Opko Health Inc (OPK)

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Emerging drugs for secondary hyperparathyroidism ( http://www.ncbi.nlm.nih.gov/pubmed/25702624 )

February 23, 2015.

Mario Cozzolino, James Tomlinson, Liron Walsh, and Antonio Bellasi

University of Milan, San Paolo Hospital, School of Medicine, Renal Division, Department of Health Sciences, Milan, Italy [phone]; [e-mail]

Excerpt:

In the United States, the estimated prevalence of SHPT in patients with CKD ranges from 2 to nearly 5 million individuals. Similarly, in Europe, as many as 86% of patients on maintenance dialysis receive treatmentfor CKD-MBD.

Secondary hyperparathyroidism (SHPT), a common, serious, and progressive complication of chronic kidney disease (CKD), is characterized by elevated serum parathyroid hormone (PTH), parathyroid gland hyperplasia, and mineral metabolism abnormalities.

These disturbances may result in CKD-- mineral and bone disorder (CKD-MBD), which is associated with poor quality of life and short life expectancy.

The goal of SHPT treatment is to maintain PTH, calcium, and phosphorus within accepted targeted ranges.

Numerous studies indicate that mineral abnormalities occur early in the course of CKD, are prevalent by the time patients enter dialysis, and foreshadow a risk of cardiovascular and all-cause mortality.

Several newly developed compounds may potentially overcome the limitations of current SHPT therapies. If emerging therapies can reduce PTH, normalize mineral metabolism, promote treatment adherence, and reduce the risk of side effects, they may provide the requisite features for improving long-term outcomes in patients with SHPT receiving dialysis and reduce the risks of CKD-MBD.

SHPT is a common, serious, and costly manifestation of CKD , with negative effects on patient outcomes.

With current treatment approaches, a considerable proportion of patients have inadequately controlled PTH, phosphorus, and/or calcium, and the levels of these often fall outside the recommended ranges.

Current treatment for SHPT comprises three main strategies: reduction of phosphorus uptake by dietary restriction or the use of phosphate binders; suppression of PTH production with the use of calcitriol or analogs; and the use of calcimimetics, currently agents that allosterically modify the CaSR to increase activation in the presence of circulating levels of calcium, thus reducing PTH. Parathyroidectomy is usually a treatment strategy of last resort, after pharmacotherapy has failed.

Low-phosphate diet and phosphate binders

Phosphate binders have long been a corner stone in the treatment of SHPT. Because of toxicity, aluminum-based phosphate binders have been replaced by those containing calcium salts. Although calcium reduces serum phosphorus and PTH, it increases the risk of hypercalcemia and calciphylaxis. Calcium-based phosphate binders can represent a significant portion of an individual’s daily calcium intake, increasing the risk of overwhelming the calcium-buffering capacity of bone in some patients on dialysis. At high doses, calcium-based phosphate binders may elevate the risk of vascular calcification.

Several agents are in development for the management of SHPT. Two agents have reached Phase III development: the long-acting injectable peptide calcimimetic AMG 416 (Amgen, Inc., Thousand Oaks, CA) and CTAP101 (OPKO Health, Inc., Miami, FL) , an oral formulation of calcifediol.

AMG 416

AMG 416 is a long acting, investigational peptide agonist of the CaSR for intravenous administration that potentially yields sustained reductions in PTH.

A recent placebo- controlled Phase III trial in patients with CKD receiving dialysis evaluated the effect of AMG 416 on the treatment of SHPT. The study’s primary endpoint was the proportion of patients with > 30% reduction from base line in PTH levels between weeks 20 and 27 of the study. In the AMG 416 group , 75% of patients achieved the primary end point, compared with 10% of patients in the placebo group .

CTAP101

In a Phase IIb/IIIb study, patients with CKD stage 3 were treated for 6 weeks with either CTAP101, a modified-release formulation of calcifediol, or placebo. CTAP 101 reduced PTH levels by>30% from base line in 74% of patients compared with a 17% increase in placebo-treated patients. Minimal changes were observed in both serum calcium and serum phosphorus, with correction of vitamin D deficiency. The AE profile of CTAP101 was similar to that seen in placebo-treated patients.

CTAP101 is also being evaluated in 2 Phase III studies in patients with stage 3--4 CKD and vitamin D insufficiency. The first of these involved 213 patients from 39 sites in the United States. Patients were randomized in a 2:1 ratio to receive either CTAP 101 or placebo for 6 months. According to the study sponsor, the trial met the primary efficacy and safety endpoints, including changes of >30% from baseline in PTH, and safety and tolerability data were similar in both treatment groups.

Three vitamin D agonists for the treatment of SHPT, CTAP018, CTAP 201 (OPKO Health, Inc.), and 2MD (Deltanoid Pharmaceuticals, Madison, WI) are in Phase II clinical testing. Results from a Phase I trial of CTAP 201, an intravenously administered modified vitamin D hormone, in patients receiving hemodialysis reported PTH levels similar to those obtained with doxercalciferol treatment but with lower serum calcium and phosphorus levels; AEs were mild to moderate. Although developed for treatment of osteoporosis, 2MD, a vitamin D analog , has demonstrated reduction of PTH levels without concomitant increases in serum calcium or phosphorus in both uremic rats and in a clinical study of postmenopausal women. CTAP018 has a dual mechanism of action as both a VDR agonist and a CYP24 inhibitor.

Expert opinion

CKD -MBD, including SHPT, is an unmet medical need associated with poor quality of life as well as short life expectancy.

Several newer compounds are anticipated to enrich the CKD -MBD therapeutic armamentarium and may potentially overcome the limitations of current agents. Preliminary data suggest that newer compounds may be more potent and/or tolerable than some currently available agents.

Full Text Sources
Informa Healthcare - PDF ( http://informahealthcare.com/doi/abs/10.1517/14728214.2015.1018177 )