Drug Database: Lefitolimod

Pharmacology

Pharmacology

Mechanism of Action

Latency-reversing agent, specifically a toll-like receptor 9 (TLR9) agonist.² Lefitolimod is a synthetic oligonucleotide that belongs to a family of molecules known as double-stem loop immunomodulators (dSLIM).^3,5

Lefitolimod works by binding to and activating TLR9, a pattern-recognition receptor (PRR) that is part of the innate host defense mechanism. In resting immune cells, TLR9 is expressed only on plasmacytoid dendritic cells (pDCs) and B cells and is activated by nonmethylated CG DNA sequences found in certain bacterial and viral genomes, as well as mammalian mitochondrial DNA from damaged cells.^3,6-9 Lefitolimod has been shown to trigger numerous inflammatory and immune responses that are associated with antipathogenic and antitumor effects.^6-8 Responses associated with lefitolimod’s anti-HIV effect include (1) induction of cytokine release, including type I interferon-alfa (IFN-alfa) and CXCL10; (2) activation of pDCs, natural killer (NK) cells, and T cells; and (3) enhancement of NK cell degranulatory potential, intracellular IFN-gamma production, and NK cell-mediated viral inhibition.^7,10

Lefitolimod has also been shown to disrupt HIV latency via an indirect mechanism of action.⁷ As such, it has been investigated in a Phase 1b/2a trial (NCT02443935) for its potential to reactivate HIV expression in latently infected cells and enhance host antiviral immune responses.¹¹ Currently, lefitolimod is being evaluated in a Phase 1/2 trial (NCT04357821) in combination with investigational therapeutic HIV vaccines and/or broadly neutralizing antibodies (bNAbs).¹²

Half-life (T_½)

In a Phase 1 crossover study of a single subcutaneous (SC) dose of lefitolimod 60 mg and a single SC dose of placebo in healthy participants, the median half-life of lefitolimod was 12.7 hours.¹³

Select Clinical Trials

Select Clinical Trials

Study Identifiers: TEACH study; NCT02443935

Sponsor: University of Aarhus
Phase: 1b/2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate whether lefitolimod could (1) reactivate HIV expression in latently infected cells, (2) enhance antiviral immune responses, (3) reduce latent HIV reservoir size, and (4) delay the time to viral rebound after analytical treatment interruption (ATI) of ART. The safety of lefitolimod was also assessed throughout the trial.
Study Population:

• Participants were adults with HIV who had been on ART for at least 12 months.
• Participants had HIV RNA <50 copies/mL and CD4 counts >350 cells/mm³ at screening.^2,11,14

Selected Study Results: Results published in Clinical Infectious Diseases (2017) and AIDS (2019) showed that lefitolimod enhanced antiviral immune responses and acted as a latency-reversing agent by increasing HIV transcription in a subset of participants. However, lefitolimod treatment had no significant impact on latent HIV reservoir size and did not delay the time to viral rebound after analytical treatment interruption of ART.^2,15
Additional Published Material:

• Mucosal Immunol article, 2018: The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon
• EBioMedicine, 2019: TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

Study Identifier: NCT04357821

Sponsor: University of California, San Francisco
Phase: 1/2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether a combination regimen can control viral load levels in participants undergoing an ATI of ART. The combination regimen includes (1) therapeutic HIV vaccines (Gag conserved element [CE]-targeted DNA + IL-12 prime/MVA boost vaccination), (2) bNAbs VRC07-523LS and 10-1074, and (3) lefitolimod.
Study Population:

• Participants are adults with HIV who have been on continuous ART for at least 12 months and a stable ART regimen that does not include an NNRTI for at least 4 weeks.
• Participants have had undetectable HIV RNA in the past 24 months and have CD4 counts ≥500 cells/mm³ at screening.^12,16

Selected Study Results: Results presented at CROI 2023 indicated that most of the participants (seven out of 10) who received combination therapy had at least partial virologic control after ART interruption. The average time to viral rebound following ART interruption was 15 weeks.¹⁶
Additional Published Material:

