RintatolimodOther Names: AMP, Ampligen, Atvogen, poly(I)-poly(C12U), poly(I:C12U), polyI:polyC12U Drug Class: Immune Modulators
Chemical Class: Oligonucleotides Organization: Hemispherx; Rega Institute For Medical Research Phase of Development: Rintatolimod is in Phase IIb development for HIV.
Chemical Image:(Click to enlarge)
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 IAS 2003 Abstract 596,3 and Immunotherapy article4)
Mechanism of Action: Immune modulator. Rintatolimod is a synthetic mismatched double-stranded RNA toll-like receptor (TLR) agonist, having specificity for TLR-3. TLR-3, located in the endoplasm of certain immune cells, recognizes and responds to RNA virus infection. TLR-3 activation by natural or synthetic ligands induces cytokine secretion (such as type I interferon, TNF-α, IL-12, and MCP-1).4-6 Rintatolimod has also been described to activate RNase-L against viral RNA transcripts.6
Half-life (T½): Rintatolimod is reported to have a half-life of approximately 35 to 40 minutes.7
Metabolism/Elimination: Rintatolimod is rapidly metabolized (via hydrolysis) into naturally occurring inactive short RNA fragments and nucleotide precursors.7
Resistance: Rintatolimod has exhibited equal in vitro activity against wild-type HIV and HIV resistant to nevirapine, PIs, or NRTIs.8
Select Clinical Trials
Study Identifiers: AMP 720; NCT00035893
Sponsor: Hemispherx Biopharma
Study Purpose: The purpose of this open-label study was to investigate the role of rintatolimod during treatment interruptions of ART.
Study Population: Participants were HIV-infected, treatment-experienced adults with HIV RNA <50 copies/mL and CD4 counts ≥400 cells/mm3.
Dosing: Participants underwent up to 3 treatment interruptions over 64 weeks during which time they received either IV infusions of rintatolimod 400 mg administered twice weekly or no study drug intervention. Treatment interruption was discontinued when HIV RNA rebounded ≥5000 copies/mL for 3 consecutive weekly tests or ≥50,000 copies/mL once.3,9
Selected Study Results:
- IAS, 2003: Interim Results of AMP720: A Phase IIB Prospective, Randomized, Controlled Study Evaluating the Immunomodulatory Role of Ampligen (Poly I:Poly C12U) Against HIV During STI
Study Identifiers: AMP 719; NCT00035581
Sponsor: Hemispherx Biopharma
Study Purpose: The purpose of this open-label study was to evaluate the safety and efficacy of adding rintatolimod as an adjunct to ongoing ART.
Study Population: Participants were HIV-infected, treatment-experienced adults with HIV RNA >500 and <30,000 copies/mL. Participants had CD4 counts >300 cells/mm3.
Dosing: Participants were randomized to receive either IV infusions of rintatolimod 200 – 400 mg administered twice weekly for 24 weeks (in combination with ART) or ART given alone.10
* This study has been terminated.
In the AMP 720 study (NCT00035893), adverse events associated with rintatolimod were described as generally mild and self-limiting. In participants receiving rintatolimod alone, no adverse effects on lactic acid levels, insulin resistance, or hyperlipidemia were reported.3,9
Drug interactions related to rintatolimod use are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/38640-92-5. Last accessed on July 10, 2017.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on July 10, 2017.
- Blick G, Greiger-Zanlungo P, Strayer DR, Mitchell WM, Carter WA. Interim results of AMP720: a Phase IIb prospective, randomized, controlled study evaluating the immunomodulatory role of ampligen (poly I:poly C12U) against HIV during STI. International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 596. Available at: http://www.abstract-archive.org/Abstract/Share/37573. Last accessed on July 10, 2017.
- Nicodemus CF, Berek JS. TLR3 agonists as immunotherapeutic agents. Immunotherapy. 2010 Mar;2(2):137-40. Available at: http://www.futuremedicine.com/doi/full/10.2217/imt.10.8. Last accessed on July 10, 2017.
- Engel AL, Holt GE, Lu H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev Clin Pharmacol. 2011 Mar;4(2):275-89. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105468/. Last accessed on July 10, 2017.
- [No authors listed]. Mismatched double-stranded RNA: polyI:polyC12U. Drugs R D. 2004;5(5):297-304. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15357629. Last accessed on July 10, 2017.
- Hemispherx Biopharma Inc. Arthritis advisory committee meeting briefing document for the 20th December 2012 meeting: Ampligen® (rintatolimod; poly I : poly C12U) treatment of chronic fatigue syndrome NDA #22-151. Available at: https://wayback.archive-it.org/7993/20170405205841/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM332517.pdf. Last accessed on July 10, 2017.
- Essey RJ, McDougall BR, Robinson WE Jr. Mismatched double-stranded RNA (polyI-polyC(12)U) is synergistic with multiple anti-HIV drugs and is active against drug-sensitive and drug-resistant HIV-1 in vitro. Antiviral Res. 2001 Sep;51(3):189-202. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11448730. Last accessed on July 10, 2017.
- Hemispherx Biopharma. The Role of Ampligen in Strategic Therapeutic Intervention (STI) of Highly Active Anti-Retroviral Therapy (HAART): A Multi-Center, Randomized, Controlled Study of Ampligen Potentiation of the HAART-Free Interval. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 6, 2002. NLM Identifier: NCT00035893. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00035893. Last accessed on July 10, 2017.
- Hemispherx Biopharma. A Multi-Center, Randomized, Controlled Study of the Biological Actions of Ampligen as an Adjunct to HAART in HIV Disease. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 3, 2002. NLM Identifier: NCT00035581. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00035581. Last accessed on July 10, 2017.
Last Reviewed: July 10, 2017