FDA representatives provide updates on drug approvals, safety issues

The U.S. Food and Drug Administration (FDA) has been busy during the COVID-19 pandemic, with emergency use authorizations for two familiar rheumatology agents, approvals for new agents, and new indications and safety warnings for both prescription and over-the-counter medications.

“There have been major actions at the FDA since ACR Convergence 2020, including the repurposing of baricitinib and tocilizumab for COVID-19 under emergency use authorizations and a joint workshop on osteoarthritis with the Arthritis Foundation and other key stakeholders to discuss a framework to develop and evaluate agents that can modify the course of the disease,” said Amit Golding, MD, PhD, Medical Officer in the FDA Division of Rheumatology and Transplant Medicine.

Dr. Golding and a panel of FDA representatives were featured in the session FDA Update on Safety Issues in the Treatment of Rheumatic Disease, which was originally presented Monday, Nov. 8, and can be viewed by registered meeting participants through March 11, 2022.

Emergency use authorization (EUA) for an agent is not an FDA approval, Dr. Golding emphasized. It is an authorization for temporary use of an unapproved product, or unapproved uses of an approved agent, during a public health emergency.

The decision to issue an EUA is discretionary, but not arbitrary, Dr. Golding said. Every EUA must meet four criteria:

• The targeted condition must be capable of causing a serious or life-threatening disease or condition
• The medicinal product may be effective to prevent, diagnose, or treat the condition
• The known and potential benefits of the product outweigh the known and potential risks of the product
• There are no adequate, approved, and available alternatives to the candidate product

The mortality and morbidity associated with COVID-19 are generally accepted to be the result of a pathogenic host response and systemic hyperinflammation, Dr. Golding continued. Inflammatory cytokines and biomarkers such as IL-1, IL-6, GM-CSF, macrophage inflammatory protein 1-α, TNF-α, C-reactive protein, ferritin, and D-dimer are significantly elevated in patients with severe disease.

Baricitinib was approved for EUA based on two randomized controlled trials in hospitalized COVID-19 patients, while tocilizumab’s EAU was based on four trials. Trial results were not uniform and both EUAs include safety concerns, Dr. Golding noted, but the agency judged that the potential benefits outweighed risks in the absence of approved agents.

New agents, indications

The agency has also approved three new molecular entities and one biosimilar for rheumatic diseases in the past year and added new indications to five agents previously approved.

The three new agents — voclosporin for lupus nephritis, anifrolumab for systemic lupus erythematosus, and avacopan for ANCA-associated vasculitis — all come with important benefits and equally important warnings, said Nadia Habal, MD, Clinical Reviewer in the FDA Division of Rheumatology and Transplant Medicine.

Voclosporin is a calcineurin-inhibitor immunosuppressant approved for adults with active LN, but it is not recommended in combination with cyclophosphamide. Warnings and precautions include nephrotoxicity, hypertension, neurotoxicity, hyperkalemia, QT prolongation, pure red cell aplasia, lymphoma, and other malignancies and serious infections. Patients taking voclosporin should not receive live vaccines.

Anifrolumab is a type 1 IFN receptor antagonist for adults with moderate-severe SLE on standard therapy. It is not recommended for patients with severe active LN or severe active central nervous system lupus. Warnings and precautions include serious infections, hypersensitivity reactions including anaphylaxis, and malignancy. It is not recommended for use with other biologics, and patients taking anifrolumab should not receive live vaccines.

Avacopan is a complement 5a receptor agonist approved as an adjunctive treatment in combination with standard therapy in adults with severe ANCA-associated vasculitis and microscopic polyangiitis. It does not eliminate glucocorticoid use. Warnings and precautions include hepatoxicity, serious hypersensitivity reactions, hepatitis B reactivation, and serious infections.

The agency also approved rituximab-arrx, a biosimilar to rituximab.

Safety updates

The most important safety news are the new boxed warnings for major cardiovascular events, malignancy, thrombosis, and mortality added to the Janus kinase (JAK) inhibitor class of drugs. The new warnings grew out of an FDA-required phase 4 safety trial of tofacitinib versus TNF inhibitors and existing black box warnings for baricitinib and upadacitinib, said Anil Rajpal, MD, MPH, Medical Team Leader in the FDA Division of Rheumatology and Transplant Medicine. The tofacitinib study failed noninferiority and increased risk for multiple adverse events.

“Many of these adverse events are not monitorable, treatable, or preventable, including mortality and malignancies,” Dr. Rajpal said. “We are also limiting the use of these agents to patients who have shown an inadequate response or intolerance to one or more TNF inhibitors.”

The agency also recommended against the use of NSAIDs in pregnant women starting at about 30 weeks gestation due to potential fetal renal dysfunction, oligohydramnios, and neonatal renal impairment. NSAIDs also carry a new warning for serious eosinophilia and systemic symptoms in all patients.