Drugs

Aldesleukin

Other Names: IL-2, Proleukin, interleukin-2, rIL-2, recombinant human interleukin-2, recombinant interleukin-2, rhIL-2 Drug Class: Immune Modulators
Molecular Formula: C690 H1115 N177 O203 S
Chemical Name: 2-133-Interleukin 2 (human reduced), 125-L-serine- Chemical Class: Recombinant interleukin Organization: Novartis Vaccines and Diagnostics, Inc. Phase of Development: Aldesleukin is in Phase III development as an immune modulator for HIV infection.

(Compound details obtained from ChemIDplus Advanced,1 Journal of Internal Medicine article,2 DailyMed Proleukin Full Prescribing Information,3 and ClinicalTrials.gov4,5)

Pharmacology


Mechanism of Action: Immune modulator. Aldesleukin (recombinant IL-2; rIL-2) is a non-glycosylated interleukin-2 (IL-2) product. It is made via recombinant DNA technology that uses an E. coli strain containing an analog of the human IL-2 gene. The biological activity of aldesleukin is similar to that of endogenous IL-2. Aldesleukin is currently FDA-approved for treating metastatic renal cell carcinoma and melanoma.3 In HIV-related clinical trials, aldesleukin is the most commonly studied IL-2 product.6

IL-2 is a type I cytokine belonging to a subfamily of cytokines that uses the common γ-chain receptor. Physiologically, IL-2 is produced in secondary lymphoid organs, primarily by CD4 cells, following activation by antigen. Once bound to the IL-2 receptor, IL-2 can activate multiple signaling pathways, including the JAK-STAT, PI3K–AKT, and MAPK pathways.2,7-9

IL-2 is a T cell growth factor that promotes T cell proliferation and survival. It stimulates the cytotoxic activity of CD8 and natural killer (NK) cells and modulates the differentiation of T cells in response to antigen. In addition, IL-2 induces the production and proliferation of antibodies by B cells, stimulates the development of regulatory T cells (Treg), and is essential for activation-induced cell death. During HIV infection, the progressive loss of CD4 cells leads to reduced IL-2 levels in the body, which is an early indicator of T cell exhaustion.2,9-11

In clinical trials, aldesleukin has been extensively studied for its potential to aid in immune restoration by increasing CD4 counts in different populations of individuals with HIV infection.12-15 In 2 Phase III trials, intermittent aldesleukin plus ART was shown to increase CD4 counts in individuals with HIV; however, the aldesleukin-mediated increases in CD4 counts ultimately did not translate into any clinical benefits in either study.4,5,12 Aldesleukin has also been explored for its ability to boost HIV-1 specific immune responses and as part of a strategy to reduce the latent HIV reservoir. Additionally, aldesleukin has been studied as an adjuvant to therapeutic HIV vaccination and CD4-zeta gene-modified T cell therapy.16-21

Half-life (T½): The elimination half-life of aldesleukin, as derived from studies in individuals with cancer who received a 5-minute intravenous (IV) infusion, was 85 minutes.3

The pharmacokinetic properties of aldesleukin have also been assessed in individuals with HIV. In a dose-escalating study of aldesleukin (12, 15, or 18 million IU per day) administered by subcutaneous (SC) injection once or twice daily for 5 consecutive days every 2 months, the elimination half-life of aldesleukin was 3.3 +/- 0.9 hours.22

Metabolism/Elimination: Following IV infusion, aldesleukin is eliminated by metabolism in the kidneys, with the majority metabolized to amino acids in cells lining the proximal convoluted tubules.3


Clinical Trials


Study Identifier: NCT03308786
Sponsor: Case Western Reserve University
Phase: II
Status: This study is not yet open for participant recruitment.
Study Purpose: The purpose of this open-label pilot study is to evaluate whether aldesleukin can decrease the number of latently infected CD4 cells and reduce the size of the latent HIV reservoir in individuals with HIV.
Study Population:
  • Participants are adults with HIV who have had undetectable viral load levels while on ART for at least 1 year.
  • Participants are receiving a stable ART regimen and are willing to continue on their current regimen for the entire study.
  • Participants have HIV RNA <50 copies/mL measured within 60 days prior to study entry and have CD4 counts ≥350 cells/mm3.

Dosing: Participants will receive 8 cycles of SC aldesleukin treatment (5 million IU administered twice daily), plus ART. One cycle of aldesleukin treatment will occur every 8 weeks, with each cycle lasting 5 consecutive days.23

Study Identifiers: ANRS118; ILIADE; NCT00071890
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: II/III
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to examine whether aldesleukin, administered prior to a treatment interruption (TI) of ART, could extend the duration of the TI and help preserve CD4 counts above 350 cells/mm3.
Study Population:
  • Participants were treatment-experienced adults with HIV who were asymptomatic and receiving ART for at least 12 months.
  • Participants had HIV RNA <50 copies/mL and CD4 counts ≥500 cells/mm3 for the 3 months before screening. Nadir CD4 counts since diagnosis of HIV infection were ≥200 cells/mm3.

