Therapeutic Focus

Secondary Hyperparathyroidism

Chronic kidney disease (CKD) patients exhibit a steady decline in blood levels of 1,25-dihydroxyvitamin D (vitamin D hormone) as the disease progresses and kidney function diminishes.  The declining level of 1,25-dihyrdoxyvitamin D is a primary cause of secondary hyperparathyroidism (SHPT) in these patients.  SHPT is characterized by abnormally elevated blood levels of intact parathyroid hormone (PTH) and is associated with parathyroid gland hyperplasia and a constellation of metabolic bone diseases, leading eventually to increased bone fracture rates, soft tissue calcifications, cardiovascular disease, muscle weakness and reduced quality of life.  Recent evidence suggests that some, if not all, of these adverse outcomes can be prevented, mitigated or reversed by early diagnosis and proper treatment. SHPT is a common complication of CKD, with rising incidence as CKD progresses.

Treatment of SHPT is often accomplished with vitamin D hormone replacement therapies. The National Kidney Foundation through its Kidney Disease Outcomes Quality Initiative (K/DOQI) has established clinical practice guidelines for bone metabolism and disease in CKD. Guideline Number 8 of that initiative specifically recommends vitamin D hormone replacement therapy for patients with CKD Stages 3, 4 & 5 who have adequate vitamin D status and still have elevated plasma levels of PTH. These clinical practice guidelines also specify target levels of iPTH, serum calcium, serum phosphorus, and calcium phosphorus product (Ca x P).

Currently administered vitamin D hormone replacement therapies are plagued with safety issues that limit the doses that can be administered and, therefore, limit efficacy. These therapies include doxercalciferol, paricalcitol and calcitriol and produce supraphysiological surges in blood and intracellular levels of vitamin D hormones, resulting in significant aberrations in calcium and phosphorus homeostasis. As a result, few CKD patients are able to meet the iPTH, serum calcium, and serum phosphorus targets set out by the K/DOQI clinical practice guidelines. In addition, these surges cause a strong upregulation in intracellular CYP24A1 enzyme. Over-expression of CYP24A1 causes destruction of both the administered therapy as well as any residual endogenous 25-hydroxyvitamin D. Chronic use of current therapies can lead to treatment “resistance”, which results from prolonged elevation of intracellular levels of CYP24A1.

Market Opportunity

Currently, there are more than 500,000 Stage 5 CKD patients and published sources indicate that approximately 90% of these patients have elevated PTH levels. The prevalence of Stage 3 & 4 CKD is over 12 million patients, and recent studies show the percentage of patients with elevated PTH is 71% for Stage 3 CKD, and 83% for Stage 4 CKD. Growth in these patient numbers is being driven by the current epidemic of diabetes, hypertension and obesity, all leading causes of CKD

A growing percentage of CKD patients is being treated for SHPT. Broader treatment is being driven by the National Kidney Foundation (NKF) through its Kidney Disease Outcomes Quality Initiative (K/DOQI) and the more recent Kidney Disease Improving Global Outcomes (KDIGO) which provides nephrologists with clear clinical practice guidelines for treating SHPT with vitamin D hormone replacement therapy. Both Guidelines and recent publications advocate the treatment of SHPT in CKD Stages 3&4, where current vitamin D hormone replacement therapies are infrequently used, due to safety concerns.