Drug Database: Panobinostat

Pharmacology

Pharmacology

Mechanism of Action:

Latency-reversing agent, specifically a histone deacetylase inhibitor (HDACi).² Panobinostat, a cinnamic hydroxamic acid analogue, is a pan-HDACi that targets many Class I, II, and IV histone deacetylases (HDACs), including the Class I HDAC-1, -2, and -3 enzymes, which are important in disruption of HIV latency.^6-8 Panobinostat was previously FDA approved under the brand name Farydak for the treatment of multiple myeloma and is no longer marketed in the United States; it is still available in other parts of the world.⁹ As an HIV therapeutic, panobinostat is currently being investigated as an agent for reactivating latent HIV expression.^2,5 In HIV-1 latency, HDACs are recruited to the proviral 5' long terminal repeat (LTR), where they catalyze deacetylation of lysine residues on histones. This results in chromatin condensing on nucleosome 1 (nuc-1), which prevents HIV transcription. Inhibition of HDAC activity promotes histone acetylation (hyperacetylation) of lysine residues by histone acetyltransferases (HATs), leading to chromatin relaxation and transcriptional activation.^8,10 Some research suggests that the activity of HDACs in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other nonhistone proteins.^7,11,12

Half-life (T_½):

In participants with advanced cancer, the estimated terminal elimination half-life of panobinostat was 37 hours.³

Metabolism/Elimination:

Panobinostat is extensively metabolized via reduction, hydrolysis, oxidation, and glucuronidation. Approximately 40% of the total dose of panobinostat is eliminated by oxidative metabolism, primarily via CYP3A4. Minor contributions to the metabolism of panobinostat are mediated by CYP2D6 and CYP2C19 enzymes.³

After a single oral dose of radiolabeled panobinostat in participants with advanced cancer, 29% to 51% of the administered dose was excreted in urine (with less than 2.5% as unchanged drug), and 44% to 77% was excreted in feces (with less than 3.5% as unchanged drug).³

Select Clinical Trials

Select Clinical Trials

Study Identifiers: CLEAR; NCT01680094

Sponsor: University of Aarhus
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and efficacy of panobinostat in reactivating HIV transcription in latently infected CD4 cells.
Study Population:

• Participants were adults with HIV who had received continuous ART for at least 2 years prior to enrollment.
• Participants were virologically suppressed with HIV RNA <50 copies/mL for at least 2 years and had CD4 counts >500 cells/mm³ at last measurement.^7,13

Selected Study Results: Results published in Lancet HIV (2014) showed that panobinostat administered to virologically suppressed participants on ART was effective in reactivating latent HIV. However, panobinostat did not reduce the size of the latent HIV reservoir.¹⁴

Additional Published Material:

• IAS Towards an HIV Cure Symposium, 2013: Cyclic panobinostat (LBH589) dosing in HIV-1 patients: findings from the CLEAR trial
• CROI, 2015: Panobinostat broadly activates latent HIV-1 proviruses in patients

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Study Identifiers: ACTIVATE; NCT02471430

Sponsor: Massachusetts General Hospital
Phase: 1/2
Status: This study is currently active but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether a combination regimen of panobinostat and the immunomodulator peginterferon alfa-2a can reduce the latent HIV reservoir.
Study Population:

• Participants are adults with HIV who have been receiving continuous ART for at least 24 months prior to screening and who have been receiving the same ART regimen for at least 12 weeks prior to screening.
• Participants have been virologically suppressed on ART, with HIV RNA <50 copies/mL, for at least 24 months prior to screening and have CD4 counts ≥400 cells/mm³.⁵

Selected Study Results: Results published at CROI 2022 indicated that panobinostat reactivated latent HIV and interferon alfa-2a induced immune activation in participants with virological suppression on ART. The combination regimen, however, produced no change in latent HIV reservoir size.¹⁵

Adverse Events

Adverse Events

In the CLEAR trial (NCT01680094), 45 adverse events (AEs) were reported, including 16 related to panobinostat. The panobinostat-related AEs were all Grade 1 in severity. The most frequently occurring panobinostat-related AE was fatigue. Declines in neutrophil and thrombocyte counts noted during the study were reversible and within normal limits, respectively. Panobinostat treatment did not alter CD4 counts.^7,14 In a substudy analysis, researchers evaluated cerebrospinal fluid (CSF) inflammation and neurodegeneration biomarkers and found that panobinostat did not result in central nervous system (CNS) AEs.^16,17

Panobinostat caused significant immunomodulatory changes, but these changes did not appear harmful and did not persist beyond 4 weeks after the end of dosing. Alterations in gene expression that had occurred during panobinostat dosing returned to normal by 24 weeks postdosing.¹⁸ Furthermore, analysis of panobinostat’s effect on HIV-specific CD8 cells found no evidence that panobinostat decreased levels or responses of HIV-1 specific effector memory (EM) CD8 cells.¹⁹

