New phosphate binders on the horizon

New Phosphate Binders on the Horizon
Wajeh Y. Qunibi, MD, FACP
July 14 2009

Hyperphosphatemia is invariably present among patients with end-stage renal disease (ESRD) and may be independently associated with increased risk of all-cause mortality, accelerated cardiovascular calcification, and cardiovascular mortality (Kidney Int Suppl. 2004;:S8-S12). The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend a target serum phosphorus of 4.6 mg/dL in CKD stages 3 and 4 and serum phosphorus 3.5-5.5 in stage 5 and in dialysis patients. Dietary phosphorus restriction and removal of phosphorus by dialysis are usually inadequate for controlling serum levels. Consequently, it becomes necessary to prescribe phosphate binders for the majority of patients with ESRD in order to reduce the amount of dietary phosphorus absorbed from the intestine.

Currently available phosphate binders, while effective, are not considered optimal agents for treating hyperphosphatemia because they may lead to unacceptable adverse effects or because of concern about potential toxicities (e.g., aluminum toxicity). Calcium carbonate and calcium acetate are suspected of contributing to cardiovascular calcification and adynamic bone disease, lanthanum carbonate is absorbed and deposited into tissues, including bone, liver, and brain; and sevelamer has the potential for intestinal obstruction and perforation. Moreover, some binders are expensive (sevelamer and lanthanum carbonate) and may require patients to take large numbers of pills for good control of serum phosphorus (sevelamer). For these reasons, there is a high degree of noncompliance with binder therapy among dialysis patients. This noncompliance may explain why fewer than 50% of patients with ESRD have achieved the recommended target for serum phosphorus. Thus, there is a clear need for newer phosphate binders that tackle some of the shortfalls of current binder therapy. Efforts are under way to develop new and potentially more effective phosphate binders that may also have fewer adverse effects. The possibilities include exchange resins, iron-based binders, magnesium binders, and nicotinic acid derivatives.

Exchange resins

Sevelamer carbonate

Among the newer phosphate-binding agents is sevelamer carbonate (Renvela; Genzyme Corporation). This buffered form of sevelamer hydrochloride is an anion exchange resin in which carbonate replaces chloride as the anion. This change in the anion provides bicarbonate ions that may avoid the acidosis that is frequently reported with sevelamer hydrochloride. Sevelamer carbonate is apparently as effective as sevelamer hydrochloride and has a GI profile that is probably similar, but more experience is needed before any conclusions can be made.

AMG 223

This investigational drug is also an exchange resin and could pose a potential threat to sevelamer. A novel polymeric phosphate binder, AMG 223 was being developed by Amgen after its June 2007 acquisition of Ilypsa. However, a phase 2 randomized, double-blind, placebo-controlled clinical trial to assess the efficacy, safety, and tolerability of fixed doses of AMG 223 in hemodialysis patients with hyperphosphatemia was halted. Shortly thereafter, in January 2009, Amgen announced that it was ending development of AMG 223.

MCI-196

This compound, also known as colestimide or colestilan, is a nonabsorbable anion exchange resin manufactured by Mitsubishi Pharma Corporation. MCI-196 has dual effects similar to those of sevelamer, binding both bile salts and dietary phosphorus in the intestine and thus reducing both LDL and serum phosphorus (Thera Apher Dial. 2008;12:126-132). MCI-196 is widely used in Japan. Constipation and abdominal distension are the main side effects and are encountered in half of patients taking the medication. Currently, phase 3 trials are ongoing in the United States and Europe.

Iron-based binders

Polynuclear iron compounds are effective in binding dietary phosphorus because the solubility product of trivalent iron and phosphate is extremely low. These compounds are not absorbed and are apparently effective phosphate binders across a wide spectrum of pH. Systemic iron absorption is minimal and could generally be desirable in hemodialysis patients who are prone to developing iron deficiency because of chronic blood loss in the dialyzer. Two compounds are in the early stages of clinical development.