• CROI, 2024: Post-intervention HIV control linked to early in vivo CD8+ T-cell proliferative response to rebound
• CROI, 2024: Effect of broadly neutralizing antibody exposure on HIV rebound following combination immunotherapy

Study Identifiers: TITAN; NCT03837756

Sponsor: University of Aarhus
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety of lefitolimod administered with the bNAbs 3BNC117 and 10-1074 and to evaluate whether this combination therapy could delay the time to viral rebound during an ATI of ART.
Study Population:

• Participants are adults with HIV who have been on ART for at least 18 months.
• Participants have had HIV RNA <50 copies/mL for at least 15 months and have CD4 counts >500 cells/mm³ at screening.
• Participants have HIV that is sensitive to 3BNC117 and 10-1074.⁴

Selected Study Results: Results published in Nature Medicine (2023) and presented at CROI 2023 showed that the groups receiving dual bNAb treatment had a significant delay in the time to viral rebound during ART interruption, as compared to groups receiving placebos only or lefitolimod plus placebo. The addition of lefitolimod to dual bNAb treatment did not confer any additional effect on viral control compared to dual bNAb treatment alone.^17,18

Adverse Events

Adverse Events

TEACH study (NCT02443935)

In the first part of the Phase 1b/2a TEACH study, 15 participants enrolled and completed 4 weeks of lefitolimod treatment while on ART plus two follow-up visits. Among a total of 81 reported adverse events (AEs), 57 were related to lefitolimod. Injection site reaction (mainly transient erythema) was the most common drug-related AE. Except for four cases of neutropenia (of which three cases were Grade 2 and one case was Grade 3), all drug-related AEs were Grade 1. All AEs, including the cases of neutropenia, resolved spontaneously.²

Researchers also analyzed participants’ colon tissue samples collected at baseline and after 4 weeks of dosing with lefitolimod and found that lefitolimod did not cause any damaging tissue inflammation in the colon.¹⁹

In the second part of the TEACH study, 14 participants were enrolled to receive an additional 24 weeks of lefitolimod treatment plus ART, followed by an ATI of ART. During this time, there were 139 drug-related AEs reported. The drug-related AEs were similar to those that have been previously reported.¹⁴

TITAN (NCT03837756)

In this Phase 2a trial, participants were randomized to receive placebo/placebo (n=10), lefitolimod/placebo (n=10), placebo/bNAbs (n=11), or lefitolimod/bNAbs (n=12). Out of 253 reported AEs, 94 were considered unrelated to any investigational drug or placebo. Eighty-one AEs, most of which were mild in intensity, were related to lefitolimod. The most common lefitolimod-related AEs were injection site reactions (n = 39) and fatigue (n = 6). Fourteen AEs were related to bNAb therapy — 11 were mild, two were moderate, and one was severe. The severe bNAb-related AE was an infusion-related reaction to 3BNC117 that resolved with treatment. The most common AE related to bNAb therapy was fatigue (n = 5).¹⁸

Drug Interactions

Drug Interactions

Drug-drug interactions associated with lefitolimod are currently unknown.

