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Targeting of Memory T Cells With Alefacept in New-Onset Type 1 Diabetes (T1DAL Study): 12 Month Results of a Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial
Study Questions:
What is the effect of alefacept on autoimmunity and preservation of residual β cells in patients newly diagnosed with type 1 diabetes?
Methods:
The T1DAL study was a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, ages 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. Randomization 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 hypoglycemic events, and glycated hemoglobin (HbA1c) concentrations.
Results:
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% confidence interval [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 hypoglycemic 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.
Conclusions:
The authors concluded that although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycemic events, suggesting efficacy.
Perspective:
Alefacept is the first targeted biological drug assessed in patients with new-onset type 1 diabetes that significantly depleted effector and central memory T cells while preserving regulatory T cells. Although the primary endpoint of the study was not met, several key secondary endpoints were significantly different between treatment groups, suggesting that alefacept may potentially preserve β-cell function during the first 12 months after diagnosis. Thus, targeting memory T cells might be a useful strategy in type 1 diabetes, but longer follow-up with alefacept as well as trials of other agents that specifically deplete memory T cells while preserving or enhancing regulatory T cells is required to confirm the preliminary signal of efficacy observed at 12 months in the current trial. Of note, alefacept was voluntarily withdrawn by the manufacturer in November 2011, citing business needs.
Keywords: Hemoglobin A, Insulin, Insulin-Secreting Cells, Follow-Up Studies, Autoimmunity, T-Lymphocytes, Recombinant Fusion Proteins, Cardiology, Cardiovascular Diseases, C-Peptide, Hypoglycemic Agents, Diabetes Mellitus
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