Patients with new-onset Type 1 diabetes were modestly better able to retain beta cell function after treatment with the B-cell depleting agent rituximab (Rituxan), researchers said.
In a placebo-controlled trial, investigators saw smaller decreases in C-peptide levels and a reduced need for exogenous insulin over one year in patients receiving rituximab, according to Mark Pescovitz, MD, of Indiana University School of Medicine in Indianapolis, and colleagues.
“This Phase II study shows that a therapy that targets B cells may have a beneficial effect on beta-cell function in early Type 1 diabetes.”
“It is unlikely that treatment with rituximab as administered in this study would be optimal,” they added, suggesting that other B-cell depleting drugs, such as anti-CD20 antibody-based agents, should be tested as well.
“Although B-cell depleted patients in this study were in no way cured, the difference in their preserved beta cell function and resultant diabetes control is significant.”
“Aside from the real, though modest benefit to the patients in the study, perhaps more important is the proof of the concept that B cells will be an important additional target in ongoing attempts to halt the autoimmune obliteration of beta cells,” Greeley wrote in an e-mail.
Type 1 diabetes has traditionally been regarded as originating with rogue T cells, but, as Pescovitz and colleagues noted, “many T lymphocyte-mediated diseases include a B-lymphocyte component.”
For example, B cells can mediate antigen presentation and otherwise modulate T-cell behavior, the researchers said. Consequently, they sought to test whether depleting B cells with rituximab would help preserve beta cell function in patients newly diagnosed with Type 1 diabetes.
To that end, they recruited 87 patients, 8 to 40 years old, who received four doses of placebo or 375 mg/m2 of rituximab over a three-week period.
The primary outcome measure was area under the curve (AUC) for stimulated C-peptide response during the first two hours of a four-hour mixed meal tolerance test, conducted one year after the first rituximab dose. Insulin secretion and glycated hemoglobin levels were secondary endpoints. Efficacy measures were also taken at months three, six, and nine.
In the rituximab group, mean AUC for C-peptide in the test was 0.56 pmol/mL, compared with 0.47 pmol/mL for the placebo group (P=0.03), on an intent-to-treat basis. Results were similar when the analysis was confined to the 71 patients who underwent all four infusions.
Pescovitz and colleagues found that C-peptide AUCs declined steadily in the placebo group over the four evaluations, at a rate of 55% per year. In contrast, mean AUCs increased from baseline at the three-month evaluation in the patients receiving ritixumab. After that, however, their mean AUC began to decline, with a slope equal to that seen in the placebo group.
At the one-year evaluation, mean doses of insulin were 0.39 IU/kg (SD 0.22) in the rituximab patients versus 0.48 IU/kg (SD 0.23) in the placebo group (P<0.001).
HbA1c levels at one year were also lower in the rituximab group, 6.76% (SD 1.24%) versus 7.00% (SD 1.30%) (P<0.001). Mean HbA1c levels had been higher at baseline in the rituximab group relative to the placebo group (7.31% versus 7.08%).
The researchers reported nonsignificant trends suggesting that children and adolescents had stronger responses to rituximab than adults.
As expected, CD19-positive cell counts dropped to near zero during the rituximab treatment, recovering to about 65% of baseline levels at one year. Pescovitz and colleagues calculated that 97% of the between-group difference in C-peptide levels at one year was explained by CD19-positive cell counts at month three.
More than 90% of the rituximab group experienced infusion reactions with the first dose, but these subsided to levels seen in the placebo group with subsequent infusions.
Overall, adverse events were about twice as common with rituximab. Most were grade 1-2 and none reached grade 4, the researchers said. There was no signs of increased infections or neutropenia with rituximab, the researchers said.
Levels of immunoglobulin M declined markedly with rituximab, as would be expected with B-cell depletion. They had not fully recovered to baseline levels at one year. IgG levels were 5% higher in the rituximab group at month three (P=0.048) relative to the placebo group.
Greeley suggested that better efficacy may be possible by combining rituximab with agents targeting T cells more directly. She pointed out that even if beta cell replacement therapy becomes available, it won’t be a cure “unless the nearly inexorable immune destruction of pancreatic beta cells is dealt with first. This study represents the next step in the slow march to finding a cure.”
A somewhat more cautionary note was sounded by Joel Zonszein, MD, of Albert Einstein College of Medicine in New York City.
“The molecule [rituximab] is not free of side effects and while fever decreases with subsequent infusions and the dose and frequency of infusions are better, the tolerability may be a problem in ‘real practice’ and more important long-term side effects are unknown,” he asserted.
Zonszein also pointed out that the efficacy was relatively minimal and transient. “It will be hard for me to sell the concept to my patients with the evidence provided by the researchers,” he commented. Still, he added, “I agree with the authors that this study opens a new pathway of exploration.”
Pescovitz M, et al “Rituximab, B-lymphocyte depletion, and preservation of beta-cell function” N Engl J Med 2009; 361: 2143-52.