First-in-class attachment inhibitor: mechanism of action for RUKOBIA (fostemsavir)

Only RUKOBIA protects CD4⁺ by directly targeting gp120, leaving healthy, uninfected cells untouched¹

VIDEO: Background music starts; shortly after the headline and subhead appear, the glow behind “CD4” animates in

VIDEO: CD4+ T-cells visible

VO: CD4 T-cells play an essential role in immune response and control of chronic viral infections.^1,2

VIDEO: HIV-1 floats into frame

VO: To initiate the viral replication cycle, HIV-1 virions must attach to target CD4 T-cells.

VIDEO: Camera zooms in closer to see gp proteins on HIV-1

VO: This attachment is mediated by viral envelope proteins comprised of gp120 gp41 subunits.³

VIDEO: Zoom in on the gp120/gp41 receptors; show the receptor transition between open/closed state

VO: The gp120 gp41 trimer transitions between an open and closed state but CD4 attachment can only occur when the gp120 gp41 trimer is in the open state.^4,5

VIDEO: HIV-1 approaches T-cell membrane

VIDEO: Show gp120 approach then bind to the CD4 molecules

VO: Binding of the trimer to the CD4 receptor results in a series of conformational changes that enable binding of cell surface co-receptors, CCR5 or CXCR4.^4,5

VIDEO: Gp120 binds to CD4 and the HIV starts sinking down and rippling into the T-cell membrane

VIDEO: Camera pulls back as we see HIV-1 fusing with T-cell, sinking down through the membrane, and creating a disruptive aqua-like ripple effect that moves across the surface

VO: Co-receptor binding causes further structural rearrangements that drive fusion of the membrane and allows viral replication to begin.³

VIDEO: Show circulating HIV virions and some soluble gp120 molecules

VO: Gp120 can also be spontaneously released from the surface of HIV-1 virions and circulate within plasma and tissues.⁶

VIDEO: Camera follows circulating proteins through environment

VIDEO: Scrolling indication + ISI OVER blurred cellular background; cells and HIV virions float and drift slowly

VO: Let's pause to consider the Indication and Important Safety Information for RUKOBIA, an antiretroviral with a unique mechanism of action.

Indication.

RUKOBIA, used with other HIV-1 medicines, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 who are failing their current ARV regimen.

Important Safety Information.

Contraindications.

Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including those listed here.

Please see additional Important Safety Information for RUKOBIA at the end of the video. Please click the link on this page to view the full Prescribing Information for RUKOBIA.

VIDEO: Close-up of RUKOBIA drug molecule

VO: RUKOBIA (fostemsavir) is the first U.S. Food and Drug Administration-approved attachment inhibitor with a first-in-class mechanism of action that blocks HIV-1 from interacting with host CD4 cells.^7,8

VIDEO: RUKOBIA drug molecules float toward the CD4+ T-cell with HIV-1 virions circulating

VIDEO: Drug molecule approaches HIV that is heading towards T-cell

VIDEO: Drug molecule intercepts HIV by binding to gp120, both on the envelope of HIV-1 and to soluble gp120 proteins floating around

VO: At a granular level, temsavir, the active moiety of RUKOBIA, binds to the gp120 subunit within the HIV-1 envelope. This locks the gp120 gp41 trimer in the closed state. RUKOBIA has also been shown to bind to circulating gp120, although the clinical significance is unknown.⁹

VIDEO: RUKOBIA binds to gp120, which initiates a “frosted glass” effect that spreads across gp120 and then continues over HIV virion

VIDEO: “Frosted glass” effect spreads across HIV to represent that it’s suspended in the closed state and cannot bind to CD4

VO: This action selectively inhibits any interaction between the HIV-1 virion and cellular CD4 receptors.^6,9

VIDEO: Gp120 is unable to bind and HIV floats away

VIDEO: RUKOBIA drug molecules approach many HIVs, and we see subsequent frosted glass effect spreading over them as result of binding to gp120s

VO: Consequently HIV-1 is targeted for elimination by the body’s immune response.¹⁰

VIDEO: Nearby macrophages engulf/digest HIV virions via phagocytosis

VIDEO: RUKOBIA rotates and sparkles in space

VO: This novel mechanism of action makes RUKOBIA the only ARV to prevent HIV-1 from attaching to CD4 cells.^11,12

VIDEO: Camera pulls back through a field of RUKOBIA molecules

VIDEO: Camera holds on one molecule as chart builds around it

VO: There is an unmet need to optimize an effective regimen for heavily treatment-experienced people living with HIV failing their current ARV regimen—whether due to resistance, intolerance, or other safety considerations.¹³Current guidelines recommend that clinicians consider a regimen with at least two fully active agents, which may include drugs with novel mechanisms of action.¹⁴

VIDEO: Camera zooms out with the RUKOBIA molecule at the top of the screen; circles and lines animate in to show the additional two components within the regimen

VIDEO: Headline fades into frame with RUKOBIA molecules floating in space; when “CD4” is mentioned, the glow behind it animates in

VO: As you develop a management plan for your heavily treatment-experienced patients, consider all aspects including viral load and CD4 cell counts. RUKOBIA, as part of an optimized regimen, provides your patients with a novel mechanism of action.

