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An Overview of Cabotegravir

July 30, 2014

Table of Contents


For Patients

Other Names: 744 LA, CAB, cabotegravir sodium, GSK1265744, GSK-1265744, GSK744, GSK744 LA, GSK744 LAP, S-265744, S/GSK1265744
Drug Class: Integrase Inhibitors
Molecular Formula: C19 H17 F2 N3 O5
Registry Number: 1051375-10-0 (CAS)
Company: ViiV Healthcare
Phase of Development: IIb

Chemical Image:

Cabotegravir chemical image

cabotegravir
Molecular Weight: 405.3553
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ViiV Healthcare website3)


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.


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What Is Cabotegravir?

Cabotegravir (also known as S/GSK1265744) is an investigational drug that is being studied for the treatment and prevention of HIV infection.4

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.

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.)5

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 or under the skin (known as GSK744 LA).6,7 (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.)4


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.8

In most cases, an investigational drug must be proven safe and effective 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.8


In What Phase of Testing Is Cabotegravir?

Cabotegravir is currently being studied in Phase IIb clinical trials.2


What Have Recent Studies Shown About Cabotegravir?

In a Phase IIb study (known as the LATTE study), investigators looked at the safety and effectiveness of three different strengths of oral cabotegravir taken once daily in HIV-infected adults. Participants had never taken HIV medicines before entering the study (also called treatment-naive). The study consisted of two parts. During the first part, which lasted 24 weeks, participants were assigned to one of the following four regimens:

Participants who were taking cabotegravir and who had successful viral suppression could continue to the second part of the study. (Viral suppression is when antiretroviral therapy [ART] reduces the amount of HIV in a person’s blood sample to an undetectable level.) In the second part of the study, participants who were taking cabotegravir stopped their two NRTI medicines and added the FDA-approved NNRTI medicine rilpivirine (brand name: Edurant). Participants in the efavirenz group continued taking efavirenz plus the two NRTIs.6,9

In this study, oral cabotegravir showed antiviral activity at all three dosing strengths studied. Week 24 results showed that viral load (the amount of HIV in a blood sample) appeared to decline significantly faster in participants taking cabotegravir than in participants taking efavirenz.9,10 Week 48 results showed that cabotegravir plus rilpivirine, when used in participants with viral suppression, was as effective at controlling viral load as efavirenz plus two NRTIs. In terms of safety, no serious adverse events related to cabotegravir treatment were reported. Fewer participants in the cabotegravir dosing groups dropped out of the study because of an adverse event than in the efavirenz group.9

Another Phase IIb study will be looking at the effectiveness and safety of using oral cabotegravir followed by the long-acting injectable formulation of cabotegravir (GSK744 LA) for lowering viral load and maintaining viral suppression in HIV-infected, treatment-naive adults.7

Cabotegravir is also being developed as a medicine for pre-exposure prophylaxis (PrEP) for adults at risk of acquiring HIV. PrEP means using a medicine before possible exposure to a virus or bacteria to reduce the risk of becoming infected with the virus or bacteria. Two Phase IIa studies will be looking at the safety of GSK744 LA: one in HIV-uninfected men, and the other in HIV-uninfected men and women.11-13


What Side Effects Might Cabotegravir Cause?

In the Phase IIb LATTE study discussed under the previous question, mild to moderately severe headache occurred in some participants taking oral cabotegravir.14

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


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.


I Am Interested in Participating in a Clinical Trial of Cabotegravir. 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.8

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

  1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on July 30, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on July 30, 2014.
  3. ViiV Healthcare website. Medicines in development. Last accessed on July 30, 2014.
  4. 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. Last accessed on July 30, 2014.
  5. 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. Last accessed on July 30, 2014.
  6. 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. Last accessed on July 30, 2014.
  7. 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. Last accessed on July 30, 2014.
  8. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Last accessed on July 30, 2014.
  9. Margolis D, Brinson C, Eron J, et al. 744 and Rilpivirine as Two-Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 91LB. Last accessed on July 30, 2014.
  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. Last accessed on July 30, 2014.
  11. 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. Last accessed on July 30, 2014.
  12. 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. Last accessed on July 30, 2014.
  13. Hankins C. Pre-Exposure Prophylaxis: state-of-the-art and roll-out. Slides presented at: 8th International Workshop on HIV Treatment, Pathogenesis and Prevention Research in Resource-Poor Settings (INTEREST); May 5-9, 2014; Lusaka, Zambia. Last accessed onJuly 30, 2014.
  14. 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. Last accessed on July 30, 2014.

