Monoclonal Antibody Trials and Innovative Insulin Updates

Dr. Fran Cogen Health Pro
  • As I have written previously, treatment of diabetes is divided into two aspects: "until the cure" and "the cure." Major diabetes organizations may have mission statements that reflect both tenants (one example is The American Diabetes Association). Other organizations such as The Juvenile Diabetes Research Foundation primarily work to find (and fund) "the cure." Major dollars are focused on finding medications and treatments that can prevent, delay, or treat diabetes. Healthcare providers typically focus on the care "until the cure" and work with you and your family on the front lines directing diabetes management in terms of medication (insulin/oral medications), diet, and exercise by providing different strategies depending on the situation.

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    However, a greater number of healthcare providers are being offered opportunities to work with academic institutions to help find "the cure" by performing pharmaceutical trials and close patient follow-up. Examples of ongoing studies include the Diamyd trial (GAD-65 vaccine) conducted in our area at The University of Maryland and several monoclonal antibody trials. At the moment, George Washington and Georgetown Universities are partnering with the DEFEND 2 Monoclonal Antibody Trials. (The Department of Endocrinology and Diabetes at Children's National Medical Center is evaluating the possibility of becoming involved in the DEFEND 2 trials in some clinical capacity as well.)


    Unfortunately, the original monoclonal antibody (Teplizumab, a humanized anti-CD3 monoclonal antibody) trial spearheaded by Dr. Kevan Herold of Yale University (The Protégé Trial-sponsored by MacroGenics and most recently by Lilly Pharmaceutical Corporation) has been suspended because the trial did not meet the primary efficacy endpoint. What does this mean? According to the Protégé Data Monitoring Committee (DMC), which is composed of independent experts in the disciplines of diabetes and biostatistics, an analysis of year one safety and efficacy (the study drug's effectiveness) data of the Protégé Phase 3 clinical trial of teplizumab concluded that the primary efficacy endpoint of the study was not met. The primary efficacy endpoint was a composite of the study patient's total daily insulin dose and Hb A1c at 12 months. It is important to note that no unanticipated safety concerns were noted in the Data Monitoring Committee's report. As a result of the DMC's report, based on the lack of efficacy, MacroGenics Inc. and Lilly Corporation have decided to suspend further enrollment and dosing of patients in two other ongoing clinical trials of Teplizumab in type 1 diabetes (the Protégé Encore Trial, a second Phase 3 trial of the same research design as Protégé, and the SUBCUE trial, a Phase 1b trial that is researching the subcutaneous administration in patients with T1DM.)


    At this point, the DEFEND-2 Phase 3Trial which employs a different anti-CD3 monoclonal antibody (Otelixzumab) is still recruiting patients. According to informational materials supplied by Tolerx, Inc. (the company that manufactures the trial drug), the structure of otelixizumab is different from other anti-CD3 monoclonal antibodies, including teplizumab. The company feels (and hopes) that "this difference distinguishes and improves the safety profile and biological effect of otelixiumab when compared to other anti-CD3 antibodies." According to Tolerx, regular reviews of unblinded efficacy are still being conducted by the DEFEND Data Monitoring Committee (DMC). The DMC has continued to recommend the trial without modification. The primary endpoint as recommended by the FDA is "C-peptide change from baseline at 12 months."


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    Where does this leave us now? Naturally, we are greatly concerned that the efficacy of Otelixzumab will not be supported. However, the only way to find out will be to continue to recruit patients to confirm whether or not the drug is effective.


    On another innovative treatment note: in the comment section of one of my blogs, a parent discussed AFREZZA, an ultra-rapid acting insulin with a different pharmacokinetic profile than other insulins. AFREZZA is an inhalable insulin with peak concentrations in 12 -14 minutes (as opposed 1.5-2 hours with rapid acting analogs) that mimics the endogenous release of bolus insulin in people without diabetes. Cartridges are single-use and inserted into the inhaler. The powder in the cartridge enters the airway by inhaling through the mouthpiece of the device and is activated by patient inhalation. Most importantly, the inhaler is a small compact device (unlike the device used for the previous inhaled insulin product). According to the MannKind Corporation, the insulin has demonstrated improved post-prandial glucose control in association with hb A1c reductions and lower risk of hypoglycemia. Most importantly, they note no clinically significant adverse long-term effects on pulmonary lung function. (For more information: check out the website.)


    The above discussion refers to drugs that are still in clinical trials and are not quite ready for "primetime." Sadly, we can see why based on the disappointing news in regard to Teplizumab. However, the theory behind these innovative trials appears to be scientifically rigorous and have demonstrated acceptable safety profiles. It is therefore a matter of time before some trial drug will actually WORK! (Hence the need to continue recruitment for these studies.)



Published On: November 09, 2010