Wednesday, June 1, 2016

Belinostat | HDAC Inhibitor | Orphan Drug | Treatment of Peripheral T-cell Lymphoma

Belinostat [(2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide] is a small-molecule hydroxamate-type inhibitor of class I, II and IV histone deacetylase (HDAC) enzymes [1, 2]. 
Belinostat was granted orphan drug status for the treatment of Peripheral T-cell lymphoma (PTCL) in the US in September 2009 and the EU in October 2012. In July 2015, an orphan drug designation has also been granted for malignant thymoma in the EU. 

Belinostat received its first global approval in the US-FDA on 3 July 2014 for the intravenous (IV) treatment of relapsed or refractory PTCL in adults.

Belinostat: 2D and 3D Structure

The IV formulation of Belinostat is currently in development around the world for a range of haematological and solid tumour malignancies; these include thymoma, acute myeloid leukaemia, non-small cell lung cancer (NSCLC), ovarian cancer, and hepatocellular carcinoma (HCC). An oral formulation of Belinostat is in early clinical development for the treatment of lymphoma and solid tumours, including NSCLC.

What is Peripheral T-cell lymphoma (PTCL)?
Peripheral T-cell lymphoma (PTCL) corresponds to a heterogeneous subgroup of relatively rare and aggressive extranodal forms of non-Hodgkin’s lymphoma (NHL). Traditionally, treatment for PTCL has been similar to that for B-cell lymphoma, with anthracycline-based chemotherapy being the most commonly used treatments, although patients with PTCL have poorer outcomes. Patients with relapsed or refractory PTCL have a particularly poor prognosis.
The prognosis for patients with PTCL varies between subtypes, with 5-year overall survival rates ranging from 14 % for patients with adult T-cell leukaemia/lymphoma to 70 % for ALK-+ anaplastic large cell lymphoma; the median 5-year survival rate for the most common form, PTCL not otherwise specified (NOS), is 32 % [1].

Belinostat Synthesis

Helv Chim Acta 2005, 88(7), 1630-1657: It is first reported synthesis for Belinostat and many other derivatives. The procedure uses oleum, thionyl chloride (SOCl2as well as oxalyl chloride (COCl)2, no wonder better procedures were derived from it.

Synth Comm 2010, 40(17), 2520–2524: The synthesis avoids the use of the extremely corrosive oleum and thionyl chloride (SOCl2and therefore is possibly better for scaled-up production. Second, synthetic steps do not involve tedious separations and give a better overall yield.

1H NMR (Estimated) for Belinostat

Experimental: 1H NMR (300 MHz, DMSO-d6): δ 6.52 (d, J=15.9 Hz, 1H), 6.81–7.12 (m, 6H), 7.33 (d, J=15.9 Hz, 1H), 7.47–7.67 (m, 3 H), 7.87 (s, 1H), 9.00–11.20 (br, 3H).


The most common Adverse Events of any grade (AE) occurring in patients (greater than 20%) with belinostat monotherapy are in order nausea (42% of patients), fatigue (37%), pyrexia (35%), anaemia (32 %), vomiting (29%), constipation (23%), diarrhoea (23%), dyspnoea (22 %), rash (20%) and peripheral oedema (20%).
The most frequent NCI-CTC grade 3 or 4 adverse events were anaemia (11%), thrombocytopenia (7%), dyspnoea (6%), fatigue (5%), hypokalaemia (4 %), QT interval prolongation (4 %), hypotension (3 %) and pruritus (3 %).
A total of 61 patients (47.3 %) experienced serious adverse events during or within 30 days of treatment with Belinostat, with pneumonia, pyrexia, infection, anaemia, creatinine elevations, thrombocytopenia and multi-organ failure being the most frequent ([2 % of patients each). There was one treatment-related death due to hepatic failure during the trial. Adverse events led to treatment discontinuation in 25 patients (19.4 %), most commonly due to anaemia, febrile neutropenia, fatigue and multi-organ failure; 12 % of patients required dose modification due to adverse events.
Belinostat comes with boxed warnings and precautions regarding the risk of thrombocytopenia and leukopenia, serious infections, hepatotoxicity and tumour lysis syndrome, and the potential for foetal harm if used in pregnant women. Monitoring of blood counts and liver function is advised for patients receiving Belinostat, with dose modification recommended if toxicities occur.
1. Poole, R. M. Belinostat: First Global Approval. Drugs 2014, 74, 1543-1554. (FMO only)
2. Plumb, J. A.; et. al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2003, 2(8), 721-8. (free copy)