吉利德idelalisib关键性II期iNHL试验取得积极数据

吉利德（Gilead）12月8日公布了有关实验性药物idelalisib的一项关键性II期研究（Study 101-09）的积极数据。该项研究是一项开放标签、单组疗效和安全性II期研究，在既往经美罗华（Rituxan，通用名：rituximab，利妥昔单抗）和含烷化剂化疗方案治疗的难治性惰性非霍奇金淋巴瘤（iNHL）患者中开展，评价了idelalisib的疗效和安全性。研究结果表明，idelalisib单药疗法取得了57%的总体响应率，其中，6%的患者实现了完全响应，50%的患者实现部分响应，1%的患者取得轻微响应。研究中，平均响应持续时间达12.5个月，距离响应的平均时长为1.9个月。平均无进展生存期为11.0个月，平均总生存期为20.3个月，90%的患者经历了淋巴结的缩小。

该项研究中所观察到的总体响应率和响应持续时长表明，对于当前治疗选择十分有限的iNHL患者群体而言，idelalisib有望成为一个有价值的新疗法。

在iNHL患者中取得的这些数据，支持了吉利德近期向FDA和欧盟提交的idelalisib的监管申请文件。

2013年9月11日，吉利德向FDA提交了idelalisib用于治疗难治性iNHL的新药申请（NDA），之后FDA授予了idelalisib治疗慢性淋巴细胞白血病（CLL）的突破性疗法认定。目前，吉利德正与FDA就idelalisib治疗CLL的监管申请文件进行对话。

华尔街分析师平均预计，若最终获批，idelalisib在2015年的销售额将达到1亿美元，2016年达到4.5亿美元，2017年达到8亿美元。

目前，吉利德已统治了HIV药物市场，同时也正在争夺C型肝炎市场的领导地位，该公司正在一些不同类型的血癌中测试idelalisib。

关于Idelalisib：

idelalisib是一种实验性、高度选择性、口服有效的磷酸肌醇3-激酶delta（PI3K-delta）抑制剂。PI3K-delta信号对于B淋巴细胞的活化、增殖、生存、迁移（trafficking）至关重要，该信号在多种B细胞恶性肿瘤中过度活动。目前，idelalisib正被开发作为单一制剂，以及与一些已获批的疗法和实验性疗法配伍。

英文原文：Gilead Announces Pivotal Phase 2 Data for Idelalisib in Refractory Indolent Non-Hodgkin’s Lymphoma

-- 57 Percent Overall Response Rate and Median Duration of Response of 12.5 Months in Heavily Pre-Treated Patients --
-- Data Presented at American Society of Hematology Annual Meeting --
NEW ORLEANS, Dec 08, 2013 (BUSINESS WIRE) --Gilead Sciences, Inc. (Nasdaq: GILD) today announced results of a Phase 2 study (Study 101-09) evaluating idelalisib, an investigational oral inhibitor of PI3K delta, for the treatment of patients with indolent non-Hodgkin’s lymphoma (iNHL) that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy. In this study, single-agent treatment with idelalisib achieved an overall response rate of 57 percent with a median duration of response of 12.5 months. The data were presented today during an oral session at the Annual Meeting of the American Society of Hematology (ASH) in New Orleans (Abstract #85).

“It has been more than ten years since a treatment with a novel mechanism of action has been approved for indolent NHL, underscoring the medical need for new treatments for patients who are no longer responsive to currently available therapies,” said Ajay Gopal, MD, Associate Professor, University of Washington School of Medicine and Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center in Seattle, Washington. “The overall response rate and durability of response observed in this study suggest that idelalisib may become a valuable new therapy for iNHL patients who have very limited treatment options.”

Of the 71 patients who responded to therapy, seven (six percent) achieved a complete response, 63 (50 percent) had a partial response and one (one percent) had a minor response. Among patients who responded, the median duration of response was 12.5 months and the median time to response was 1.9 months. Median progression-free survival for all patients was 11.0 months and median overall survival was 20.3 months. Ninety percent of patients experienced shrinkage in lymph node size.

