Lenacapavir

Last updated

Lenacapavir
Lenacapavir.svg
Clinical data
Trade names Sunlenca
Other namesGS-CA1, GS-6207
License data
Pregnancy
category
Routes of
administration
By mouth, subcutaneous
Drug class Capsid inhibitors
ATC code
Legal status
Legal status
Identifiers
  • N-[(1S)-1-{3-[4-chloro-3-(methanesulfonamido)-1-(2,2,2- trifluoroethyl)-1H-indazol-7-yl]-6-[3-(methanesulfonyl)-3- methylbut-1-yn-1-yl]pyridin-2-yl}-2-(3,5-difluorophenyl)ethyl]-2- [(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro- 1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamide
CAS Number
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C39H32ClF10N7O5S2
Molar mass 968.28 g·mol−1
3D model (JSmol)
  • CC(C)(C#Cc1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(CC(F)(F)F)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1)S(C)(=O)=O
  • InChI=1S/C39H32ClF10N7O5S2/c1-36(2,63(3,59)60)10-9-21-5-6-22(23-7-8-26(40)30-32(23)57(17-37(43,44)45)54-35(30)55-64(4,61)62)31(51-21)27(13-18-11-19(41)14-20(42)12-18)52-28(58)16-56-34-29(33(53-56)39(48,49)50)24-15-25(24)38(34,46)47/h5-8,11-12,14,24-25,27H,13,15-17H2,1-4H3,(H,52,58)(H,54,55)/t24-,25+,27-/m0/s1
  • Key:BRYXUCLEHAUSDY-WEWMWRJBSA-N

Lenacapavir, sold under the brand name Sunlenca, is an antiretroviral medication used to treat HIV/AIDS. [9] [10] It is taken by mouth or by subcutaneous injection. [9] [10]

Contents

The most common side effects include reactions at the injection site and nausea. [10] [11]

Lenacapavir was approved for medical treatment in the European Union in August 2022, [10] [12] in Canada in November 2022, [5] [6] and in the United States in December 2022. [9] [11] [13] [14] It is the first of a class of drugs called capsid inhibitors to be approved by the US Food and Drug Administration (FDA) for treating HIV/AIDS. [11] [15]

Medical uses

Lenacapavir, in combination with other antiretrovirals, is indicated for the treatment of HIV/AIDS. [9] It is used in heavily treatment-experienced adults with multiple drug resistance in whom current antiretroviral therapy is ineffective due to resistance, intolerance or safety considerations. [9] [11] It has also been found to be highly effective as HIV pre-exposure prophylaxis (PrEP) in heterosexual women in Africa. [16] Further studies are ongoing assessing effectiveness in men who have sex with men and people who inject drugs. [17]

Mechanism of action

Lenacapavir works by binding directly to the interface between HIV-1 viral capsid protein (p24) subunits in capsid hexamers, interfering with essential steps of viral replication, including capsid-mediated nuclear uptake of HIV-1 proviral DNA[ clarification needed ], virus assembly and release, production of capsid protein subunits, and capsid core formation. [9] [11] The US Food and Drug Administration considers it to be a first-in-class medication. [15] [18]

History

Lenacapavir was developed by Gilead Sciences. [19]

The safety and efficacy of lenacapavir were established through a multicenter clinical trial with 72 participants whose HIV infections were resistant to multiple classes of HIV medications. [11] These participants had to have high levels of virus in their blood despite being on antiretroviral drugs. [11] Participants were enrolled into one of two study groups. [11] One group was randomized to receive either lenacapavir or placebo in a double-blind fashion, and the other group received open-label lenacapavir. [11] The primary measure of efficacy was the proportion of participants in the randomized study group who achieved a certain level of reduction in virus during the initial 14 days compared to baseline. [11]

The US Food and Drug Administration granted the application for lenacapavir priority review, fast track, and breakthrough therapy designations. [11]

In 2024, Science named lenacapavir "2024 Breakthrough of the Year", citing its "astonishing 100% efficacy" in one large efficacy trial in women and "99.9% efficacy in gender diverse people who have sex with men," while highlighting that research providing a "new understanding of the structure and function of HIV’s capsid protein" led to the drug's "off-the-charts success". [20]

Society and culture

In June 2022, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Sunlenca, intended for the treatment of adults with multidrug‑resistant human immunodeficiency virus type 1 (HIV‑1) infection. [21] The applicant for this medicinal product is Gilead Sciences Ireland UC. [21]

Lenacapavir was approved for medical use in the European Union in August 2022, [10] [22] in Canada in November 2022, [5] [6] and in the United States in December 2022. [11]

Economics

As of 2024 the drug, produced by Gilead, costs US$42,250 for the first year. A study presented in July 2024 [23] found that mass production of a generic version would allow a profit margin of 30% on an annual price of $40 if used by 10 million people. The authors said that lowering HIV levels significantly would probably require 60 million people to take the drug preventatively. [24]

Research

As of 2021, it is in phase II/III clinical trials. [25] It is being investigated as a treatment for HIV patients infected with multidrug-resistant virus and as a twice-yearly injectable for pre-exposure prophylaxis. [25] [26]

Studies have been conducted for the use of lenacapavir in treatment-naive individuals. [27] For virally suppressed individuals switching treatment, early studies have tested lenacapavir injections in combination with infusions of the broadly neutralizing antibodies teropavimab and zinlirvimab [28] as well as lenacapavir with islatravir. [29]

A phase 3 clinical trial study examined efficacy for pre-exposure HIV prevention (PrEP). [30] [31] [32] [33] It found an incidence rate ratio of 0.00 (as no cases occured in the lenacapavir group) with a 95% confidence interval of 0.00-0.04 with p<.001. Injection site reactions led to discontinuation by 0.2% of lenacapavir patients

Another lenacapavir phase III study, examined the incidence compared to the background rate for men persons. [34] It found an incidence rate ratio of 0.04 with a 95% confidence interval of 0.01 to 0.18, at p<.001. Injection site reactions led to discontinuation by 1.2% of patients.

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References

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