Immune responses to the biosimilar infliximab ‘Inflectra’ very closely resemble those to the originator product ‘Remicade’, and consistent clinical outcomes have been obtained from the two products when treating patients with inflammatory bowel disease, international experts have told Australian clinicians.
Speaking at a series of meetings hosted by Hospira, a Pfizer Company, Dr Shomron Ben-Horin from Tel-Aviv, Israel, said the active substance of a biosimilar and its reference medicine were essentially substances with essentially the same biological properties.
The European Medicines Agency had noted that there may be minor differences due to their complex nature and production methods, but they did not affect safety or effectiveness. Similarly, the FDA had said that a biosimilar was highly similar to the reference product, notwithstanding minor differences in clinically inactive components.
“Biologics are generated by complex processes involving living cells,” said Dr Ben-Horin, who is Director of the IBD Service and Gastro-Immunology Laboratory at Sheba Medical Center in Israel.
“In fact, many changes can occur during the lifetime of the product, in consultation with regulatory authorities, in contrast to simple chemical moieties which remain the same over time.”
For example, more than 35 changes have been made to the manufacturing process for Remicade after its initial approval.1
Investigating immune response
The evaluation of biosimilars is based on comparability studies which consider physicochemical characteristics, biological activity, pharmacodynamics and pharmacokinetics, pre-clinical toxicology studies and clinical trials.
“Once these processes have been completed, we can also investigate the immune response to the new product,” Dr Ben-Horin told healthcare professionals attending the meeting in Sydney.
“The immune system has immense scope to recognise multiple antigens, and recognise subtle differences between antigens.”
In 2003 Baert et al described the clinical consequences of an immune response to infliximab in patients with Crohn’s disease.2
“The development of antibodies to infliximab (ATI) was associated with reduced duration of response in patients treated with episodic therapy,” Dr Ben-Horin said. “We subsequently showed that high ATI levels in patients treated with regular, scheduled therapy were also more likely to experience a complete loss of response.”3
Dr Ben-Horin and his colleagues recently reported that ATI are detrimental, independently of the circulating level of infliximab.
In patients with Crohn’s disease who had measurable levels of infliximab >3 μg/mL, the presence of antibodies was associated with a lower rate of mucosal healing compared with patients with similar drug level but without antibodies (16% vs 50%, respectively, P=0.003).4
His research team also established that among patients who develop ATI, the majority do so within the first 12 months of treatment.5 These findings are consistent with a study reported by Louis et al.6 They enrolled patients who had been in sustained remission during infliximab treatment, ceased the medication, and then were re-treated on relapse.
“Re-treatment was effective. Patients in sustained remission during treatment were likely to have not generated ATI, and had a low susceptibility to do so when re-treated,” Dr Ben-Horin said.
No noticeable differences in immunogenicity between the drugs
The efficacy of treatment is reduced in the subset of patients who develop ATI, but when it does occur, the immune response can provide a useful comparison of the immunological profiles of originator and biosimilar products, and therefore the degree of their similarity.
“A wide range of product-related, host-related and treatment-related factors affect the immunogenicity of a biologic,” Dr Ben-Horin said. “A similar immunogenicity profile of Remicade and Inflectra is testimony to the similarity of the molecules.
“In the PLANETRA and PLANETAS studies comparing Remicade and Inflectra in patients with rheumatoid arthritis and ankylosing spondylitis, respectively, there were no noticeable differences in the immunogenicity of the two drugs.”7,8
Dr Ben-Horin and his colleagues confirmed the similarity of the immunological profiles of Remicade and Inflectra in a study using sera from 86 IBD patients, with or without measurable ATI, and 22 healthy controls.9
“All 56 anti-Remicade ATI-negative controls (14 healthy individuals, 42 patients with IBD) were also negative for anti-Inflectra ATI,” he said. “All 69 positive anti-Remicade IBD sera were cross-reactive with Inflectra. ATI titres against Remicade or Inflectra were strongly correlated.
“We concluded that anti-Remicade antibodies in patients with IBD recognise and functionally inhibit Inflectra to a similar degree, suggesting similar immunogenicity and shared immunodominant epitopes on these two infliximab agents.”
The immunological similarity of the two products was further supported by an open-label extension of the 48 week PLANETRA study.10 Patients initially randomised to Remicade were switched to Inflectra after 54 weeks, and no increase in the incidence of ATI was observed.
“This is very strong evidence that these two molecules are equivalent in terms of immunogenicity,” Dr Ben-Horin said.
- Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis 2013; 72: 315-8.
- Baert F et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003; 348: 601-8.
- Ben-Horin S et al. The immunogenic part of infliximab is the F(ab’)2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut 2011; 60: 41-8.
- Ungar B et al. Optimizing anti-TNF-α therapy: Serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2016; 14: 550-557.
- Ungar B et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut 2014; 63: 1258-64.
- Louis E et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012; 142: 63-70.
- Yoo DH et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013; 72: 1613-20.
- Park W et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013; 72: 1605-12.
- Ben-Horin S et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut 2016; 65: 1132-8.
- Yoo DH et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis 2016 Apr 29. pii: annrheumdis-2015-208786.