Sunlenca® (lenacapavir)
Mechanism of Action

Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.

 

Sunlenca® (lenacapavir)

Mechanism of Action

This document is in response to your request for information regarding Sunlenca® (lenacapavir [LEN]) and its mechanism of action.

Some data may be outside of the US FDA-approved Prescribing Information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA approved prescribing information.

The full indication, important safety information, and boxed warnings are available at: www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi

Product Labeling1

LEN is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of LEN to cross-linked wild‑type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. LEN inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids).

Mechanism of Action Video

A video of the mechanism of action of LEN is available for your review at: http://ssshare.it/Sv6G

Available Data on the Mechanism of Action of LEN

Mechanism of Action

LEN is a novel, first-in-class, HIV-1 capsid inhibitor with a multistage mechanism of action and a desirable in vitro profile. The HIV capsid protein is part of the group‑specific antigen (gag) region of the HIV-1 gene and plays multiple roles in the HIV replication cycle. LEN binds to the viral capsid protein and prevents nuclear transport, virus assembly and release, and capsid assembly in new virions (Figure 1).2,3 The sustained duration of LEN release from the injection site and its low systemic clearance (in vivo) make LEN an attractive candidate for a long-acting HIV therapy. Additionally, LEN exhibited synergistic effects and remained efficacious against resistant HIV-1 variants in vitro when combined with other antiretroviral therapies.4

Figure 1. Mechanism of Action of LEN4-9


Abbreviations: EC50=half maximal effective concentration; pM=picomolar.

References

  1. Enclosed, Gilead Sciences Inc. SUNLENCA® (lenacapavir) tablets, for oral use. SUNLENCA® (lenacapavir) injection, for subcutaneous use. U.S. Prescribing Information. Foster City, CA.
  2. Daar E, McDonald C, Crofoot G, et al. Dose-response Relationship of Subcutaneous Long-Acting HIV Capsid Inhibitor GS-6207 [Presentation]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 08-11 March, 2020; Boston, MA.
  3. Yant SR, Mulato A, Stepan GJ, et al. GS-6207, A Potent and Selective First-in-Class Long-Acting HIV-1 Capsid Inhibitor [Poster 1504]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 04-07 March, 2019; Seattle, WA.
  4. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020.
  5. Bester SM, Wei G, Zhao H, et al. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020;370(6514):360-364.
  6. Muller B. Track me, if you can - the journey of the HIV-1 capsid through the cell [Presentation]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI) Virtual; 06-10 March, 2021.
  7. Pathak VK. Live-Cell Imaging of HIV-1 Nuclear Import, Uncoating, and Proviruses [Presentation]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI) Virtual; 06-10 March, 2021.
  8. Ganser-Pornillos B. Visualization of HIV-1 Capsid-Dependent Replication in vitro [Presentation]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI) Virtual; 06-10 March, 2021.
  9. Cihlar T. Lenacapavir (GS-6207): The First Clinically Active Long-Lasting Inhibitor of HIV Capsid [Presentation]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI) Virtual; 06-10 March, 2021.

 

 


Product Label

For the full indication, important safety information, and boxed warning(s), please refer to the Sunlenca US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.

Follow-Up

For any additional questions, please contact Gilead Medical Information at:

☎1‐866‐MEDI‐GSI (1‐866‐633‐4474) or   www.askgileadmedical.com

Adverse Event Reporting

Please report all adverse events to:

Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
www.gilead.com/utility/contact/report-an-adverse-event

FDA MedWatch Program by ☎ 1-800-FDA-1088 or MedWatch, FDA, 5600 Fishers Ln, Rockville, MD 20852 or   www.accessdata.fda.gov/scripts/medwatch

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