Drugs

Cabotegravir

Cabotegravir

Other Names: 744 LA, CAB, GSK-1265744, GSK1265744, GSK744, GSK744 LA, GSK744 LAP, S-265744, S/GSK1265744, cabotegravir LA, cabotegravir sodium Drug Class: Integrase Inhibitors Molecular Formula: C19 H17 F2 N3 O5 Registry Number: 1051375-10-0 (CAS) Chemical Name: (3S,11aR)-N-((2,4-difluorophenyl)methyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo(3,2-a)pyrido(1,2-d)pyrazine-8-carboxamide Chemical Class: Carbamoyl pyridone Organization: ViiV Healthcare Phase of Development: Cabotegravir is in Phase III development for both HIV treatment and HIV prevention.

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 HIV/AIDS (Auckland, N.Z.) article, and ViiV Healthcare website4)

What is an investigational drug?

What is an investigational drug?

An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.

To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.

What is cabotegravir?

What is cabotegravir?

Cabotegravir is an investigational drug that is being studied to treat and prevent HIV infection.5

Cabotegravir belongs to a class (group) of HIV drugs called integrase inhibitors.2 Integrase inhibitors block an HIV enzyme called integrase. (An enzyme is a protein that starts or increases the speed of a chemical reaction.) By blocking integrase, integrase inhibitors prevent HIV from multiplying and can reduce the amount of HIV in the body.

Unlike some integrase inhibitors, cabotegravir does not require boosting with an additional drug. (Boosting involves the use of a second drug to increase the effectiveness of the main [first] drug.)6

Two forms of cabotegravir are being studied: tablets that are taken by mouth (known as oral cabotegravir or oral CAB) and a long-acting injectable form that is injected into the muscle (known as cabotegravir LA or CAB LA; LA stands for "long-acting").7,8 (A long-acting drug formulation works over a long period of time. Using this type of drug might mean that the drug could be taken less often, making a treatment or prevention regimen simpler to take.)5

How are clinical trials of investigational drugs conducted?

How are clinical trials of investigational drugs conducted?

Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.9

  • Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
  • Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
  • Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.9

In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.9

Some clinical trials are categorized as “a” or “b,” such as “Phase Ia” or “Phase IIb.” These different sublevels typically mean that a study is researching certain types of information or using a certain type of participant population.

In what phase of testing is cabotegravir?

In what phase of testing is cabotegravir?

Cabotegravir is currently being studied in Phase III testing for HIV treatment and prevention.2,4

What are some studies on cabotegravir?

What are some studies on cabotegravir?

Cabotegravir for HIV Treatment

Study Names: LAI116482 (LATTE); NCT01641809
Sponsor: ViiV Healthcare
Phase: IIb
Status: This study is ongoing, but not recruiting participants.
Location: United States and Canada
Participants

  • The participants are adults with HIV who have never taken HIV medicines before starting the study. 
  • Participants have viral load levels of at least 1,000 copies/mL at the start of the study. (Viral load is the amount of HIV in a blood sample.)
  • Participants have CD4 counts of at least 200 cells/mm3. (A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function.

Purpose: The purpose of this study is to find a safe and effective dose of oral cabotegravir, given as HIV maintenance therapy with the HIV oral medicine rilpivirine (brand name: Edurant). (Maintenance therapy is an ongoing treatment used to help an initial treatment succeed or to prevent a return of disease or infection.)7,10,11 

Study Names: LATTE-2; NCT02120352
Sponsor: ViiV Healthcare
Phase: IIb
Status: This study is ongoing, but not recruiting participants.
Location: United States, Canada, France, Germany, Spain
Participants:

  • The participants are adults with HIV who have never taken HIV medicines before starting the study.
  • Participants have viral load levels of at least 1,000 copies/mL at the start of the study.
  • Participants have CD4 counts of at least 200 cells/mm3.
Purpose: The purpose of this study is to look at the safety and effectiveness of using 2 investigational long-acting injectable medicines together as HIV maintenance therapy. The 2 medicines are cabotegravir LA and rilpivirine LA. (Rilpivirine LA is also known as TMC278 LA.) Other participants in the study will receive oral cabotegravir. On the basis of results from this study, investigators also plan to choose a dosing regimen to be used in Phase III studies.8,12

