FDA核准第1型糖尿病幹細胞治療孤兒藥

2010年5月7日 - 美国食品药物管理局（FDA）的以孤儿药方式核准一种干细胞治疗（商品名Prochymal;奥西里斯治疗公司），用于新诊断为第1型糖尿病的患者。

这项产品是静脉注射型的成人间叶干细胞（骨髓基质干细胞），从健康年轻捐赠者的骨髓分离，因此避免胚胎和胎儿细胞来源的争议，细胞培养也使得可以从单一捐赠者大量制造数千次的剂量。

根据药厂新闻稿，骨髓基质细胞可藉由控制发炎，促进组织新生，预防疤痕形成而有治疗助益。临床前研究指出，骨髓基质细胞可以藉由保留β细胞功能而延缓第1型糖尿病恶化。

目前以一个在美国20个医学中心进行，有62个病患的双盲安慰剂控制第2期研究评估治疗安全性与效果，适合的病患是年纪12-35岁，纳入研究前已经诊断2 -20周。

海安治疗在之前被美国FDA核准为孤儿药，扩大核准用于移植物之抗宿主疾病，允许用于有生命危险的状况。

其他研究中的可能适应症包括克隆氏症，心肌梗塞，肺病。

COLUMBIA, Md.--(BUSINESS WIRE)--Jan 15, 2009 - Osiris Therapeutics, Inc. announced today that it has held a successful pre-Biologics License Application (pre-BLA) meeting for Prochymal used in the treatment of graft-versus-host disease (GvHD). A BLA is a comprehensive regulatory submission prepared by a biologic drug's sponsor to obtain full marketing approval from the Food and Drug Administration (FDA). As an outcome of the meeting between Osiris and FDA, the parties finalized the content and timing of what is expected to be the first BLA submission for a stem cell product.

"Agreement on the timing and content of the BLA marks an important milestone in our quest to make Prochymal the world's first fully approved stem cell therapy," said C. Randal Mills, Ph.D., President and Chief Executive Officer of Osiris. "We thank FDA for their significant efforts over the past several years as we have forged a highly productive partnership in this new and exciting area of medicine. Having proactively addressed issues critical to a successful review, we have created a clear understanding of the regulatory path to market approval."

A pre-BLA meeting is a mechanism by which FDA and the sponsor can discuss the application in advance of submission to avoid potential pitfalls in review process. In the Prochymal pre-BLA meeting there were three main areas of discussion. The first was the type and extent of safety and efficacy data that would be included. The second was manufacturing and quality data that would comprise the submission. The third was the process and format of the submission itself. Prior to the meeting, Osiris submitted a comprehensive outline of the proposed content and structure of the BLA.

Key results of the pre-BLA meeting are below:

FDA agreed with the proposed content and structure of the BLA for Prochymal for the treatment of GvHD.
The primary endpoint of the Phase III trial that will be reviewed by FDA for approval was confirmed to be GvHD Complete Response (CR). A CR is complete remission of the disease.
FDA indicated that the statistical analysis plan was appropriate.
The overall safety database (Integrated Summary of Safety) of Prochymal is sufficient in scope for the indication. No additional clinical data beyond what was presented is anticipated to be necessary for the BLA.
Agreement was reached on BLA requirements for Chemistry, Manufacturing and Controls (CMC) data.
The FDA concurred with the proposed product stability and process validation plan for submission and provided guidance on how to present the data for ease of review.
Agreement was reached on the timing and content of the BLA in rolling submission format. The rolling submission is an FDA provision available to drug candidates that have received Fast Track designation, which allows for completed sections of a BLA to be submitted on an ongoing basis. It can facilitate the process by allowing FDA to complete review of sections as soon as they are available. It is anticipated that the nonclinical sections, such as toxicology, will be the first submitted for review.
The BLA will be in the electronic Common Technical Document (eCTD) format. The eCTD format facilitates the review of the BLA and allows parallel submission of the dossier in other territories.
At the time of submission, Osiris will also submit the request for Priority Review of the Prochymal BLA. Investigational drugs with Fast Track designation are eligible for consideration for Priority Review, which provides for an accelerated six month application review by FDA.

Osiris and FDA also discussed the need for an Expanded Access Program (EAP) to make Prochymal available to critically ill steroid-refractory adult GvHD patients in the interim period until a final regulatory decision is reached. Osiris currently has an EAP in place for pediatric GvHD patients in the US and Canada. Osiris committed to work with FDA to determine the details of the new EAP.

In November 2008, Osiris and Genzyme announced a strategic alliance for the development and commercialization of Prochymal. Under the terms of the agreement, Osiris will commercialize Prochymal in the United States and Canada, and Genzyme will commercialize the treatment in all other countries.

About ProchymalProchymal is a preparation of mesenchymal stem cells specially formulated for intravenous infusion. The stem cells are obtained from the bone marrow of healthy adult donors. Prochymal is currently being evaluated in Phase III trials for steroid refractory GvHD, acute GvHD, and Crohn's disease. Prochymal has been granted Fast Track status by FDA for all three of these indications. Prochymal also obtained Orphan Drug status by FDA and the European Medicines Agency for GvHD. Prochymal is being studied in Phase II trials for the treatment of COPD, type 1 diabetes, and acute myocardial infarction.Additionally,theDepartment of Defense recently awarded Osiris a contract to develop Prochymal as a treatment for acute radiation syndrome.

