Parents who have children with congenital hyperinsulinism (HI) and adults living with the condition continue to wish there were more HI treatment options. While treatment does exist in most cases, it is far from ideal. With the goal of introducing a more effective treatment for patients who are not responsive to diazoxide, researchers at the Children’s Hospital of Philadelphia (CHOP) have been studying exendin (9-39). In a pilot study that will be published in the journal Diabetes in October (currently available online), CHOP researchers share the exciting news that exendin (9-39) in its investigational form does control blood sugar levels in patients with HI.
In order to provide the HI community with more information about the study and the drug’s future trajectory as a potential treatment option, Congenital Hyperinsulinism International (CHI) interviewed Dr. Diva De Leon, one of the lead CHOP researchers. In the interview Dr. De Leon provides more detail about the study and what we can expect in the future.
Julie Raskin: “When will the next phase of research begin?”
Dr Diva De Leon: “The proof-of-concept studies that we have done with exendin-(9-39) were with an intravenous preparation, not an optimal treatment route for outpatient management. We are developing a subcutaneous formulation of this investigational drug for the next set of studies. Currently, studies are ongoing to support a future clinical trial with a subcutaneous preparation of exendin-(9-39), including: pre-clinical studies to evaluate the toxicology profile of this investigational drug as well as pharmacologic studies to evaluate the drug half-life, etc.
We estimate that we will be ready to start the clinical trial with subcutaneous exendin-(9-39) in 2014, or sooner, if we succeed in getting a commercial partner for this project.”
Julie Raskin: “If HI families are interested in participating in the clinical trial, with whom should they be in touch or should they just wait for CHOP to reach out to them?”
Dr. Diva De Leon: “They can contact us by email or by phone at: [email protected] and 215-590-7682. In addition, information about our research studies can be found at:
www.research.chop.edu/research/clinical_research/clini and www.clinicaltrials.gov. When we are ready to start enrollment we will reach out to our patients for participation.”
Julie Raskin: “What will the criteria be for inclusion in the study?”
Dr. Diva De Leon: “For the next trial we will recruit children with persistent hypoglycemia due to hyperinsulinism, with or without history of prior pancreatectomy.”
Julie Raskin: “If exendin (9-39) does prove to be effective and safe in the treatment of HI, when can patients expect it to be available?”
Dr. Diva De Leon: “My best estimate is that if exendin-(9-39) does prove to have a good profile in terms of safety and efficacy, the product could be on the market within the next 5 years. I think the critical factor will be to find a commercial entity to partner with. In this sense, the work CHI is doing with NORD in raising awareness about CHI as a rare disease is very important.”
Julie Raskin: “Is it possible that exendin will be beneficial to patients who are currently treated with diazoxide? Could it be an alternative medication for those HI patients as well?”
Dr. Diva De Leon: “I think it is possible. Wouldn’t it be great to have multiple options for treatment? It is very frustrating when we are asked by families what are the treatment options for their children, only to have such a limited number of them. I am hoping that we could change that.”
Julie Raskin: “How in layman’s terms does exendin deactivate mutations in the ATP-sensitive Potassium Channel?”
Dr. Diva De Leon: “Exendin-(9-39) acts in the insulin producing cell by inhibiting a receptor that stimulates insulin secretion downstream of the potassium channel. We believe that this receptor, the glucagon-like peptide-1 receptor or GLP-1 receptor, plays an important role in regulating insulin secretion when ATP-sensitive potassium channels are dysfunctional or not existing (because of inactivating mutations). Thus, the hypothesis is that by inhibiting the GLP-1 receptor we can turn off insulin secretion even in these cases with defective ATP-sensitive potassium channels.”
Julie Raskin: “What is the derivation of exendin (9-39)?”
Dr. Diva De Leon: “Exendin-(9-39) is a small protein (peptide) synthesized in the laboratory (by a company that specializes in making peptides). It was first derived by truncating another peptide, exendin-4, a naturally occurring product in the saliva of the gila monster. By eliminating part of the protein (exendin-4) it was found that the effect on insulin was the contrary: exendin-4 stimulates insulin secretion and exendin-(9-39) inhibits insulin secretion. A synthetic form of exendin-4 is now in the market for the treatment of type 2 diabetes (Byetta).”
Julie Raskin: “We are delighted that you are committed to a career in HI research as the future of HI patients depends on people like yourself and there are so few of you! How did you get interested in the field?”
Dr. Diva De Leon: “I came to CHOP in 1999 for my fellowship in pediatric endocrinology with the goal of becoming a diabetes researcher, but during my first year of fellowship I was inspired by the children I saw with hyperinsulinism and their families to shift the focus of my research to hyperinsulinism.
It is amazing to realize how much progress has been made on understanding the disease process, on finding the molecular causes of hyperinsulinism, on realizing that some of these children have focal lesions that can be cured by surgery, and on developing the tools to identify these children. But I think there is still a lot that needs to be done to improve the treatment options for these children, particularly for those who don’t respond to diazoxide and who don’t have focal lesions. The identification of new targets for treatment is an important part of this, and this is what the major focus of my research is.”
Julie Raskin: “What can be done to encourage more physicians to take up a specialization in HI research and clinical work?”
Dr. Diva De Leon: “By creating more awareness about congenital hyperinsulinism and increasing funding opportunities we could encourage new generations of pediatricians, pediatric endocrinologists and scientists to focus their careers on this field.”
This is the full citation for the research paper: “The GLP-1 Receptor Antagonist Exendin-(9-39) Elevates Blood Fasting Glucose Levels in Congenital Hyperinsulinism due to Inactivating Mutations in the ATP-sensitive Potassium Channel,” Diabetes, published online July 31, 2012, to appear in print, October 2012. doi: 10.2337/db12-0166
