新龟兔赛跑：拉住乌龟 让兔子先跑

临时起意，提下昨天刷屏的Teplizumab：

• Teplizumab是一种人源化抗CD3单抗药物，抗原识别区源自预防移植排斥的OKT3，另外对Fc做了改造，失去了结合FcR和补体的能力

• 通过识别并结合成熟T细胞表面的CD3的ε链，从而削弱了TCR-CD3复合物的形成，能下调T细胞在多类自免疫疾病中的免疫功能，比如1型糖尿病，通常认为是T细胞不加选择的进攻胰岛β细胞，而Teplizumab被认为可以保护胰岛β细胞免于攻击；

• 最早的临床由礼亲王主导，07年转手给Macrogenics，后来又由Provention接盘至现在，期间各种disappointing data不是今天讨论的主题。

下面来看下结果，文章也于昨日NEJM在线

主要是为了研究Teplizumab在T1DM患者的自身抗体阳性的高危亲属中是否可以预防或推迟中T1DM的发生，是一项多中心、随机、双盲、安慰剂对照的双臂研究。

主要终点及统计假设

基线其实并不平衡，高亮部分可以对照后面的亚组分析

患者接受了连续14d的Tpelizumab或安慰剂

主要终点：Tepolizumab和安慰剂组诊断为T1DM的中位时间 48.4 vs 24.4 mo，随访期间分别43%(19/44)和72%(23/32)人被诊断为T1DM： HR 0.412 (95% CI, 0.216-0.783; P = 0.006)。年化后的T1DM诊断率分别14.9% 和35.9% 。

安全性方面：实验组中白细胞计数下降和皮肤毒性比较显著，和先前报道的类似：

治疗后第5天淋巴细胞计数见底——减少了72.3%，前30天内75%的不良事件均与淋巴细胞减少相关，在第45天的时候Teplizumab组除1人外，其余淋巴细胞数目恢复正常——那1例在105天的时候回复正常

再看一个，T细胞亚型的指标：之前发现接受Teplizumab后应答的新发T1DM患者中无反应性的TIGIT+ KLRG1+EOMES+ CD8+ T细胞占比上升。为了确认在本预防性研究中是够有类似的变化，研究人员分析了两组群体的CD3+ T细胞中TIGIT+ KLRG1+EOMES+ CD8+ T细胞的占比，结果显示Tepolizumab组和安慰剂组的这一比值在3mo、6mo和18mo的差值分别46.5% (95% CI, 8.23%-98.4%)、49%  (95% CI, 41.3% to 113%)和15.9%(95% CI, −14.2%-56.4%)。而CD4+ Treg和KLRG1− TIGIT− CD8+ T细胞的比例没有这么大的差异，提示Teplizumab的选择性作用。 但是，从这个角度看，14d的给药对T细胞亚群的影响也就是3-6mo。

其实hin多银都觉得奇怪为什么，前4-5mo的图形差异决定了整个曲线的走势，

那么再回去看基线——之前提过，两组基线并不均衡：比如＜18岁、兄弟姐妹的亲属、部分自身抗体阳性（如micro insulin、anti-IA-2和ICA）的占比

Templizumab组中＜18岁患者、anti-IA-2及ICA的自身抗体阳性的占比更少，而micro insulin自身抗体阳性的占比更高，而根据亚组分析的森林图：这几个特征正好相比overall更加favor Teplizumab，极有可能Teplizumab的优势很可能是这些因素拉动

总之有点尴尬了

正文凑数

A Single Course of Provention's PRV-031 (Teplizumab) Delays Type 1 Diabetes Onset in High-Risk Individuals by at Least Two Years

• Results from the NIH-Sponsored "At-Risk" Study Published in The New England Journal of Medicine and Presented at the American Diabetes Association Annual Meeting

• Company to Host Conference Call on Monday, June 10th at 8:30 AM Eastern Time

OLDWICK, N.J., June 9, 2019 /PRNewswire/ -- Provention Bio, Inc. (Nasdaq:PRVB), a clinical stage biopharmaceutical company dedicated to intercepting and preventing immune-mediated disease, today announced that results from the National Institutes of Health (NIH)-sponsored "At-Risk" Study were published on-line in The New England Journal of Medicine and presented at the Scientific Sessions of the 79th Annual American Diabetes Association (ADA) meeting.  The "At-Risk" Study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), with additional support from JDRF. The study was conducted by the Type 1 Diabetes TrialNet, an international collaboration aimed at discovering ways to delay or prevent type 1 diabetes (T1D), and evaluated Provention's PRV-031 (teplizumab) for the prevention or delay of clinical T1D in relatives of type 1 diabetics at high-risk of developing the disease.  PRV-031 (teplizumab) is an anti-CD3 monoclonal antibody in development for the interception and prevention of clinical T1D.

