Pam Harrison

June 09, 2015

LONDON, United Kingdom — The addition of a long-acting intravenous calcimimetic, AMG416, to standard care improves the management of secondary hyperparathyroidism in hemodialysis patients, new research suggests.

"AMG416 has a very long duration of action, which means it can be administered at the end of a dialysis session and will remain active right through to the next session," John Cunningham, DM, from University College London, United Kingdom, said during a news conference here at the European Renal Association–European Dialysis and Transplant Association 52nd Congress.

"This should completely overcome any compliance issues we have with oral agents because the drug will be given by dialysis-unit staff," he added.

Parathyroid overactivity can become a real problem in dialysis patients because it weakens the skeleton and increases fracture risk, Dr Cunningham explained. "The milieu that arises in chronic kidney disease favors soft tissue calcification as well, particularly in the vasculature, which is probably heavily associated with the very high mortality risk these patients face."

Dr Cunningham and his team conducted two parallel phase 3 randomized placebo-control trials that lasted 26 weeks.

A total of 1023 hemodialysis patients with moderate to severe secondary hyperparathyroidism — defined as parathyroid hormone levels above 400 pg/mL — were randomized to standard of care, which included phosphate binders and active vitamin D compounds, or to standard of care plus AMG416.

Hyperparathyroidism

More patients in the AMG416 group than in the standard group achieved a reduction in parathyroid hormone of at least 30%, which was the primary end point of the study (74.7% vs 8.9%).

And more patients in the AMG416 group than in the standard group achieved a parathyroid level of 300 pg/mL or less (51.5% vs 5.0%).

"The dramatic reduction in parathyroid we observed in the AMG416 group was similar across gender, race, and in those above and below the age of 65, and independent of baseline severity of disease," Dr Cunningham reported.

In addition, a reduction in fibroblast growth factor (FGF) 23 was seen in the majority of patients treated with AMG416. This is potentially important because high FGF23 levels are strongly associated with adverse cardiovascular outcomes, including mortality, Dr Cunningham explained.

There was a modest drop in mean serum calcium levels, "but there were a few patients whose serum calcium dropped quite a bit," he reported. "This is something that needs to be watched very carefully because excessive falls in serum calcium can be potentially quite hazardous."

However, he pointed out that calcium loading in hemodialysis patients is a much more frequent problem than low serum calcium and, in general, it is likely that a modest fall in calcium provoked by AMG416 will be advantageous for patients.

There was also a significant decrease in serum phosphate. But as with serum calcium, any fall in serum phosphate is likely to be beneficial because hemodialysis patients typically have a high phosphate burden.

The favorable effects of AMG416 on the metabolic profile were sustained over the 26-week trial.

"The metabolic changes we saw with AMG416 are all potentially for the better in terms of patient outcomes, but we don't yet know if these effects will translate into something that really matters to the patient," Dr Cunningham cautioned. "That's the critical question here that we still need to answer."

Adverse event rates in both groups were very high, as expected in hemodialysis patients, but were slightly higher in the AMG416 group than in the standard group (92% vs 80%).

Head-to-Head Comparison

A head-to-head comparison between the oral calcimimetic cinacalcet and the intravenous formulation has been completed. Results will likely be released later this year.

Most calcimimetics are very short-acting because peptides can be metabolized very quickly by various circulating peptidases. In contrast, "AMG416 is a small synthetic peptide and has a structure that makes it virtually resistant to these circulating peptidases," Dr Cunningham explained.

For patients with normal kidney function, the calcimimetic is excreted by the kidneys. However, "in dialysis patients, the only way it is excreted is with dialysis, so levels remain stable until the next session" and then decrease, he told Medscape Medical News.

"This strategy is meant to improve patient compliance; it will be given after dialysis three times a week, unlike oral calcimimetics," said Magdi Yaqoob, MD, from Queen Mary's College, University of London, United Kingdom.

It was thought that the various gastrointestinal adverse effects seen with oral calcimimetics would be attenuated with intravenous administration of the drug. Unfortunately, this was not the case, he added.

"My main concern is that because of its long half-life, AMG416 may oversuppress parathyroid consistently during the interdialytic period, with loss of parathyroid diurnal variability," said Dr Yaqoob told Medscape Medical News.

In theory, this could either cause or worsen adynamic bone disease and promote vascular calcification.

As Dr Cunningham said, "parathyroid levels may have to be measured monthly rather than less frequently," as is recommended in international guidelines, Dr Yaqoob explained.

And "when AMG416 gets the license to be used widely," an addendum to current guidelines might be required, he added.

This study was funded by Amgen. Dr Cunningham has served as an advisor to Amgen, Shire, Cytochroma, FMC, Vifor, and Pfizer; and has received grant support from Amgen. Dr Yaqoob has disclosed no relevant financial relationships.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 52nd Congress: Abstract LBA-3558. Presented May 29, 2015.

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