Lefitolimod is in Phase 2a development as an HIV therapeutic.
(Compound details obtained from PubChem,1 Clinical Infectious Diseases article,2 NCI Drug Dictionary,3 Gilead Sciences website,4 and ClinicalTrials.gov5)
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).3,6
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.3,7-10 Lefitolimod has been shown to trigger numerous inflammatory and immune responses that are associated with antipathogenic and antitumor effects.7-9 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.8,11
Lefitolimod has also been shown to disrupt HIV latency via an indirect mechanism of action.8 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.12 Currently, lefitolimod is being evaluated in two early- to mid-phase trials (NCT03837756 and NCT04357821) where it will be administered with investigational therapeutic HIV vaccines and/or broadly neutralizing antibodies (bNAbs).5,13
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.14
Select Clinical Trials
Study Identifiers: TEACH study; NCT02443935
Sponsor: University of Aarhus
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.
- 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.2,12,15
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.2,16
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
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether using a combination approach can control viral load levels during an ATI of ART. Combination therapy includes (1) therapeutic HIV vaccines (DNA prime/boost [p24CE/p24CE plus p55gag] with IL-12 adjuvant and MVA/HIV62B boost), (2) bNAbs VRC07-523LS and 10-1074, and (3) lefitolimod.
- 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 HIV RNA below detectable levels during the past 24 months.
- Participants have CD4 counts ≥500 cells/mm3 at screening.13
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.17
Study Identifiers: TITAN; NCT03837756
Sponsor: University of Aarhus
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety of lefitolimod administered with the bNAbs 3BNC117 and 10-1074 and to evaluate whether this combination therapy can delay the time to viral rebound during an ATI of ART.
- 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 10-1074.5
Selected Study Results: Results presented at CROI 2023 showed that the groups receiving dual bNAb treatment had a significant delay in time to viral rebound during ATI, 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.18
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.15
In this Phase 2a trial, participants were randomized to receive placebo/placebo (n=11), lefitolimod/placebo (n=11), placebo/bNAbs (n=12), or lefitolimod/bNAbs (n=12). Two severe AEs occurred. One severe AE was unrelated to study treatment and the other (infusion reaction) was related to 3BNC117. Mild AEs occurred more frequently in the lefitolimod/bNAbs group than in other treatment groups.5,18
Drug-drug interactions associated with lefitolimod are currently unknown.
- National Center for Biotechnology Information. PubChem Substance Record for SID 472407762, Lefitolimod, Source: FDA Global Substance Registration System (GSRS). Accessed July 13. 2023
- 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 July 13. 2023
- National Cancer Institute (NCI). NCI Drug Dictionary: TLR9 agonist MGN1703. Accessed July 13. 2023
- Gilead Sciences website. Pipeline. Accessed July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- Mologen AG: Press release, dated March 14, 2016. Extension of TEACH study based on supportive first study results. Accessed July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
- 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 July 13. 2023
Last Reviewed: July 13, 2023