赛诺菲（Sanofi）2013年6月3日公布了关于实验性药物iniparib及首个静脉注射型Xa因子抗凝血剂otamixaban的III期临床试验的数据，同时宣布终止这2个药物的临床开发。
Iniparib：
有关iniparib的随机III期ECLIPSE试验，在初诊鳞状非小细胞肺癌（squamous non-small cell lung cancer，Sq NSCLC）患者中开展，试验中将iniparib结合化疗对患者进行了治疗，与仅接受化疗相比，iniparib+化疗未能改善整体存活率（OS），该试验未能达到研究的主要终点。
此外，在铂耐药性患者中开展的有关iniparib的一项II期临床数据，并不能支持iniparib在这一患者群体中的进一步开发。
基于这些结果，赛诺菲决定终止iniparib的内部开发计划。
Otamixaban（奥米沙班）：
otamixaban是一种实验性、快速起效、直接选择性、注射型凝血因子Xa抑制剂。因子Xa是体内凝血级联反应中的一个重要组成部分，otamixaban是首个静脉注射型Xa因子抗凝血剂。已完成的III期临床研究（TAO）数据表明，该试验未能达到研究的主要终点。TAO研究在非ST段抬高急性冠脉综合征（non-ST elevation acute coronary syndrome，NSTE-ACS）患者中开展，由于疗效低于预期，otamixaban未能表现出相对于普通肝素（UFH）+/-依替巴肽（eptifibatide，一种GP IIb/IIIa抑制剂）组合在效益/风险（benefit/risk）上的优越性。TAO研究的主要终点是，减少全因死亡率（All-Cause Mortality）或新的心脏病发作（heart attack）。
基于TAO研究的数据，赛诺菲已决定终止有关otamixaban的开发项目。
英文原文：Sanofi terminates Phase III lung cancer and heart drugs
Paris, France - June 3, 2013 - Sanofi (EURONEXT: SAN and NYSE: SNY) today announced topline results of two Phase 3 clinical studies of its investigational compounds iniparib and otamixaban respectively.
Iniparib:
The randomized Phase 3 ECLIPSE trial of iniparib in squamous non-small cell lung cancer (Sq NSCLC) did not meet its primary endpoint. In the study, newly diagnosed, metastatic Sq NSCLC patients treated with iniparib plus chemotherapy did not achieve improvement in overall survival compared to patients who received chemotherapy alone. There were no clinically meaningful differences in the main safety parameters between the two arms.
The topline results of a Phase 2 study of iniparib in platinum-resistant ovarian cancer do not support further development of iniparib in this patient population. Following these findings, Sanofi has decided to terminate the internal development program with iniparib. As a consequence, the intangible assets related to iniparib will be fully impaired on the June 30, 2013 consolidated balance sheet. The related charge will have an estimated net impact of US $285 million after tax on consolidated net income (or approximately € 219 million). This non-cash charge will have no impact on Business Net Income.
Otamixaban:
Topline results of the completed Phase 3 study of the investigational anticoagulant otamixaban showed the study did not meet its primary endpoint of superiority over current therapy. In the TAO study (Treatment of non-ST elevation Acute coronary syndrome with otamixaban), due to efficacy lower than expected, otamixaban did not show superior benefit/risk to the combination of unfractionated heparin (UFH) +/- eptifibatide (a GP IIb/IIIa inhibitor) in non-ST elevation acute coronary syndrome (NSTE-ACS) patients planned for early invasive strategy. The primary endpoint of the Phase 3 TAO study was the reduction of all-cause mortality or new heart attacks.
Following the results of the TAO study the company has decided to discontinue the investigational program with otamixaban, an injectable factor Xa inhibitor.
The results of both of these studies will be presented at upcoming scientific meetings and submitted for publication in peer-reviewed journals.
About the Phase 3 ECLIPSE trial of Iniparib
In this NSCLC study, previously untreated patients received iniparib in combination with gemcitabine/carboplatin versus gemcitabine/carboplatin alone. The study enrolled 780 patients with metastatic (stage IV) Sq NSCLC at more than 140 sites in 16 countries. Patients were randomized to receive a standard chemotherapy regimen of carboplatin AUC 5 on Day 1 and gemcitabine 1000 mg/m2 on Day 1 and 8 of each 21-day cycle, with or without iniparib 5.6 mg/kg on Day 1, 4, 8 and 11. Patients in the study received this treatment as first-line chemotherapy in the metastatic setting. The primary endpoint of the trial was overall survival. Secondary endpoints were progression-free survival and response rate.
Iniparib (BSI-201; SAR240550) is a benzamide (4-iodo-3-nitrobenzamide) that is structurally related to nicotinamide. Iniparib was initially designed as a poly (ADP-ribose) polymerase (PARP) 1 inhibitor based on the benzamide structure. Recent research has demonstrated that iniparib cannot inhibit PARP1 at pharmacologic concentrations.
About the Phase 3 TAO study of Otamixaban This multicenter, phase 3, randomized, double-blind active-controlled trial evaluated otamixaban compared to unfractionated heparin (UFH) plus eptifibatide (a GP IIb/IIIa platelet inhibitor) in patients with NSTE-ACS who were treated with dual oral antiplatelet therapy and an invasive strategy. Over 13,000 moderate- to-high-risk patients in 55 countries were randomized to receive UFH plus downstream eptifibatide (started before and continued as per label) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion).
Otamixaban is an investigational, rapid-onset/offset, direct selective injectable inhibitor of the blood clotting factor Xa, a key component of the body’s blood clotting cascade that was in Phase 3 clinical development with the just completed TAO study in NSTE-ACS. Otamixaban was the first intravenous factor Xa anticoagulant tested against UFH +/- GP IIb/IIIa inhibitor on the occurrence of death or new heart attack.
