PHILADELPHIA—Officials from the U.S. Food & Drug Administration discussed recent drug approvals and drug safety issues at ACR Convergence in November in a session that captured the flurry of activity in the rheumatology sphere at the agency over the past year.
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Sabiha Khan, MD, clinical reviewer in the Division of Rheumatology and Transplant Medicine at the FDA, reviewed approvals for new indications, new populations and new dosing regimens for a a variety of drugs for rheumatic conditions.
New Drugs & Indications
Over the past year, the FDA approved several drugs with new indications, including the Janus kinase (JAK) inhibitor tofacitinib for ankylosing spondylitis (AS); the JAK inhibitor upadacitinib for AS, psoriatic arthritis (PsA) and non-radiographic axial spondyloarthritis (nr-axSpA); the monoclonal antibody secukinumab for enthesitis-related arthritis (ERA) in patients 4 years or older; and the monoclonal antibody risankizumab for PsA.
Officials also expanded the PsA indication for secukinumab to patients 2 years or older; the lupus nephritis (LN) indication for belimumab to patients 5 years or older; and the PsA indication for ustekinumab to patients 6 years or older.
Other approvals included the intravenous use of tocilizumab for giant cell arteritis (GCA); baricitinib for COVID-19; pegloticase plus methotrexate for gout; and approvals of biosimilars.
“This has been another busy year,” Dr. Khan said. “The last year has been an exciting year for the division.”
Raj Nair, MD, clinical team leader in the Division of Rheumatology and Transplant Medicine, reviewed new safety information for several therapies.
Because of better responses seen for co-administration of pegloticase and methotrexate in trials, the FDA approved 8 mg of pegloticase intravenously co-administered with methotrexate every two weeks in adults with chronic gout who are refractory to conventional treatment. Pegloticase can be used alone in patients for whom methotrexate is contraindicated or otherwise inappropriate.
Infusion reactions are more common when pegloticase is used alone—seen in 31% of cases without methotrexate, but seen only in 4% when co-administered with methotrexate.
“There was one case of anaphylaxis in the study,” said Dr. Nair, “and that did occur in the co-administered pegloticase and methotrexate arm, so it’s still important to keep all the precautions when administering this product.”
For risinakizumab in PsA, Dr. Nair noted a slightly elevated occurrence of hepatic events and hypersentivity reactions that were not previously in the prescribing information, but said they were “not considered serious” and there was no drug-induced liver injury seen for risankizumab in the psoriatic arthritis studies.
A much higher risankizumab dose is recommended for Crohn’s disease, and drug-induced liver injury has been seen, so monitoring for liver enzymes and bilirubin is recommended, Dr. Nair said.
A new warning has been issued for collagenase clostridium histolyticum, which is used to treated Dupuytren contracture, regarding syncope and pre-syncope seen in post-marketing trials. These symptoms usually occur immediately after an injection procedure, and the recommendation is that patients remain lying down until they resolve, said Dr. Nair.
He also discussed new concerns with hydroxychloroquine and phospholipidosis, a lysosomal storage disorder involving excessive accumulation of intracellular phospholipids in various tissues, such as the heart, liver, kidney and skeletal muscle, causing cardiomyopathy and renal toxicity, both of which have been reported with hydroxychloroquine use, Dr. Nair said.
“The first step is to see whether you suspect someone that has phospholipidosis to any of these organ systems, and then you may need to do further evaluation which may include biopsy,” he said. “And the recommendation is that if you do have someone who has biopsy-proven phospholipidosis, that you halt hydroxychloroquine.”
A rheumatologist in the audience expressed surprise about the new concerns about hydroxychloroquine: “Hydroxychloroquine is very important to us and to tell me it is not very safe it’s really like a shock to me,” she said.
Dr. Nair said that any risk seems to be with chronic use rather than acute use.
“When we’re talking about renal toxicity and we’re talking about a condition like lupus, there can be many different reasons somebody could be having renal toxicity,” he said. “Basically, it is looking at the patient to see what’s going on, and if it does seem that phospholipidosis could be occurring in that patient, you would investigate further.”
Nikolay Nikolov, MD, director of the Division of Rheumatology and Transplant Medicine of the FDA, underscored that the problem doesn’t seem to be widespread.
“We just want to emphasize that this signal came from post-marketing data with a limited number of cases,” he said. “So we assume that based on the wide prescription of hydroxychloroquine, this toxicity is not common. And we certainly recognize that hydroxychloroquine has a significant role in the management of our patients.”
After being questioned about the practicality of the FDA’s recommendation that TNF blockers be used before JAK inhibitors in RA, given that TNF inhibitors may not be the most effective option for every patient, Dr. NIkolov acknowledged that it’s not a simple scenario to navigate, but that the only available data directly comparing safety of JAK inhibitors is with TNF inhibitors.
“I’m not sure that we can provide any further guidance,” he said. “This is in the context of serious toxicities, based on a specifically designed safety study. I wish we had more of these to inform comparative safety and effectiveness for other products as well. That would provide much more meaningful answers to the questions that you’re raising.”
Thomas R. Collins is a freelance medical writer based in Florida.