SBR759

Novartis' SBR759 is a complex compound consisting of iron (III) oxide-hydroxide, starch, and sucrose. In phase 1 and 2 trials funded by Novartis, this compound was found to be effective, safe, and well-tolerated at doses up to 15 g/day in dialysis patients, according to a report by Block and colleagues presented during The American Society of Nephrology's Renal Week 2008 (abstract no. F-PO1801; available at www.abstracts2view.com/asn/view.php?nu=ASN08L1_3701a, accessed May 21, 2009). A phase 3 trial is currently under way to compare SBR759 with sevelamer hydrochloride in terms of safety and efficacy.

PA21

The second iron-based phosphate binder is PA21, a new product currently under development by Vifor Pharma. PA21 is intended to be used particularly in hemodialysis patients. Regulatory filling is anticipated in 2011. In a phase 2 trial, PA21 was thought to be effective and have a good safety profile. Recruitment for another phase 2 trial is under way (ClinicalTrials.gov identifier: NCT00824460).

Magnesium salts

Magnesium salts, such as magnesium hydroxide and magnesium carbonate, can bind dietary phosphorus but are considered less effective than calcium salts. Thus, large doses are often required, and these may result in significant hypermagnesemia, diarrhea, and hyperkalemia. Hypermagnesemia can be prevented by reducing or eliminating magnesium from the dialysate. An alternative approach is to use a combination of magnesium carbonate and calcium carbonate or magnesium carbonate and calcium acetate, as proposed by Spiegel and colleagues at the 2006 NKF Clinical Spring Meeting (abstract no. 152; available at download.journals.elsevierhealth.com/pdfs/journals/0272-6386/PIIS0272638606002605.pdf, accessed May 21, 2009). These compounds have been used as phosphate binders in the United States and in Europe.

A third combination is magnesium iron hydroxycarbonate (Alpharen; Ineos Healthcare), which contains magnesium and ferric iron. A phase 2 study in hemodialysis patients showed that almost 50% of the patients taking Alpharen 3 g/day and most patients taking 6 g/day achieved the KDOQI target serum phosphate level, according to a report by McIntyre and colleagues presented at the American Society of Neprhology's 2006 Renal Week (abstract no. F-PO108; available at www.asn-online.org/education_and_meetings/renal_week/archives/2006-abstracts-archive.pdf, accessed May 21, 2009). There were no significant differences compared with pre-study standard treatment using either calcium carbonate or sevelamer. The GI effects of Alpharen 3 g/day did not differ significantly from placebo. However, about half of the patients on the 6-g/day dosage withdrew from the study mainly because of GI intolerance.

Nicotinic acid derivatives

Phosphorus transport through the apical membrane of small intestinal epithelial cells is coupled with sodium. Type IIb sodium-dependent phosphate co-transporter is a plasma membrane-bound symporter that mediates the movement into cells of extracellular phosphorus coupled with sodium ions. A novel approach to controlling intestinal absorption of dietary phosphorus is to inhibit this intestinal co-transporter with nicotinic acid derivatives, such as nicotinamide, MCI-196, or niceritrol. Nicotinamide was found to decrease the transport of phosphorus by reducing the activity of sodium phosphate co-transporter in rodents (Nephrol Dial Transplant. 2005;20:1378-1384). Moreover, nicotinamide has shown some efficacy in a small preliminary human study in Japan (Kidney Int. 2004;65:1099-1104).

Other binders

Phosphorus may be secreted in the saliva, which when swallowed contributes to hyperphosphatemia. Adding a salivary phosphate binder such as the natural polymer chitosan as a chewing gum may improve treatment of hyperphosphatemia in dialysis patients (J Am Soc Nephrol. 2009;20:639-644). Chitosan is a natural polymer derived from chitin, a polysaccharide found in the exoskeleton of shellfish, such as shrimp, lobster, and crabs, and used in water-purification plants.

Conclusion

Untreated hyperphosphatemia independently increases the risk of mortality in dialysis patients. Evidence suggests that treatment with currently available phosphate binders is suboptimal. Consequently, there is need for new agents that address some of the challenges associated with current binder therapy. These newer phosphate binders are being evaluated and, when approved, will give our patients a wider range of products to choose from for more effective control of hyperphosphatemia.

Dr. Qunibi is Professor of Medicine and Medical Director of Dialysis Services at the University of Texas Health Sciences Center at San Antonio.

http://www.renalandurologynews.com/New-Phosphate-Binders-on-the-Horizon/PrintArticle/140045/