Fostemsavir is an antiretroviral drug used for treatment of multidrug-resistant HIV. Fostemsavir is an HIV attachment inhibitor. Its active form, called temsavir, binds to the gp120 portion of the HIV envelope protein that makes up the spikes on the surface of the virus. This prevents the virus from attaching to the CD4 receptor on T cells and other immune cells, which it uses to gain entry to the cells.
Fostemsavir is marketed as Rukobia by ViiV Healthcare. It was approved for use in the treatment of multidrug-resistant HIV in the United States in July 2020 and the European Union in February 2021.
Fostemsavir should be used as part of a drug combination that has been selected after resistance testing.
Fostemsavir was approved based on the results of the BRIGHTE study (Kozal). The study randomised 272 people with viral loads above 400 copies/ml who were unable to assemble a regimen that was likely to be fully suppressive from currently available agents and only had sensitivity to drugs in one or two classes of antiretrovirals. Less than half of participants in the randomised arm had more than one fully active agent in their optimised background regimen (42%).
Participants were assigned to receive 600mg of fostemsavir twice daily (or placebo).
The study also included an open-label arm for 99 participants without any fully active drug options in the existing classes of antiretroviral agents, who started treatment with fostemsavir, and a background regimen optimised by resistance testing.
The primary study endpoint was the mean change in viral load (HIV RNA) from day 1 to day 8 in the randomised cohort. Viral load fell by a mean of 0.79 log10 in the fostemsavir group and 0.17 log10 in the placebo group, a difference of 0.625 log10 (p < 0.001). Just under half the fostemsavir group experienced a viral load reduction of > 1 log10 (46%) and 65% experienced a reduction of > 0.5 log10.
Among those with a baseline viral load > 1000 copies/ml (90% of all participants) the median decrease in viral load was 1 log10.
At week 24, 54% in the randomised arm had a viral load below 40 copies/ml, 32% had a viral load above 40 copies/ml and were still taking study medication, 3% had discontinued due to lack of efficacy, adverse events or death, and 6% had changed their optimised background regimen and were classified as virologic failures. The remainder had discontinued treatment due to lack of efficacy, adverse events or death.
Study participants were followed for 96 weeks. By week 96, the proportion of randomised patients with viral suppression rose to 60% in an intention-to-treat analysis. People who changed their optimised background regimen for efficacy reasons were counted among the 30% who experienced virologic failure. The other 10% had no virologic data due to treatment discontinuation or death. In an observed or as-treated analysis, the viral suppression rate was higher, with 79% having less than 40 copies/ml and 88% having less than 400 copies/ml.
In the non-randomised cohort, the 96-week viral suppression rate remained stable at 37% by intention-to-treat analysis. Here, 43% experienced virologic failure and 19% had no virologic data. In the observed analysis, 59% had HIV RNA less than 40 copies/ml and 68% had less than 400 copies/ml.
Viral load reduction was accompanied by improved CD4 counts. The mean gain at 96 weeks in the randomised cohort was 205 cells/mm3 – an increase of 66 cells/mm3 from week 48. The greatest improvement (240 cells/mm3) was seen in those with less than 20 cells/mm3 at baseline. Among the 71 people who started with less than 50 cells/mm3 at baseline, 56% had at least 200 cells/mm3 at week 96, the threshold for an AIDS diagnosis and increased risk of opportunistic infections.
Fostemsavir was also tested in a phase 2b study in comparison to atazanavir/ritonavir. The study recruited participants who had experienced failure of at least one antiretroviral regimen but who were sensitive to all study drugs. All participants received raltegravir and tenofovir disoproxil fumarate (TDF) and were randomised to receive one of four doses of fostemsavir or atazanavir/ritonavir. Virologic responses were similar in all study arms at week 24. (Lalezari)
Fostemsavir (Rukobia) is taken as one 600mg tablet, twice a day with or without food.
The most common side effects were nausea, diarrhoea, headache, abdominal pain, rash, indigestion, vomiting, sleep disturbance and fatigue, each reported by less than one in ten study participants. People with hepatitis B or C co-infection were more likely to experience liver enzyme elevations
The use of fostemsavir is contraindicated with the following medications:
- Androgen receptor inhibitor: Enzalutamide
- Anticonvulsants: Carbamazepine, phenytoin
- Antimycobacterial: Rifampicin
- Antineoplastic: Mitotane
- Herbal product: St John’s wort (Hypericum perforatum)
Viruses resistant to fostemsavir remain susceptible to the gp120 post-attachment inhibitor ibalizumab. Fostemsavir resistance does not lead to cross-resistance to agents in other drug classes.
Due to a lack of information on the use of fostemsavir during pregnancy, it is not recommended for pregnant women.
Fostemsavir has not been tested in children or adolescents.
Kozal M et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. New England Journal of Medicine, 382: 1232-1243, 2020.
Lataillade JM et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. The Lancet HIV, 7:e740-e751, 2020.
Lalezari J et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. The Lancet HIV, 2: e427-437, 2015.