FDA Approves First HDAC Inhibitor, with Speedy Action on Merck & Co’s Zolinza

A New Type of Cancer Drug

U.S. drug giant Merck & Co. announced late on Friday (6 October) that the U.S. FDA has approved oral Zolinza (vorinostat) 400 mg once-daily for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL). This is a form of non-Hodgkin's lymphoma that strikes T-cells—a type of white blood cell that affects the skin. Zolinza will be used in patients who have progressive, persistent or recurrent disease, and are on (or have been on) two systemic therapies. There are around 20,000 patients in the United States with this cancer.

Zolinza is a histone deacetylase (HDAC) inhibitor, and the FDA’s clearance represents a first for this class of drugs. As such, the drug will have a premium wholesale price of US$240 per recommended daily dose, according to a Merck representative speaking to Global Insight. That equates to around US$87,600 per year, and while it will be launched almost immediately, its impact will be limited until decisions are made on reimbursement.

Zolinza inhibits the enzymatic activity of HDAC1, HDAC2, HDAC3 (Class I) and HDAC 6 (class II), which activate genes that control normal cell activity. It is believed that this mechanism helps to slow or stop the growth of cancerous cells, though this HDAC research still represents a new area for the drug industry, and Zolinza’s mechanism (and potential indications) have yet to be fully evaluated. This is true for the whole class of drugs, and drug companies involved in HDAC research will view the approval as a positive, indicating that their candidates are approvable.

The approval is based on an open-label, single-arm pivotal study, in which the overall objective response rate was 29.7% (objective response was defined as at least four weeks of either a complete response, defined as no evidence of disease, or partial response, defined as a greater-than-49% decrease in a skin assessment score compared to baseline). In the study, the median time to response was less than two months in all patients, although it took up to six months in rare cases for patients to achieve an objective response to Zolinza. The most common side-effects, regardless of causality, included fatigue (52%), diarrhoea (52%), nausea (41%), change in taste (28%), low platelet count (26%), anorexia (24%), weight decrease (21%) and muscle spasms (20%).

Outlook and Implications

The approval represents an important step forward for Merck, bolstering the company's new cancer portfolio. It also nicely precedes the mid-October FDA action date for DPP-IV inhibitor Januvia (sitagliptin), for which we do not expect any major problems. Merck is clearly enjoying a strong pipeline year in 2006, and commercial fruits will begin to become visible in 2007, when we expect a reduced level of late-stage pipeline activity.