Dosing: Participants were randomly assigned to receive either 3 cycles of SC aldesleukin (6 million IU administered twice daily) plus ART or ART alone. One cycle of aldesleukin occurred every 8 weeks, with each cycle lasting 5 consecutive days. At Week 24, participants with CD4 counts of 500 cells/mm3 or greater underwent a TI. (Aldesleukin was not administered during the TI of ART.) ART was resumed if CD4 counts fell below 350 cells/mm3 or when clinically indicated.24,25

Selected Study Results:

Study Identifiers: (1) ESPRIT; NCT00004978 and (2) SILCAAT; NCT00013611
Sponsor: (1) National Institute of Allergy and Infectious Diseases (NIAID) and (2) University of Minnesota - Clinical and Translational Science Institute
Phase: III
Status: Both studies have been completed.
Study Purpose: The purpose of these open-label studies was to evaluate whether intermittent aldesleukin plus ART could lower the risk of opportunistic infection and death in individuals with HIV.
Study Population:

  • ESPRIT: Participants were adults with HIV who had CD4 counts ≥300 cells/mm3 within 45 days of study entry. Participants were receiving ART or were beginning ART at the time of study entry.
  • SILCAAT: Participants were adults with HIV who had HIV RNA <10,000 copies/mL and CD4 counts between 50 and 299 cells/mm3. Participants were receiving ART for at least 4 months prior to study entry.
Dosing:
  • ESPRIT: Participants were randomly assigned to either 3 cycles of SC aldesleukin (7.5 million IU administered twice daily) + ART or ART alone. Each cycle of aldesleukin lasted 5 consecutive days, with 8-week intervals between cycles.
  • SILCAAT: Participants were randomly assigned to either 6 cycles of SC aldesleukin (4.5 million IU administered twice daily) + ART or ART alone. Each cycle of aldesleukin lasted 5 consecutive days, with 8-week intervals between cycles. After the third cycle, the aldesleukin dose could be increased to 6.0 or 7.5 million IU.

In both the ESPRIT and SILCAAT studies, additional cycles could be administered to maintain CD4 counts above predefined target levels. Dose reductions could be implemented to manage aldesleukin toxicity.4,5,12

Selected Study Results:

Numerous other HIV-related studies involving aldesleukin have also been conducted. These include (1) the STALWART study (NCT00110812), which evaluated the effects of aldesleukin with/without ART on CD4 counts in participants who were either ART-naive or off ART, (2) ANRS 119 (NCT00120185), which evaluated whether aldesleukin without ART could increase CD4 counts and defer initiation of ART in participants who were either ART-naive or off ART, and (3) the COSMIC trial, which assessed the effects of aldesleukin with/without ART on latent HIV.13,14,17,26,27 A Phase I/II study (NCT01013415) evaluating ART plus autologous CD4-zeta gene-modified T cells with/without aldesleukin is ongoing.21


Adverse Events


ANRS 118 (NCT00071890):
In this Phase II/III study, 148 total participants were randomized to either aldesleukin plus ART (n = 81) or ART alone (n = 67). During the first 24 weeks of the trial, numerous aldesleukin-related adverse events (AEs) occurred; however, most were Grade 1 to 2 in severity. The most common AEs, which accounted for 50% of all AEs, were constitutional symptoms, such as asthenia, fever, and nausea. Eleven of 17 participants who discontinued aldesleukin reported aldesleukin-related AEs as the main reason for discontinuing treatment. Severe AEs occurred in 7 participants in the aldesleukin group and in 3 participants in the ART-alone group. Grade 3 or 4 laboratory abnormalities occurred in 11 (14%) aldesleukin participants and 16 (24%) ART-alone participants. One participant in the aldesleukin group and 3 participants in the ART-alone group experienced an AIDS-defining event. Six cardiovascular events occurred in 4 participants after Week 24, 1 of which occurred in the aldesleukin group.24,25

ESPRIT (NCT00004978):
In this Phase III trial, 4111 total participants were enrolled to receive either aldesleukin plus ART (n = 2,071) or ART alone (n = 2,040). Grade 4 events occurred in 466 participants receiving aldesleukin and in 383 participants receiving ART alone. Among the 466 participants in the aldesleukin group who experienced a Grade 4 event, a total of 711 Grade 4 events occurred (with 82.4% occurring more than 60 days after the last aldesleukin dose). Vascular disorders and AEs within the category of “general disorders and administration site conditions” were more common in the aldesleukin group than in the ART-alone group. The most frequent type of vascular event was deep-vein thrombosis, which was experienced by 10 participants in the aldesleukin group and by 2 participants in the ART-alone group.4,12

SILCAAT (NCT00013611):
In this Phase III trial, 1,695 total participants were enrolled to receive either aldesleukin plus ART (n = 849) or ART alone (n = 846). A Grade 4 event occurred in 203 participants receiving aldesleukin and in 186 participants receiving ART alone. Among the 203 participants in the aldesleukin group who experienced a Grade 4 event, a total of 342 Grade 4 events occurred (with 78.4% occurring more than 60 days after the last aldesleukin dose). Gastrointestinal and psychiatric disorders were more common in the aldesleukin group than in the ART-alone group.5,12

Additional AEs known to be associated with aldesleukin are described in the FDA-approved Proleukin Full Prescribing Information.


Drug Interactions


A pharmacokinetic interaction study between indinavir (800 mg every 8 hours) and a 5-day continuous infusion of aldesleukin was conducted in individuals with HIV infection. Between Days 1 and 5 of the aldesleukin infusion, the indinavir area under the curve (AUC) increased by a mean of 88% in 8 out of 9 participants. Indinavir clearance significantly decreased, while indinavir trough concentrations significantly increased. Changes in indinavir drug concentrations during aldesleukin infusions were possibly related to induction of IL-6.28

Additional known interactions between aldesleukin and coadministered drugs are described in the FDA-approved Proleukin Full Prescribing Information.


References


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Last Reviewed: November 13, 2017