BOSTON– Alefacept, an immunosuppressive biologic drug approved to treat psoriasis but later withdrawn by its manufacturer, appears to stem the progression of new-onset type 1 diabetes more than a year after therapy is stopped.
In type 1 diabetes, pancreatic beta cells are destroyed by autoreactive effector T cells, which alefacept targets as one of its mechanisms of action.
“What we think is happening – the most likely conservative hypothesis – is that we’ve rescued beta cells that were traumatized but not killed,” resulting in some restoration of beta-cell function and endogenous insulin secretion, said Dr. Gerald Nepom, director of Benaroya Research Institute at Virginia Mason in Seattle.
At the 75th annual sessions of the American Diabetes association, Dr. Mario Ehlers, another researcher involved with the study, presented 24-month results from T1DAL (Targeting of memory T cells with alefacept in new onset type 1 diabetes).
The study randomized 49 people aged 12-35 years who had been diagnosed with type 1 diabetes within the previous 100 days to treatment with weekly injections of alefacept (n = 33) or placebo (n = 16). Active treatment occurred over two 12-week periods, with the last treatment administered 36 weeks into the study.
In 2013, the T1DAL investigators published their results from 12 months (about 4 months after treatment was stopped). They found that alefacept did not bring about statistically significant differences over placebo in insulin production 2 hours after a meal (measured as mean C-peptide secretion area under curve), but at 4 hours, the differences reached statistical significance (Lancet 2013;1:284-94). In addition, insulin use and hypoglycemic events were found to be significantly reduced in the treatment arm.
New results from 24 months’ follow-up of the T1DAL cohort showed a more impressive effect.
At 15 months after cessation of therapy, the 2-hour postprandial mean C-peptide AUC was significantly greater in the treatment group (P = .002) than the placebo group, as was the 4-hour measure (P = .015). Insulin requirements remained significantly lower (P = .002) and rates of major hypoglycemic events were reduced by about half (P < .001) among subjects who had received alefacept.
Dr. Nepom stressed that while these results were “spectacular” for patients who responded, only about one-third of the treatment arm showed higher C peptide at 24 months than at baseline. “So while there was sustained and significant benefit, it was not in everybody,” he said.
“There’s a responder and a nonresponder situation here, and we’re continuing to evaluate all kinds of biologic biomarkers to try and understand the differences between patients who improved in the second year and those who didn’t.”
Investigators will continue following up the T1DAL patients who responded for as long as patients consent, without further medication, to see how durable the effect is, Dr. Nepom said.
An optimal clinical treatment protocol with alefacept needs to be investigated in a separate trial, he said. Currently, the focus is on adding an immunomodulatory drug after induction treatment with alefacept in the hope that this prolongs the “honeymoon period” seen in the T1DAL responders, and/or extends the benefit to more than just a third of patients.
“Durable clinical responses are likely to require therapies that address more than a single immunological pathway, such as a sequential combination of treatments that first interrupt ongoing disease and secondly restore normal function,” Dr. Nepom said.
Like T1DAL, the new trial will be conducted under the Immune Tolerance Network, a publicly funded research consortium headed by Dr. Nepom that makes all its trial data available to the public. The results from T1DAL will be also published this year in the Journal of Clinical Investigation.
Alefacept (Amevive, Astellas Pharma) was approved by the U.S. Food and Drug Administration in 2003 to treat moderate to severe chronic plaque psoriasis in adults. In 2011, its manufacturer withdrew it from the market, citing business reasons. “We are actively working with interested parties to fix that situation,” Dr. Nepom said.
The Immune Tolerance Network is also investigating whether tocilizumab (Actemra, Genentech), an antibody that targets the interleukin-6 receptor, can slow disease progression and help maintain insulin production in people with new-onset T1D.
The Immune Tolerance Network is funded by the National Institute of Allergy and Infectious Diseases. Dr. Nepom disclosed financial support from Genentech, GlaxoSmithKline, and Pfizer, and research support from Astellas and Bayer. A T1DAL coauthor and former lead investigator, Mark Rigby, recently joined Janssen pharmaceuticals as an employee. Dr. Ehlers disclosed no conflicts of interest.