“Skin drug shows ‘promising’ results on type 1 diabetes,” reports BBC News.
This story is based on a small trial of alefacept in people with newly diagnosed type 1 diabetes. The immune system of people with type 1 diabetes attacks the insulin producing cells in their pancreas. Most people with type 1 diabetes have to regularly inject themselves with insulin.
Alefacept is approved for use to treat the skin condition psoriasis in the US. Researchers hoped it might help people with type 1 diabetes, because both conditions are autoimmune conditions (where the symptoms develop due to the body’s immune system ‘malfunctioning’ and attacking its own healthy tissue).
Alefacept suppresses one type of immune system cell associated with the autoimmune response, and the researchers hoped that it could also stop these cells from further attacking the insulin-producing cells.
Although the drug did not improve how much insulin was produced in the two hours after a meal, people taking the drug needed lower doses of insulin than those taking placebo and experienced fewer hypoglycaemia events – where blood glucose levels drop to an abnormally low level.
These results should be seen as very preliminary, with larger and longer term trials now needed to determine whether alefacept does offer any benefit for people with newly diagnosed type 1 diabetes.
Where did the story come from?
The study was carried out by researchers from Indiana University and other research centres in the US. It was funded by the US National Institutes of Health and the Juvenile Diabetes Research Foundation. Astellas Pharma, the US drug company that made alefacept, provided the drug for this study but was not involved in the development, design or implementation of the trial or the interpretation of the results.
The study was published in the peer-reviewed medical journal The Lancet Diabetes and Endocrinology.
The small trial was covered reasonably by the BBC News, although it is not yet clear how “promising” this drug is.
What kind of research was this?
Type 1 diabetes is caused by the body’s own immune system attacking the insulin producing cells in the pancreas (called an autoimmune response). When it is first diagnosed, some of these cells are still producing insulin, but their ability to do this is gradually lost. The disease usually starts in childhood or adolescence, and requires lifelong treatment with insulin.
There has been interest in whether giving immune suppressing treatments at the time of diagnosis might be able to prevent further loss of these cells. However, so far the side effects of these treatments, such as increased vulnerability to infection, have outweighed any benefits, or they have shown little or no benefit.
The drug alefacept suppresses the actions of a specific set of immune system cells, called T-cells, which in type 1 diabetes, are involved in attacking the insulin producing cells. Alefacept is already approved in the US for treating psoriasis – another auto-immune condition that affects the skin. The researchers wanted to test whether alefacept might stop T-cells from attacking the insulin producing cells and therefore stabilise insulin production in people with newly diagnosed type 1 diabetes.
This type of trial is a standard step in determining whether a drug works well enough to go forward for testing in larger, full scale phase III clinical trials.
What did the research involve?
This trial, called the T1DAL trial, randomly assigned people with newly diagnosed type 1 diabetes to either two 12-week courses of alefacept separated by a 12-week pause, or matching placebo. The researchers assessed how much insulin was being produced in the two groups over time, to see if alefacept was having the desired effect.
The study included 49 people aged 12 to 35 years of age, who had been diagnosed with type 1 diabetes in the past 100 days and had the auto-antibodies which are associated with the condition.
People with infections were excluded, as were people with:
- a history of hepatitis B
- a history of hepatitis C
- a history of HIV
- a reduced numbers of blood cells
- previous substantial heart disease
- a history of cancer
During the study all participants had intensive diabetes management using treatment goals as set out by the American Diabetes Association.
Alefacept or placebo were given as weekly injections into a muscle. These injections were received in the study centres, so the participants could be observed for any adverse effects. After 12 injections, the participants had a 12-week break from injections, followed by another 12 weeks of injections.
The main outcome that the researchers were interested in was insulin production. They measured this by measuring levels of a protein called C-peptide – a by-product of the insulin-making process which provides a good measure of how much insulin the pancreas is producing. Participants were given what is described as a “mixed meal”, and then had blood samples taken to assess the amount of C-peptide being produced at the start of the study, 24 weeks into the study, and one year.
The researchers also assessed insulin use by participants at one year, any hypoglycaemic events (where blood glucose levels are too low), a measure of diabetes control (called HbA1c) at one year, and frequency and severity of adverse events in the alefacept group versus placebo group.
What were the basic results?
Enrolment in the study stopped early as the manufacturers withdrew the drug from the US market. This decision was reported (PDF, 311Kb) to have been based on commercial factors rather than any safety or other concerns.
Of the 49 people enrolled, 33 received alefacept and 16 placebo.
In the study’s main analysis at one year, people in the alefacept group showed a slight increase in their C-peptide levels in the two hours after the mixed meal test, while the placebo group showed a slight decrease. The difference between groups was not large enough to convincingly rule out the possibility that it occurred by chance (that is, it was not “statistically significant”).
If the C-peptide response was measured over four hours then the difference between alefacept and placebo was statistically significant. People taking alefacept were taking lower doses of insulin at one year than those taking placebo. People taking alefacept had also had fewer hypoglycaemic events than those taking placebo (average 10.9 events per person per year versus 17.3 events per person per year). Diabetes control, as measured by mean HbA1c levels, did not differ significantly between the groups at one year.
All patients in the study had at least one adverse event, but no serious adverse events were reported in the trial. Major hypoglycaemic events were counted as adverse events, with 85% of the alefacept group and 94% of the placebo group experiencing these events. Infections were also common events (76% of the alefacept group and 69% of the placebo group). In the alefacept group, 29 participants (88%) had an adverse event that was judged to be related to study drug compared to 15 participants (94%) in the placebo group.
How did the researchers interpret the results?
The researchers concluded that although alefacept did not improve their main outcome of interest at 12 months (C-peptide protein levels in the two hours after the mixed meal test), it did improve some of the other outcomes they looked at and seemed to be similarly tolerable to placebo. They suggested that, “Alefacept could be useful to preserve [insulin-producing cell] function in patients with new-onset type 1 diabetes.”
This small phase II trial has shown some improvement with alefacept compared with placebo in people with newly diagnosed diabetes.
The fact that the drug did not produce significant improvements in the study’s main outcome may be because the study had to be stopped early, and was not large enough to show an effect. The researchers had calculated that they would need 66 patients to show an effect of the size they expected, but they only managed to enroll 49 people. The authors note that longer term follow up is needed to confirm the findings, as there is quite a lot of variability between people with type 1 diabetes in how fast they lose their insulin producing cells in the year after diagnosis. The study’s participants are being followed up, with assessments planned at 18 months and two years. They also note that larger trials of alefacept or similar drugs in type 1 diabetes are needed.
Alefacept (brand name Amevive) was approved in the US for treating psoriasis, but has not been approved in Europe. The manufacturer decided to stop producing it for business reasons. It is not clear whether this drug is still commercially available.
Although the trial did not find an increase in adverse effects with the drug, this type of drug needs to be monitored carefully as in suppressing a part of the immune system it can increase susceptibility to infections.
While this small trial provides some suggestion of a possible beneficial effect of alefacept in people with type 1 diabetes, this needs to be confirmed by further studies. In particular, it will be important to determine how long any effect might last, exactly how long alefacept treatment is required for, and the longer term safety of this treatment especially as type 1 diabetes is a lifelong disease. Read more advice about how you can have a healthier life with type 1 diabetes.