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Maturation inhibitor advances into clinical trials

Approved anti-HIV drugs can be grouped into different classes depending on how they work. These drugs target different parts of HIV-infected cells and interfere with their ability to make new copies of HIV. The following proteins or enzymes inside HIV-infected cells are affected by the following drugs:

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  • RT (reverse transcriptase) – tenofovir, 3TC, FTC, efavirenz, rilpivirine
  • protease – darunavir (Prezista and in Prezcobix), atazanavir (Reyataz)
  • integrase – bictegravir (in Biktarvy), cabotegravir (in Cabenuva), dolutegravir (Tivicay and in Dovato and Triumeq), raltegravir (Isentress)

As mentioned earlier in this issue of TreatmentUpdate, an emerging class of drugs is called capsid inhibitors. The first capsid inhibitor—lenacapavir—is developed by Gilead Sciences. Another company, ViiV Healthcare, also has a capsid inhibitor but it is in very early stages of development.

Maturation inhibitors

ViiV is also developing another class of anti-HIV drugs called maturation inhibitors. As the name suggests, maturation inhibitors affect the final stage of virus production inside infected cells. These drugs prevent new copies of HIV from maturing and render them non-infectious.

GSK ’254

ViiV is developing a maturation inhibitor code-named GSK 3640254 (we will shorten this to compound ’254). In clinical trials, when compound ’254 was the only anti-HIV drug given to participants, no resistance to the drug appeared up to seven days of dosing. However, when it was used as the only anti-HIV drug for 10 days, resistance did appear. Therefore, in the future, compound ’254 will need to be used as part of a combination of anti-HIV drugs in order to minimize the risk of resistance developing. In that clinical trial of 34 people with HIV, researchers tested different doses of compound ’254. Depending on the dose used, viral load fell between 10- and 100-fold over the course of the study (seven to 10 days).

The researchers stated that nine participants (26%) reported 14 drug-related side effects. According to the researchers, the most common side effects were “diarrhea, abdominal pain, and vomiting.” They also stated that these side effects were “mild to moderate in intensity.”

No one prematurely left the study or died because of drug-related side effects.

Other research

Researchers have done small and short studies to assess how combinations of compound ’254 might affect other drugs (and vice versa). The combinations tested included the following:

  • compound ’254 and dolutegravir
  • compound ’254 and the combination of TAF + FTC (sold in a pill called Descovy)
  • compound ’254 and oral contraceptives

In all cases, there were no significant interactions.

For the future

ViiV will likely put compound ’254 into larger and longer clinical trials with other anti-HIV drugs to assess its safety and effectiveness. 

As with other relatively new drugs, such as the long-acting injectable Cabenuva (cabotegravir + rilpivirine), it is plausible that ViiV will eventually develop and test both oral and injectable formulations of compound ’254. Clinical trials will be needed to assess the safety and effectiveness of long-acting formulations of compound ’254, and this will take time. Therefore, it may be several years before compound ’254 is approved in Canada and other high-income countries as a new option for HIV treatment.

—Sean R. Hosein

REFERENCES:

  1. Regueiro-Ren A, Sit SY, et al. The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation. Journal of Medicinal Chemistry. 2022 Sep 22;65(18):11927-11948. doi: 10.1021/acs.jmedchem.2c00879. 
  2. Wen B, Zhang Y, Young GC, et al. Investigation of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of the HIV-1 Maturation Inhibitor GSK3640254 Using an Intravenous Microtracer Combined with EnteroTracker for Biliary Sampling. Drug Metabolism and Disposition. 2022 Nov;50(11):1442-1453. 
  3. Spinner CD, Felizarta F, Rizzardini G, et al. Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254. Clinical Infectious Diseases. 2022 Sep 14;75(5):786-794.  
  4. Johnson M, Pene Dumitrescu T, et al. Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants. Clinical Pharmacology in Drug Development. 2022 May;11(5):632-639.  
  5. Pene Dumitrescu T, Greene TJ, et al. Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women. British Journal of Clinical Pharmacology. 2022 Feb;88(4):1704-1712. 
  6. Pene Dumitrescu T, Joshi SR, Xu J, et al. A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants. Antimicrobial Agents and Chemotherapy. 2021 May 18;65(6):e02173-20. 
  7. Pene Dumitrescu T, Joshi SR, Xu J, et al. Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults. British Journal of Clinical Pharmacology. 2021 Sep;87(9):3501-3507
  8. Joshi SR, Fernando D, Igwe S, et al. Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor. Pharmacology Research and Perspectives. 2020 Dec;8(6):e00671.