Amgen's Parsabiv's EU Approval Contrasts With US FDA Rejection

Follow-on hyperparathyroidism product likely needs to resolve safety issues with US agency, analysts say, but extensive data package, including a head-to-head trial, has satisfied European regulators.

Amgen Inc.’s Mimpara (cinacalcet) follow-on Parsabiv (etelcalcetide) has been waved through in the EU despite it hitting a US regulatory hurdle, but analysts believe the US FDA will eventually approve the drug – despite likely safety concerns – for treating secondary hyperparathyroidism (sHPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.

Parsabiv had seemed set for a smooth regulatory review in the US with a data package made up of three Phase III clinical trials, including a head-to-head study comparing etelcalcetide to cinacalcet, but its road to launch hit a bump in August when the FDA issued a complete response letter (CRL) for the application, which Amgen declined to provide details on. (Also see "Amgen's Reticence On Parsabiv Complete Response Letter Revives Transparency Issue" - Pink Sheet, 25 Aug, 2016.)

Still, the European Medicines Agency a few weeks later backed the drug and on Nov. 11 the European Commission formally approved it for commercial use in the 28-nation EU.

Biomedtracker analyst David Dahan said the positive CHMP opinion and the subsequent approval of Parsabiv by the EU commission "is somewhat surprising" given the CRL issued by the FDA.

Mitigating The Risks

"There has been speculation that the FDA is concerned about the imbalance in treatment-emergent events related to cardiac failure in the head to head trial of Parsabiv and Mimpara. Hypocalcemia is a known side-effect of calcimimetic drugs and these cardiac failures are likely related to the increased incidence of hypocalcemia in the Parsabiv arm. Nevertheless, this issue does not seem to have been overly concerning to the EMA," Dahan told the Pink Sheet.

Parsabiv and Mimpara (called Sensipar in the US) are both calcimimetics, drugs that mimic the action of calcium by activating the calcium-sensing receptors on the parathyroid gland. Parsabiv binds to and activates the calcium-sensing receptor on the parathyroid gland, thereby decreasing PTH levels.

In their head to head trial, Parsabiv showed statistical superiority on both the primary and secondary endpoints measuring reductions in PTH. Another advantage is that Parsabiv is given intravenously while Mimpara/Sensipar is available as oral tablets. Calcimimetics result in nausea and vomiting and so the intravenous formulation is preferred as it assures patient compliance.

"With the last patent on Mimpara expiring in 2018, the approval of Parsabiv by the EMA should help Amgen make up some of the revenue that it will lose to generic Mimpara," Dahan said.

Analysts at Leerink Research believe the drug will eventually get approved by FDA but with significant warning language, and probably a Risk Evaluation and Mitigation Strategy (REMS) program, regarding cardiac safety.

"We believe the main risks and issues that the FDA will need reassurances from the company are: how to manage the risk of serious hypocalcemia in patients treated with the drug; and how to manage or avoid the risks of serious cardiac rhythm disturbances as a consequence of the changes in serum calcium, phosphate, and potassium. Developing the labeling and associated REMS program, if required, could take months, however, and would likely to involve several proposals from the company and responses from the agency," the analysts said in a note.

A spokesperson for Amgen said the company would not comment on ongoing discussions with regulatory agencies, saying only that "we are engaged with the FDA right now in working toward an approval. We are hoping that the approval will happen in the reasonably near future."

[Editor’s note: Amgen said Nov. 17 that the CRL “was not based on safety concerns.”]