阿法赛特有望治疗1型糖尿病

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一种治疗银屑病的药物阿法赛特似乎可以用来治疗1型糖尿病。在针对美国患者的一项小型试验中,阿法赛特(alefacept)可以帮助人体产生胰岛素,从而治疗1型糖尿病。研究结果发表在The Lancet Diabetes & Endocrinology。

阿法赛特在美国曾获批治疗银屑病,但在2011年被厂家撤销,该药从未在欧洲上市。

银屑病和1型糖尿病一样,是一种自体免疫性疾病,即免疫系统攻击自身健康皮肤细胞所致。

在对银屑病患者的临床试验中,该药攻击特殊类型的T细胞,而这种T细胞和1型糖尿病中胰岛素分泌细胞的功能有关。

印第安纳大学的研究小组决定探讨该药是否对新诊断的1型糖尿病患者有作用。研究招募33例患者,每周注射阿法赛特,连续12周,之后中断12周,然后再开始另一疗程。其他16例参与者给予安慰剂。

结果发现,餐后2小时两组的胰腺分泌胰岛素状况没有显著差别,但是餐后4小时两组的胰岛素分泌则有显著差别,此时治疗组能够维持胰岛素分泌,而安慰剂组胰岛素水平则下降。

治疗12个月后,治疗组的胰岛素使用没有出现显著增加,而安慰剂组则出现增加。治疗组还具有较少的血糖过低发生率,血糖过低在1型糖尿病中很常见。

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial

Summary

Background

Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes.

Methods

The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12—35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered withClinicalTrials.gov, number NCT00965458.

Findings

Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0·015 nmol/L (95% CI −0·080 to 0·110) in the alefacept group and decreased by 0·115 nmol/L (-0·278 to 0·047) in the placebo group, and the difference between groups was not significant (p=0·065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0·015 nmol/L [95% CI −0·076 to 0·106] vs decrease of −0·156 nmol/L [—0·305 to −0·006]; p=0·019), and daily insulin use (0·48 units per kg per day for placebo vs 0·36 units per kg per day for alefacept; p=0·02) and the rate of hypoglycaemic events (mean of 10·9 events per person per year for alefacept vs 17·3 events for placebo; p<0·0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0·75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred.

Interpretation

Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.

Funding

US National Institutes of Health and the Juvenile Diabetes Research Foundation.

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