Development of anti-velaglucerase alfa antibodies in clinical trial-treated patients with Gaucher disease

Abstract

Anti-drug antibodies may develop with biological therapies, possibly leading to a reduction of treatment efficacy and to allergic and other adverse reactions. Patients with Gaucher disease were tested for anti-drug antibodies every 6 or 12weeks in clinical studies of velaglucerase alfa enzyme replacement therapy, as part of a range of safety endpoints. In 10 studies between April 2004 and March 2015, 289 patients aged 2-84years (median 43years) were assessed for the development of anti-velaglucerase alfa antibodies. Sixty-four patients were treatment-naïve at baseline and 225 patients were switched to velaglucerase alfa from imiglucerase treatment. They received velaglucerase alfa treatment for a median of 36.4weeks (interquartile range 26.4-155.4weeks). Four patients (1.4%) became positive for anti-velaglucerase alfa IgG antibodies, two of whom had antibodies that were neutralizing in vitro, but there were no apparent changes in patients' platelet counts, hemoglobin levels or levels of CCL18 and chitotriosidase, suggestive of clinical deterioration after anti-velaglucerase alfa antibodies were detected, and no infusion-related adverse events were reported. Less than 2% of patients exposed to velaglucerase alfa tested positive for antibodies and there was no apparent correlation between anti-velaglucerase alfa antibodies and adverse events or pharmacodynamic or clinical responses.

Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan

“…Producing velaglucerase alfa using human cell lines and gene activation technology may assist in limiting the risk of IRRs by theoretically lowering the risk of immunogenicity and the formation of anti-velaglucerase alfa antibodies [ 21 ]. A pooled analysis of patients with GD treated with velaglucerase alfa in clinical trials between 2004 and 2015, also found that only four (1.4%) patients developed anti-velaglucerase alfa antibodies, including two patients with neutralizing antibodies, without apparent pharmacodynamic impact or effect on clinical response [ 40 ]. In this surveillance, details of the two patients who returned positive tests for anti-velaglucerase alfa antibodies were not sufficiently described to determine any impact on clinical benefit.…”

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…Since the recombinant enzyme needs to be repeatedly administrated into the patient, and a life-long therapy is required, some patients may develop antibodies against the recombinant protein. This has been observed, e.g., in the case of Gaucher disease [104]. In some cases, the properties of the recombinant enzyme may be improved by chemical modifications, such as PEGylation, as has been shown for phenylalanine ammonia lyase in phenylketonuria [105], or by packing the recombinant enzyme into carriers, such as nanoparticles [106,107].…”

Long-Term Safety and Effectiveness of Velaglucerase Alfa in Gaucher Disease: 6-Year Interim Analysis of A Post-Marketing Surveillance in Japan

“…Producing velaglucerase alfa using human cell line using gene activation technology may assist in limiting the risk of IRRs by theoretically lowering the risk of immunogenicity and the formation of antivelaglucerase alfa antibodies [20]. A pooled analysis of patients with GD treated with velaglucerase alfa in clinical trials between 2004 and 2015, also found that only four (1.4%) patients developed antivelaglucerase alfa antibodies, including two patients with neutralizing antibodies, without apparent pharmacodynamic impact or effect on clinical response [35]. In this surveillance, details of the two patients who returned positive tests for anti-velaglucerase alfa antibodies were not su ciently detailed to determine any impact on clinical bene t. However, data continue to be collected relating to the incidence and effects of developing antibodies to velaglucerase alfa in Japanese patients.…”