Drugs

Panobinostat

Other Names: Farydak, LBH589, PNB, panobinostat lactate Drug Class: Latency-Reversing Agents
Molecular Formula: C21 H23 N3 O2
Registry Number: 404950-80-7 (CAS) Chemical Name: 2-Propenamide, N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)-, (2E)- Chemical Class: Hydroxamic acid Organization: Novartis Pharmaceuticals Corporation Phase of Development: I/II

Chemical Image:

(Click to enlarge)
panobinostat

panobinostat

Molecular Weight: 349.4317

(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group website,2 Farydak Full Prescribing Information,3 Journal of Biomedicine and Biotechnology article,4 and ClinicalTrials.gov5)

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 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.8,9 Some research suggests that the activity of HDACis in inducing HIV transcription may not be caused by direct effects on histone acetylation, but may be caused by effects on other nonhistone proteins.7,10,11

Half-life (T½): 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 hepatic elimination of panobinostat is through CYP3A4 metabolism. In vitro, minor contributions to the metabolism of panobinostat are mediated by CYP2D6 and CYP2C19 enzymes. In vitro, the following UGT enzymes contribute to the glucuronidation of panobinostat: UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT2B4.3

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

Resistance: Resistance to panobinostat in the context of HIV infection has not been described.


Clinical Trials


Study Identifiers: CLEAR trial; NCT01680094
Sponsor: University of Aarhus
Phase: I/II
Study Purpose: The purpose of this open-label study was to evaluate the safety and effectiveness of panobinostat in reactivating HIV transcription in latently infected CD4 cells.
Study Population:

  • Participants were HIV-infected adults 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.
Dosing: Participants received panobinostat 20 mg administered orally 3 times per week (on Mondays, Wednesdays, and Fridays) every other week for a period of 8 weeks. A total of 12 panobinostat doses were given. Participants maintained their ART regimens while receiving panobinostat treatment. Post-treatment follow-up was performed for 24 weeks.

Participants had the option to take part in an analytical treatment interruption of ART after completing panobinostat treatment and after the primary outcome analysis was completed. During the treatment interruption, participants resumed ART if certain criteria were met.7,12-14

Selected Study Results:

Study Identifiers: ACTIVATE trial; NCT02471430
Sponsor: Massachusetts General Hospital
Phase:I/II
Study Purpose: The purpose of this open-label study is to evaluate whether a combination regimen consisting of panobinostat and the immunomodulator peginterferon alfa-2a can reduce latent HIV reservoirs.
Study Population:
  • Participants are HIV-infected adults 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.
Dosing: Participants will be randomly assigned to 1 of the following 2 groups:

Group A: Participants will receive 1 week of treatment with oral panobinostat 5 mg (given on Days 0, 2, and 4), followed by 3 weeks off treatment.

Group B: Participants will receive 1 week of treatment with oral panobinostat 5 mg (given on Days 0, 2, and 4) + 1 subcutaneous (SC) injection of peginterferon alfa-2a 180 mcg (given on Day 0). This will be followed by 3 weeks off treatment.

All participants in both Groups A and B will continue to receive ART during the entire treatment period. The total study duration will be 2 months.5
* This study is currently recruiting participants.


Adverse Events


In the CLEAR trial (NCT01680094), 45 adverse events (AEs) were reported, of which 16 were related to panobinostat. The panobinostat-related AEs were all Grade 1 in severity. The most frequently occurring panobinostat-related AE was fatigue. Changes in leukocyte, neutrophil, monocyte, and thrombocyte counts were noted during the study; however, these changes were reversible and were considered minor. Panobinostat treatment did not alter CD4 counts and total lymphocyte counts.13 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.15,16

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.17 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.18

Additional AEs known to be associated with panobinostat use are described in the FDA-approved Farydak Full Prescribing Information.


