Allergy and Immunogenicity Revisited

After the pause in answering the Rare Disease Day video questions to consolidate them into the aHUS Patients Research Agenda; and before more questions are looked at, something further has been found about allergy  to  and immunogenicity to eculizumab in a previous news blog see here.

Although the alliance was not aware of any publication which reported that allergic reactions had led to treatment stoppage, further search was done to find out if there was anything in the public domain which said it had not. A document was found which had been issued by the FDA  ( click here)  which covers this issue. It says :

 “As with all protein products, administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion reaction which required discontinuation of Soliris.”

While the active ingredient of Soliris is  eculizumab there are inactive ingredients, which are  sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80 (vegetable origin) and Water for Injection. These inactive ingredients are found in many foods , medicines and even cosmetics  and allergies have been reported to them.  So it would seem that it could be possible to be allergic to them in their infusions for aHUS treatment so the issue  is worthy of a place on a research agenda if only to assess the likelihood whether small or not at all.

Within the same document the issue of immunogenicity , the body creating antibodities to prevent a drug from working appeared . The section taken from the document explains what was found for eculizumab.

“As with all proteins, there is a potential for immunogenicity with eculizumab. The immunogenicity of Soliris has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS indication, as well as for additional patients with PNH.

In the PNH population, antibodies to Soliris were detected in 3/196 12 Reference ID: 3855296 (2%) patients with PNH treated with Soliris using the ELISA assay and in 5/161 (3%) patients treated with Soliris using the ECL assay.

In patients with aHUS treated with Soliris, antibodies to Soliris were detected in 3/100 (3%) using the ECL assay. An ECL based neutralizing HAHA assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 3 patients with aHUS and also for the 5 patients with PNH with positive samples using the ECL assay. 2/161 patients in the PNH group (1.2%) and 1/100 patients in the aHUS group (1%) had low positive values for neutralizing antibodies.

No apparent correlation of antibody development to clinical response was observed in either indication. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to Soliris in an ELISA-based assay and/or an ECL-based assay and are highly dependent on the sensitivity and specificity of the assay used. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Soliris with the incidence of antibodies to other products may be misleading.”

So tests for neutralising antibodies against eculizumab have been found in a small number (  between 1 and 3% ) of PNH /aHUS patients  and tests may not yet be specific nor sensitive enough to be accurate. There was no evidence of them affecting the effectiveness of eculizumab

It is now at least 10 years since eculizumab was first used on PNH patients, and neither allergy nor immunogenicity has been reported so far.