Other ongoing studies on cabotegraivr LA for HIV treatment include the FLAIR study (NCT02938520) and the ATLAS study (NCT02951052). Both are Phase III studies that are looking at the safety and effectivness of cabotegravir LA plus rilpivirine LA for maintaining viral suppression after a switch from other HIV medicines. (Viral suppression is when HIV medicines reduce a person’s viral load to an undetectable level. HIV still remains in the body but in a resting, inactive state.) Both studies involve switching participants from HIV medicines that are suppressing their viral load levels to cabotegravir LA and rilpivirine LA every 4 weeks.13,14

Cabotegravir for HIV Prevention

Study Names: ECLAIR; NCT02076178
Sponsor: ViiV Healthcare
Phase: IIa
Status: This study has been completed.
Location: United States
Participants: The participants were adult males who did not have HIV at the start of the study and who had a low risk of being infected with HIV. 
Purpose: The purpose of this study was to look at the safety, tolerability, and acceptability of cabotegravir LA for pre-exposure prophylaxis (PrEP). (PrEP involves the use of HIV medicine to prevent HIV infection in people who don’t have HIV but who are at high risk of being infected with the virus.) Participants received both oral cabotegravir and cabotegravir injections over the course of the study, and cabotegravir was compared to a placebo. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.)15,16

Study Identifiers: HPTN 077; NCT02178800
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: IIa
Status: This study is ongoing, but not recruiting participants.
Locations: United States, Brazil, Malawi, South Africa
Participants: The participants are men and women without HIV who are at low risk of being infected with HIV.
Purpose: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of cabotegraivr LA. (Pharmacokinetics is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body.) In this study, cabotegraivr LA is being compared to a placebo.17

Additional studies will be evaluating cabotegravir LA for HIV prevention:

  • HPTN 083 (NCT02720094): This Phase IIb/III study will look at the safety and effectiveness of cabotegravir LA for PrEP and compare cabotegravir LA to the FDA-approved HIV drug tenofovir disoproxil fumarate/emtricitabine (brand name: Truvada). (Truvada is approved for use as PrEP.) Participants are men and transgender women, both of whom have sex with men and are at high risk of being infected with HIV. This study is currently recruiting participants.18
  • HPTN 084 (NCT03164564): This Phase III study will also look at the safety and effectiveness of cabotegravir LA for PrEP and compare cabotegravir LA to Truvada. In this study, participants will be women without HIV who are at risk of being infected with HIV. HPTN 084 is not yet open for participant recruitment.19

For more details on the studies listed above, see the Health Professional version of this record.

What side effects might cabotegravir cause?

What side effects might cabotegravir cause?

One goal of HIV research is to identify new drugs that have fewer side effects. The following side effects were observed in some of the studies of cabotegravir listed above.

LATTE (NCT01641809):
In this study, headache that was mild to moderate in intensity was more common in participants taking oral cabotegravir than in participants taking efavirenz (an HIV medicine used in the control arm of the study). Researchers reported that oral cabotegravir was generally well tolerated.7,11,20,21

LATTE-2 (NCT02120352):
The most common side effect among participants receiving injections was pain at the location of the injection. Most injection site reactions were mild to moderate in severity and went away on their own. Two participants receiving cabotegravir LA stopped participating in the study because of injection site reactions. Other common side effects during the study were cold symptoms, diarrhea, and headache. Cabotegravir may have caused liver damage in 2 participants receiving oral cabotegravir. In both participants, their liver tests returned to normal after they stopped cabotegraivr.22

Overall, participants receiving cabotegravir LA in the LATTE-2 study reported being satisfied with their treatment and were willing to continue with the injections after 32 weeks. Participants were also more satisfied with cabotegravir LA injections than with oral cabotegravir when it came to the drug’s convenience, flexibility, and fit with their lifestyle.24

ECLAIR (NCT02076178):
The most common injection site reactions related to cabotegravir LA were pain, swelling, and itching.15,16 Seven participants dropped out of the study while receiving oral cabotegravir. One participant left the study because of excessive tiredness, 3 left because of signs of muscle or organ injury, and 3 left because of low levels of infection-fighting cells called neutrophils.25

HPTN 077 (NCT02178800):
Injection site reactions occurred frequently in participants receiving cabotegravir LA but were generally mild. Injection site pain and headache were more common among participants receiving cabotegravir than among those receiving placebo injections.17,26

Because cabotegravir is still being studied, information on possible side effects of the drug is not complete. As testing of cabotegravir continues, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying cabotegravir?