VIDEO: Scrolling ISI OVER blurred bright background; cells and HIV virions float and drift slowly

VO: Important Safety Information, continued.

Warnings and precautions.

Immune Reconstitution Syndrome and autoimmune disorders have been reported with the use of RUKOBIA. QTc Prolongation has occurred with higher than recommended dosages of RUKOBIA. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible.

Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Diligence should be applied when starting RUKOBIA in patients receiving hepatitis B therapy.

Adverse reactions or loss of virologic response due to drug interactions may occur when using RUKOBIA with other drugs.

Adverse reactions. The most common adverse reaction reported with RUKOBIA was nausea.

Drug interactions. See the full Prescribing Information for RUKOBIA for all significant drug interactions. Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible. Use the lowest possible starting dose for statins with careful monitoring. Patients receiving RUKOBIA should not take estrogen-based therapies that contain more than 30 micrograms per day of ethinyl estradiol. Use RUKOBIA with caution in patients with additional risk factors for thromboembolic events.

Use in specific populations. There are insufficient data on the use of RUKOBIA during pregnancy to assess drug-associated risks. Potential risks of breastfeeding include HIV 1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in the infant.

Please click the link on this page to view the full Prescribing Information for RUKOBIA.

VIDEO: References fade into frame

VIDEO: A and ViiV logos fade in with trademark line; background music fades out

Temsavir, the active moiety of RUKOBIA, attaches directly to gp120 on the surface of HIV-1 virions, near the CD4⁺ attachment site. The attachment of temsavir locks gp120 into a closed formation that prevents the initial interaction between the virus and host immune cells.^1,2

This action prevents the first step of viral entry.³

Line drawing depicting RUKOBIA, HIV-1 virions, gp120, and CD4+ T-cell

PREVENTS

RUKOBIA prevents HIV-1 from attaching to host immune cells¹

Gp120 is locked into a closed formation, leaving healthy, uninfected CD4⁺ T-cells untouched.

Line drawing depicting RUKOBIA and gp120

TARGETS

RUKOBIA targets both circulating soluble and viral-bound gp120¹

Other classes block entry following attachment of gp120. RUKOBIA acts on the HIV-1 virion before attachment.

Line drawing depicting CD4+ T-cells and HIV-1 virions

PROTECTS

RUKOBIA protects CD4⁺ T-cells, leaving healthy, uninfected cells untouched¹

HIV-1 virions unable to attach to CD4⁺ T-cells are a target for elimination by the body’s immune response.

VO: RUKOBIA Educational Series

Visual: RUKOBIA EDUCATIONAL SERIES and logos appear on screen.

VO: Mechanism of action.

Visual: MECHANISM OF ACTION appears on the screen.

VO: Indication. RUKOBIA, used with other HIV-1 medicines, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 who are failing their current ARV regimen. Important Safety Information. Contraindications. Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including those listed here. Please see additional Important Safety Information for RUKOBIA at the end of the video. Please click the link on this page to view the full Prescribing Information for RUKOBIA.

Visual: The RUKOBIA indication, contraindications, redirect to the additional Important Safety Information at the end of the vid

VO: First-in-class RUKOBIA

Visual: FIRST-IN-CLASS RUKOBIA is written on screen.

VO: is the first FDA-approved HIV-1 attachment inhibitor.

Visual: FIRST FDA-APPROVED HIV-1 ATTACHMENT INHIBITOR is written.

VO: Unlike previously approved classes that act by blocking entry following attachment of the glycoprotein 120, or gp120, viral envelope protein,

Visual: ARV CLASSES THAT BLOCK ENTRY, HIV-1, and CD4+ T-CELL are drawn.

VO: RUKOBIA acts on the HIV-1 virion before attachment of gp120 to prevent the earliest stage of HIV-1 and CD4+ T-cell engagement.

Visual: RUKOBIA, HIV-1, and CD4+ T-CELL are added to complete the frame.

VO: Temsavir, the active moiety of RUKOBIA, attaches to gp120 on the surface of HIV-1 virions, near the CD4 attachment site.

Visual: HIV-1, GP120, and TEMSAVIR are drawn.

VO: The attachment of temsavir locks gp120 into a closed formation that prevents the initial interaction between the virus and host immune cells, leaving CD4+ T-cells untouched.

Visual: PREVENTS INITIAL INTERACTION arm and CD4+ T-CELL membrane are drawn on screen.

VO: With the HIV-1 virions unable to attach to CD4+ T-cells, they are a target for elimination by the body’s immune response.

Visual: The HIV-1 virions and CD4+ T-cell are drawn. The arrow and IMMUNE RESPONSE are added to the frame.

