Alpelisib Therapy in 2 Patients With Congenital Hyperinsulinism

Abstract

Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion, leading to severe hypoglycemia in most cases. We previously described the adjunct use of alpelisib therapy in a 3-month-old patient with CHI. We now describe our observations in 2 additional patients with severe CHI treated with alpelisib therapy, resulting in discontinuation of all existing treatments and normalization of feeding. Two children (aged 3 and 4 years) with CHI (homozygous ABCC8 and KCNJ11 pathological variants) who were unresponsive to conventional therapies were treated with alpelisib. Treatment was initiated at 12.5 mg daily, with gradual dose adjustments based on clinical responses. Outcome measures included blood glucose variability, frequency of hypoglycemic episodes, need for supplemental feeding, and treatment safety. In both cases, alpelisib significantly improved glucose levels, reducing the frequency of hypoglycemic episodes. This allowed for the tapering and discontinuation of other medications (diazoxide and octreotide) and facilitated a transition to bolus gastrostomy-tube/oral feeding. No significant adverse effects were reported. Alpelisib shows promise as both an adjunctive and primary therapy for CHI, improving glucose levels and reducing dependence on continuous feeding and other medications. Randomized controlled trials are needed to assess its long-term safety and efficacy for CHI.

Keywords: KCNJ11 pathological variant; Usher syndrome; alpelisib; congenital hyperinsulinism; hypoglycemia.

Figure 1.

Treatment progress with alpelisib therapy over a 4-month period in case 1. The patient's treatment progress with alpelisib therapy, as reflected by changes in the serum insulin level and the percentage of time with glucose values below the target range of 63 mg/dL (3.5 mmol/L). To convert values for insulin to µU/mL, divide by 7.175. At 3 weeks, the patient was able to receive bolus G-tube feeding every 3 hours. Over time, the bolus G-tube feeding intervals were gradually spaced until reaching every 5 hours by the second month of treatment. The alpelisib dose was increased gradually until it reached 20 mg twice daily but was later reduced to 15 mg twice daily due to hyperglycemia. The percentage of time below the target glucose range dropped to 0% by 4 to 5 weeks. Continuous glucose monitoring was maintained throughout the observation period. Injections with octreotide long-acting release were discontinued in the second month of treatment.

Figure 2.

Treatment progress with alpelisib therapy over a 5-month period in case 2. The patient's treatment progress with alpelisib therapy, as reflected by changes in the serum insulin level and the percentage of time with glucose values below the target range of 63 mg/dL (3.5 mmol/L). To convert values for insulin to µU/mL, divide by 7.175. By 6 weeks the patient was able to discontinue continuous overnight feeding. The alpelisib dose was gradually increased until reaching 25 mg twice daily. Over time, the percentage of time below the target glucose range dropped to nearly 0% by month 5. Continuous glucose monitoring was maintained throughout the observation period. Injections with octreotide long-acting release were discontinued in the second month of treatment.