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Drugs

Tucaresol

Other Names: 589C80 Drug Class: Immune Modulators
Molecular Formula: C15 H12 O5
Registry Number: 84290-27-7 (CAS) Chemical Name: 4-[(2-formyl-3-hydroxy-phenoxy)methyl]benzoic acid Chemical Class: Benzoic Acids Organization: GlaxoSmithKline Phase of Development: II (discontinued)

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tucaresol

tucaresol

Molecular Weight: 272.2548


(Compound details obtained from ChemIDplus Advanced1 and NIAID Therapeutics Database2)

NOTE: The development of tucaresol for HIV treatment has been discontinued.


The study of tucaresol as an immune modulator appears to be discontinued. Searching ClinicalTrials.gov for tucaresol trials related to HIV shows no ongoing or planned trials. The last published clinical trial results for tucaresol as an HIV treatment were released in 2005.


Pharmacology


Mechanism of Action: Immune modulator. Tucaresol, a substituted benzaldehyde, is a low-molecular-weight compound that enhances co-stimulatory signaling to CD4 cells. Immune induction is dependent on transient covalent bonding (Schiff base formation) between carbonyls and amines expressed on antigen presenting cell (APC) and T-cell surfaces. Tucaresol substitutes for the natural donor of carbonyl groups to mimic the transient bonding that is essential for T-cell activation.4-6

In preliminary studies, tucaresol has been shown to stimulate HIV-specific cytotoxic T lymphocyte responses and generation of naive T cells via thymopoiesis in patients receiving ART who have suppressed viremia. Tucaresol appears to specifically increase type 1 cytokine production. The clinical benefits of tucaresol use as an adjuvant agent to enhance immune response and restoration in patients receiving ART are still unknown.7-9

Half-life (T½): In a study of single, oral doses of tucaresol (200 mg) administered on 2 separate occasions to healthy, HIV-uninfected men and women (under fed and fasted states), the tucaresol terminal elimination half-life ranged from 105 to 113 hours.10

Resistance: Tucaresol’s effect on HIV-1 envelope V3 sequences was analyzed using viral samples obtained from tucaresol-treated patients in a Phase I/II trial at study entrance and at Week 16. Tucaresol administration was found to not accelerate V3 evolution.3


Clinical Trials


Study Identifier: Not available
Sponsor: Not available
Phase: I/II
Study Purpose: The purpose of this open-label pilot study was to determine the safety and immunomodulating effects of tucaresol.
Study Population: Participants were HIV-infected and treatment-experienced or treatment–naive in different stages of infection:

  • Group A: Participants were on ART >1 year, with CD4 counts 300-500 cells/mm3 and HIV RNA <80 copies/mL.
  • Group B: Participants were treatment-naive, with CD4 counts >500 cells/mm3 and HIV RNA >10,000 copies/mL.
  • Group C: Participants were treatment-naive, with CD4 counts >500 cells/mm3 and HIV RNA <10,000 copies/mL.
  • Group D: Participants were on ART >1 year, with CD4 counts <200 cells/mm3 and HIV RNA <80 copies/mL. (Participants were considered immunological nonresponders.)

Dosing: Groups A and D participants added tucaresol to ongoing ART; Group B participants started on both tucaresol and ART together; Group C participants received tucaresol alone (without ART). Tucaresol was administered to all participants according to the following pulse-dose-escalation protocol, with about a 3-week washout between each dose level:

  • Tucaresol 25 mg administered as a single dose during Week 1
  • Tucaresol 25 mg once daily for 4 days during Week 4
  • Tucaresol 50 mg once daily for 4 days during Week 8
  • Tucaresol 100 mg once daily for 4 days during Week 127-9

Selected Study Results:

Other HIV-related clinical trials involving tucaresol have also been completed, including a Phase II study (NCT00343941) that evaluated 2 different dose levels of tucaresol in participants who were virologically suppressed on ART.11


Adverse Events


In the Phase I/II pulse-dose-escalation study of tucaresol administered over a 12-week period, 2 tucaresol-related serious adverse events (SAEs) occurred in the first week of treatment: 1 in a patient taking tucaresol alone (Group C) and the other in a patient starting both tucaresol and ART (Group B). Both SAEs involved constitutional signs and symptoms, as well as a decrease in HIV RNA and CD4 counts. After discontinuation of the study drug and administration of either anti-inflammatories or prednisone, all tucaresol-related symptoms subsided and immunovirological abnormalities reverted to prior states.7

No SAEs were reported in patients who were receiving tucaresol as an adjuvant to ongoing ART (Groups A and D). In these patients, the most common adverse events were low-grade fever and mild constitutional symptoms.7


Drug Interactions


Tucaresol drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/84290-27-7. Last accessed on July 14, 2017.
  2. 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 14, 2017.
  3. Bulgheroni E, Bandera A, Galli M, Gori A, Rusconi S. Analysis of the env V3 sequences obtained from patients with HIV type 1 infection treated with the immune modulant agent tucaresol. AIDS Res Hum Retroviruses. 2005 Sep;21(9):815-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16218807. Last accessed on July 14, 2017.
  4. Chen H, Rhodes J. Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. J Mol Med (Berl). 1996 Sep;74(9):497-504. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8892054. Last accessed on July 14, 2017.
  5. Rhodes J. Discovery of immunopotentiatory drugs: current and future strategies. Clin Exp Immunol. 2002 Dec;130(3):363-9. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906540/. Last accessed on July 14, 2017.
  6. Rhodes J. Therapeutic potential of Schiff base-forming drugs. Expert Opin Investig Drugs. 1996 Mar;5(3):257-268 doi:10.1517/13543784.5.3.257. Available at: http://www.tandfonline.com/doi/abs/10.1517/13543784.5.3.257. Last accessed on July 14, 2017.
  7. Gori A, Trabattoni D, Bandera A, et al. Immunomodulation induced by tucaresol in HIV infection: results of a 16 week pilot Phase I/II trial. Antivir Ther. 2004 Aug;9(4):603-14. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=51adea26-5a12-4d62-bca1-3164eb7a9222. Last accessed on July 14, 2017.
  8. Bandera A, Gori A, Trabattoni D, et al. Positive Immunomodulatory Effects of Tucaresol in HIV-infected Patients: Results from a Phase I/II Trial after 40 Weeks of Follow-up. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 10-14, 2003; Boston, MA. Abstract 654. Available at: http://www.aegis.org/DisaplayConf/?Abstract=107218. Last accessed on April 23, 2014.
  9. Gazzola L, Marchetti G, Bandera A, et al. Dynamics of T Cells Homeostasis Induced by Tucaresol. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2004; San Francisco, CA. Abstract 523. Available at: http://www.aegis.org/DisaplayConf/?Abstract=108015. Last accessed on April 23, 2014.
  10. Peck RW, Wootton R, Wiggs R, Layton G, Posner J. Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers. Br J Clin Pharmacol. 1998 Jul;46(1):83-6. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873973/. Last accessed on July 14, 2017.
  11. GlaxoSmithKline. A Phase II multicentre, randomized, double blind, parallel group, placebo controlled pilot study of tucaresol at two dosing levels (25,50 mg) in HIV-1 infected adult subjects with plasma HIV-1 RNA < 50 copies/ml on stable highly active antiretroviral therapy regimen for at least 3 months. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 22, 2006. NLM Identifier: NCT00343941. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00343941. Last accessed on July 14, 2017.


Last Reviewed: July 14, 2017