Drug Interactions

Drug Interactions

Panobinostat undergoes non-CYP mediated metabolism (reduction, hydrolysis, oxidation, and glucuronidation), as well as CYP mediated metabolism. Approximately 40% of a panobinostat dose is metabolized by CYP3A4, with minor contributions from CYP2D6 and CYP2C19. Panobinostat pharmacokinetics may therefore be affected by CYP3A4 inhibitors and inducers. Panobinostat is also a P-gp substrate.³

Drug-drug interactions between panobinostat and concomitant medications have been previously described. These include interactions between panobinostat and strong CYP3A and/or P-gp inhibitors, including the HIV PIs ritonavir and saquinavir; strong CYP3A inducers; sensitive CYP2D6 substrates or CYP2D6 substrates that have a narrow therapeutic index; and drugs that are known to prolong the QT interval.³

References

References

1. National Center for Biotechnology Information: PubChem compound summary for CID 6918837, panobinostat: Accessed May 17, 2023
2. Treatment Action Group. Research toward a cure trials. June 2020. Accessed May 17, 2023
3. Secura Bio Limited. Farydak 10mg hard capsules summary of product characteristics (SmPC), March 11, 2021. Electronic Medicines Compendium (EMC). Accessed May 17, 2023
4. Masetti R, Serravalle S, Biagi C, Pession A. The role of HDACs inhibitors in childhood and adolescence acute leukemias. J Biomed Biotechnol. Published online Article ID 148046 2011. doi:10.1155/2011/148046. Accessed May 17, 2023
5. Massachusetts General Hospital. A Phase I-II pilot study to assess the safety and efficacy of combined administration with pegylated interferon-alpha2a and the histone deacetylase inhibitor (HDACi) panobinostat for reducing the residual reservoir of HIV-1 infected cells in cART-treated HIV-1 positive individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 11, 2015. NLM Identifier: NCT02471430. Accessed May 17, 2023
6. Shirakawa K, Chavez L, Hakre S, Calvanese V, Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013;21(6):277-285. doi:10.1016/j.tim.2013.02.005. Accessed May 17, 2023
7. Tolstrup M. Cyclic Panobinostat (LBH589) dosing in HIV-1 patients: findings from the CLEAR trial. Slides presented at: International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; June 30–July 3, 2013; Kuala Lumpur, Malaysia. Accessed May 17, 2023
8. Matalon S, Rasmussen TA, Dinarello CA. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med. 2011;17(5-6):466-472. doi:10.2119/molmed.2011.00076. Accessed May 17, 2023
9. Secura Bio, Inc.: Press Release, dated November 30, 2021. Secura Bio announces U.S. withdrawal of FARYDAK ® (panobinostat) NDA. Accessed May 17, 2023
10. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccines Immunother. 2013;9(4):790–799. Accessed May 17, 2023
11. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10(11).doi:10.1371/journal.ppat.1004473. Accessed May 17, 2023
12. Jamaluddin MS, Hu PW, Jan Y, Siwak EB, Rice AP. Short communication: the broad-spectrum histone deacetylase inhibitors vorinostat and panobinostat activate latent HIV in CD4(+) T cells in part through phosphorylation of the T-loop of the CDK9 subunit of P-TEFb. AIDS Res Hum Retroviruses. 2016;32(2):169-173. doi:10.1089/aid.2015.0347. Accessed May 17, 2023
13. University of Aarhus. The safety and efficacy of the histone deacetylase inhibitor panobinostat for purging HIV-1 from the latent reservoir (CLEAR) study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 3, 2012. NLM Identifier: NCT01680094. Accessed May 17, 2023
14. Rasmussen TA, Tolstrup M, Brinkmann CR, et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a Phase 1/2, single group, clinical trial. Lancet HIV. 2014;1(1):e13-21. doi:10.1016/S2352-3018(14)70014-1. Accessed May 17, 2023
15. Armani-Tourret M, Hartana CA, Rassadkina Y, et al. HIV-1 viral reservoir disruption with panobinostat and IFN-⍺. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI)); February 12-16, 2022; Virtual. Poster 357. Accessed May 17, 2023
16. Rasmussen TA, Tolstrup M, Møller HJ, et al. Activation of latent human immunodeficiency virus by the histone deacetylase inhibitor panobinostat: a pilot study to assess effects on the central nervous system. Open Forum Infect Dis. 2015;2(1). doi:10.1093/ofid/ofv037. Accessed May 17, 2023
17. Rasmussen TA, Søgaard OS, Møller HJ, et al. HIV reactivation by the histone deacetylase inhibitor panobinostat: effects on CNS. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 482. Accessed May 17, 2023
18. Tolstrup M, Brinkmann CR, Rasmussen TA, Olesen R, Kj AS. Panobinostat dosing has broad but transient immunomodulatory effects in HIV-patients. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 405. Accessed May 17, 2023
19. Olesen R, Rasmussen TA, Lichterfeld M, et al. In vivo effects of panobinostat and romidepsin on HIV-1-specific CD8 T cell immunity. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 369. Accessed May 17, 2023

Last Reviewed: May 17, 2023