For Health Professionals

Other Names: 744 LA, CAB, cabotegravir sodium, GSK1265744, GSK-1265744, GSK744, GSK744 LA, GSK744 LAP, S-265744, S/GSK1265744
Drug Class: Integrase Inhibitors
Molecular Formula: C19 H17 F2 N3 O5
Registry Number: 1051375-10-0 (CAS)
Company: ViiV Healthcare
Phase of Development: IIb

Chemical Image:

Cabotegravir chemical image

cabotegravir
Molecular Weight: 405.3553
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ViiV Healthcare website3)


Pharmacology

Mechanism of Action: HIV-1 integrase strand transfer inhibitor. Cabotegravir (also known as S/GSK1265744) prevents viral DNA integration into the host genome and is being developed for both HIV treatment and prevention.4,5

Half-life (T½): 21 to 50 days (long-acting parenteral [LAP] nanosuspension administered via intramuscular [IM] or subcutaneous [SC] injection); 40 hours (oral dosing).6

Metabolism/Elimination: Cabotegravir is primarily metabolized via glucuronidation by UGT1A1 (main pathway) and UGT1A9 (minor pathway). Cytochrome P450 (CYP)-mediated metabolism is expected to have a minimal role in cabotegravir metabolism.7

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Resistance: In vitro, cabotegravir has exhibited activity against raltegravir-resistant isolates.8

Exposure of MT-2 cells infected with HIV-1 IIIB to increasing concentrations of cabotegravir for up to 112 days did not produce highly resistant mutants. Eight site-directed molecular clones containing single raltegravir mutations exhibited less than a 2-fold change (FC) in cabotegravir susceptibility (except Q148K/R, which demonstrated a 5.6/5.1 FC, respectively). Fifteen site-directed molecular clones containing 14 double mutations exhibited less than a 12 FC. Cross-resistance to raltegravir and elvitegravir is limited.9

In vitro analysis was performed on the susceptibility of recombinant viruses with patient-derived integrase from various clades of HIV-1 to cabotegravir. Fifty percent and 90% inhibitory concentrations (IC50 and IC90) of cabotegravir against each virus was comparable to cabotegravir’s activity against the wild-type control. No virus exhibited significant resistance to cabotegravir. Cabotegravir demonstrated a modest reduction in activity against two common integrase resistant viruses with the mutations G140S plus Q148H or E92Q plus N155H. These viruses, however, had significant resistance to raltegravir.10

Virologic failure with treatment-emergent integrase inhibitor (INI) mutation (Q148R) and non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (E138Q) has been reported in one patient receiving once-daily oral cabotegravir (CAB) 10 mg plus rilpivirine (RPV) in a Phase IIb study. This patient, however, had very low drug concentrations of both oral CAB and RPV.11


Dosing in Clinical Trials

Study Identifiers: LAI116482 (LATTE)11; NCT0164180912
Phase: IIb
Study Purpose: Dose-ranging efficacy study of oral CAB to select oral dose and evaluate oral CAB plus rilpivirine as a two-drug antiretroviral therapy (ART) regimen for suppressive maintenance therapy
Study Population: HIV-infected, treatment–naive adults
Dosing:

(See references cited above for information on study results.)

Study Identifier: NCT0212035213
Phase: IIb
Study Purpose: Safety and efficacy study to evaluate the antiviral activity, tolerability, and safety of two intramuscular (IM) dosing regimens of the long-acting injectables GSK744 LA plus TMC278 LA and to compare the IM dosing regimens to oral CAB plus abacavir/lamivudine (ABC/3TC)
Study Population: HIV-infected, treatment-naive adults
Dosing:

Two Phase IIa studies of GSK744 LA will be undertaken to develop the safety profile of the long-acting injectable for pre-exposure prophylaxis (PrEP). The ECLAIR study will investigate GSK744 LA in HIV-uninfected men at risk of acquiring HIV, and HPTN 077 will examine GSK744 LA in HIV-uninfected women and men.14-16


Adverse Events

In the Week 48 analysis of the LATTE study involving 243 treatment-naive patients, drug-related adverse events ≥ Grade 2 occurred in 14% of participants in the oral CAB arm and in 19% of participants in the EFV arm. Drug-related adverse events ≥ Grade 2 were uncommon during the maintenance phase, occurring in 4% of participants in both the oral CAB and EFV study arms. Serious adverse events occurring in the oral CAB arm were all unrelated to oral CAB treatment. Three percent of oral CAB participants and 13% of EFV participants withdrew from the study because of an adverse event. Headache, mostly Grade 1 and 2, was more common with oral CAB treatment (22%) than with EFV treatment (11%). Treatment-emergent laboratory abnormalities ≥ Grade 3 were reported in 21% of oral CAB participants and in 31% of EFV participants. Alanine aminotransferase (ALT) elevations of any grade were seen in 17% of oral CAB participants and in 21% of EFV participants.11,17