VO: Important Safety Information, continued. Warnings and Precautions. Immune Reconstitution Syndrome and autoimmune disorders have been reported with the use of RUKOBIA. QTc prolongation has occurred with higher than recommended dosages of RUKOBIA. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or cardiac disease, or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Diligence should be applied when starting RUKOBIA in patients receiving hepatitis B therapy. Adverse reactions or loss of virologic response due to drug interactions may occur when using RUKOBIA with other drugs. Adverse Reactions. The most common adverse reaction reported with RUKOBIA was nausea.

Visual: Important Safety Information scrolls on screen.

VO: Drug Interactions. See the full Prescribing Information for RUKOBIA for all significant drug interactions. Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen, if possible. Use the lowest possible starting dose for statins with careful monitoring. Patients receiving RUKOBIA should not take estrogen-based therapies that contain more than 30 micrograms per day of ethinyl estradiol. Use RUKOBIA with caution in patients with additional risk factors for thromboembolic events. Use in Specific Populations. There are insufficient data on the use of RUKOBIA during pregnancy to assess drug-associated risks. Potential risks of breastfeeding include HIV 1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in the infant. Please click on the link on this page to view the full Prescribing Information for RUKOBIA.

Visual: Important Safety Information scrolls on screen.

REFERENCES:

Thompson M, Lalezari JP, Kaplan R, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: week 48 analysis of AI438011, a Phase IIb, randomized controlled trial. Antivir Ther. 2017;22(3):215-223.
FDA Approval of HIV Medicines. AIDSinfo website. https://aidsinfo.nih.gov/understanding-hiv-aids/infographics/25/fda-approval-of-hiv-medicines. Updated April 30, 2019. Accessed May 9, 2020.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Updated December 18, 2019. Accessed May 7, 2020.
Cahn P, Fink V, Patterson P. Fostemsavir: a new CD4 attachment inhibitor. Curr Opin HIV AIDS. 2018;13(4):341-345.

See how RUKOBIA prevents HIV-1 from interacting with host immune cells

Explore clinical evidence, including long-term data

Clinical Trial & Efficacy

ARV=antiretroviral; gp120=glycoprotein 120; HIV-1=human immunodeficiency virus type-1.

References:

Ackerman P, Thompson M, Molina JM, et al. Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1 AIDS 2021;35(7):1061-1072.
Thompson M, Lalezari JP, Kaplan R, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: week 48 analysis of AI438011, a Phase IIb, randomized controlled trial. Antivir Ther. 2017;22(3):215-223.
Cahn P, Fink V, Patterson P. Fostemsavir: a new CD4 attachment inhibitor. Curr Opin HIV AIDS. 2018;13(4):341-345.

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INDICATION

RUKOBIA, in combination with other antiretrovirals (ARVs), is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current ARV regimen due to resistance, intolerance, or safety considerations.

IMPORTANT SAFETY INFORMATION

Contraindications

Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum).

INDICATION

IMPORTANT SAFETY INFORMATION

Contraindications

Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum).

Warnings and precautions

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection:

Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.
Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B.

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

Adverse reactions

The most common adverse reaction (all grades, randomized cohort) observed in ≥5% of subjects was nausea (10%).
81% of adverse reactions reported with RUKOBIA were mild or moderate in severity.

Drug interactions

See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions.
Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible.
Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.
Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 mcg/day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events.

Use in specific populations

Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.
Lactation: Potential risks of breastfeeding include HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant.

Please see full Prescribing Information for RUKOBIA.

FSTWCNT230034

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This site is funded and developed by ViiV Healthcare.

This site is intended for US healthcare professionals only.

FSTWCNT230032 December 2023

Produced in USA.

First-in-class attachment inhibitor: mechanism of action for RUKOBIA (fostemsavir)

Only RUKOBIA protects CD4+ by directly targeting gp120, leaving healthy, uninfected cells untouched1

PREVENTS

RUKOBIA prevents HIV-1 from attaching to host immune cells1

TARGETS

RUKOBIA targets both circulating soluble and viral-bound gp1201

PROTECTS

RUKOBIA protects CD4+ T-cells, leaving healthy, uninfected cells untouched1

See how RUKOBIA prevents HIV-1 from interacting with host immune cells

Explore clinical evidence, including long-term data

INDICATION

IMPORTANT SAFETY INFORMATION

Contraindications

INDICATION

IMPORTANT SAFETY INFORMATION

Contraindications

Warnings and precautions

Adverse reactions

Drug interactions

Use in specific populations

Only RUKOBIA protects CD4⁺ by directly targeting gp120, leaving healthy, uninfected cells untouched¹

RUKOBIA prevents HIV-1 from attaching to host immune cells¹

RUKOBIA targets both circulating soluble and viral-bound gp120¹

RUKOBIA protects CD4⁺ T-cells, leaving healthy, uninfected cells untouched¹