An Expert View on Immunogenicity and Biosimilars

The potential for all biologics, including biosimilars to elicit an immunogenic response has become a hot-button issue among physicians, some of whom are concerned about switching their patients to biosimilars or among multiple biosimilars. During the BioTech Pharma third annual Biosimilars and Biologics Summit, held March 21 to 22 in Porto, Portugal, João Gonçalves, PhD, group leader and principal investigator at Research Institute for Medicines in Portugal, discussed ways in which biosimilar developers can anticipate—and avoid—issues with immunogenicity.

Gonçalves acknowledged the fact that any switch in which a patient loses efficacy of their therapy is not an ethical one; additionally, physicians are concerned about issues including secondary failure, acute reactions, or differences in safety profiles. However, Gonçalves pointed out that “the data that we have in Europe over 10, 12 years, doesn’t show any danger signal in terms of immunogenicity…we don’t have an elephant in the room” with biosimilars.

He also noted that, on the originator product side, there are very few data about switching between batches of reference products. However, over the last 3 to 4 years, the literature on originator adalimumab’s immunogenicity has been growing, not because of problems with the quality of brand-name Humira, but because improved technology has resulted in more sensitive detection. “We are detecting more immunogenetic responses against Humira than we were,” he explained.

Gonçalves also noted that, unfortunately, some data are published in the literature that are misleading on the topic of immunogenicity because they do not consider the nuances of the topic; antidrug antibodies (ADAs) may be transient (detectable at a single time point and not detectable at all other time points) or they may be persistent (detectable at 2 or more time points at least 42 days apart). It is also important to be aware that ADAs generally appear within the first 12 months of therapy; in looking at potential differences between biosimilars and reference products, it is key to assess the time at which the ADAs appear, not simply the appearance of ADAs alone.

It is also important, in assessing the risks of immunogenicity, to consider the probability of harm and the potential severity of harm to a patient; those with life-threatening or chronic disease for whom a product is a sole therapy may have a more serious risk than a patient taking other therapies concomitantly for non—life-threatening or end-stage disease, for example. The probability of harm is likely lower in immunosuppressed patients and those who take intravenous administrations or receive single doses than in patients with autoimmune diseases who take subcutaneous doses or chronic therapy.

Particularly crucial to any discussion of immunogenicity is the amplification of anti-drug immune responses by low-quality biologics. Aggregates induce immunogenicity, explained Gonçalves, and “companies must be strongly devoted to develop methods” to prevent aggregation. “The immune system, if it sees aggregated forms of a drug, it sees it as a virus,” he said, eliciting an immune response. Thus, companies should focus on stability studies—involving the drug substance, the drug product, or changes to either one—and ensuring that the biosimilar and the reference are highly comparable in this respect.

Furthermore, immunogenicity studies should consider how epitope-specific antibodies associate with therapeutic failure, how ADAs evolve along with disease activity in indications like rheumatoid arthritis or inflammatory bowel disease, and how titer kinetics, rather than ADA positivity alone, predict secondary failure.

Going forward, clinical trials of biosimilars should be powered to detect immunogenicity, and should be conducted in a sensitive patient population. The population should be homogeneous in terms of comorbidities, disease severity, and concomitant medications, and should be immunocompetent. The duration of these studies should be 6 months to 1 year, neutralizing ADAs should be an area of focus, and assays should be robust. End points should be clinically relevant, readily assessable, and able to detect differences; continuous endpoints may be especially useful in this context. Immunogenicity should also be compared with pharmacodynamic data, not looked at in isolation.

Finally, it is important to translate immunogenicity data to the practicing clinician. Helping providers to understand what biomarkers they should use in practice give clinicians the tools that they seek as they grapple with the idea of using biosimilars and overcoming their concerns about immunogenicity, said Gonçalves.