Biologic holiday a question of risk management

January 21, 2016

Intermittent dosing of biologic agents can make the therapies more immunogenic and lead to a decreased patient response, but the initiation of methotrexate preceding a decrease in the use of biologic therapy will reduce the potential for immunogenicity of the biologics.

Clinicians need to consider that taking patients off a biologic agent may decrease the possibility of response when the patient is put back on biologic therapy, one expert says. Patients can develop antibodies while they are off the drug that can nullify the impact of the biologic therapy down the road, according to Kim A. Papp, M.D., Ph.D., F.R.C.P.C., president of Probity Medical Research Inc., in Waterloo, Ontario, Canada.

“Why is it an issue to go off the drugs (biologics)?” Dr. Papp asks. “It is (because of) the formation of antibodies. Not everyone forms antibodies in sufficient volume to abrogate the effect of the drug, but it’s a real effect,” he explained to colleagues during a presentation Dermatology Update 2015. A dermatologist and leader in clinical trial research in Canada, Dr. Papp discussed the risks of taking patients off biologic therapy.

For the time being, sufficiently sensitive assays do not exist to detect the extent of antibody formation in a patient who has discontinued biologic therapy, according to Dr. Papp.

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Because biologic agents are very large molecules, their immunogenicity is pretty wide, Dr. Papp notes. “The worst thing you can do is to give intermittent dosing because when the level (of drug) decreases, that is when the compound is more immunogenic,” Dr. Papp says.

When serum levels of a drug in the body are decreased, it increases the likelihood that the body recognizes the biologic agent as foreign, Dr. Papp explains.

“Serum levels drop, efficacy drops, and antibodies go up,” he says. “Sometimes the (level of) antibodies stay up, meaning the next time you put someone on the drug, they won’t respond.”

The route of administration of biologic agents is typically subcutaneous, which contributes to the immunogenicity of the therapies. “That is the most immunogenic way to deliver a drug,” Dr. Papp says. “That is why it is critical to make sure you and your patients store the drug properly.”

NEXT: Curbing loss of response

 

Curbing loss of response

In terms of a management plan to reduce the potential of loss of response to a biologic, Dr. Papp advises fellow dermatologists to adjunctively use methotrexate for a period of weeks before decreasing the dose of biologic therapy.

“The reason I do that is that they (patients) reserve the opportunity to go back on the drug, and they won’t form antibodies,” Dr. Papp says. “It is not a perfect solution, but it is the best shot that they (patients) have (of continuing to respond to biologic therapy).”

A recent study looking at the immunogenicity of tumor necrosis factor inhibitors used to treat rheumatoid arthritis and other auto-immune conditions found that 25.3% of patients using infliximab developed anti-drug antibodies in patients, and that the formation of these anti-drug antibodies had a statistically significant impact on response. The use of concomitant immunosuppressive therapy like methotrexate mitigated the risk of anti-drug antibodies forming.1

Some biologics are more forgiving than others in terms of their ability to be dosed in an aberrant fashion, Dr. Papp adds.

Therapeutic use of a biologic may involve adjustment of a dose, either reduction or escalation of a dose, Dr. Papp explains.

“That is part of personalized medicine, knowing when to adjust the dose and knowing when it is appropriate (to adjust it),” Dr. Papp says. “Personalized medicine for me is to avoid the situation where a patient is hanging onto a tenuous thread because of their misadventures in dosing themselves and our misadventures in giving them incorrect guidance or advice on how to use these biologics.

“Using simple principles, we can keep our patients in a secure spot,” Dr. Papp says. “Less exposure (to a drug) means it is safer. If we can get away with (using) less drug and get to a lower dose, everyone (clinicians and patients) is happy.”

Clinicians may opt to escalate a dose of a biologic agent with the goal to obtaining a response, Dr. Papp notes.

Overall, the decision to take a drug holiday from using a biologic agent is a question of risk management, Dr. Papp says. “If the risk is low, then go for it,” Dr. Papp says, noting toxicity is reasonable grounds for taking a holiday from biologic therapy.

Reference

1Thomas SS, Borazan N, Barroso N, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs. 2015 Aug;29(4):241-58.

Disclosure: Dr. Papp has done consulting, speaking, has received clinical grants, honoraria, and sat on advisory boards for AbbVie. He has done consulting, speaking, has received clinical research grants, honoraria, and sat on advisory boards for Amgen. He has done speaking , received clinical research grants, honoraria, and sat on advisory boards for Janssen Biotech. He has done consulting, received clinical research grants, received honoraria, and sat on a steering committee and advisory board for UCB.

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