JDRF Research

“Insulin Fragment” Therapy Safe And Promising In Its First Evaluation In Humans

JDRF-funded researchers from the United Kingdom have shown that “proinsulin peptide,” a fragment of insulin being evaluated as a potential immune system therapy for type 1 diabetes, is safe to use in people who have had the disease for some time. JDRF supported the research through the Diabetes Vaccine Development Center (DVDC), a joint venture between JDRF and Australia’s National Health and Medical Research Council.

The research, published in the journal Clinical and Experimental Immunology, showed that people with type 1 diabetes who were given three doses of the peptide did not have an acute allergic reaction or experience any adverse immune responses, such as the activation of potentially damaging T cells. Allergic reactions or the activation of T cells are major risks associated with this type of therapy. Their absence thus signifies “an important milestone in the clinical evaluation of peptide immunotherapy for type 1 diabetes,” the scientists noted.

Peptide immunotherapy is a type of treatment that uses small proteins to “reset” the immune system to a healthy state, much like the common allergy shot. In the case of proinsulin peptide therapy, the goal is to train the immune system to tolerate the insulin-producing beta cells that are the target of the immune response that causes type 1 diabetes. Peptide therapy is like a method of presenting new instructions to the immune system: by delivering a T cell trigger in a different way, the intent is to “induce tolerance” and stop the immune system from firing on itself.

Proinsulin is a natural precursor protein to insulin made by the beta cells of the pancreas; proinsulin peptide, a segment of proinsulin, is a target of immune T cells, making it a good candidate as an immune system therapy for type 1 patients.

Trial design and results
In this clinical trial, scientist Mark Peakman and colleagues from King’s College London and the University of Bristol investigated the safety of proinsulin peptide in two groups of patients with established diabetes. People were randomly assigned to either a low-dose or high-dose treatment, given by injection, but both the scientists and the trial participants knew the drug assignment they were given—a trial design known as “open label.” Subjects ranged in age from 21 to 53 years old.

In addition to the favorable immune findings, no serious adverse events occurred in any of the treated patients, nor were notable changes observed in routine blood tests. The researchers concluded that proinsulin peptide did not have a negative effect on the participants’ diabetes for two reasons. First, they found no antibodies directed against proinsulin, which would have signaled an unwanted immune response to the peptide. Second, they found no T cells targeting proinsulin, which would have indicated that the treatment caused an inflammatory state.

An additional positive finding was that the peptide appeared to have temporarily triggered the activation of T cells that can regulate the immune response. However, this finding was based on in vitro, or laboratory, tests using the patients’ white blood cells, and was only observed in a small number of participants in the trial. So determining if proinsulin peptide injections actually created a regulated immunological environment—one that minimizes beta cell destruction and allows those cells to go about their intended purpose and produce insulin—will need to be resolved in more advanced studies, the researchers said.

Next steps and strategic basis
Because proinsulin peptide appears to be safe, a next-step clinical trial in people who have been newly diagnosed is likely to follow, perhaps within six months or so. JDRF will support these studies through the DVDC. Such a trial—which JDRF sees as a high priority—will establish whether this therapy is safe in newly diagnosed patients. Though the full impact of the treatment on type 1 diabetes will not be the primary focus of the trial, it will look at whether beta cell mass is impacted.

Among the potential benefits of peptide immunotherapy is the relatively modest cost of synthesizing these small molecules. And because they are small and mobile, they deliver a better bang-for-the-buck in that they are “seen” by the immune system at a rate about 50 times higher than is achieved with larger molecules.

Key Point:
The first human trial of proinsulin peptide indicates that it is a safe and promising therapy for resetting the immune response in people with type 1 diabetes. The results set the stage for a Phase Ib clinical trial in the newly diagnosed.