Previous studies used higher doses of otelixizumab, an anti-CD3 monoclonal antibody, but also saw a reactivation of the Epstein Barr virus….
In patients with type 1 diabetes, a higher C-peptide concentration is associated with a controlled HbA1c and fewer complications. Otelixizumab is an anti-CD3 monoclonal antibody that works by upregulating T regulatory cells and downregulating pathogenic T cells. In doing so, it could inhibit the autoimmune process of this disease in which T cells destroy pancreatic β-cells responsible for insulin production.
A previous study showed positive results in using otelixizumab to preserve β-cell function in recent-onset type 1 diabetes patients. However, the dose used, 48-64mg over 6 days, was found to cause some adverse events in these patients. About 75% of patients receiving otelixizumab saw a reactivation of the Epstein Barr virus.
Researchers conducted a phase III, randomized, placebo-controlled trial to determine the safety and efficacy of otelixizumab using a lower dose than in the previous study. A lower dose, a total dose of 3.1mg over eight days, was used to see if β-cell function could be preserved while preventing Epstein Barr virus reactivation. A total of 272 patients were randomized to receive either otelixizumab or placebo. The primary end point studied in this trial was the change in C-peptide area under the curve from a 2-h mixed-meal tolerance test at month 12. Secondary end points included daily insulin use and difference from baseline in HbA1c at month 12.
Results of the primary end point, change in 2-h C-peptide AUC from a mixed-meal tolerance test at month 12 did not show a statistically significant difference between the treatment and placebo groups (-0.20 + 0.037nmol/L vs. -0.22 + 0.025nmol/L, P=0.58). No statistically significant differences were observed in the secondary end points with regards to HbA1c difference from baseline to month 12 (P=0.289) or daily insulin use (P=0.276). Adverse events seen with other anti-CD3 antibodies were reported in the otelixizumab group, but no Epstein Barr virus reactivation was reported with the lowered dose.
While the results showed a smaller dose of otelixizumab led to a better safety profile than in the previous trial, it sacrificed efficacy in preserving β-cell function. A dose of 3.1mg cannot be recommended as a viable option for type 1 diabetes patients. Further research needs to be performed with different dosing regimens to determine if this type of therapy is an option for recent-onset type 1 diabetes patients.
- Otelixizumab has shown the ability to preserve β-cell function in a previous phase II trial, but it also caused Epstein Barr virus reactivation in a high amount of patients.
- This study used a lower dose (3.1mg) of the medication to determine if similar efficacy could be obtained while providing better safety outcomes.
- While safety improved, no statistically significant efficacy outcomes were observed while using the lower dose of the medication when compared to placebo.
Aronson R, Gottlieb PA, Christiansen JS, Donner TW, et al. Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Type 1 Diabetes. Diabetes Care. October 2014.