Safety data from eight Phase I or IIa clinical studies of oral CAB and the long-acting injectable formulation, GSK744 LA, were evaluated in a meta-analysis. One hundred eighty-seven healthy and HIV-infected participants received oral CAB 5 mg to 50 mg for up to 14 days. Ninety-eight healthy participants received IM or SC GSK744 LA in single or repeat doses up to 800 mg. No drug-related serious adverse events occurred. The most common adverse events not related to an injection site reaction (ISR) were headache (22%) and nausea (5%). ISRs related to GSK744 LA were predominately mild (93%) and Grade 1. No Grade 3 ISR adverse events were reported. The most frequent ISRs related to the IM and SC long-acting injectables were pain (71% for IM; 24% for SC), erythema (9% for IM; 23% for SC), and nodules (7% for IM; 23% for SC). All ISRs were self-limited, and there were no study withdrawals because of an ISR.18


Drug Interactions

Cabotegravir does not affect the pharmacokinetics of midazolam in human study participants, indicating that cabotegravir is neither a CYP inhibitor nor inducer. In vitro, cabotegravir does not inhibit UGT enzymes, except UGT1A3. (Cabotegraivr, however, is predicted to have no clinically significant effect on UGT1A3 substrates.) Cabotegravir does not inhibit hepatic, intestinal, or renal drug transporters, except for organic anion transporters 1 and 3 (OAT1/3). Drug-drug interactions are possible between cabotegravir and sensitive OAT1/3 substrates having a narrow therapeutic index (such as methotrexate).7,19


References

  1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on July 30, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on July 30, 2014.
  3. ViiV Healthcare website. Medicines in development. Last accessed on July 30, 2014.
  4. Karmon SL, Markowitz M. Next-generation integrase inhibitors: where to after raltegravir? Drugs. 2013 Mar;73(3):213-28. Last accessed on July 30, 2014.
  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. Last accessed on July 30, 2014.
  6. Spreen W, Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE040. Last accessed on July 30, 2014.
  7. Reese M, Ford S, Bowers G, et al. In vitro drug interaction profile of the HIV integrase inhibitor, GSK1265744, and demonstrated lack of clinical interaction with midazolam. Abstract presented at: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; May 19-21, 2014; Washington, DC. Abstract P_20. Last accessed on July 30, 2014.
  8. Underwood M, St Clair M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1265744: a next generation integrase inhibitor (INI) with activity against raltegravir-resistant clinical isolates. Abstract presented at: 18th International AIDS Conference; July 18-23, 2010; Vienna, Austria. Abstract MOAA0103. Last accessed on July 30, 2014.
  9. Yoshinaga T, Kobayashi M, Seki T, et al. Antiviral Characteristics Of S/GSK1265744, An HIV Integrase Inhibitor (INI) Dosed By Oral Or Long-acting Parenteral Injection. Abstract presented at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Abstract H-550. Last accessed on July 30, 2014.
  10. Karmon SL, Mohri H, Spreen W, Hong Z, Ho D, Markowitz M. GSK1265744 Demonstrates Robust in Vitro Activity Against Various Clades of HIV-1. 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. Last accessed on July 30, 2014.
  11. Margolis D, Brinson C, Eron J, et al. 744 and Rilpivirine as Two-Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 91LB. Last accessed on July 30, 2014.
  12. 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. Last accessed on July 30, 2014.
  13. 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. Last accessed on July 30, 2014.
  14. 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. Last accessed on July 30, 2014.
  15. 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. Last accessed on July 30, 2014.
  16. Hankins C. Pre-Exposure Prophylaxis: state-of-the-art and roll-out. Slides presented at: 8th International Workshop on HIV Treatment, Pathogenesis and Prevention Research in Resource-Poor Settings (INTEREST); May 5-9, 2014; Lusaka, Zambia. Last accessed on July 30, 2014.
  17. Margolis DA, Brinson CC, Eron JJ, et al. 744 and Rilpivirine as TwoDrug 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. Last accessed on July 30, 2014.
  18. Lou Y, Gould E, Chen S, et al. Meta-Analysis of Safety Data from 8 Clinical Studies with GSK1265744, an HIV Integrase Inhibitor, Dosed Orally or as Injection of Long-Acting Parenteral Nanosuspension. Abstract presented at: 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 11, 2013; Denver, CO. Abstract H-672. Last accessed on July 30, 2014.
  19. Reese M, Ford S, Bowers G, et al. In Vitro Drug Interaction Profile of the HIV Integrase Inhibitor, GSK1265744, and Demonstrated Lack of Clinical Interaction with Midazolam. 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; May 19-21, 2014; Washington, DC. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Last accessed on July 30, 2014.
  20. 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. Last accessed on July 30, 2014.
  21. Ford SL, Gould E, Chen S, et al. Lack of Pharmacokinetic (PK) Interaction between Rilpivirine and the Integrase Inhibitors Dolutegravir and S/GSK1265744. Abstract presented at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Abstract A-1249. Last accessed on July 30, 2014.




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