2009年11月9日，美国食品药品监督管理局（FDA）批准注射药物Istodax (romidepsin)用于治疗一种名为皮肤T细胞淋巴瘤（CTCL）的罕见癌症。
 
皮肤T细胞淋巴瘤是一种名为T-淋巴细胞的抗感染白细胞缓慢生长的癌症。大多数病例在开始时伴有皮肤干燥、红疹和瘙痒，并可能加重。可能发生肿瘤的皮肤会出现溃疡并引发感染。在一些病例中，CTCL可扩散至血液、淋巴结或内部器官。在美国，每年约有1500个新的CTCL病例。伴有皮肤局部CTCL的患者可接受局部药物或光疗治疗，一旦病情恶化，则可能需要进行化疗。
 
Istodax可干扰细胞复制程序。该药被计划用于在已使用至少一种其他类型的化疗后病情仍趋于恶化或复发的CTCL患者。FDA药物评估和研究中心的肿瘤药品办公室主任Richard Pazdur博士表示，“这次批准证明了FDA有关发展和批准用于治疗罕见和少见疾病药物的承诺。” FDA于2009年11月6日批准Istodax上市。之前已批准用于治疗CTCL的药物包括Zolinza (vorinostat)、Ontak (denileukin difitox)和Targretin (bexarotene)。
 
Istodax的评估是基于2项共纳入167名患者的临床研究。在这2项试验中约有35%的患者出现治疗反应，表现为肿瘤的大小减小。在其中1项研究中，治疗反应的持续中位时间为15个月，另一项研究为11个月。研究中有6%的患者已完成治疗，并通过体格、实验室和X-射线检查未发现肿瘤迹象。
 
常见副作用包括恶心、疲劳、感染、呕吐、食欲减退、血红细胞计数降低、血小板计数减少以及白细胞组成减少。Istodax由位于美国马萨诸塞州剑桥市的Gloucester制药公司销售。

预计Istodax将于2010年1月上市。

Gloucester Pharmaceuticals’ ISTODAX® Demonstrates Synergistic Activity with Velcade® in B-cell Non-Hodgkin's Lymphoma Cell Lines

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Gloucester Pharmaceuticals announced today the presentation of preclinical data demonstrating that the combination of ISTODAX^® (romidepsin) and Velcade^® (bortezomib) resulted in synergistic anti-tumor activity in B-cell non-Hodgkin's lymphoma cell lines. ISTODAX is a member of a new class of cancer drugs known as histone deacetylase (HDAC) inhibitors. The results were presented during a poster presentation entitled, “The Combination of Romidepsin and Bortezomib Results in Synergistic Induction of Apoptosis in Human B-Lymphoma Cell Lines” at the 51st American Society of Hematology (ASH) Annual Meeting being held in New Orleans, LA.

“The results in this in vitro combination study of ISTODAX and Velcade suggest this may be an important clinical combination to test in patients with relapsed or refractory B-cell malignancies,” said Sagar Lonial, MD, Associate Professor, Hematology and Medical Oncology at Emory University School of Medicine and an author of the study. “We are currently conducting mechanistic studies with the goal of identifying predictors of response that can be validated in prospective clinical trials and look forward to presenting these results at a future scientific meeting.”

“ISTODAX has been studied extensively in T-cell lymphomas and was recently approved by the FDA for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy,” said Jean Nichols, PhD, President and Chief Operating Officer of Gloucester Pharmaceuticals. “These preclinical results in B-cell lymphoma cell lines build on previous work presented in multiple myeloma and suggest that the combination of ISTODAX and Velcade may have a potential role in the broader hematologic space and merit additional study.”

Study Results:

Four B-cell lymphoma lines (Daudi, HT, Ramos and SUDHL-4) were exposed to different combinations of ISTODAX and Velcade separately, concurrently and sequentially. The combination of ISTODAX and Velcade resulted in synergistic B-cell apoptosis. Order-of-addition experiments demonstrated definite sequence specificity. When ISTODAX was administered first and followed six hours later by administration of Velcade, cell growth was arrested in the G2/M phase and cell death was increased compared to both agents being given concurrently or Velcade being administered first. Protein level expression analyses suggest that the combination affected both aggresome formation and autophagy. The observed effects of the combination of ISTODAX and Velcade on B-cell lymphoma lines at low nanomolar concentrations suggests that this may be an important clinical combination to test in patients with relapsed or refractory B-cell malignancies.

About ISTODAX^®

ISTODAX, a novel histone deacetylase (HDAC) inhibitor, has been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. For full prescribing information, please visit www.istodax.com. Gloucester is currently conducting a registration trial in peripheral T-cell lymphoma (PTCL) and additional studies of ISTODAX are being conducted in other hematologic and solid tumors. ISTODAX is not approved for the treatment of PTCL or other indications.

Important Safety Information

ISTODAX^® is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

Warnings and Precautions

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX.

Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary.

Several treatment-emergent morphological changes in ECGs including T-wave and ST-segment changes have been reported in clinical studies. The clinical significance of these changes is unknown. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions, such as the monitoring of electrolytes and ECGs should be considered.

Based on its mechanism of action, ISTODAX may cause fetal harm. Woman should avoid becoming pregnant while being treated with ISTODAX and pregnant women should be advised of the potential harm to the fetus.

ISTODAX binds to estrogen receptors. Women of childbearing potential should be advised that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives.

Adverse Reactions

Safety data was available and evaluated in 185 patients with CTCL in two clinical trials. Adverse reactions are presented separately for each study due to methodological differences between the studies. The most common reported adverse reactions in Study 1 were nausea (56%), fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 were nausea (86%), fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG T-wave changes (63%), neutropenia (57%), and lymphopenia (57%). Most of the adverse reactions were reported to be mild or moderate in severity. Most deaths in the studies were due to disease progression. Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Serious adverse reactions reported in > 2% of patients in Study 1 were infection, sepsis, and pyrexia. In Study 2, serious adverse reactions in > 2% of patients were infection, supraventricular arrhythmia, neutropenia, fatigue, edema, central line infection, ventricular arrhythmia, nausea, pyrexia, leukopenia, and thrombocytopenia.

Drug Interactions

Prothrombin time (PT) and International Normalized Ratio (INR) should be carefully monitored in patients concurrently administered ISTODAX and Coumadin derivatives.

Co-administration of strong CYP3A4 inhibitors may increase concentrations of ISTODAX and should be avoided.

Co-administration of potent CYP3A4 inducers may decrease concentrations of ISTODAX and should be avoided.

Caution should be exercised if ISTODAX is administered with drugs that inhibit P-glycoprotein.

Use in Specific Patient Populations

Patients with moderate and severe hepatic impairment or end-stage renal disease should be treated with caution.

For additional important safety information, please see full prescribing information for ISTODAX at www.ISTODAX.com or call 1-866-223-7145.

About Gloucester Pharmaceuticals

Gloucester Pharmaceuticals acquires clinical-stage oncology drug candidates and advances them through regulatory approval and commercialization. The Company’s first candidate, ISTODAX^® (romidepsin), a novel histone deacetylase (HDAC) inhibitor, is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Gloucester is currently conducting a registration trial in peripheral T-cell lymphoma (PTCL) and anticipates data from this study in 2010. In addition, the Company is continuing further investigation of ISTODAX in other hematologic indications and solid tumors. For more information, please visit www.gloucesterpharma.com.

Velcade^® is a registered trademark of Millennium: The Takeda Oncology Company.