The most common Grade greater-than or equal to 3 adverse event was diarrhea, which was reported in 16 patients (13 percent). Grade greater-than or equal to 3 transaminase elevations (a measure of liver function) were reported in 16 patients (13 percent). Of the 16 patients who had Grade greater-than or equal to 3 transaminase elevations, 14 were retreated with idelalisib and of those, 10 (71 percent) had no recurrence. Grade greater-than or equal to 3 neutropenia occurred in 34 patients (27 percent). Twenty-five patients (20 percent) discontinued therapy because of adverse events.

These results in iNHL support Gilead’s recent regulatory filings for idelalisib in the United States and European Union. On September 11, 2013, Gilead submitted a New Drug Application to the U.S. Food and Drug Administration for idelalisib for the treatment of refractory iNHL. Following Gilead’s NDA submission for iNHL, FDA granted idelalisib a Breakthrough Therapy designation for chronic lymphocytic leukemia (CLL) in relapsed patients. Gilead is now engaging in a dialogue with the FDA regarding a regulatory filing in CLL.

Gilead’s Marketing Authorization Application (MAA) for idelalisib for the treatment of iNHL and CLL was validated by the European Medicines Agency (EMA) on November 20. Review of the MAA will be conducted under the centralized licensing procedure, which, when finalized, provides one marketing authorization in all 28 member states of the European Union (EU). The Committee for Medicinal Products for Human Use (CHMP) has accepted Gilead’s request for accelerated assessment for idelalisib, a designation that is granted to new medicines of major public health interest. Although accelerated assessment could shorten the review time of idelalisib by approximately two months, it does not guarantee a positive opinion from the CHMP or final approval by the European Commission. If approved, idelalisib could be available for marketing in the EU in the second half of 2014.

About Study 101-09

Study 101-09 is a Phase 2, open-label, single-arm efficacy and safety study of idelalisib in patients with previously treated iNHL that is refractory both to rituximab and to alkylating-agent-containing chemotherapy (refractory defined as no response while on therapy or progression within six months of completion of therapy).

The study enrolled 125 patients from approximately 50 study sites in the United States and Europe. Patients were a median age of 64 and had confirmed diagnoses of follicular lymphoma (n=72), small lymphocytic lymphoma (n=28), lymphoplasmacytic lymphoma / Waldenström macroglobulinemia (n=10) or marginal zone lymphoma (n=15). Patients had received a median of four prior treatment regimens before study entry, with 79 percent of patients refractory to two or more prior regimens and 90 percent refractory to their most recent regimen. All patients received idelalisib 150 mg twice daily and are allowed to continue daily dosing as long as they benefit from therapy. The primary endpoint of the study is overall response rate, defined as the proportion of patients achieving a confirmed complete or partial response with idelalisib treatment (response definitions based on standard criteria; responses assessed by study investigators and an independent review committee).

About Idelalisib

Idelalisib is an investigational, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta. PI3K delta signaling is critical for the activation, proliferation, survival and trafficking of B lymphocytes and is hyperactive in many B-cell malignancies. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.

Gilead’s clinical development program for idelalisib in iNHL includes Study 101-09 in highly refractory patients and two Phase 3 studies of idelalisib in previously treated patients. In addition to Study 116, the development program in CLL includes two ongoing Phase 3 studies of idelalisib in previously treated patients. Combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, also is being evaluated in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid malignancies.

Idelalisib and GS-9973 are investigational products and their safety and efficacy have not been established.

About Indolent Non-Hodgkin’s Lymphoma

Indolent non-Hodgkin’s lymphoma refers to a group of largely incurable slow-growing lymphomas that run a relapsing course after therapy and can lead ultimately to life-threatening complications such as serious infections and marrow failure. Most iNHL patients are diagnosed at an advanced stage of disease, and median survival from time of initial diagnosis for patients with the most common form of iNHL, follicular lymphoma, is 8 to 10 years. The outlook for refractory iNHL patients is significantly poorer.