Therapeutic focus - HDAC inhibitors gathering evidence of broader utility

The backing of an FDA advisory panel last week for Gloucester Pharmaceuticals' romidepsin, which has been filed for approval to treat the rare blood cancer cutaneous T-cell lymphoma (CTCL), was strong endorsement for a class of drug that has received growing attention over the last decade, histone deacetylase inhibitors (HDAC).

Their mechanism of action, inhibiting growth proliferation and survival pathways, lends them to oncology. One candidate has made it to the market, Merck & Co’s Zolinza (vorinostat), which was approved for advanced CTCL in 2006. A raft of other products are in development, both in haematological cancers and in the much larger field of solid tumours (see table). All of which points to potential for exciting news from the field in the next couple of years.

Broad activity

Since the HDAC inhibitors were first discovered and named they have been found to regulate far more proteins than histones alone, inhibiting pathways involved in apoptosis, angiogenesis and vascularisation. Dr Bernd Hentsch, chief development officer of 4SC, who has been working in the field for a decade, says that a more accurate name would be protein deacetylase inhibitors, given their broad activity.

“If you inhibit these enzymes you do not only regulate the histone but also quite a number of proteins that play a role in the onset of a tumour disease, and by this means you can target a tumour from different angles with one drug, which is an advantage. You target the whole balance of oncological pathways that are present in a tumour cell,” he says.

For reasons not fully understood HDAC inhibitors appear to be more effective in fighting haematological cancers – leukaemia, lymphoma and myeloma – and the table below reveals that much work is still being conducted in this area.

However, newer and more potent agents have been showing increasing promise in solid tumours, which in commercial terms is a much larger market; haematological cancers account for less than 5% of all registered cancers.

Stabilising disease

Dr Hentsch believes that HDAC inhibitors’ role in solid tumours will be in stabilising disease and prolonging life. The relatively benign side effect profile seen with the successful HDAC candidates lends them to this setting, a profile resulting from the compounds’ preferential activity on tumour cells.

“They will not blow tumours away, but rather achieve stabilisation and a bit of response in terms of tumour shrinkage, not like classic chemotherapies where you see complete responses. You see that only in rare cases in CTCL, as the haematological cancers seem to be more sensitive to the HDAC inhibitors,” he says.

Clearly, for a drug that will potentially be used for a number of months, good tolerability and oral administration is a major advantage. As such, much work in solid tumours is being conducted in late stage disease, when the tumour is not operable or the patient has had several treatments, a tough setting to treat.

“There might still be possibilities to place HDACs in monotherapy in a selected clinical setting, and you might see stabilisation of the disease, but generally speaking for very late stage tumours I would expect HDACs to find their place in combination approaches. This could be chemotherapy, but also other targeted therapies like kinase inhibitors or possibly antibodies.

“The community is further in development in haematological cancers than solid cancer, but we are getting there. I’m fairly convinced over the next two years or so we will see some good results in solid tumours,” Dr Hentsch says.

Strong potency

Dr Hentsch is particularly enthusiastic about 4SC’s candidate, 4SC-201 (resminostat), which last month started a phase II trial in hepatocellular carcinoma, or liver cancer. The condition is not treatable with chemotherapy and the only product to be approved to fight the aggressive type of cancer was Bayer’s Nexavar, in 2007. The trial is examining resminostat in patients who have failed on Nexavar, in combination and as a monotherapy, to see if the disease can be stabilised.

With nothing approved for second line liver cancer there is a clear niche to be filled, and the drug’s potency gives Dr Hentsch cause for optimism. Results are due late next year.

The company also wants to start trials with resminostat before the end of the year in Hodgkin's lymphoma (HL), where there is somewhat of a vacuum in research following the suspension of trials of another HDAC inhibitor, MethlyGene’s MGCD0103.

Cardiac toxicity, one side effect that has been associated with the class, prompted a clinical hold to be placed on the compound in 2007, which was in trials for both HL and non-Hodgkin’s lymphoma (NHL). Since then Celgene has handed back rights to the product, and its future is still uncertain.

