Secondary Hyperparathyroidism Program

Secondary hyperparathyroidism is a disorder which develops primarily because of Vitamin D hormone insufficiency. It is characterized by abnormally elevated blood levels of parathyroid hormone (PTH) and, in the absence of early detection and treatment, it becomes associated with parathyroid gland hyperplasia and a constellation of metabolic bone diseases, leading eventually to increased bone fracture rates and soft tissue calcifications. It is a common complication of CKD, with rising incidence as CKD progresses.

Treatment of secondary hyperparathyroidism is often accomplished with traditional 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 Numbers 7 & 8 of that initiative specifically recommend Vitamin D hormone replacement therapy for patients with CKD Stages 3, 4 & 5 who have elevated plasma levels of iPTH. These clinical practice guidelines also specify target levels of iPTH, serum calcium, serum phosphorus, and calcium phosphorus product (Ca x P) in CKD patients.

However, currently administered Vitamin D hormone replacement therapies are less than ideal. These therapies, which include doxercalciferol, paricalcitol and calcitriol, produce supraphysiological surges in blood Vitamin D hormone levels, resulting in significant aberrations in calcium and phosphorus homeostasis. As a result, very few CKD patients are able to meet the iPTH, serum calcium, serum phosphorus and (Ca x P) targets set out by the K/DOQI clinical practice guidelines. In addition, these surges cause increases in intracellular hormone levels, stimulating a strong upregulation in intracellular CYP24 enzyme, which catabolizes administered hormone as well as any residual endogenous Vitamin D hormones and prohormones. CYP24 has the intended function of protecting the targeted cells from excessive intracellular levels of Vitamin D hormones, but it acts as a significant barrier to effective Vitamin D hormone replacement therapy in CKD.

Cytochroma, in collaboration with the research group of Prof. Gary H. Posner at The Johns Hopkins University, has developed a portfolio of candidates that address these weaknesses. In particular, Cytochroma’s dual mechanism compounds are rationally designed to increase safety and efficacy by activating the Vitamin D signaling pathway as traditional Vitamin D hormone replacement therapies do, but also inhibiting CYP24 and thereby preventing the catabolism of active Vitamin D hormone and its prohormone. Cytochroma’s candidates will therefore have greater therapeutic windows resulting in efficacious lowering of iPTH to target levels, while better maintaining serum calcium and (Ca x P) target levels. These products will therefore allow more CKD patients to preserve Vitamin D, calcium and phosphorus homeostasis and meet the targets set by the K/DOQI clinical practice guidelines.

Market Opportunity

SHPT is a common complication of CKD with rising incidence as CKD advances. Disturbances in mineral and bone metabolism are common in patients with CKD. However, the processes causing altered mineral metabolism and bone disease can be influenced beneficially by Vitamin D hormone replacement therapy.

Currently, there are over 500,000 Stage 5 CKD patients and published sources indicate that approximately 90% of these patients have PTH levels above the established target range (150 to 300 pg/mL). The prevalence of Stage 3 & 4 CKD is 8 million and 400 000 patients respectively. Recent studies show the percentage of patients with elevated iPTH and therefore eligible for Vitamin D hormone replacement therapy is 40% for Stage 3 CKD, and 60% for Stage 4 CKD. With the rapid growth seen in Stage 1 and Stage 2 CKD over the past decade, the prevalence of Stages 3 & 4 CKD is expected to rise to over 9 million by 2010.

In addition to the rapid increase in prevalence of CKD, a growing percentage of patients are being treated for SHPT. Broader treatment is being driven by the National Kidney Foundation (NKF) through its Kidney Disease Outcomes Quality Initiative (K/DOQI) which provides nephrologists with clear clinical practice guidelines for treating SHPT with Vitamin D hormone replacement therapy. In 2004, approximately 80% of Stage 5 CKD patients were treated for SHPT with Vitamin D hormone replacement therapy, according to the United States Renal Data System (USRDS). It is anticipated that the number of Stage 5 CKD patients treated with Vitamin D hormone replacement therapy will increase due to safer and more effective therapies such as CTA018 Injection. Both the K/DOQI Guidelines and recent publications also advocate the treatment of SHPT in CKD Stages 3&4, which is expected to drive growth in the treatment of these patient populations.

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