The three histone deacetylase inhibitors on the market could be the leading edge of a wave, with more than a dozen candidates from the class in the clinic and a pool of potential indications that could widen beyond malignant cancers to central nervous system, inflammatory, metabolic and immunologic disorders.

The class is well-suited for the oncology setting, where the drugs interfere with a way that cancer can inactivate genes that play a role in cancer defense. Some cancers seem to be facilitated by epimutations, changes not in DNA itself but in the pattern of acetylation, a process necessary for genetic expression. Histone deacetylase enzymes modify proteins; inhibition of HDACs influences the cancer cell macro-environment epigenetically, inhibiting that suppressive action and essentially reactivating those cancer defenses.

Companies developing HDAC inhibitors are scrambling to identify and support biomarkers for their candidates’ activity. Syndax thinks it might have the first surrogate marker of HDACi activity with lysine hyperacetylation; Pharmacyclics is looking at RAD51 gene expression as a potential biomarker.

Merck & Co. Inc. introduced the HDAC inhibitor class with the 2006 approval of Zolinza (vorinostat) for cutaneous T-cell lymphoma. Vorinostat is in Phase III trials in multiple myeloma and is in investigator-initiated studies to see if it can be used to shock the HIV/AIDS virus out of latency so it can be eradicated by antiretrovirals.

The next HDAC inhibitor to clear FDA, Istodax (romidepsin), is also indicated for cutaneous T-cell lymphoma, as a second-line therapy. A month after the drug’s 2009 approval, Istodax originator Gloucester Pharmaceuticals Inc.was snapped up by Celgene Corp. Also see "Celgene Pays $340 Million For Gloucester And Its New Drug" - Pink Sheet, 7 December, 2009.. Celgene has expanded Istodax’s label, receiving accelerated approval in June 2011 for second-line peripheral T-cell lymphoma. Celgene is also studying romidepsin’s effectiveness against solid tumors (see chart, below, for the status of HDAC inhibitors in the clinical pipeline).

In April 2011, Zytiga (abiraterone), which Johnson & Johnson gained in its 2009 acquisition of Cougar Biotechnology Inc., was approved for a solid tumor indication: chemotherapy-experienced patients with advanced metastatic prostate cancer. Zytiga is in late-stage trials for chemo-naïve prostate cancer populations, as well as for metastatic breast cancer.

A handful of the lead companies working in the area of HDAC inhibition updated their clinical progress during a Nov. 2-3 Cambridge HealthTech Institute conference, Targeting Histone Deacetylases, sharing their scientific insights into how exactly HDAC inhibition works – and how HDACi should be positioned to treat disease. Because they can thwart resistance mechanisms, HDACis are in many cases being developed with co-administration or resensitization in mind.

Syndax Seeks A Surrogate Marker For HDACi Activity In Breast Cancer

One HDACi drug developer has discovered a link between a patient’s ability to maintain acetylation levels and her response to breast cancer therapy, a possible predictor for the likelihood of epigenetic success in which a driver of the disease is both the drug target and a predictive marker.

Syndax Pharmaceuticals Inc., in Waltham, Mass., plans to take its HDAC inhibitor entinostat into a Phase III trial for estrogen receptor-positive metastatic breast cancer early in 2012 with what the company believes to be the first surrogate marker of HDACi activity, a measure of lysine hyperacetylation, Peter Ordentlich, executive director and founder of the company, said.

In the Phase II ENCORE 301 trial, the company investigated whether hyperacylation due to HDACi treatment would be associated with lower risk of disease progression. The trial enrolled 130 post-menopausal women with metastatic or locally advanced ER+ breast cancer progressing on a non-steroidal aromatase inhibitor, AstraZeneca PLC’s Arimidex (anastrozole) or Novartis AG’s Femara (letrozole).

Blood samples were taken in a planned subset of 49 patients before treatment with exemestane (Pfizer Inc.’s Aromasin) and either entinostat or placebo and again within two weeks of starting treatment. The comparison revealed that patients treated with the combination who also had increased lysine acetylation had prolonged progression-free survival. The implication is that a patient’s ability to ward off de-acetylation could be a predictive marker for who would benefit most from hyperacetylation caused by entinostat’s HDAC interference. In the 27 patients who added entinostat and were acetylation positive, median PFS was 8.5 months versus 2.7 months for non-acetylators.

