April 11, 2006 — 美国食品药物
管理局（FDA）以孤儿药方式核准：CEP-701于治疗急性骨髓性白血病；单株抗体ChAglyCD3于初发病之第一型
糖尿病患；EPI-A001于治疗
遗传性粒腺体呼吸链疾病。
孤儿药 CEP-701 (Lestaurtinib) 用于治疗急性骨髓性白血病
4月4日，FDA以孤儿药方式核准CEP-701 (商品名 lestaurtinib, Cephalon公司制造)用于治疗急性骨髓性白血病 (AML)。
CEP-701是一口服、具抗
肿瘤性质、生体可用性之indolocarbazole衍生物；抑制FLT3的自磷酸化反应，进而抑制FLT3 活性、且使肿瘤细胞过度表现FLT3而诱导死亡。
根据该公司的新闻稿，将近三分之一的AML病患有FLT3基因突变，而此突变与升高复发风险和降低存活率有关。
以复发AML病患为对象之进行中的第二期
临床试验初步结果显示，化疗后给予CEP-701和仅用化疗相比，在42天内显著地增加部分病患达到再度完全消退的治疗效果(46% vs. 27%)；该药系在化疗结束后两天开始给予，以每次口服80 mg、一天两次，疗程可达113天。
研究结果也显示基准的血癌细胞敏感性可作为临床反应的标记；和其他低基准敏感性或低FLT3血浆值相比，细胞在基准对CEP-701敏感、且有至少85%抑制FLT3活性的病患，显示出显著的反应。
研究中，CEP-701一般耐受性良好；肠胃道不适如恶心和消化不良较常被报告。
CEP-701也用于严重多发性骨髓瘤病患的第二期临床试验，和前列腺癌以及年轻复发的或难治的高风险神经母细胞瘤者之第一期临床试验。
孤儿药 ChAglyCD3 (TRX4) 于初发病之第一型糖尿病
2月14日，FDA以孤儿药方式核准 ChAglyCD3 (商品名TRX4, TolerRx公司制造) 用于初发病之第一型糖尿病患。
ChAglyCD3是一种单株抗体，和T细胞的CD3受体结合；用以阻断免疫活化T致效体细胞调节T细胞活性的功能，因而改善免疫耐受力。
此次核准系基于一临床试验的数据，数据显示：6天ChAglyCD3疗程，可以使胰脏β细胞维持至少18个月的产生胰岛素的功能，因而降低了以注射胰岛素控制血糖的需求。
此研究中，和使用剂量有关之副作用为短暂的，诸如类
流感症状和活化Epstein-Barr病毒；美国最近有一关于使用时适当剂量范围的临床研究。
根据该公司的新闻稿，现正研究中之ChAglyCD3，其其他可能适应症，包括中到重度牛皮癣和皮肤性红斑狼疮症。
孤儿药EPI-A0001用于粒腺体呼吸链疾病
4月4日，FDA以孤儿药方式核准EPI-A0001 (Edison Pharmaceuticals公司制造)用 于治疗遗传性粒腺体呼吸链疾病。
对于此项影响神经系统、骨骼肌和心肌而使病患非常衰弱的疾病，目前还没有核准使用的药物；此病通常分类于粒线体脑肌病，系能量制造所需之粒线体内膜蛋白质合成时的基因异常所导致。
根据该公司的新闻稿，此次核准系基于验证此药对粒线体电子传递和能量制造的安全性与有效性的临床前数据。
FDA Orphan Drug Approvals: Lestaurtinib, TRX4, and EPI-A0001
By Yael Waknine
Medscape Medical News
April 11, 2006 — The US Food and Drug Administration (FDA) has approved orphan drug status for CEP-701 in the treatment of acute myeloid leukemia; the monoclonal antibody ChAglyCD3 for new-onset type 1 diabetes mellitus; and EPI-A001 for the treatment of inherited mitochondrial respiratory chain diseases.
Orphan Drug CEP-701 (Lestaurtinib) for Acute Myeloid Leukemia
On April 4, the FDA approved orphan drug status for CEP-701 (lestaurtinib, made by Cephalon, Inc) in the treatment of acute myeloid leukemia (AML).
CEP-701 is an orally bioavailable indolocarbazole derivative with antineoplastic properties. It inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3.
According to a company news release, nearly one third of AML patients have a mutation in the gene for FLT3, which is linked to an increased risk for relapse and reduced survival.
Preliminary results from an ongoing phase 2 trial in patients with relapsed AML have shown that CEP-701 given in sequence with induction chemotherapy significantly increased the proportion of patients who achieved a second complete remission within 42 days compared with chemotherapy alone (46% vs 27%, respectively). The drug was administered in an oral dose of 80 mg twice daily beginning 2 days after the end of chemotherapy for a duration of up to 113 days.
Study results also showed that susceptibility of leukemia cells at baseline may be a marker for clinical response. Patients whose cells were susceptible to CEP-701 at baseline and had an 85% or greater inhibition of FLT3 activity showed significant response compared with those having low baseline sensitivity or FLT3 plasma levels.
CEP-701 was generally well-tolerated in the study; gastrointestinal events such as nausea and dyspepsia were most commonly reported.
CEP-701 is also being investigated in a phase 2 trial of patients with advanced multiple myeloma and phase 1 trials of patients with prostate cancer and young patients with recurrent or refractory high-risk neuroblastoma.
Orphan Drug ChAglyCD3 (TRX4) for New-Onset Type 1 Diabetes
On February 14, the FDA approved orphan drug status for ChAglyCD3 (TRX4, made by TolerRx, Inc) in the treatment of new-onset type 1 diabetes mellitus.
ChAglyCD3 is a monoclonal antibody that binds to the CD3 receptor on T cells. It is designed to block the function of autoreactive T-effector cells while promoting regulatory T-cell activity, thereby improving immunologic tolerance.
The approval was based on data from a clinical study showing that a single 6-day course of ChAglyCD3 preserved the function of insulin-producing pancreatic beta cells, thereby reducing the amount of insulin needed to control blood glucose levels for at least 18 months.
Adverse events related to use of the study dose were transient and included flu-like syndrome and Epstein-Barr virus activation. A US clinical trial has recently been initiated for the purpose of determining the optimal dosing regimen for use in future trials.
According to a company news release, other potential indications for ChAglyCD3 currently under investigation include moderate to severe psoriasis and cutaneous lupus erythematosus.
Orphan Drug EPI-A0001 for Mitochondrial Respiratory Chain Diseases
On April 4, the FDA approved orphan drug status for EPI-A0001 (made by Edison Pharmaceuticals, Inc) in the treatment of inherited mitochondrial respiratory chain diseases.
There are currently no approved drugs for these highly debilitating diseases, which frequently affect the nervous system as well as skeletal and cardiac muscle. Often classified as mitochondrial encephalomyopathies, they are caused by genetic errors in the synthesis of inner mitochondrial membrane proteins that are needed for energy production.
According to a company news release, the approval was based on preclinical data demonstrating the drug's safety and efficacy in targeting mitochondrial electron shuttling and energy production.
Reviewed by Gary D. Vogin, MD
作者：
Yael Waknine 2007-6-16