Psoriasis Drug Shields Beta Cells in Type 1 Diabetics

Jenni Laidman

September 23, 2013

The psoriasis drug alefacept (Amevive, Astellas Pharma) preserved insulin secretion and led to reduced use of exogenous insulin in people with recently diagnosed type 1 diabetes, according to the newly published results of a phase 2 study.

Although the drug failed to meet the trial's primary 1-year end point, it met 3 secondary end points, including significantly improving C-peptide levels in the treatment group 4 hours after eating, at 1 year. The primary end point looked at C-peptide levels 2 hours after eating.

"Alefacept is the first targeted biological drug assessed in patients with new-onset type 1 diabetes that significantly depleted the T cells that attack the pancreas in type 1 diabetes, while preserving other immune cells that are important for pancreatic function," said lead author Mark R. Rigby, MD, director, pediatric translational research core, Indiana University and Riley Hospital for Children at Indiana University Health, Indianapolis. Dr. Rigby and colleagues' paper is published online September 23 in Lancet Diabetes & Endocrinology.

"Although the primary end point was not met, several key secondary end points were significantly different between treatment groups, suggesting that alefacept might preserve pancreas-cell function during the first 12 months after diagnosis. [This] might be a useful strategy in type 1 diabetes, but longer follow-up is required to confirm the preliminary signal of efficacy observed at 12 months," he says in a Lancet statement. The study is ongoing, and Dr. Rigby and colleagues intend to perform further assessments at 18- and 24-month follow-up.

Unfortunately, alefacept has now been withdrawn from the US market for business reasons, notes the author of an accompanying editorial, Kevan C. Herold, MD, deputy director for translational science, Yale University, New Haven, Connecticut. He says the study results are encouraging, criticizing the choice of primary end point rather than the study's inability to meet it.

"Insulin use decreased in the group receiving alefacept, as did the frequency of major hypoglycemic events — a secondary end point not previously captured in type 1 diabetes clinical trials of immune modulators. Thus, despite the unfortunate selection of the 2-hour area under the curve (AUC) as the primary end point for the trial (the 4-hour test shows the complete response, since some individuals have a delayed response to the meal), the evidence strongly supports clinical efficacy of this treatment strategy in the first year following diagnosis," Dr. Herold writes.

Alefacept Patients Used Less Insulin, Had Less Hypoglycemia

Dr. Rigby and colleagues explain that because type 1 diabetes results from autoimmune targeting of the pancreatic beta cells, it has been postulated that immune modulators such as alefacept could arrest autoimmunity and preserve residual beta cells in patients newly diagnosed with the condition.

In the double-blind Inducing Remission in New-Onset Type 1 Diabetes With Alefacept (T1DAL) study, the researchers recruited subjects, ages 12 to 35 years, within 100 days of type 1 diabetes diagnosis at 14 US centers. There were 33 patients randomly assigned to the alefacept group and 16 to the placebo group. Each participant received a weekly intramuscular injection with either alefacept (15 mg) or placebo for 12 weeks, followed by a 12-week break in treatment, and completed with another cycle of 12 weeks of treatment.

In the primary-end-point measure, the mean C-peptide AUC at 2 hours increased by 0.015 nmol/L in the alefacept group and fell by 0.115 nmol/L in the placebo group, a difference that was not significant (P = .065). However, in the secondary end point — measuring mean C-peptide AUC at 4 hours — the results were significantly different, with a mean increase of 0.015 nmol/L in the treatment group and a decrease of 0.156 nmol/L in the placebo group ( P = .019).

In addition, the treatment group used less insulin — 0.36 units/kg per day in the treatment group vs 0.48 units/kg per day in the placebo group (P = .02) — and experienced fewer hypoglycemic events, with a mean 10.9 events per person per year for alefacept compared with 17.3 events per person per year in the placebo group (P < .0001).

Dr. Herold and the study's authors attribute the treatment success to alefacept's ability to disrupt and destroy effector-memory T (Tem) cells and central-memory  T (Tcm) cells thought to attack beta cells in the pancreas, while sparing regulatory T (Treg) cells. Specifically, the drug targets CD2 proteins expressed predominantly on Tcm and Tem cells, blocking T-cell stimulation and inducing apoptosis.

"The T1DAL trial is the first demonstration, to our knowledge, that it is possible to specifically and effectively deplete memory T cells in new-onset type 1 diabetes," the authors write.

The T1DAL trial was initially designed to include more patients, but the December 2011 business decision to pull alefacept from the US market disrupted the plans. The company, Astellas Pharma US,stressed at the time that this was voluntary and not the result of any safety concern.

In his editorial, Dr. Herold calls the company's move "disappointing — particularly as we move closer to finally reaching the ultimate goal: to prevent, stop, and even reverse type 1 diabetes."

This study was sponsored by the National Institute of Allergy and Infectious Diseases and supported by the Juvenile Diabetes Research Foundation and the National Institute of Diabetes and Digestive Kidney Diseases. Dr. Rigby has reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr. Herold has reported no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online September 23, 2013. Abstract Editorial


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