Medical Research: Congratulations, Dr. Sprague, on your presentation of another successful phase 3 clinical trial program at the recently concluded Annual Meeting of the American Society of Nephrology. Your presentation unveiled a new vitamin D repletion therapy that effectively controls secondary hyperparathyroidism in chronic kidney disease. Can you give us a little background for the presented studies?
Dr. Sprague: Thanks! Vitamin D insufficiency is a big problem in chronic kidney decease (or CKD): it afflicts more than 20 million adults in the United States who have stages 1 through 4 CKD. Its prevalence increases with CKD severity and it drives secondary hyperparathyroidism. The studies which I presented evaluated a novel therapy to treat secondary hyperparathyroidism (SHPT) arising from vitamin D insufficiency in patients diagnosed with stage 3 or 4 CKD. This new therapy is a modified-release formulation of calcifediol.
Medical Research: Can you tell us more about vitamin D insufficiency?
Dr. Sprague: Vitamin D insufficiency is a condition in which the body has low vitamin D stores. It is characterized by inadequate blood levels of the vitamin D, known as 25-hydroxyvitamin D. An estimated 70-90% of CKD patients have vitamin D insufficiency, which can lead to SHPT and resultant debilitating bone diseases. Vitamin D insufficiency has also been associated with increased mortality in CKD.
Medical Research: And secondary hyperparathyroidism? What is it?
Dr. Sprague: Secondary hyperparathyroidism is generally abbreviated as SHPT. It is a condition commonly associated with CKD in which the parathyroid glands secrete excessive amounts of parathyroid hormone, or PTH. SHPT arises most frequently as a result of vitamin D insufficiency or as a consequence of CKD. In CKD patients both retention of phosphorus and slight decrease in calcium also contributes to SHPT in addition to the vitamin D deficiency. Prolonged elevation of plasma PTH causes excessive calcium and phosphorus to be released from bone, leading to elevated serum calcium and phosphorus, weakening of the bones and calcification of vascular and other soft tissues. SHPT affects 40-60% of patients with moderate CKD and approximately 90% of patients with severe CKD. Vitamin D therapy for SHPT is associated with improvement in the SHPT and reduced mortality in CKD patients
Medical Research: Most people take vitamin D supplements. Aren’t these sufficient to treat CKD patients?
Dr. Sprague: Unfortunately, no. Vitamin D supplementation isn’t reliably effective to treat SHPT in CKD patients. That’s why we evaluated a modified-release formulation of calcifediol. Calcifediol is an overlooked therapy that reliably corrects vitamin D insufficiency by raising serum levels of 25-hydroxyvitamin D. The modified-release formulation is designed to correct vitamin D insufficiency in a gradual (rather than abrupt) manner, which makes the product more effective.
Medical Research: Can you describe the phase 3 studies that you conducted with modified-release calcifediol?
Dr. Sprague: Of course. Two randomized, double-blind, placebo-controlled trials that involved 429 patients with stage 3 or 4 CKD, elevated plasma PTH and vitamin D insufficiency were performed. The patients were recruited from 77 U.S. sites and randomized 2:1 to receive daily doses of either modified-release calcifediol (30 or 60 mcg) or placebo. Patients who completed these trials were treated, at their election, for an additional 6 months with modified-release calcifediol during an open-label extension study which is still ongoing.
Medical Research: And what did the trials show?
Dr. Sprague: The two completed trials successfully met all primary efficacy and safety endpoints. Plasma PTH gradually and progressively declined to near normal levels over the course of 1 year of treatment with modified-release calcifediol, but remained elevated with placebo treatment. The primary efficacy endpoint was a responder analysis in which “responder” was defined as a subject who demonstrated an average 30% decrease in plasma PTH from pre-treatment baseline. The observed response rates for the combined studies with modified-release calcifediol were 40% after 26 weeks of treatment and 60% after 52 weeks, compared with <8% for placebo (P<0.001), and were similar in CKD stages 3 and 4. Modified-release calcifediol corrected vitamin D insufficiency in 97% of treated patients vs. <6% with placebo.
Medical Research: The results are impressive. Was the product safe to use?
Dr. Sprague: Safety and tolerability data were comparable in both treatment groups, with modified-release calcifediol causing minimal changes in serum calcium or phosphorus, and no discernible changes in urine calcium or phosphorus.
Medical Research: What should clinicians and patients take away from your report?
Dr. Sprague: The reported data support the conclusion that modified-release calcifediol is effective for treating SHPT by correcting vitamin D insufficiency in patients with stage 3 or 4 CKD.
Medical Research: What recommendations do you have for future research as a result of these studies?
Dr. Sprague: We need to better understand the mechanisms by which modified-release calcifediol lowers elevated PTH. We also need to see how much more effective it can be when administered for longer periods of time and if it is effective in other patient populations that experience SHPT, such as patients with stage 5 CKD. We also should determine if long term treatment with calcifediol can prevent cardiovascular disease in patients with CKD.
Medical Research: Are you planning to do more research with modified-release calcifediol?
Dr. Sprague: Absolutely. I’m encouraged by the excellent results obtained so far, and optimistic that further research will be positive.
Medical Research: Thanks for your time and good luck with future research.
Dr. Sprague: Thank you.
Poster Presentation: “Safety and Efficacy of Modified-release Calcifediol for Secondary Hyperparathyroidism in Patients with Stage 3 or 4 CKD and Vitamin D Insufficiency.” (Stuart M. Sprague et al.)
Presentation Date: Saturday, November 15, 2014