In the study as a whole, median PFS was 4.3 months for the entinostat group but 2.3 months for the placebo arm. At a median of 18 months follow-up, overall survival favored entinostat: 26.9 months compared with 20.3 months for placebo, indicating that entinostat may re-sensitize tumors to aromatase inhibitors ([A#110915d1]).

Syndax is also investigating the effectiveness of entinostat in second-line non-small cell lung cancer, where the HDACi is paired with Roche’s Tarceva (erlotinib) to test whether it can re-sensitize cancer cells to EGFR inhibition. In the Phase II ENCORE 401 trial the combination conferred a four-month survival benefit over Tarceva plus placebo.

The company licensed entinostat in 2007 from Bayer AG with an eye toward developing mechanistically driven cancer drug combinations Also see "Syndax Leverages Novel IP for Cash, Phase II HDAC" - Scrip, 1 May, 2007.. It has also completed a Phase II trial in 3^rd and 4^th-line ER+ metastatic breast cancer and is entering Phase III with the NSCLC combination.

4SC Examines Resminostat’s Ability To Resensitize Tumors

4SC AG is developing its pan-HDAC inhibitor resminostat in three cancer indications: Hodgkin lymphoma, hepatocellular carcinoma and colorectal cancer – each in Phase II with a goal of entering a specific geographic market. The German biotech gained the molecule in its 2008 acquisition of Takeda Nycomed AS’ oncology business [See Deal].

With the Phase II SAPHIRE trial, testing resminostat as monotherapy for third-line treatment of Hodgkin lymphoma in patients resistant to second-line therapy, 4SC is aiming for a short development timeline and fast worldwide market entry,Senior Project Manager-Development Stephan Henning explained.

Malignant Reed-Sternberg cells, the malignant cells in Hodgkin lymphoma, evade immune surveillance, but inhibiting HDAC increases their susceptibility by reactivating T-cell target antigens on the cell surface. The open-label trial enrolled 33 relapsed/refractory patients in Eastern Europe, with a 33% response rate. An additional seven patients achieved stabilization of disease, and 18 patients overall (54.5%) had a clinical benefit (complete or partial response or stable disease).

HDAC inhibitors may have a special role in combination therapy, resensitizing tumors to chemotherapy.

The Phase II SHELTER trial in hepatocellular carcinoma tests resminostat in combination with Bayer/Onyx Pharmaceuticals Inc.’s Nexavar (sorafenib) with the goal of resensitizing tumors to sorafenib, the sole therapy available for advanced HCC. The trial, which compares the combination to resminostat monotherapy, enrolled patients in Germany and Italy because the Mediterranean countries have a high incidence of HCC; 4SC plans to market resminostat for that indication in the Asia-Pacific region. Earlier this year, the firm entered an exclusive licensing deal with Yakult Honsha Co. Ltd. in Japan to develop resminostat for HCC in its territory [See Deal].

HDAC-1 is over-expressed in patients with HCC and correlates with a higher incidence of cancer cell invasion into the portal vein, Henning said. Further, expression rates for HDAC-1, -2 and -3 correlate with HCC recurrence rate after liver transplantation.

Preliminary12-week results (the end of the main treatment phase) from the two-arm, open-label trial show that 50% of 16 patients in the combined arms have hit the endpoint of progression-free survival, while the other half achieved stable disease.

The Phase I/II SHORE trial launched earlier this year in Germany with the goal of enrolling 70 colorectal cancer patients. The trial set out to test resminostat with and without FOLFORI chemotherapy as a second line therapy in colorectal cancer patients with KRAS-mutated tumors, but had to open to wild-type KRAS because of slow enrollment, Henning said. The goal is to enter the U.S. and European markets, which have a high frequency of the cancer.

As with HCC, high HDAC expression is an indicator for reduced survival times. HDAC-3 is over-expressed in about 50% of CRC, while HDAC-2 is upregulated in APC-mutant cells and in most colon cancers, giving cancer cells a survival edge. However, despite the correlation of HDAC expression levels with poor survival, 4SC has not been able to connect the correlation as a biomarker, Henning said.

