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The debut of fostemsavir

Fostemsavir is a drug that has completed phase III clinical trials. It is intended for use by people who have strains of HIV that are resistant to many classes of anti-HIV drugs.

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Fostemsavir is the first of a new class of drugs called attachment inhibitors. It works by binding to an HIV protein called gp120 found on the surface of HIV. The virus uses gp120 to help attach itself to a cell and then infect the cell. By binding to gp120, fostemsavir prevents HIV from infecting cells.

Subtypes of HIV

There are many major strains, or subtypes, of HIV. Laboratory experiments have found that fostemsavir is active against most strains of HIV that are commonly found in North America, Western Europe, East Asia, Australia and New Zealand.

However, fostemsavir is not active against a subtype of HIV called Group O (Outlier). This strain is concentrated in parts of West-Central Africa and is not commonly distributed. Fostemsavir is not active against HIV-2. This strain of HIV is commonly found in West Africa.

Fostemsavir is active against strains of HIV-1 that are resistant to other treatments, including the following drugs that work as receptor or fusion inhibitors:

  • T-20, enfuvirtide (Fuzeon)
  • maraviroc (Celsentri)
  • Ibalizumab (Trogarzo)

A prodrug

Fostemsavir is called a “prodrug” by chemists. When a fostemsavir pill is swallowed and the drug is absorbed in the intestines, it is converted into its active form—temsavir. It is this active form (temsavir) that has antiviral activity. Prodrugs are often developed to help overcome absorption problems with the original formulation of the drug.

In clinical trials

The dose of fostemsavir that was used in the phase III clinical trial was 600 mg twice daily, together with other anti-HIV drugs. In phase II and III clinical trials, the most common side effects that were considered generally mild were headache and rash.

Adverse effects of moderate to severe intensity occurred in 18% of participants and were as follows:

  • diarrhea
  • headache
  • nausea
  • vomiting
  • weakness or lack of energy

Note that people who enrolled in clinical trials of fostemsavir were not in general good health because their pre-study regimens had been failing. On average, people in the phase III study had CD4+ counts below the 100 cell/mm3 mark. Such people could be experiencing low-grade and other infections that accompany a low CD4+ cell count. However, it is likely that some of the adverse effects listed previously are side effects of fostemsavir and/or some of the other medicines that people in the study took.

Opioid use

Fostemsavir, taken at a dose of 600 mg twice daily, has been studied in 32 HIV-negative people (72% men, 28% women) who were being treated for substance dependency with stable doses of the following opioid substitution medicines:

  • methadone (between 40-120 mg) – 16 participants
  • a combination of buprenorphine (between 8-24 mg) and naloxone (between 2-6 mg) – 16 participants

According to the scientists monitoring the study, over the course of 10 days “there were no deaths, serious adverse events or adverse events leading to discontinuation of study therapy.”

Methadone or a combination of buprenorphine and naloxone did not reduce the concentration of fostemsavir in the blood.

Next in TreatmentUpdate we discuss results from the phase III trial of fostemsavir.

—Sean R. Hosein

REFERENCES:

  1. Wang T, Ueda Y, Zhang Z, et al. Discovery of the human immunodeficiency virus type 1 (HIV-1) attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir. Journal of Medicinal Chemistry. 2018 Jul 26;61(14):6308-6327.
  2. Cahn P, Fink V, Patterson P. Fostemsavir: a new CD4 attachment inhibitor. Current Opinion in HIV/AIDS. 2018 Jul;13(4):341-345.
  3. Moore K, Magee M, Sevinsky H, et al. Methadone and buprenorphine pharmacokinetics and pharmacodynamics when co-administered with fostemsavir to opioid-dependent, human immunodeficiency virus seronegative participants. British Journal of Clinical Pharmacology 2019 Aug;85(8):1771-1780.
  4. Alessandri-Gradt E, Charpentier C, Leoz M, et al. Impact of natural polymorphisms of HIV-1 non-group M on genotypic susceptibility to the attachment inhibitor fostemsavir. Journal of Antimicrobial Chemotherapy. 2018 Oct 1;73(10):2716-2720.
  5. Lataillade M, Zhou N, Joshi SR, et al. Viral drug resistance through 48 weeks, in a phase 2b, randomized, controlled trial of the HIV-1 attachment inhibitor prodrug, fostemsavir. Journal of Acquired Immune Deficiency Syndromes. 2018 Mar 1;77(3):299-307.