FDA News: Issue 1-1 January 2023

Author: [AUTHOR] Published on 1/27/2023 5:00:00 AM

FDA Approves SUNLECA (Lenacapavir) for the Treatment of HIV-1 in Adults with Limited Treatment Options

On December 22, 2022, the US Food and Drug Administration (FDA) approved SUNLENCA (lenacapavir), in combination with other antiretroviral(s), for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations.

The approved recommended regimen of SUNLENCA consists of two initiation dosing options followed by maintenance dosing:
  • Initiation (two options):
    • Option 1: 927 mg subcutaneous (SC) injection and 600 mg orally on Day 1, then 600 mg orally on Day 2
    • Option 2:  600 mg orally on Day 1, 600 mg orally on Day 2, 300 mg orally on Day 8, then 927 mg SC injection on Day 15
  • Maintenance:
    • 927 mg SC injection every 6 months (26 weeks) from the date of the last injection +/-2 weeks
Additional information regarding dosage and administration, including missed doses, as well as warnings and precautions about immune reconstitution syndrome, long-acting properties and potential associated risks with SUNLENCA, and injection site reactions can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Lenacapavir, a capsid inhibitor, works by blocking the HIV-1 virus’ protein shell (the capsid), thereby interfering with multiple essential steps of the viral lifecycle.
General PK: The PK properties of lenacapavir are provided in Table 1 and Table 2.

Table 1. PK Properties of Lenacapavir

 Oral SC
% Absolute Bioavailability 6 to 10 100a
Tmaxb 4 hours 77 to 84 daysc
Effect of Food
Effect of low-fat meal (relative to fasting) AUCinf ratio 98.6 (58.2, 167.2) -
Cmax ratio 115.8 (55.4, 242.1) -
Effect of high-fat meal (relative to fasting)e AUCinf ratio 115.2 (72.0, 184.5) -
Cmax ratio 145.2(77.9, 184.5) -
Apparent volume of distribution (Vd/f, L)
19240 9500 to 11700
% bound to human plasma proteins >98.5
Blood-to-plasma ratio 0.5 to 0.7f
t1/2 10 to 12 days 8 to 12 weeks
Clearance (mean apparent clearance, L/h) 55 4.2
% of dose of unchanged drug in plasmag  69
Metabolic pathway(s) CYP3A (minor)
UGT1A1 (minor)
Major routes of elimination Excretion of unchanged drug into fecesh
% of dose excreted in urineg <1
% of dose excreted in feces (% unchanged)h 76 (33)

a Values reflect absolute bioavailability following SC administration of the 927 mg dose.
b Values reflect administration of lenacapavir with or without food.
c Due to slow release from the site of SC administration, the absorption profile of SC administered lenacapavir is complex.
d Values refer to geometric mean ratio (90% confidence interval) in PK parameters [low-fat meal/fasting]. Low fat meal is approximately 400 kcal, 25% fat.
e Values refer to geometric mean ratio (90% confidence interval) in PK parameters [high-fat meal/fasting]. High fat meal is approximately 1000 kcal, 50% fat.
f Values reflect the blood-to-plasma ratio of lenacapavir following a single dose intravenous administration of [14C] lenacapavir through 336 hours post-dose.
g Dosing in mass balance studies: single dose intravenous administration of [14C] lenacapavir to subjects without HIV-1 infection.
h Metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A and UGT1A1 and no single circulating metabolite accounted for >10% of plasma drug-related exposure.

Table 2. Lenacapavir Exposures Following Oral and SC Administration of SUNLENCA in Heavily Treatment-Experienced Subjects with HIV

Parameter Mean (% CV) Recommended Dosing Regimen, Option 1a Recommended Dosing Regimen, Option 2b
Day 1: 600 mg (oral) + 927 mg (SC),
Day 2: 600 mg (oral)
Days 1 and 2: 600 mg (oral),
Day 8: 300 mg (oral),
Day 15: 927 mg (SC)
Day 1 to end of Month 6 Days 1 to 15 Day 15 to end of Month 6
Cmax (ng/mL) 97.1 (61.6) 124.4 (85.1) 87.3 (49.4)
AUCtau (h•ng/mL) 234294.8 (65.1) 25962.9 (67.8); 251907.2 (48.2)
Ctrough (ng/mL) 29.2 (90.8) 48.6 (52.1) 35.1 (59.2)

CV: Coefficient of variation; SC: subcutaneous
a Predicted exposures.
b Post hoc exposures from efficacy study.

The estimated exposures of lenacapavir were 43% to 100% higher in subjects with HIV-1 infection compared to subjects without HIV-1 infection.

Drug Interactions
Effect of Other Drugs on SUNLENCA: Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A.
  • Strong or Moderate CYP3A Inducers: Concomitant administration of SUNLENCA with strong CYP3A inducers during SUNLENCA treatment is contraindicated. Concomitant administration of SUNLENCA with moderate CYP3A inducers during SUNLENCA treatment is not recommended. Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of lenacapavir, which may result in loss of therapeutic effect of SUNLENCA and development of resistance.
  • Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors: Concomitant administration of SUNLENCA with these inhibitors is not recommended. Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of SUNLENCA.
Effect of SUNLENCA on Other Drugs: Lenacapavir is a moderate inhibitor of CYP3A. Due to the long half-life of lenacapavir following SC administration, SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A initiated within 9 months after the last SC dose of SUNLENCA, which may increase the potential risk of adverse reactions. For drugs primarily metabolized by CYP3A [e.g., narcotic analgesics (fentanyl, oxycodone); anticoagulants (rivaroxaban, dabigatran, edoxaban)], see the prescribing information of the sensitive CYP3A substrate for dosing recommendations with moderate inhibitors of CYP3A.

Established and Other Significant Drugs: Concomitant administration of SUNLENCA is contraindicated with the following agents: anticonvulsants (carbamazepine or phenytoin), antimycobacterial (rifampin), and St. John’s wort. Concomitant administration of these agents with SUNLENCA may result in loss of therapeutic effect and development of resistance. Additional information on established and other potential drug interactions, including necessary titration and monitoring, can be found in the full prescribing information linked below.

Use in Specific Populations
There were no clinically significant differences in the PK of lenacapavir based on age (18 to 78 years), sex, ethnicity (hispanic or non-hispanic), race (white, black, asian, or other), body weight (41.4 to 164 kg), severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the PK of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir.

Efficacy and Safety
Efficacy of SUNLENCA was demonstrated in HIV-1 infected, heavily treatment-experienced subjects with multidrug resistance participating in a 52-week, randomized, placebo-controlled, double-blind, multicenter trial. The primary efficacy endpoint was the proportion of subjects in cohort 1 achieving ≥ 0.5 log10 copies/mL reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions.

Full prescribing information is available at: SUNLENCA Full Prescribing Information on Drugs@FDA.

Visit Drugs@FDA at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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