Chroma’s Point Of Differentiation For Tefinostat

Tefinostat (CHR02845), U.K. biotech Chroma Therapeutics Ltd.’s macrophage-target HDACi, is unique in the class in that it selectively affects monocytes in the blood, Chief Scientific Officer Alan Drummond explained. Created using Chroma’s Esterase Sensitive Motif technology, the molecule uses carboxylesterases to deliver the drug intracellularly, with the intent of improving tolerability Also see "Chroma: Next Generation UK Biotech" - Scrip, 1 November, 2004..

In a Phase I European study involving 18 patients with a variety of hematological cancers, one chronic myelomonocytic leukemia patient achieved a bone marrow response in the absence of a hematological response after nine months and a further six patients were treated for more than two cycles, while a patient with high-risk myelodysplastic syndrome remained on the drug through 15 cycles.

Henning said Chroma plans to take the drug into a Phase I/II trial in advanced acute myelogenous leukemia, as well as a Phase I/II trial in HCC with sorafenib, noting that cytokines and growth factors derived from tumor-associated macrophages drive the disease.

Pharmacyclics Hopes Abaxinostat Data Will Debut At ASCO 2012

San Diego-based Pharmacyclics Inc. is trying its broad-spectrum HDAC inhibitor abaxinostat (PCI-24781) against solid tumors, lymphoma and soft tissue carcinoma, the latter in combination with doxorubicin. The molecule is partnered outside the U.S. with French pharmaceutical company Servier SA, which is conducting six Phase I and I/II trials in Europe in lymphoma and solid tumors.

As a single agent against follicular and mantle cell lymphoma, abaxinostat is moving into the Phase II portion of a Phase I/II trial, Pharmacyclics Senior Director for Translational Research Siram Balasubramanian said, adding that the company hopes to have data for the 2012 American Society of Clinical Oncology meeting.

The company is also testing the possibility that RAD51, a gene involved in DNA repair that is over-expressed in certain soft tissue sarcoma cell lines, could be a biomarker for abaxinostat efficacy.

In sarcoma, he said, the goal is to reverse resistance to doxorubicin and cisplatin in refractory disease. After eight cycles of therapy in the IS-0404-CA Phase I sarcoma dose-escalation trial, among 15 patients evaluable for response to date, one had a partial response, eight had stable disease, and seven have had five or more cycles of treatment, with one patient at 10 cycles, Balasubramanian reported. Those results also are planned for ASCO.

Tracking The Progress Of HDAC Inhibitors In The Clinic
Company	Drug	Indication(s)	Phase
Merck	Zolinza (vorinostat) Aka SAHA	Cutaneous T-cell lymphoma (3^rd line)	Approved 2006
Celgene (Gloucester)	Istodax (romidepsin) (FK228)	Cutaneous T-cell lymphoma (2^nd line) Peripheral T-cell lymphoma (2^nd line)	Approved 2009 Approved 2011
J&J (Cougar)	Zytiga (abiraterone)	Metastatic castration-resistant prostate cancer (2^nd line)	Approved 2011
Novartis	Panobinostat (LBH589)	Relapsed multiple myeloma Post-transplant Hodgkin lymphoma maintenance	Phase III Phase III
Syndax	Entinostat	ER+ breast cancer Non-small cell lung cancer	Phase III-ready Phase III-ready
Spectrum/TopoTarget	Belinostat	Peripheral cutaneous T-cell lymphoma Carcinoma of unknown primary origin NSCLC	Phase II (pivotal trial) Phase II Phase I
4SC	Resminostat	Hodgkin lymphoma Liver cancer Colorectal cancer	Phase II Phase II Phase II
Pharmacyclics/Servier	Abaxinostat (PCI-24781)	Follicular and mantle cell lymphoma Sarcoma	Phase II Phase I
Acetylon	ACY-1215	Relapsed/refractory multiple myeloma	Phase I/II
Chroma	Tefinostat (HCR-2845)	Hematological cancers	Phase I
Sources: Elsevier Business Intelligence’s Inteleos database, company websites, EBI archives

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