Amgen Osteoporosis Drug Prolia Is Hit With FDA’s Strictest Warning

A blockbuster Amgen drug for osteoporosis now carries the FDA’s strictest warning that its use can lead to dangerously low levels of calcium in the blood.

This complication, hypocalcemia, is a particular risk for patients with advanced kidney disease, the black box warning states. In these patients, this adverse effect resulted in hospitalization, life-threatening events, and in some cases death. Severe hypocalcemia can be asymptomatic but symptoms the FDA warned that patients and physicians should watch for include confusion, irregular heart rhythm, fainting, muscle spasms, and weakness.

Prolia, a monoclonal antibody administered every six months as a subcutaneous injection, was first approved in 2010 as a treatment for osteoporosis in postmenopausal women at high risk of fracture. The drug works by binding to a protein key to the function and survival of cells involved in the natural process in which bone is broken down and absorbed by the body. Reducing this bone resorption is intended to increase bone mass and strength.

While the black box warning is new, the hypocalcemia risk is not. This complication was among those listed on the drug’s original label. Approval of Prolia came with a Risk Evaluation and Mitigation Strategy, an FDA program that imposes strict oversight of a drug to guard against safety problems. The FDA also required Amgen to conduct additional clinical testing to further assess safety.

In 2022, the FDA issued an alert stating it is investigating the risk that Prolia may cause severe hypocalcemia in patients with advanced kidney disease that requires dialysis treatment. That alert stemmed from the ongoing review of Amgen’s longer-term testing of its osteoporosis drug.

The black box warning comes after an FDA review of Centers for Medicare & Medicaid Services studies found that treatment with Prolia led to a significant increase in the risk of developing severe hypocalcemia compared to bisphosphonates, an older class of osteoporosis drugs. The FDA said the complication typically developed two to 10 weeks following each Prolia injection, with the greatest risk during weeks two to five. The agency also reviewed 25 cases submitted through the FDA Adverse Event Report System database.

The FDA said patients taking Prolia should maintain adequate calcium and vitamin D intake. For those with advanced kidney disease, the FDA advises frequent monitoring of calcium levels in the blood. The FDA also said clinicians should consider Prolia’s hypocalcemia risk in the context of other osteoporosis drugs available.

Last year, Prolia accounted for $2.9 billion in revenue in the nine months ending Sept. 30, according to Amgen’s most recent financial report. Amgen also sells a newer osteoporosis drug called Evenity, though hypocalcemia has also been reported in patients treated with this product. Alternative osteoporosis therapies include Eli Lilly’s Forteo and Tymlos from Radius Health. The labels of all of these products carry black box warnings that flag various safety risks.

Here’s a recap of other recent regulatory news:

—Vertex Pharmaceuticals gene therapy Casgevy landed FDA approval as a treatment for the rare blood disease beta thalassemia. This approval comes about six weeks after the agency first approved the therapy as a treatment for sickle cell disease. Vertex set a $2.2 million price for the one-time therapy, the same price it charges in the sickle cell disease indication. It will compete against Bluebird Bio’s Zynteglo, the $2.8 million gene therapy approved in 2022 for treating beta thalassemia.

—Authorities in Japan approved AstraZeneca drug danicopan as a new treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder in which the complement system attacks red blood cells. The oral drug will be marketed under the brand name Voydeya. AstraZeneca already markets the PNH drugs Soliris and Ultomiris, both of which work by blocking a complement system protein called C5. Voydeya addresses a different protein called factor D.

Japanese authorities approved Voydeya as an add-on therapy for patients whose disease is not sufficiently addressed by a C5 inhibitor. The approval is the first anywhere in the world for this drug.

—The European Commission approved a subcutaneously injected version of Roche cancer immunotherapy Tecentriq. The drug, which blocks the checkpoint protein PD-L1 on cancer cells, has been available as an intravenous infusion that takes between 30 and 60 minutes. Roche said the subcutaneous version will take between four and eight minutes.

—The FDA turned down Satsuma Pharmaceuticals’ drug/device combination treatment for migraine, citing manufacturing issues, Satsuma parent company Shin Nippon Biomedical Laboratories announced. Satsuma’s product candidate, STS101, is a dry powder formulation of the old migraine drug dihydroergotamine. It’s administered via an intranasal device intended to bring patients faster pain relief.

The FDA complete response letter is the latest in a string of setbacks for Satsuma. In 2020, STS101 failed a Phase 3 clinical trial. Analysis of the trial data found problems with the device and the way patients were using it. Satsuma modified the device and ran another Phase 3 study.

—Manufacturing issues were also to blame for the FDA rejection of zolbetuximab, an Astellas Pharma drug developed for treating gastric or gastroesophageal junction adenocarcinoma. The antibody drug is at the front of a competitive pack of drug candidates designed to target claudin 18.2, a protein abundant on cancerous stomach cells.

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