Novartis' panobinostat impresses in myeloma trial

panobinostat
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DECEMBER 06, 2013

Novartis has posted promising late-stage data on a new treatment for multiple myeloma which shows that the drug improves progression-free survival when combined with two already-marketed drugs.

The compound in question is called panobinostat and top-line results from a Phase III trial demonstrate that the drug, also known as LBH589, significantly extended PFS in patients with relapsed or relapsed and refractory MM in combination with Johnson & Johnson's Velcade (bortezomib) and dexamethasone, compared with the latter two drugs alone. Full results from the study will be presented at an upcoming medical congress and discussed with regulatory authorities worldwide, Novartis noted.

LBH589, a novel hydroxamate analog HDAC inhibitor, has been shown to induce acetylation of histone H3 and H4, increase p21 levels, disrupt the chaperone function of hsp90, and induce cell-cycle G1 phase accumulation and apoptosis of K562 cells and acute leukemia MV4-11 cells. The anti-tumor effect by Panobinostat was also demonstrated in multiple myeloma, NSCLC as well as castrate-resistant prostate cancer cell lines.

Synonyms: LBH-589; LBN-589; LBH589; NVP-LBH589
Technical Data: Molecular Weight - 349.44; Molecular formula - C21H23N3O2; CAS No - 404950-80-7

Panobinostat is an oral pan-inhibitor of class I, II, and IV histone and non-histone deacetylase enzymes (HDACs/DACs). It works by blocking a set of key enzymes which ultimately leads to cellular stress and death of these cells.

Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid^[1] and acts as a non-selective histone deacetylase inhibitor (HDAC inhibitor).^[2]

As of August 2012, it is being tested against Hodgkin's Lymphoma, cutaneous T cell lymphoma (CTCL)^[3] and other types of malignant disease in Phase III clinical trials, against myelodysplastic syndromes, breast cancer and prostate cancer in Phase II trials, and against chronic myelomonocytic leukemia (CMML) in a Phase I trial.^[4][5]

Panobinostat is currently being used in a Phase I/II clinical trial that aims at curing AIDS in patients on highly active antiretroviral therapy (HAART). In this technique panobinostat is used to drive the HI virus's DNA out of the patient's DNA, in the expectation that the patient's immune system in combination with HAART will destroy it.^[6][7]

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studied were all resistant to the effects of chemotherapy – as are many pancreatic tumors.^[8]

Panobinostat has also been found to significantly increase in vitro the survival of motor neuron (SMN) protein levels in cells of patients suffering fromspinal muscular atrophy.^[9]

Panobinostat was able to selectively target triple negative breast cancer (TNBC) cells by inducing hyperacetylation and cell cycle arrest at the G2-M DNA damage checkpoint; partially reversing the morphological changes characteristic of breast cancer cells.^[10]

Panobinostat, along with other HDAC inhibitors, is also being studied for potential to induce virus HIV-1 expression in latently infected cells and disrupt latency. These resting cells are not recognized by the immune system as harboring the virus and do not respond to antiretroviral drugs.^[11]

Panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.^[1]

1. Revill, P; Mealy, N; Serradell, N; Bolos, J; Rosa, E (2007). "Panobinostat". Drugs of the Future 32 (4): 315. doi:10.1358/dof.2007.032.04.1094476. ISSN 0377-8282
   Jump up to: Revill, P; Mealy, N; Serradell, N; Bolos, J; Rosa, E (2007). "Panobinostat". Drugs of the Future 32 (4): 315. doi:10.1358/dof.2007.032.04.1094476. ISSN 0377-8282.
2. Jump up Table 3: Select epigenetic inhibitors in various stages of development from Mack, G. S. (2010). "To selectivity and beyond". Nature Biotechnology 28 (12): 1259–1266.doi:10.1038/nbt.1724. PMID 21139608. edit
3. Jump up ClinicalTrials.gov NCT00425555 Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma
4. Jump up ClinicalTrials.gov: LBH-589
5. Jump up Prince, HM; M Bishton (2009). "Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma". Hematology Meeting Reports (Parkville, Australia: Peter MacCallum Cancer Centre and University of Melbourne) 3 (1): 33–38.
6. Jump up Simons, J (27 April 2013). "Scientists on brink of HIV cure". The Telegraph.
7. Jump up ClinicalTrials.gov NCT01680094 Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART (CLEAR)
8. Jump up Mayo Clinic Researchers Formulate Treatment Combination Lethal To Pancreatic Cancer Cells
9. Jump up Garbes, L; Riessland, M; Hölker, I; Heller, R; Hauke, J; Tränkle, Ch; Coras, R; Blümcke, I; Hahnen, E; Wirth, B (2009). "LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate". Human Molecular Genetics 18 (19): 3645–3658. doi:10.1093/hmg/ddp313.PMID 19584083.
10. Jump up^Tate, CR; Rhodes, LV; Segar, HC; Driver, JL; Pounder, FN; Burow, ME; and Collins-Burow, BM (2012). "Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat". Breast Cancer Research 14 (3).
11. Jump up TA Rasmussen, et al. Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation. Human Vaccines & Immunotherapeutics 9:5, 1-9, May 2013.