Most advanced

The most advanced HDAC in the clinic is Topotarget’s belinostat, which is in a pivotal trial in peripheral T-cell lymphoma (PCTL) in IV form, and various phase II studies. A filing is planned for December 2010.

The company’s cash-strapped partner Curagen sold it full rights to the drug in May last year, and since then TopoTarget has been promising a new licensing deal. However, this has failed to materialise and the company raised DKr133m ($26m) in a rights issue in July, enough cash to allow TopoTarget to take belinostat to the FDA for review by itself.

Why a partner has failed to materialise is unclear, possibly the lack of confirmatory later stage data, despite a raft of early stage studies having been completed. A trial in multiple myeloma was ended in 2007 following adverse events; although these were unlikely to have been caused by the active drug, it could have worried partners. The competitive environment could also have been a factor, as Gloucester’s romidepsit is also targeted for PTCL.

Gaining traction

The table below lists only products in clinical development, the pre-clinical pipeline is expansive, with EvaluatePharma listing 27 candidates.

With Gloucester looking likely to gain a marketing license for romidepsin by its end-of-November PDUFA date, the field is certainly gaining traction, at least in haematological cancers. Further proof of concept data will be required in solid tumours to really establish whether the class has a future beyond these tumour types. However, if this does emerge, and further approvals, companies like TopoTarget and 4SC should find it easier to sign up partners in the future.

In the meantime, with data due over the next few years from a number of the candidates, this field of oncology is entering an interesting phase.

Clinical stage HDAC inhibitors
Product Generic Name Company Originator Routes of Admin. Indication Summary
Marketed Zolinza vorinostat Merck & Co Sloan-Kettering Institute/Columbia University Oral Lymphoma [Marketed]; Multiple myeloma [Phase III]; Numerous earlier trials including Non-Hodgkin's lymphoma (NHL) [Phase II]; Glioblastoma multiforme [Phase II]; Prostate cancer [Phase II].
Filed Istodax romidepsin Gloucester Pharmaceuticals Fujisawa Injection Non-Hodgkin's lymphoma (NHL) [Filed]; Numerous earlier trials including Prostate cancer [Phase II]; Multiple myeloma [Phase II].
Phase III Belinostat (PXD101) belinostat TopoTarget Prolifix iv/oral Lymphoma [Phase III]; Numerous earlier trials including Ovarian cancer [Phase II]; Leukaemia, acute myeloid (AML) [Phase II].
Phase II LBH589 panobinostat Novartis Novartis Oral Lymphoma [Phase II]; Multiple myeloma [Phase II]; Solid tumour indications [Phase I]
PCI-24781 (CRA-024781) - Pharmacyclics Axys Pharmaceuticals Oral General blood malignancies [Phase II]; Solid tumour indications [Phase II]
Savicol valproic acid TopoTarget Sanofi Oral Familial adenomatous polyposis (FAP) [Phase II]
SNDX-275 (MS-275) entinostat Syndax Pharmaceuticals Mitsui Pharmaceuticals Oral Lung cancer [Phase II]; Melanoma [Phase II]; Solid tumour indications [Phase I]; General blood malignancies [Phase I]
4SC-201 resminostat 4SC Altana Oral Advanced hepatocellular carcinoma (HCC); Solid tumour indications [Phase I]; General haematological indications [Phase I]
Phase I CUDC-101 - Curis Curis - General cancer indications [Phase I]
JNJ-26481585 - Johnson & Johnson Johnson & Johnson - General cancer indications [Phase I]
MGCD290 - MethylGene MethylGene - General fungal infections [Phase I]
TIK-201 sodium phenylbutyrate Tikvah Therapeutics Tikvah Therapeutics - Spinal muscular atrophy [Phase I]; Amyotrophic lateral sclerosis (ALS) [Phase I]; Multiple sclerosis (MS) [Pre-clinical]
CHR-3996 - Chroma Therapeutics Chroma Therapeutics Oral Solid tumour indications [Phase I]
CHR-2845 - Chroma Therapeutics Chroma Therapeutics - General blood malignancies [Phase I]
SB939 - S*BIO S*BIO - General haematological indications [Phase I]; Solid tumour indications [Phase I]

Source: EvaluatePharma

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