Early Alefacept in Type 1 Diabetes Shows Benefit at 2 Years

Miriam E Tucker

July 24, 2015

Treatment with alefaceptan (Amevive, Astellas), an immunosuppressant drug formerly used for psoriasis, may have led to preservation of insulin-producing beta-cell function at 1 year after treatment cessation in patients with newly diagnosed type 1 diabetes, suggests a follow-up analysis from the Inducing Remission in New-Onset Type 1 Diabetes With Alefacept (T1DAL) study.

The study was published July 21 in the Journal of Clinical Investigation by lead author Mark R Rigby, MD, who is currently with Janssen R&D, Spring House, Pennsylvania, but was with Indiana University and Riley Hospital for Children, Indianapolis, during the study.

Type 1 diabetes results from destruction of insulin-producing beta cells by self-reactive T cells that have escaped central and peripheral tolerance. The rationale for the current study, according to Rigby and colleagues, is based on the fact that "patients with newly diagnosed type 1 diabetes have residual beta-cell function, providing a window of opportunity for a targeted intervention that can preserve islet function for years or decades after diagnosis."

In the randomized, double-blind, multicenter trial of 49 patients with new-onset (within 100 days) type 1 diabetes, treatment with alefacept (weekly injections in two 12-week courses separated by 12 weeks) was compared with placebo. At 1 year, the drug didn't meet the primary end point based on 2-hour postmeal C-peptide levels but did meet several other secondary end points, suggesting beta-cell preservation, including improvement in 4-hour C-peptide.

Now, at 2 years — at least 1 year since the last alefacept dose — both 2- and 4-hour C-peptide levels improved compared with placebo, and the 33 patients given alefacept had less exogenous insulin requirements. The treatment cut the risk of major hypoglycemic events by one-half compared with placebo.

The manufacturer of alefacept had pulled the drug from the market after the study began, but the results demonstrate that the immune-modulating approach is valid, Rigby and colleagues say.

"This study provides proof of concept that intermittent dosing with a targeted and well-tolerated immunotherapy can improve islet function in type 1 diabetes and encourages further investigations to develop an immunologically based therapy for type 1 diabetes," they write.

Kevan Herold, MD, professor of immunobiology and medicine at Yale University School of Medicine, New Haven, Connecticut, agrees, noting that even though the therapy doesn't eliminate the need for exogenous insulin, any approach that eases the burden of type 1 diabetes is a major benefit, given that the average HbA1c for adolescents is still about 9%.

"It's really scary. Even though we have all these new technologies and better insulins, control is awful....The ease of metabolic control is much better when you still have residual beta-cell function reflected by C-peptide. I would say the clinical value is that if you can maintain C-peptide where you were at the time of diagnosis, it just would be tremendous," Dr Herold, who was not involved in the current study, told Medscape Medical News.

Inducing Tolerance

At 24 months, a mean of 15 months after the last dose of alefacept, the decline in C-peptide area under the curve for both 2- and 4-hour mixed-meal tolerance tests was significantly less than with placebo: 0.185 vs 0.334 nmol/L at 2 hours (P = .015) and 0.134 vs 0.368 nmol/L at 4 hours (P = 0.002), respectively.

Results of sensitivity analyses based on sex, age, baseline insulin use, and HbA1c produced similar results.

HbA1c didn't differ between the alefacept and placebo groups at 24 months, with levels of 7.4% to 7.5% in both groups. However, those in the alefacept group had significantly lower insulin requirements, 0.43 vs 0.60 U/kg/day (P = .002), equal to a nearly threefold greater increase in insulin use from baseline in the placebo group compared with alefacept (0.28 vs 0.10 U/kg/day).

Alefacept-treated participants had substantially fewer episodes of major hypoglycemia vs placebo (defined < 55 mg/dL), with 9.6 vs 19.1 events/patient/year (P < .001) over the study period, both on and off treatment.

There were no differences between groups in adverse events. Just one serious adverse event occurred in the alefacept group, but it was deemed unlikely to be related to the study drug. Four of the alefacept patients had transient, asymptomatic declines in CD4 counts, Rigby and colleagues reported.

Immunophenotyping demonstrated that alefacept treatment depleted both CD4+ and CD8+ central memory T cells (believed to be the primary causes of beta-cell destruction in type 1 diabetes) and effector memory T cells, while at the same time preserved regulatory T cells. As a result, the ratio of regulatory to memory T cells was increased.

The two effects together are believed to be important in achieving immune tolerance, Dr Herold explained.

"The concern is that just getting rid of T or B cells doesn't restore tolerance. The goal is to try to restore a balance between cells that turn off immune responses — regulatory T cells — and cells that carry them out — T effector cells," he said. "There's also a fair amount of work suggesting that regulatory T cells are disordered in autoimmune diseases like type 1 diabetes. So, the goal is to restore the balance and function of regulatory T cells. The authors are suggesting that might have happened here."

Dr Herold has done similar work with the investigational anti-CD3 monoclonal antibody teplizumab. With that agent, some of the patients who responded initially have continued to show benefit up to 7 years beyond initial treatment.

"We wouldn't expect the same biologic to work the same in everybody. Some could respond very well and have very long-lasting effects. We don't know how it will play out in the future," he told Medscape Medical News.

The trial was conducted by the Immune Tolerance Network and sponsored by the National Institute of Allergy and Infectious Diseases. Astellas provided alefacept  and gave input only regarding dosage and safety. Dr Rigby is an employee of Janssen R&D,\ Pharmaceutical Companies of Johnson & Johnson. Disclosures for the coauthors are listed in the article. Dr Herold reported no disclosures.

J Clin Invest. Published online July 20, 2015. Article

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