Multicenter study reveals anti-tumor necrosis factor drug preserved beta cell function at onset
By the University at Buffalo
A multicenter study led by a University at Buffalo pediatric endocrinologist has found that a drug currently on the market for other autoimmune conditions can preserve the beta cells of children and young adults recently diagnosed with Type 1 diabetes for at least a year after diagnosis.
The research, published Nov. 19 in The New England Journal of Medicine, represents a major step forward in the effort to find ways to preserve the insulin-making capabilities of children and young adults newly diagnosed with Type 1 diabetes.
The NEJM paper reports on the 52-week treatment period. This is being followed by a period where participants are monitored but are not taking the drug.
The phase 2 study demonstrated that golimumab, an anti-tumor necrosis factor (TNF) therapy, reduced the amount of injected insulin required by children and young adults with newly diagnosed Type 1 diabetes by preserving their ability to produce insulin on their own, called endogenous insulin.
The need for less injected insulin is a major quality of life improvement for patients with Type 1 diabetes, according to the researchers.
The World Without Disease Accelerator, a group within Janssen Research & Development LLC, funded the study.
Golimumab, marketed as Simponi, is currently approved to treat rheumatoid arthritis, ulcerative colitis and other autoimmune conditions. However, it is not approved by the U.S. Food and Drug Administration for the treatment of Type 1 diabetes.
The study was led by Teresa Quattrin, M.D., first author, UB Distinguished Professor in the department of pediatrics, senior associate dean for research integration in the Jacobs School of Medicine and Biomedical Sciences at UB, and director of special populations at UB’s Clinical and Translational Science Institute. She is the attending pediatric endocrinologist at the Diabetes Center at UBMD Pediatrics and John R. Oishei Children’s Hospital.
Preserving Beta-Cell Function
“The most important finding of our work is that this drug, golimumab, is a potential disease-modifying agent for newly diagnosed Type 1 diabetes,” Quattrin said. “The main goal of the study was to see if golimumab could preserve beta-cell function in these newly diagnosed patients, and it does.”
The team determined beta-cell function was preserved based on the amount of C-peptide in patients’ blood during a four-hour mixed meal tolerance test. Because C-peptide reflects only insulin made by the body and not injected insulin, C-peptide levels reveal how well the pancreas is producing insulin.
Patients treated with golimumab had higher C-peptide levels at week 52 compared to placebo.
“This was statistically significant; thus the study met its primary goal,” Quattrin said. “In fact, 41% of participants receiving golimumab had an increase or less than 5% decrease in C-peptide compared to only 11% in the placebo group.”
Culmination of Decades of Work
The current study is the culmination of decades of work that Quattrin has been conducting at UB and at the Diabetes Center at UBMD Pediatrics and John R. Oishei Children’s Hospital. An internationally known researcher in pediatric endocrinology, she has been interested in finding ways to extend the remission, or honeymoon period, to preserve the ability of recently diagnosed Type 1 diabetes patients to continue to make insulin on their own.
Patients newly diagnosed with Type 1 diabetes generally have elevated levels of tumor necrosis factor alpha, which is directly toxic to the pancreatic beta cells that produce insulin. In 2009, building on positive findings in animal models treated with anti-TNF therapy, Quattrin and her team published a randomized pilot study where 10 patients received another TNF inhibitor and eight received placebo starting within 28 days from diagnosis. The results of that small proof-of-concept study strongly suggested this class of drugs might be able to preserve beta-cell function in newly diagnosed patients with Type 1 diabetes.
“Patients newly diagnosed with Type 1 diabetes don’t stop making insulin all of a sudden,” Quattrin said. “During the period just after diagnosis, called partial remission or the honeymoon period, patients are still able to make some insulin on their own. That is the period we have targeted with this study of golimumab.”
Nearly 43% of those in the current study who received golimumab were in partial diabetes remission versus 7% of those receiving placebo. The definition of partial remission was based on insulin dose and blood sugar control levels as indicated by hemoglobin A1C, a measurement of average blood sugar levels over three months.
Achieving Good Blood Sugars with Less Insulin
While both groups of patients in the current study achieved good blood sugar control, those receiving golimumab did so with less injected insulin, which Quattrin described as a critical benefit.
“During the 52 weeks of the study, insulin dose increased only slightly for those on golimumab, 0.07 units per kilogram per day, versus 0.24 units per kilogram per day for those on placebo. Moreover, in a post-hoc analysis, an analysis conducted after the conclusion of the clinical trial, those who were younger than 18 years had 36% fewer episodes where blood sugar was less than 54 mg per deciliter, designated by the American Diabetes Association as level 2 hypoglycemia,” Quattrin said.
This is important clinically because low blood sugar reactions are dangerous and can even be fatal if untreated. Episodes of low blood sugar require immediate attention, often causing disruption to the child (e.g., they have to be removed from class or recreation/sports activities), thereby compromising quality of life.
Quattrin explained a child with Type 1 diabetes requires about 1 unit of insulin per kilogram of body weight per day. That means a child weighing about 65 pounds typically requires about 30 units of injected insulin per day once they are out of the partial remission period, about three to six months after diagnosis.
Golimumab was administered by parents or self-administered by participants as a subcutaneous injection every two weeks. No serious side effects related to the study drug, such as serious infections, were reported.
The randomized, controlled clinical trial was conducted at 27 centers throughout the U.S., including at the Diabetes Center at UBMD Pediatrics and Oishei Children’s Hospital in Buffalo. It involved 84 patients, aged 6 to 21 years, with two-thirds receiving golimumab and one-third receiving placebo starting within 100 days from diagnosis.
Co-authors are Michael J. Haller of the University of Florida, Andrea K. Steck of the University of Colorado, Eric I. Felner of Emory University and Yinglei Li, Yichuan Xia, Jocelyn H. Leu, Ramineh Zoka, Joseph A. Hedrick, Mark R. Rigby and Frank Vercruysse, all of Janssen Research & Development LLC.