WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved oral ZOLINZA(TM) (vorinostat) 400 mg once daily for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin’s lymphoma, who have progressive, persistent or recurrent disease on or following two systemic therapies. CTCL is a cancer of the T-cells, a type of white blood cell, which affects the skin.
ZOLINZA is a histone deacetylase (HDAC) inhibitor. Based on in vitro studies, ZOLINZA inhibits the enzymatic activity of HDAC1, HDAC2, HDAC3 (Class I) and HDAC 6 (class II) at nanomolar concentrations (IC50<86 nM). In some cancer cells, excess amounts of the enzyme HDAC prevent the activation of genes that control normal cell activity. ZOLINZA is believed to decrease the activity of HDAC. Decreasing the activity of HDAC allows for the activation of genes that may help to slow or stop the growth of cancer cells. The exact mechanism of the anticancer effect of ZOLINZA has not been fully characterized.
“With today’s FDA approval of ZOLINZA, there is now an effective new option in the fight against cutaneous manifestations of cutaneous T-cell lymphoma, specifically in patients who have tried and failed other cancer treatment options,” said Elise Olsen, M.D., director, CTCL Clinic & Research Center at Duke University Medical Center and lead investigator of one of the studies that led to the approval.
The approval is based on two open-label clinical studies in which CTCL patients with refractory CTCL were evaluated to determine their response rate to oral ZOLINZA. One study was a Phase IIb, single-arm pivotal clinical study and the other assessed several dosing regimens. In both studies, patients were treated until disease progression or intolerable toxicity.
In the open-label, single-arm, pivotal study, the median age of patients was 60 years. Fifty-one percent of the patients were male and 49 percent were female. Eighteen percent of patients had Stage IB or IIA CTCL and 82 percent of patients had Stage IIB and higher CTCL. The median number of prior systemic therapies was three. Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT).
The overall objective response rate in this study was 29.7 percent (22 of 74, 95% CI (19.7 to 41.5%)) in all patients treated with ZOLINZA. 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 greater than or equal to 50 percent decrease in a skin assessment score compared to baseline.
Secondary endpoints in this study included: time to objective response, time-to-progression, and duration of objective response. In the study, the median time to response was less than two months (55 days) in all patients, however, in rare cases, it took up to six months for patients to achieve an objective response to ZOLINZA. The median duration of response was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed six months in all patients. The median time to progression approached five months (148 days) in all patients, based on a criterion for tumor progression of a 25 percent increase in SWAT score from the nadir.
The safety of ZOLINZA was evaluated in 107 cutaneous T-cell lymphoma patients in two single-arm clinical studies in which 86 patients received ZOLINZA 400 mg once daily. The most common side effects, regardless of causality, included fatigue (52 percent), diarrhea (52 percent), nausea (41 percent), change in taste (28 percent), low platelet count (26 percent), anorexia (24 percent), weight decrease (21 percent), and muscle spasms (20 percent).
“It is very gratifying to have ZOLINZA approved by the FDA for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who have tried and failed other therapies. I am confident it will be an important new addition to treat patients with CTCL,” said Paul Marks, M.D., president emeritus and member of the Sloan-Kettering Institute. “ZOLINZA was developed in an academic collaboration between the chemistry group of Ronald Breslow at Columbia University and my cancer biology group at Memorial Sloan-Kettering. It is exciting to have Merck as a partner in the clinical development and FDA approval of ZOLINZA.”
Dosing and administration
The recommended dose of ZOLINZA is 400 mg orally once daily with food. If the patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. The dose may be further reduced to 300 mg once daily with food for five consecutive days each week.
Treatment with ZOLINZA may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. ZOLINZA capsules should not be opened or crushed.
Important safety information about ZOLINZA
As pulmonary embolism and deep vein thrombosis have been reported as adverse reactions, physicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events. Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. If platelet counts and/or hemoglobin are reduced during treatment with ZOLINZA, the dose should be modified or therapy discontinued. Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with ZOLINZA.
Based on reports of dehydration as a serious drug-related adverse event in clinical trials, patients should be instructed to drink as least two L/Day of fluids for adequate hydration. Hyperclycemia has been observed in patients receiving ZOLINZA. Serum glucose should be monitored, especially in diabetic or potentially diabetic patients. Adjustment of diet and/or therapy for increased glucose may be necessary. QTc prolongation has been observed. Monitor electrolytes and ECGs at baseline and periodically during treatment. Hypokalemia or hypomagnesemia should be corrected prior to administration of ZOLINZA.
The most common serious adverse events, regardless of causality, in the 86 CTCL patients in two clinical studies were pulmonary embolism reported in 4.7 percent (4/86) of patients, squamous cell carcinoma was reported in 3.5 percent (3/86) of patients and anemia was reported in 2.3 percent (2/86) of patients.
Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every two weeks for the first two months.
ZOLINZA was not evaluated in patients with hepatic impairment. As ZOLINZA is predominately eliminated through metabolisym, patients with hepatic impairment should be treated with caution.
Availability and access
ZOLINZA will be made accessible to patients through Merck’s Accessing Coverage Today (ACT) program. ACT is a three-part program specifically designed to assist patients in obtaining ZOLINZA, help with insurance reimbursement issues, and provide support for those qualified individuals lacking insurance coverage for ZOLINZA. Patients without insurance coverage may be eligible for Merck’s Patient Assistance Program, which allows them to receive ZOLINZA free of charge. Merck is also contributing to co-pay assistance foundations that provide co-pay assistance to qualified individuals. To enroll in the ACT program, patients need to call 1-866-363-6379 once they receive a prescription for ZOLINZA.
About CTCL
CTCL, a type of non-Hodgkin’s lymphoma, is a form of cancer in T-cells, a type of white blood cell. Normal T-cells function by regulating the body’s immune system in its job of fighting infections and other foreign antigens. In CTCL, the malignant T-cells are drawn to the skin, where some are deposited. Patients usually develop CTCL after age 50. CTCL affects up to 20,000 patients in the United States, with another 1,500 new cases reported each year.
About Merck Oncology
Merck Oncology focuses on all aspects of cancer care -- prevention, treatment, and supportive care. Through strong internal research capabilities, selective alliances and acquisitions, and enabling technologies such as the Molecular Profiling platform of Rosetta, Merck Oncology is looking to lead in the discovery, development and delivery of targeted anticancer therapies customized for patient subpopulations. Merck Oncology conducts research at sites in Boston, Seattle, West Point, Japan and Italy.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-looking statement
This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management’s current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck’s business, particularly those mentioned in the cautionary statements in Item 1 of Merck’s Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.
Prescribing information and patient product information for ZOLINZA are attached.
ZOLINZA(TM) is a registered trademark of Merck & Co., Inc.