Further study details as provided by Osiris Therapeutics:

 Primary Outcome Measures:
C-peptide AUC response (MMTT) [ Designated as safety issue: No ]

Secondary Outcome Measures:
Peak C-peptide response (MMTT) [ Designated as safety issue: No ]

Basal C-peptide response [ Designated as safety issue: No ]

Total daily insulin dose (units/kg) [ Designated as safety issue: No ]

Glycosylated hemoglobin (HbA1c) levels [ Designated as safety issue: No ]

Number of severe and documented hypoglycemic events [ Designated as safety issue: No ]

Changes in levels of GAD or IA-2 autoantibodies [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	June 2008
Estimated Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A: Experimental PROCHYMAL®	Drug: PROCHYMAL® Intravenous infusion of ex vivo cultured adult human mesenchymal stem cells
B: Placebo Comparator Placebo	Drug: Placebo Intravenous infusion of excipients of PROCHYMAL®

Detailed Description:
Diabetes mellitus refers to disorders in which the body has trouble controlling its blood glucose levels.
There are two main types of diabetes: type 1 and type 2. Type 1 diabetes mellitus (T1DM), which is being studied in this trial, is an autoimmune disorder in which the body's own immune system attacks and destroys the cells that makeinsulin.
These cells are called beta cells. As beta cells are destroyed, less insulin can be made.
This causes blood sugar levels to increase above normal and can cause life-threatening hypo- and hyper-glycemic reactions. For this reason, people with type 1 diabetes must take insulin to help control their blood sugar levels. Over time, poorly controlled diabetes can lead to a variety of serious health conditions, including heart disease, stroke, blindness, amputations, kidney disease, and nerve damage.
Insulin is the primary method of controlling diabetes by regulating blood glucose levels, but it may not reverse or prevent disease progression.
The active ingredient in ROCHYMAL® is adult human mesenchymal stem cells (MSCs). MSCs have been shown to interact with the immune cells in the body, reducing inflammation and assisting in tissue repair.
This study will help determine whether MSCs can protect normal pancreatic tissue from autoimmune attack and repair damaged pancreatic tissue, leading to an increase in insulin production and decrease in circulating blood glucose.
The characteristics and biologic activity of PROCHYMAL®, along with a good safety profile in human trials to date, suggest that PROCHYMAL® may be a good candidate for addressing Type 1 Diabetes.

Eligibility

Ages Eligible for Study:    12 Years to 35 Years
Genders Eligible for Study:    Both
Accepts Healthy Volunteers:    No

Criteria
Inclusion Criteria:

Subject must have a diagnosis of type 1 diabetes mellitus based on the ADA criteria
Subject must be screened between 2 and 20 weeks from initial T1DM diagnosis
Subject must be between the ages of 12 and 35 (inclusive)
Subject must have at least one diabetes-related autoantibody present (either GAD or IA-2)
Subject must have some beta cell function as determined by C-peptide testing
Subject must be willing to comply with "intensive diabetes management" as directed by the Investigator with the goal of maintaining blood glucose as close to normal as possible
Subject must be willing to comply with the schedule of study visits and protocol requirements
Exclusion Criteria:

Subject has Body Mass Index (BMI) ≥ 30
Subject has evidence of retinopathy at baseline
Subject has abnormally high lipid levels
Subject has abnormal blood pressure
Subject has abnormal serum creatinine
Subject has evidence of clinically significant proteinuria
Subject has diabetic ketoacidosis
Subject is being treated for severe active infection of any type
A female subject who is breast-feeding, pregnant, or intends to become pregnant during the study
Subject with clinically relevant uncontrolled medical condition not associated with diabetes (e.g. hematologic, renal, hepatic, neurologic, cardiac, or respiratory)
Subject is allergic to bovine or porcine products
Subject has evidence of active malignancy, or prior history of active malignancy that has not been in remission for at least 5 years

奥西里斯治疗公司（纳斯达克股票代码：OSIR）宣布，它已被授予为1型糖尿病的孤儿药物获得美国食品和药物管理局（FDA）指定为商品名Prochymal今天。美国食品药物管理局提起的孤儿药法案，促进为缺医少药的病人群体治疗的发展。要获得孤儿药资格，治疗必须针对一种疾病，它影响不到20万新患者每年在美国。

孤儿药提供了长达七年以下批准独占市场，消除美国FDA申请和注册费，并提供多达50个临床开发成本的百分之税收优惠政策。奥西里斯还拥有孤儿药方式为商品名Prochymal在移植物抗宿主病（GVHD）的治疗。

商品名Prochymal，一个成人间质干细胞可藉由控制炎症的治疗效果（海安），制定促进组织再生，并防止疤痕的形成，目前正在评估在双盲，安慰剂对照的II期临床试验1型糖尿病。奥西里斯是发展与青少年糖尿病研究基金会（JDRF）作为新诊断1型糖尿病患者治疗的伙伴关系商品名Prochymal。

在1型糖尿病，患者的自身免疫系统攻击并破坏胰腺中产生胰岛素的胰岛细胞，在血糖控制损失。目前，没有批准改变了这些关键胰岛细胞的破坏率处理，称为β细胞。在临床前研究Genzyme公司的研究人员首次发现，干细胞可以进行延迟保留β细胞功能的1型糖尿病的进展。