Where can I get more information about clinical trials studying cabotegravir?

More information about cabotegravir-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

How can I find more information about participating in a clinical trial?

How can I find more information about participating in a clinical trial?

Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.9

Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/1051375-10-0. Last accessed on October 19, 2017.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on October 19, 2017.
  3. Whitfield T, Torkington A, van Halsema C. Profile of cabotegravir and its potential in the treatment and prevention of HIV-1 infection: evidence to date. HIV AIDS (Auckl). 2016 Oct 14;8:157-164. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074732/. Last accessed on October 19, 2017.
  4. ViiV Healthcare website. Medicines in development. Available at: https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx. Last accessed on October 19, 2017. 
  5. Ford SL, Margolis D, Chen S, Gould E, Spreen W. Plasma and tissue GSK1265744 pharmacokinetics following long-acting parenteral administration in healthy male and female subjects. Abstract presented at: 14th International Workshop on Clinical Pharmacology of HIV Therapy; April 22-24, 2013; Amsterdam, The Netherlands. Abstract O_02. Available at: http://regist2.virology-education.com/abstractbook/2013_3.pdf. Last accessed on October 19, 2017.
  6. Ford SL, Gould E, Chen S, et al. Effects of Etravirine on the Pharmacokinetics of the Integrase Inhibitor S/GSK1265744. Antimicrob Agents Chemother. 2013 Jan;57(1):277-80. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535890/. Last accessed on October 19, 2017.
  7. ViiV Healthcare. A Phase IIb, Dose Ranging Study of Oral GSK1265744 in Combination With Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic Suppression Followed by an Evaluation of Maintenance of Virologic Suppression When Oral GSK1265744 is Combined With Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2012. NLM Identifier: NCT01641809. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01641809. Last accessed on October 19, 2017.
  8. ViiV Healthcare. A Phase IIb Study Evaluating a Long-Acting Intramuscular Regimen of GSK1265744 Plus TMC278 For The Maintenance of Virologic Suppression Following an Induction of Virologic Suppression on an Oral Regimen of GSK1265744 Plus Abacavir/Lamivudine in HIV-1 Infected, Antiretroviral Therapy-Naive Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 17, 2014. NLM Identifier: NCT02120352. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02120352. Last accessed on October 19, 2017.
  9. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: https://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on October 19, 2017.
  10. Margolis D, Bhatti L, Smith G, et al. Once-daily Oral GSK1265744 (GSK744) as Part of Combination Therapy in Antiretroviral Naïve Adults: 24-week Safety and Efficacy Results from the LATTE Study (LAI116482). Abstract presented at: 14th European AIDS Conference; October 16-19, 2013; Brussels, Belgium. Abstract PS7/1. Available at: http://www.professionalabstracts.com/eacs2013/planner/index.php?go=abstract&action=abstract_iplanner&print=0&lprID=148&highlight=GSK1265744&PSID=IVXPCJJQVIXZCSVVMQWX. Last accessed on October 19, 2017.
  11. Margolis DA, Brinson CC, Smith GHR, et al. Cabotegravir and Rilpivirine As Two-Drug Oral Maintenance Therapy: LATTE Week 96 Results. Poster presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 554LB. Available at: http://www.croiconference.org/sites/default/files/posters-2015/554LB.pdf. Last accessed on October 19, 2017.
  12. Margolis DA, Gonzalez-Garcia J, Stellbrink H-J, et al. Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 32 Results. 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Available at: http://www.natap.org/2016/CROI/croi_06.htm. Last accessed on October 19, 2017.
  13. ViiV Healthcare. A Phase III, randomized, multicenter, parallel-group, open-label study evaluating the efficacy, safety, and tolerability of long-acting intramuscular cabotegravir and rilpivirine for maintenance of virologic suppression following switch from an integrase inhibitor single tablet regimen in HIV-1 infected antiretroviral therapy naive adult participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 15, 2016. NLM Identifier: NCT02938520. Available at: https://clinicaltrials.gov/ct2/show/NCT02938520. Last accessed on October 19, 2017.
