According to the two trials, lanthanum carbonate is well tolerated and associated with the reduced occurrence of high calcium levels, a side effect of some current therapies that has been linked to increased calcification of the coronary arteries in the heart.
Shire has submitted lanthanum carbonate under the trade name of FOSRENOL for regulatory review in the United States, European Union and Canada. The product is under development in Japan.
"Data from the two trials illustrate that lanthanum carbonate has the potential to reduce dangerously high phosphate levels safely and effectively. Previous data from a separate phase 3 long-term safety study indicate that there is no demonstrable link between lanthanum administration and bone toxicity. These data suggest that lanthanum carbonate will deliver tangible clinical benefits to dialysis patients," says William F. Finn, M.D., professor of medicine at the University of North Carolina School of Medicine at Chapel Hill, regarding his interim analysis of 1,203 ESRD dialysis patients enrolled in a two-year trial at 96 U.S. sites, presented at the ASN meeting.
Studies show lanthanum carbonate has a good safety and efficacy profile in the treatment of hyperphosphatemia in dialysis patients
Finn's study [ASN Poster SA-P0600] showed that after one year of therapy, patients receiving lanthanum carbonate had similar reductions in average phosphorus levels compared to those on standard therapies, including aluminum salts, calcium salts or sevelamer. The study also showed that patients in the Fosrenol group had significantly fewer serious adverse events, including deaths. These interim data demonstrate a statistically significant reduction in mortality in favor of patients receiving Fosrenol compared with those receiving standard therapies. Data collection and analyses are ongoing.
The proportion of all participants in whom pre-dialysis serum phosphorus levels were controlled, less than or equal to 5.9 milligrams/deciliter (mg/dL), was similar in both treatment groups at the end of the two-year study. The investigators found no evidence that lanthanum accumulated in the blood with prolonged use, averaging concentrations of 0.5 nanograms per milliliter (ng/ml) at the study beginning and 0.5 to 0.6 ng/ml at all subsequent visits.
Study shows lanthanum carbonate reduces calcium levels in blood compared to calcium carbonate
Data from another trial presented at ASN [ASN Poster SA-P0599], a six-month phase 3 trial in 805 chronic renal failure (CRF) patients on dialysis at 67 European sites, found because of lanthanum carbonate's potency, similar reductions of phosphate in blood were achieved with smaller amounts of lanthanum carbonate than calcium carbonate (5.36mg/dL ± 1.426 versus 5.33 mg/dL ± 1.479), with similar treatment-related side effects, after six months of therapy. The study, conducted by Alastair J. Hutchison, F.R.C.P., M.D., consultant nephrologist and clinical director of the Renal Unit at The Royal Infirmary in Manchester, England, also showed that lanthanum yielded reduced calcium levels in the blood and confirmed previous reports that very little absorption of lanthanum occurs (less than 0.001 percent).
The lanthanum patients also had significantly lower rates of elevated calcium levels than did those on calcium carbonate at week nine (p = 0.009), with a positive trend to lower rates at week 25 (p = 0.061). Also, calcium-treated patients had significantly greater incidences of hypercalcemia compared to those treated with lanthanum, 37.9 percent vs. 5.7 percent (p < 0.001), respectively.
Hutchison found that fewer serious side effects occurred among the lanthanum patients, 21.4 percent, compared to those treated with calcium carbonate, 30.0 percent. The incidence of side effects that emerged during treatment was similar in both treatment groups and most were mild to moderate in severity. The most frequently reported side effects were nausea, vomiting, diarrhea and constipation, which are common among all phosphate binding therapies. The patients initially enrolled in this trial for 20 weeks, but Hutchison is continuing the study for six months to collect more long-term effectiveness and tolerability data.
During Finn's trial, side effects that occurred were comparable between the lanthanum and the standard treatment groups, 93.0 and 94.1 percent, respectively. Drug-related side effects were higher in the lanthanum group as expected, Finn explains, and might in part be attributed to this being an open-label trial and that physicians may have been more likely to attribute adverse events to a novel therapy than to established agents. The reported drug-related side effects occurred in 21.2 and 12.6 percent of the patients receiving lanthanum and conventional treatments, respectively.
Managing hyperphosphatemia
Phosphorus, an element found in nearly all foods, is absorbed from the gastrointestinal tract into the blood stream. When the kidneys fail, they no longer effectively filter out phosphates, even with the help of blood-cleansing dialysis machines. Consequently, hyperphosphatemia occurs when phosphorous levels in the blood reach higher than normal levels and is considered significant when levels are greater than 5 mg/dL. Most dialysis patients, including some 243,000 Americans, develop hyperphosphatemia.
Hyperphosphatemia disrupts the delicate interplay between the body's levels of calcium, parathyroid hormone (PTH) and vitamin D. Over time, hyperphosphatemia can ultimately lead to calcification of the heart, lung and some arteries. This calcification may increase the incidence of cardiovascular disease. Heart disease accounts for nearly 50 percent of all deaths in dialysis patients.
Hyperphosphatemia also can lead to renal osteodystrophy, the painful, thinning and malformation of bone that increases the likelihood of fractures. Some 90 percent of ESRD patients develop this bone disease.
Even with a low-phosphorus diet, dialysis patients develop hyperphosphatemia, so patients traditionally manage this condition with phosphate binder agents, typically calcium or aluminum salts or sevelamer. Although these agents can be effective, they can cause potentially serious side effects including hypercalcemia, bone toxicity and tolerability problems.
Lanthanum carbonate (FOSRENOL™)
FOSRENOL works by binding to dietary phosphate in the stomach. Once bound, the lanthanum carbonate/phosphate complex cannot pass through the stomach lining into the blood stream and is eliminated from the body. Consequently, a patient's overall absorption of phosphate from the diet significantly decreases. Shire has conducted an extensive clinical research program for lanthanum carbonate involving more than 1,700 patients, some of whom have been treated for 36 months or more. These clinical trials demonstrate that lanthanum carbonate is an effective phosphate binder with a proven safety profile for long-term use.
Shire Pharmaceuticals Group plc
Shire Pharmaceuticals Group plc (Shire) is a rapidly growing international specialty pharmaceutical company with a strategic focus on three therapeutic areas - central nervous system disorders (CNS), oncology and anti-infectives. Shire also has two platform technologies: advanced drug delivery and Biologics. Shire's core strategy is based on research and development combined with in licensing and a focus on eight key pharmaceutical markets. For further information on Shire, please visit the company's Web site: www.shire.com. Shire was granted an exclusive agreement to develop, manufacture, use and sell lanthanum carbonate worldwide by the patent holder, AnorMed Inc.
The statements in this press release that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event that such risks or uncertainties materialise, Shire's results could be materially affected. The risks and uncertainties include, but are not limited to, risks associated with the inherent uncertainty of pharmaceutical research, product development and commercialisation, the impact of competitive products, patents, government regulation and approval, and other risks and uncertainties detailed from time to time in periodic reports produced by Shire, including the Annual Report filed on Form 10K by Shire with the Securities and Exchange Commission.
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