First results with long-acting capsid inhibitor GS-6207: oral and subcutaneous formulations for use in naïve and multidrug resistance

Simon Collins, HIV i-Base

Several posters at CROI 2020 – surprisingly none of them included as oral presentations – included new information about a new capsid inhibitor called GS-6207. This is a highly potent compound which works at multiple stages of the viral lifecycle, including early uncoating, viral assembly and maturation.

First results on viral efficacy were presented from an ongoing phase 1b dose-finding study in 39 HIV positive people not on ART. Participants were randomised to receive a single infusion of one of five doses (20, 50, 150, 450, or 750 mg) or placebo. At day 10, all participants started ART with bictegravir/F/TAF.

Each group included 8 participants (6 active and 2 placebo), except for the highest dose (where only five people received active drug).

Baseline characteristics included: median age 33 years (range: 19 to 65); 10% were women (n=4); 54% were white, 31% black, 8% Asian and 8% other. Median (IQR) CD4 and viral load at baseline were 463 cells/mm3 (IQR: 359 to 614) and approximately 31,000 copies/mL (20,000 to 50,000), respectively.

Median BMI was 25 kg/m2 (range: 19 to 35). Seven participants had previously used ART (18%), but not during the previous 12 months.

Mean reductions in viral load at day 10 were 1.3, 1.8, 1.8, 2.1 and 2.3 log copies/mL in the 20, 50, 150, 450, or 750 mg groups respectively compared to 0.2 with placebo. Maximum reductions were seen with the 450 and 750 doses (ranges: –2.9 to –1.6 and 3.0 to –1.5, respectively).

Trough levels at day ten were generally very good. Across all doses, means levels of GS-6207 were reported as being 0.7 to 22.5-fold higher than the protein adjusted EC95 for wild-type HIV (although at 0.7 this technically means at least one person would have been below this level).

However, PK modelling reported that mean concentrations >4.4 ng/mL were predicted to achieve near maximal activity, and these were reached by all but the lowest 20 mg dose group.

Pooled safety data (still blinded) were from a median follow up of 225 days (median: 156 to 227; range 16 to 247). Although side-effects were commonly reported (in 85% or participants) these were nearly all grade 1 or 2 with only one grade 3 – mainly injection site reactions (58%, n=22). The two participants with serious adverse events were not judged related to the study drugs and did not lead to discontinuations. One was a small intestine obstruction at day 57 and another was a participant with preexisting cardiovascular risk who had multiple cardiovascular events after methamphetamine use.

A second poster presented results from two phase 1 studies in HIV negative participants (n=8 for each study). One looked at PK and safety from a single escalating dose (50, 300, 900, 1800 mg) and the second reported the impact of food interactions from a single 300 mg dose with either a high or low fat meal compared to fasted. [2]

Side effects/adverse events for both studies were all mild (grade 1) and none were judged related to study drug.

PK results included maximal concentrations achieved between 4 to 8 hours and median half-life of 11 to 13 days, allowing “less frequent dosing”, though further details were not specified.

Mean concentrations of GS-6207 for fasted, low fat and high fat meals were similar and overlapping with the conclusion that the compound can be taken with or without food.

A third poster looked at the activity of GS-6207 in-vitro in presence of 19 single or double Gag cleavage site mutations (including naturally occurring polymorphisms associated with resistance to maturation inhibitors), and with mutations associated with resistance to NRTI, NNRTI, PI and INSTI classes. [3]

Phenotypic fold-changes in EC50 with GS-6207 compared to wild-type (WT) ranged from 0.3 to 2.1 with Gag mutants, similar to the control drug, and from 0.3 to 1.1 against mutations associated with current four classes. These results suggest that GS-6207 would provide life-saving options for people with multidrug HIV resistance.

Two phase 2 studies are already recruiting using 900 mg subcutaneous dose, one in treatment-naïve (n=175) and one in heavily treatment-experienced (n=100) participants. All sites are in the US or Puerto Rico. [4, 5]

The oral formulation is also being used in a two-week lead-in period in these studies and is being developed to be used in association with the infusion or separately in combination with other antiretroviral drugs.


These data support the importance of future development GS-6207 both in naïve and heavily treatment experienced people.

Future studies should therefore expand to include participants in other countries who have no other options for treatment.

Although the exact mechanisms of action are not yet understood, other presentations at CROI 2020 included data supporting capsid that capsid remains largely intact until integration into the cell nucleus. [6, 7]

If this is the case, the majority of reverse transcription must also occur in the nucleus, challenging the prevailing view for decades that this occurs in the cytoplasm soon after cell entry.


  1. Daar E et al. Dose-response relationship of subcutaneous long-acting HIV capsid inhibitor GS-6207. CROI 2020. Poster abstract 469. (abstract and poster)
  2. Begley R et al. PK, food effect, and safety of oral GS-6207, a novel HIV-1 capsid inhibitor. CROI 2020. Poster abstract 470. (abstract and poster)
  3. Margot NA et al. Absence of GS-6207 phenotypic resistance in HIV Gag cleavage site and other mutants. CROI 2020. Poster abstract 529. (abstract and poster)
  4. Study to evaluate the safety and efficacy of GS-6207 in combination with other antiretroviral agents in people living with HIV (CALIBRATE).
  5. Study to evaluate the safety and efficacy of GS-6207 in combination with an optimized background regimen in heavily treatment experienced participants living with HIV-1 infection with multidrug resistance (CAPELLA).
  6. Burdick RC et al. Nuclear uncoating of HIV-1 occurs near sites of integration. CROI 2020. Oral abstract 23. (abstract)
  7. Munshi MH et al. HIV-1 capsid-nuclear envelope interactions that facilitate nuclear import. CROI 2020. Poster abstract 165. (abstract and poster)

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