Palopegteriparatide treatment for hypoparathyroidism in autoimmune polyendocrinopathy-candidiasis-ectodermal...

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1, is an autosomal recessive disorder of thymic T cell negative selection that results in autoimmune destruction of various endocrine and extra-endocrine tissues. The classic clinical triad of the syndrome includes hypoparathyroidism (hypoPT), chronic mucocutaneous candidiasis (CMC), and adrenal insufficiency, while involvement of thyroid, pancreas, gonads, and ectodermal tissues are also frequently observed. Historically, treatment for hypoPT, the most common endocrine manifestation of APECED, has posed a unique challenge. Conventional therapy with oral calcium and active vitamin D analogs is often complicated by the presence of malabsorption and esophageal disorders, which are prevalent in APECED patients. Moreover, supplementation with oral calcium and active vitamin D analogs without correction of the underlying PTH insufficiency can result in renal and other soft-tissue calcifications. Short-acting PTH therapies, which have been used off-label in the treatment of hypoPT, fail to mimic normal parathyroid physiology due to their brief half-lives and can result in fluctuations of serum calcium levels between hypocalcemia and hypercalcemia. Long-acting PTH analogs have recently been developed to more closely mimic physiologic PTH activity. One such agent, palopegteriparatide, a prodrug of PTH (1,34), has shown promise to be the first hormone replacement therapy for hypoPT. We report our experience in 4 patients with APECED-associated hypoPT who initiated treatment with palopegteriparatide and were followed over the subsequent 4-15 mo period. We observed a robust calcemic response to treatment during this follow-up window with wide fluctuations in serum calcium during this period of dose titration. These early observations highlight the effectiveness of palopegteriparatide in patients with APECED, enabling the discontinuation of oral calcium and active vitamin D supplements. They also highlight the question of whether etiology-specific differences in responsiveness may influence dose requirements and calcemic stability.