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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
Company: Novartis Pharmaceuticals Corp
Phase of Development: Phase III, as an immune modulator for HIV infection
Patent Version Content

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 a genetically engineered 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. The IL-2 receptor (IL-2R) consists of 3 subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and IL-2Rγ (CD132). IL-2 acts on cells expressing either the high-affinity trimeric IL-2R (all 3 subunits together) or the low-affinity dimeric IL-2R (CD122 and CD132). Following receptor binding, 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, treatment with aldesleukin has been extensively studied in different populations of HIV-infected individuals for its potential to aid in immune restoration by increasing CD4 counts.12-15 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 In 2 Phase III trials, intermittent aldesleukin plus ART was shown to increase CD4 counts in HIV-infected individuals; however, the aldesleukin-mediated increases in CD4 counts ultimately did not translate into any clinical benefits in either study.4,5,12 Because of these results and because of an excess of aldesleukin-related Grade 4 adverse events that occurred in the 2 trials, use of aldesleukin as an investigational HIV therapeutic has been questioned.12,16,22 

Half-life (T½): As an FDA-approved treatment for metastatic renal cell carcinoma and melanoma, the pharmacokinetic properties of aldesleukin have been previously described. 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 were also assessed 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 in HIV-infected individuals. A total of 28 cycles of therapy was analyzed. The SC aldesleukin elimination half-life was 3.3 +/- 0.9 hours.23 

Metabolism/Elimination: Following IV infusion, aldesleukin is eliminated by metabolism in the kidneys. More than 80% of the amount of aldesleukin that is distributed to plasma, cleared from circulation, and presented to the kidneys is metabolized to amino acids in cells lining the proximal convoluted tubules.3

Resistance: Resistance to aldesleukin in the context of HIV infection has not been described.


Clinical Trials


Study Identifiers: ANRS118; ILIADE; NCT00071890 
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: II/III
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 HIV-infected, treatment-experienced adults 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) + 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 ≥500 cells/mm3 underwent a TI. (Aldesleukin was not administered during the TI of ART.) ART was resumed if CD4 counts <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
Study Purpose: The purpose of these open-label studies was to evaluate whether intermittent aldesleukin + ART could lower the risk of opportunistic infection and death in HIV-infected individuals.
Study Population:

  • ESPRIT: Participants were HIV-infected adults with 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 HIV-infected adults with HIV RNA <10,000 copies/mL and CD4 counts between 50 to 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 ESPIRT 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 been conducted. These include (1) the STALWART study (NCT00110812), which evaluated the effects of aldesleukin +/- ART on CD4 counts in participants who were either ART-naïve 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-naïve or off ART, and (3) the COSMIC trial, which assessed the effects of aldesleukin +/- ART on latent HIV.13,14,17,26,27 A Phase I/II study (NCT01013415) evaluating ART + autologous CD4-zeta gene-modified T cells +/- aldesleukin is ongoing.21


Adverse Events


In the ANRS 118 study (NCT00071890), 148 total participants were randomized, with 81 participants in the aldesleukin + ART group and 67 participants in the ART-alone group. A high number of aldesleukin-related adverse events (AEs), the majority of which were Grade 1 to 2 in severity, occurred during the first 24 weeks of the trial. Constitutional symptoms (such as asthenia, fever, and nausea) were the most frequently reported AEs and accounted for 50% of all AEs. Among 17 participants who discontinued aldesleukin, AEs related to aldesleukin were the main reason for discontinuation in 11 participants. 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.25

In the ESPRIT study (NCT00004978), 4111 total participants (2071 receiving aldesleukin + ART and 2040 receiving ART alone) enrolled in the study. 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.12

In the SILCAAT study (NCT00013611), 1695 total participants (849 receiving aldesleukin + ART and 846 receiving ART alone) enrolled in the study. 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.12

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


Drug Interactions


In a pharmacokinetic study of 17 HIV-infected individuals receiving indinavir (800 mg every 8 hours) plus a 5-day continuous infusion of aldesleukin, between Days 1 and 5 of the aldesleukin infusion, the area under the curve (AUC) of indinavir increased by a mean of 88% in 8 out of 9 participants. IL-6 concentrations increased in all participants and indinavir clearance significantly decreased. Indinavir trough concentrations also significantly increased.28

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


References


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Last Reviewed: October 21, 2016