase 2 and Phase 3. The primary objectives of this study are: Phase 2: To evaluate the efficacy of switching to oral weekly GS-1720 in combination with GS-4182 versus continuing BVY in virologically suppressed people with HIV-1 (PWH) at Week 24. Phase 3: To evaluate the efficacy of switching to oral weekly GS-1720/GS-4182 Fixed-dose combination (FDC) tablet regimen ve

Purpose

Study of Oral Weekly GS-1720 and GS-4182 Versus Biktarvy in People With HIV-1 Who Are Virologically Suppressed

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-08-20

Anticipated Date of Last Follow-up
2026-01-01

Estimated Primary Completion Date
2028-01-01

Estimated Completion Date
2029-06-01

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

Key Inclusion Criteria: * Documented plasma HIV-1 RNA \< 50 copies/mL for ≥ 24 weeks before and at screening. * Receiving BVY for ≥ 24 weeks prior to screening. Key Exclusion Criteria: * Prior use of, or exposure to LEN, GS-1720, or GS-4182. * History of virologic failure while on an integrase strand-transfer inhibitor (INSTI)-based regimen. * Documented integrase strand-transfer inhibitor (INSTI) resistance, specifically, resistance-associated mutations (RAMs) E92G/Q, G118R, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, or R263K in the integrase gene. * Prior use of any long-acting (LA) parenteral antiretrovirals (ARV) such as monoclonal antibodies (mAbs) or broadly neutralizing antibodies (bNAbs) targeting HIV-1, injectable cabotegravir (including oral cabotegravir lead-in), or injecta

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

675

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key resources

WONDERS2

Identifier

NCT06613685

Link

https://clinicaltrials.gov/study/NCT06613685

Phase

Phase II/III

Status

Terminated

Sponsor

Gilead Sciences

More details

The goal of this clinical study is to learn more about the experimental drugs GS-1720 (an oral, long-acting integrase strand transfer inhibitor (INSTI)) and GS-4182 (a prodrug of Lenacapavir (LEN)); to compare the combination of GS-1720 and GS-4182 with the current standard-of-care treatment bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (Biktarvy), to see if the combination of GS-1720 and GS-4182 is safe and if it works for treating human immunodeficiency virus type 1 (HIV-1) infection in treatment-naive people with HIV-1 (PWH). This study has two phases: Phase 2 and Phase 3. The primary objectives of this study are: Phase 2: To evaluate the efficacy of oral weekly GS-1720 coadministered with GS-4182 versus continuing Biktarvy (BVY) in treatment-naive PWH at Week 24. Phase

Purpose

Study of Oral Weekly GS-1720 and GS-4182 Compared With Biktarvy in People With HIV-1 Who Have Not Been Treated

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-10-21

Anticipated Date of Last Follow-up
2026-03-26

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2026-03-16

Actual Completion Date
2026-03-16

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

Key Inclusion Criteria: * HIV-1 RNA ≥ 500 copies/mL at screening. * Antiretroviral (ARV) treatment-naive, except the use of oral pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or F/TAF, up to 1 month prior to screening. Key Exclusion Criteria: * Prior use of any long acting parenteral antiretrovirals (ARVs) such as monoclonal antibodies, broadly neutralizing antibodies targeting HIV-1, LEN, injectable cabotegravir (including oral cabotegravir lead-in), and/or injectable rilpivirine. * Documented resistance to the integrase strand-transfer inhibitor class, specifically, resistance-associated mutations E92G/Q, G118R, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, or R263K in the integrase gene. * Any of the follow

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

73

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

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

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Hoffmann C, Rockstroh JK. Standardisation of monitoring routines for new long-acting antiretrovirals in development. Lancet HIV. 2026;13(4):e282-e286. doi:10.1016/S2352-3018(25)00329-7

The US Food and Drug Administration's clinical hold on Gilead Sciences' once-weekly combination of GS-1720 and GS-4182 due to unexpected CD4 T-cell and lymphocyte count declines represents a key safety signal in long-acting HIV therapy development. This event parallels the earlier islatravir trials, in which similar immunological effects led to a downsized development programme with lower doses of the drug. The current safety signal must involve different mechanisms, as the combination contains an integrase inhibitor and a capsid inhibitor rather than a nucleoside reverse transcriptase translocation inhibitor. Although GS-1720 appears well tolerated in early studies, the high doses used might have contributed to toxicity. As GS-4182 is a prodrug that converts to lenacapavir, the parent compound warrants careful evaluation, particularly given lenacapavir's anticipated widespread use for HIV prevention. Existing lenacapavir data show favourable safety profiles. However, CD4 T-cell reporting has been inconsistent across trials, and different study populations and dosing regimens might not fully capture all potential immunological effects. CD4 T-cell declines represent a key concern for people with HIV. Future trials should implement standardised monitoring protocols with individual participant trajectories, predefined decline thresholds, and clear discontinuation criteria. As long-acting antiretroviral therapy advances, maintaining rigorous immunological surveillance becomes essential to balance dosing convenience against potential immunological risks.

Additional documents

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Useful links

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