Drug Interactions


Panobinostat is a CYP3A substrate and a P-gp substrate. In vitro studies have indicated that panobinostat inhibits the CYP2D6, CYP2C19, and CYP3A4 enzymes in a time-dependent manner. Panobinostat, however, neither inhibited CYP1A2, CYP2C8, CYP2C9, and CYP2E nor induced CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP3A, and UGT1A1.3

In vitro studies have demonstrated that panobinostat is an inhibitor of the following drug transporter proteins: OAT3, OCT1, OCT2, OATP1B1, and OATP1B3. However, panobinostat did not inhibit P-gp, BCRP, or OAT1 and did not induce P-gp or MRP2 transporters.3

Panobinostat is an FDA-approved treatment for multiple myeloma, and its interactions with other drugs have been previously described. These include interactions between panobinostat and strong CYP3A inhibitors, including the HIV PIs indinavir, lopinavir/ritonavir, nelfinavir, 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

Additional drug-drug interactions between panobinostat and coadministered drugs are described in the FDA-approved Farydak Full Prescribing Information.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/404950-80-7. Last accessed on February 8, 2017.
  2. Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on February 8, 2017.
  3. Novartis Pharmaceuticals Corporation. FARYDAK – panobinostat capsule: Full Prescribing Information, June 2016. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7774972a-eeaa-4b9a-9e56-3fc1b968e86a. Last accessed on February 8, 2017.
  4. Masetti R, Serravalle S, Biagi C, and Pession A. The Role of HDACs Inhibitors in Childhood and Adolescence Acute Leukemias. J Biomed Biotechnol. Vol 2011; Article ID 148046. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026992/pdf/JBB2011-148046.pdf. Last accessed on February 8, 2017.
  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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02471430. Last accessed on February 8, 2017.
  6. Shirakawa K, Chavez L, Hakre S, Calvanese V, and Verdin E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 2013 Jun; 21(6): 277–285. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685471/. Last accessed on February 8, 2017.
  7. Tolstrup M. Cyclic Panobinostat (LBH589) dosing in HIV-1 patients: Findings from the CLEAR trial. Slides presented at: 7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; June 30 – July 3, 2013; Kuala Lumpur, Malaysia. Available at: https://www.iasociety.org/Web/WebContent/File/HIV_Cure_Symposium_2013/Session%203_Martin%20Tolstrup.pdf. Last accessed on February 8, 2017.
  8. Matalon S, Rasmussen TA, and Dinarello CA. Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir. Mol Med. 2011 May-Jun; 17(5-6): 466–472. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105138/. Last accessed on February 8, 2017.
  9. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, and Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013 Apr 1; 9(4): 790–799. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903897/. Last accessed on February 8, 2017.
  10. 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 Nov; 10(11): e1004473. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231123/. Last accessed on February 8, 2017.
  11. 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 Feb;32(2):169-73. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761808/. Last accessed on February 8, 2017.
  12. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01680094. Last accessed on February 8, 2017.
  13. 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. Oct 2014; 1(1):e13-e21. Available at: https://www.researchgate.net/publication/280290228. Last accessed on February 8, 2017.
  14. Barton KM, Rasmussen TA, Tolstrup M, et al. Panobinostat Broadly Activates Latent HIV-1 Proviruses in Patients. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 109. Available at: http://www.croiconference.org/sessions/panobinostat-broadly-activates-latent-hiv-1-proviruses-patients. Last accessed on February 8, 2017.
  15. 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 Mar 30;2(1):ofv037. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438909/. Last accessed on February 8, 2017.
  16. Rasmussen TA, Søgaard OS, Møller HJ, et al. HIV Reactivation by the Histone Deacetylase Inhibitor Panobinostat: Effects on CNS. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 482. Available at: http://www.croiconference.org/sessions/hiv-reactivation-histone-deacetylase-inhibitor-panobinostat-effects-cns. Last accessed on February 8, 2017.
  17. Tolstrup M, Brinkmann CR, Rasmussen TA, et al. Panobinostat dosing has broad but transient immunomodulatory effects in HIV-patients. Poster presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 405. Available at: http://www.croiconference.org/sites/default/files/posters-2015/405.pdf. Last accessed on February 8, 2017.
  18. 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: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 369. Available at: http://www.croiconference.org/sessions/vivo-effects-panobinostat-and-romidepsin-hiv-1-specific-cd8-t-cell-immunity. Last accessed February 8, 2017.


Last Reviewed: February 8, 2017