  14. ViiV Healthcare. A Phase III, randomized, multicenter, parallel-group, non-inferiority, open-label study evaluating the efficacy, safety, and tolerability of switching to long-acting cabotegravir plus long-acting rilpivirine from current INI- NNRTI-, or PI-based antiretroviral regimen in HIV-1-infected adults who are virologically suppressed. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 15, 2016. NLM Identifier: NCT02951052. Available at: https://clinicaltrials.gov/ct2/show/NCT02951052. Last accessed on October 19, 2017.
  15. ViiV Healthcare. A Phase IIa Study to Evaluate the Safety, Tolerability and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ECLAIR). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 27, 2014. NLM Identifier: NCT02076178. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02076178. Last accessed on October 19, 2017.
  16. Murray M, Markowitz M, Frank I, et al. Tolerability and Acceptability of Cabotegravir LA Injection: Results From the ECLAIR Study. Poster presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Poster 471. Available at: http://www.croiconference.org/sites/default/files/posters-2016/471.pdf. Last accessed on October 19, 2017.
  17. National Institute of Allergy and Infectious Diseases (NIAID). A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 27, 2014. NLM Identifier: NCT02178800. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02178800. Last accessed on October 19, 2017.
  18. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women Who Have Sex With Men. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 21, 2016. NLM Identifier: NCT02720094. Available at: https://clinicaltrials.gov/ct2/show/NCT02720094. Last accessed on October 19, 2017.
  19. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 3 double blind safety and efficacy study of long-acting injectable cabotegravir compared to daily oral TDF/FTC for pre-exposure prophylaxis in HIV-uninfected women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 22, 2017. NLM Identifier: NCT03164564. Available at: https://clinicaltrials.gov/ct2/show/NCT03164564. Last accessed on October 19, 2017.
  20. Margolis DA, Brinson CC, Eron JJ, et al. 744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/CROI/croi_27.htm. Last accessed on October 19, 2017.
  21. Margolis DA, Brinson C, Smith GH, et al. Long-term safety and efficacy of CAB and RPV as 2-drug oral maintenance therapy. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Poster 442. Available at: http://www.croiconference.org/sites/default/files/posters-2017/442_Margolis.pdf. Last accessed on October 19, 2017.
  22. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017 Jul 24. [Epub ahead of print]. Available at: http://www.natap.org/2017/IAS/PIIS0140673617319177(1).pdf. Last accessed on October 19, 2017.
  23. Margolis DA, Podzamczer D, Stellbrink H-J, et al. Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 48 Results. 21st International AIDS Conference; July 18-22, 2016; Durban, South Africa. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Available at: http://www.natap.org/2016/IAC/IAC_48.htm. Last accessed on October 19, 2017.
  24. Murray M, Dorey D, Griffith S, Mrus J, Spreen W, Margolis D. Satisfaction, Tolerability, and Acceptability of Cabotegravir (CAB) + Rilpivirine (RPV) Long-Acting Therapy: LATTE-2 Results. Poster presented at: 21st International AIDS Conference; July 18-22, 2016; Durban, South Africa. Poster THPEB052. Available at: http://programme.aids2016.org/PAGMaterial/eposters/0_5385.pdf. Last accessed on October 19, 2017.
  25. Markowitz M, Frank I, Grant R, et al. ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Abstract 106. Available at: http://www.croiconference.org/sessions/%C3%A9clair-phase-2a-safety-and-pk-study-cabotegravir-la-hiv-uninfected-men. Last accessed on October 19, 2017.
  26. Landovitz R, Li S, Grinsztejn B, et al. Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected women and men HPTN 077. Slides presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. Available at:  http://programme.ias2017.org/PAGMaterial/PPT/2899_91/IAS2017_Landovitz_Final_072417.pptx. Last accessed on October 19, 2017.

Last Reviewed: October 19, 2017