Trials & Tribulations: Advances in the Development of Histone Deacetylase (HDAC) Inhibitors for the Treatment of Cancer

Histone deacetylase (HDAC) inhibitors, having received considerable R&D attention, are now being led through the clinic by SAHA which is currently in phase II development. A second HDAC inhibitor, Titan's Pivanex, has now been shown to be effective as a single agent therapeutic in patients with non-all cell lung cancer. Due to toxicity observed when used in combination with docetaxel, development for this indication has been terminated. Studies have however recently been initiated to investigate Pivanex in patients with refractory chronic lymphocytic leukemia.

(Editorial note: In depth reports on cancer can be found at 's report center or click here for suggested reading on the treatment of leukemias)

DailyUpdates 10th September, 2004: The drive to develop improved treatments of cancer has resulted in the development of a number of strategies designed to regulate transcription. The field of histone deacetylation represents one such field and centers on the structural plasticity of chromatin. This plasticity is key to the regulation of transcription and is controlled by the level of histone acetylation. Increasing acetylation through the inhibition of the histone deacetylase (HDAC) class of enzymes can therefore regulate, potentially in a highly specific manner, transcription thereby offering a much more targeted approach to the treatment of cancer (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer").

The fast-moving field of histone deacetylase inhibitors is now witnessing the development of candidates through the clinic. Most advanced is SAHA developed by Aton Pharma, a biotech recently purchased by Merck & Co. SAHA is currently in Phase II clinical trials for the treatment of cutaneous T-cell lymphoma but shows promise in other cancers. Another candidate is Titan Pharmaceuticals' pivaloyloxymethyl butyrate (Pivanex, AN-9).

In this month's edition of the journal Lung Cancer, Reid et al report on the results of a multicenter phase II trial evaluating the therapeutic activity and safety profile of Pivanex as a single agent in refractory non-all cell lung cancer. Pivanex was administered as a 6-h continuous intravenous infusion, daily for 3 days, and repeated every 21 days until disease progression. Forty-seven patients were treated. More than 90% of patients had received both a platinum compound and a taxane and 32% had received three or more prior chemotherapy regimens. The most common toxicities were transient grade 1-2 fatigue (34%), nausea (17%), and dysgeusia (11%). Three patients had partial responses and 14 patients had stable disease for at least 12 weeks. Median survival for all patients was 6.2 months with 1-year survival of 26%.

This study therefore shows that Pivanex is well tolerated and appears to be active as a single agent in patients with advanced non-all cell lung cancer refractory to previous chemotherapy. The clinical journey of Pivanex is however becoming a roller coaster ride for Titan. Since this trial, a further Phase IIb study of Pivanex in combination with docetaxel in non-all cell lung cancer was terminated early due to significant safety issues. Analysis of the data has not yet been made public and it is therefore not clear what the safety issues are. The data have certainly surprised Titan however since "Pivanex has not been associated with any significant, dose limiting toxicity in previous studies that might explain these preliminary findings". Of note it is not clear whether they are specific to this combination of therapeutic agents or whether similar problems are likely to be encountered when Pivanex, or indeed other HDAC inhibitors, is used in combination with alternate chemotherapeutic agents.

Despite the results of this trial the tribulations surrounding Pivanex have not been terminal. According to company statements, Pivanex will not be pursued for the treatment of non-all cell lung cancer, however Titan is continuing to investigate its efficacy and safety in the treatment of refractory chronic lymphocytic leukemia. A 14-30 patient, open label Phase IIa single agent clinical study has now been initiated.

Although the market potential for drugs developed to treat chronic lymphocytic leukemia is extremely all compared to that of non-all cell lung cancer, targeting this indication does have the advantage that Titan may be able to apply for orphan drug classification. This status is awarded by the FDA to select approaches that offer potential therapeutic value in the treatment of rare diseases and conditions and enables companies to receive pre-filing regulatory guidance as well as reduced filing fees, and provides for market exclusivity in the US for a period of seven years if the orphan drug approval is granted by the FDA. Success in this niche indication could reopen the door for Pivanex in more common cancers.

Source: Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-all cell lung cancer. Lung Cancer. 2004 Sep;45(3):381-6

This article is highlighted in the September 10th edition of DailyUpdates-Oncology, 's unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today's bulletin click here

(Editorial note: In depth reports on cancer can be found at 's report center or click here for suggested reading on the treatment of leukemias)