The "At Risk" Study enrolled 76 participants ages 8 to 49 who were "At-Risk" because they had two or more T1D autoantibodies and abnormal glucose metabolism (dysglycemia); 72% of participants were under the age of 18.  Subjects were randomized to receive either PRV-031 (teplizumab) or placebo.

Results from the study showed that a single 14-day course of PRV-031 (teplizumab) significantly delayed the onset and diagnosis of clinical T1D, as compared to placebo, by a median of 2 years in children and adults considered to be at high risk. The median time to clinical diagnosis of T1D for placebo participants was just over 24 months.  In comparison, the median time for PRV-031 (teplizumab)-treated participants to clinical diagnosis of T1D was just over 48 months (p=0.006). During the trial, 72% in the placebo group developed clinical diabetes compared to only 43% of the PRV-031 (teplizumab) group. PRV-031 (teplizumab) was well tolerated and the safety data were consistent with prior studies in newly diagnosed patients.

"This groundbreaking study demonstrates that we can use immunotherapy, specifically PRV-031 (teplizumab), to prevent or significantly delay the onset of clinical type 1 diabetes by at least two years in individuals who will almost certainly progress to clinical disease," said Dr. Eleanor Ramos, Provention's Chief Medical Officer and Chief Operating Officer.  "More importantly, approximately 60% of subjects in the study did not develop T1D following only one course of PRV-031 therapy, double the placebo group. Teplizumab is the first immune modulator to show a delay in the clinical onset of type 1 diabetes."

Dr. Kevan Herold, M.D., Professor of Immunobiology and Medicine at Yale University, lead author of the study, stated, "These results have real clinical meaning for individuals at-risk of developing clinical type 1 diabetes such as family members of patients. Delaying the onset of clinical T1D may mean the disease burden could be postponed to a point at which patients are better able to manage their disease such as after infancy, elementary school, high school or even college. With PRV-031 (teplizumab), we may now be able to intervene and fundamentally change the progression of T1D for these at-risk subjects. In addition, we look forward to learning more as we observe patients during the study's follow-up period, which will also evaluate the long-term outcomes for those in whom the diagnosis of disease has been delayed to see if they will be diagnosed with T1D or are protected."

"It's remarkable to see that a single course of two-week therapy cut the incidence of diabetes by almost 50 percent during this trial. These data clearly tell us short-term immunotherapy can significantly slow down clinical onset of diabetes. Developing immuno-modulatory drugs that don't require continuous treatment to impact autoimmune disease is a major paradigm shift," said Jeffrey Bluestone, PhD, A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology at the UC San Francisco (UCSF) Diabetes Center, President, CEO of the Parker Institute for Cancer Immunotherapy, and a Director of Provention Bio.

"We especially want to congratulate TrialNet for conducting this landmark study, and to thank the patients and families involved, as well as the JDRF for their commitment to this study and the patient community," stated Ashleigh Palmer, CEO of Provention Bio.  "We are delighted with the results, which reinforce our confidence not only in PRV-031 (teplizumab), but in Provention's strategic intent to intercept and prevent immune-mediated disease. The ability to delay the onset of clinical T1D is an enormous breakthrough, given that a recent study indicated the life expectancy for patients diagnosed with T1D before the age of ten is reduced by as much as 16 years on average."

Mr. Palmer continued, "Based on these results, we are evaluating a regulatory path forward for PRV-031 in at-risk individuals.  We are also assessing PRV-031 in newly-diagnosed T1D patients in our Phase 3 PROTECT study, which commenced in April. Our broader goal for PRV-031 is to address the continuum of T1D and provide therapeutic options for this life-impacting and life-threatening autoimmune disease that, until now, has seen no disease-modifying innovation since the development of insulin a century ago."