References

References

1. National Center for Biotechnology Information. PubChem Substance Record for SID 472407762, Lefitolimod, Source: FDA Global Substance Registration System (GSRS). Accessed August 1, 2024
2. Vibholm L, Schleimann MH, Højen JF, et al. Short-course toll-like receptor 9 agonist treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection. Clin Infect Dis. 2017;64(12):1686-1695. doi:10.1093/cid/cix201. Accessed August 1, 2024
3. National Cancer Institute (NCI). NCI Drug Dictionary: TLR9 agonist MGN1703. Accessed August 1, 2024
4. University of Aarhus. Combining a TLR9 agonist with broadly neutralizing antibodies for reservoir reduction and immunological control of HIV infection: an investigator-initiated randomized, placebo-controlled, Phase IIa trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 7, 2019. NLM Identifier: NCT03837756. Accessed August 1, 2024
5. Schmidt M, Hagner N, Marco A, König-Merediz SA, Schroff M, Wittig B. Design and structural requirements of the potent and safe TLR-9 agonistic immunomodulator MGN1703. Nucleic Acid Ther. 2015;25(3):130-140. doi:10.1089/nat.2015.0533. Accessed August 1, 2024
6. Wittig B, Schmidt M, Scheithauer W, Schmoll HJ. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Crit Rev Oncol Hematol. 2015;94(1). Accessed August 1, 2024
7. Offersen R, Nissen SK, Rasmussen TA, et al. A novel toll-like receptor 9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1-infected autologous CD4+ T cells. J Virol. 2016;90(9):4441-4453. doi:10.1128/JVI.00222-16. Accessed August 1, 2024
8. Kapp K, Kleuss C, Schroff M, Wittig B. Genuine immunomodulation with dSLIM. Mol Ther Nucleic Acids. 2014;3(6):e170. doi:10.1038/mtna.2014.28. Accessed August 1, 2024
9. Horscroft NJ, Pryde DC, Bright H. Antiviral applications of toll-like receptor agonists. J Antimicrob Chemother. 2012;67(4):789-801. doi:10.1093/jac/dkr588. Accessed August 1, 2024
10. Mologen AG: Press release, dated March 14, 2016. Extension of TEACH study based on supportive first study results. Accessed August 1, 2024
11. University of Aarhus. Toll-like receptor 9 enhancement of antiviral immunity in chronic HIV-1 infection: a Phase 1b/2a trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 30, 2015. NLM Identifier: NCT02443935. Accessed August 1, 2024
12. University of California, San Francisco. Combinatorial therapy with a therapeutic conserved element DNA vaccine, MVA vaccine boost, TLR9 agonist and broadly neutralizing antibodies: a proof-of-concept study aimed at inducing an HIV remission. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 18, 2020. NLM Identifier: NCT04357821. Accessed August 1, 2024
13. Zurlo A, Schmidt M, Dax A, et al. Safety, pharmacokinetics and pharmacodynamics from a clinical trial with healthy volunteers using the immunotherapeutic TLR-9 agonist MGN1703. Ann Oncol. 2015;26:viii5. doi:10.1093/annonc/mdv514.20. Accessed August 1, 2024
14. Vibholm LK, Frattari G, Schleimann MH, et al. Effect of 24 weeks TLR9 agonist therapy on CTL responses and viral rebound during ATI. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI): March 4-7, 2018; Boston, MA. Poster 357. Accessed August 1, 2024
15. Vibholm LK, Konrad CV, Schleimann MH, et al. Effects of 24-week toll-like receptor 9 agonist treatment in HIV type 1+ individuals. AIDS Lond Engl. 2019;33(8):1315-1325. doi:10.1097/QAD.0000000000002213. Accessed August 1, 2024
16. Peluso M, Deitchman A, Magombedze G, et al. Rebound dynamics following immunotherapy with an HIV vaccine, TLR-9 agonist, and broadly neutralizing antibodies. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22, 2023; Seattle, WA. Poster 435. Accessed August 1, 2024
17. Gunst JD, Reikvam DH, McMahon JH, et al. The impact of 3BNC117, 10-1074, and lefitolimod on HIV-1 persistence: the TITAN trial. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22, 2023; Seattle, WA. Abstract 136. Accessed August 1, 2024
18. Gunst JD, Højen JF, Pahus MH, et al. Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nat Med. 2023;29(10):2547-2558. doi:10.1038/s41591-023-02547-6. Accessed August 1, 2024
19. Krarup AR, Schleimann MH, Vibholm LK, et al. TLR9 agonist triggers potent intestinal antiviral response in HIV+ individuals on ART. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 314. Accessed August 1, 2024

Last Reviewed: August 1, 2024