Autoimmune Drug Reactions To Get Further FDA Research After Ziagen Side Effect Findings
This article was originally published in The Pink Sheet Daily
Executive Summary
Carriers of the HLAB*57:01 allele who take Ziagen can come down with severe autoimmune reactions due to a mechanism traced by agency researchers.
FDA is planning further research studies on the autoimmune basis for drug hypersensitivity, following the publication of a study by its staff that found the precise mechanism by which carriers of a certain gene can develop severe reactions to ViiV Healthcare ’s HIV drug Ziagen (abacavir).
Abacavir causes the immune system to mistake a patient’s own healthy tissues and proteins for foreign invaders and attack them if the patient is a carrier of the HLAB*57:01 allele.
“The effect is similar to what happens when the immune system recognizes a viral or bacterial protein during an infection,” FDA explained in a statement about an article in the professional journal AIDS, the lead author of which is Michael Norcross of CDER’s Office of Pharmaceutical Sciences. “The research team’s work will provide the FDA with new tools to analyze the safety of drugs that have the potential to cause severe allergic reactions. This latest discovery will advance the FDA’s ability to approve therapies that are personalized for safety.”
The HLAB*57:01 gene is part of a group of “HLA Class I and Class II alleles” that are linked to immune-mediated or idiosyncratic drug reactions. Patients with the HLAB*57:01 gene also are vulnerable to drug-induced liver injury if they take the Actavis’s antibiotic Floxapen (flucloxacillin) (which is approved in Europe but not the U.S.), Norcross and co-authors noted.
Prevalence of the gene varies by region and racial group. “In the U.S., prevalence is 8%, 4%, 2% and 1% in Caucasians, African-Americans, Hispanics and Asians, respectively,” FDA noted in an email. The study was triggered by reports of adverse reactions, the agency said, but added that “no changes are currently planned in the FDA-approved labeling as a result of this study.”
With its research continuing on the autoimmune basis for drug hypersensitivity, FDA noted that “other drugs with reactions associated with HLA are carbamazepine and allopurinol.”
Limited Impact On Ziagen
The FDA researchers did in vitro tests and found that Ziagen, but not Bristol-Myers Squibb Co.’s HIV drug Videx/Videx EC (didansosine) or Floxapen, “enhanced binding of the FITC labeled self-peptide LF9 to HLA-B*57:01 in a dose dependent manner.” This leads to “drug-induced autoimmunity” and “generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multi-organ systemic toxicity.”
“The science presented in the AIDS journal article deepens our understanding of how a drug may affect how the body identifies its own cells and material from those of pathogens, which is the mechanism behind human leukocyte antigens, or HLAs,” Viiv said in an email.
The company noted that a 2002 article in the journal The Lancet first pinpointed the strong association between HLAB*57:01 and abacavir hypersensitivity reaction. This led to a study by GlaxoSmithKline Inc., which held the rights to Ziagen before passing them on to Viiv, and a 2008 revision of the label to note the association between the HLAB*57:01 allele and hypersensitivity reactions, and recommending HLAB*57”01 testing before initiation or re-initiation of treatment (Also see "GSK’s Ziagen Relabeled: REMS And The Path To Personalized Medicine" - Pink Sheet, 4 Aug, 2008.).
“Anyone that has had a suspected abacavir HSR previously should never be reinitiated on the medicine. The reference to re-initiation is for patients who have been on and tolerated abacavir treatment previously,” the company added.
[Editor’s note: This article has been corrected; the original version incorrectly listed the prevalence of the HLAB*57:01 gene in African Americans as 5%. It is in fact 4%.]