Biosimilar agents are biologic agents with a molecular structure that is highly similar to but not an exact match with the original reference product. According to the Food and Drug Administration (FDA), these agents must have no clinically meaningful difference in terms of safety profile, purity and potency. First approved in Europe and other markets in 2013, anti-TNF biosimilars are now available in an expanding list of countries. And the number of new biosimilars in the pipeline for the treatment of inflammatory bowel disease (IBD) is growing. In 2016, the U.S. approved biosimilars for infliximab (-dyyb) and adalimumab (-atto).
While many assume that this new wave of agents will provide patients with lower cost alternatives to biologic therapies, some questions and confusion about biosimilars persist. Edward V. Loftus Jr., M.D., a gastroenterologist specializing in IBD at Mayo Clinic's campus in Rochester, Minnesota, answers several key questions about biosimilars and their potential role in treating IBD.
Drug development differences
According to Dr. Loftus, the biosimilar drug development pathway is different from the pathway for conventional drugs. The goal of a biosimilar development program is to demonstrate that the biosimilar is highly similar to the reference product and not to independently establish its safety and effectiveness. The type and extent of analyses and testing that are needed to demonstrate biosimilarity is product specific.
Dr. Loftus says, "The pathway for a biosimilar involves a lot of work at the cellular level and the pharmacokinetics level to prove that the drug is essentially similar to the originator product. When the drug is approved for clinical use, the company that makes the biosimilar generally has to show that it's similar to the originator product in one indication for which it's approved."
Is extrapolation automatic?
According to Dr. Loftus, no. The FDA requires clinical and scientific justification to extend approval to other indications that were not directly studied with the biosimilar. Clinical testing in specific additional disease states may be required, especially if there are concerns that the mechanism of action, pharmacokinetic and biodistribution characteristics, immunogenicity, and toxicities or adverse events associated with the biosimilar agent might differ across the approved indications. However, it's important to note that the manufacturer of the first biosimilar to infliximab, which is approved for multiple indications, only had to demonstrate that the biosimilar was clinically equivalent to the originator in patients with rheumatoid arthritis, and of similar pharmacokinetic properties to the originator in patients with ankylosing spondylitis.
How are biosimilars named, and how are agents designated as interchangeable?
Manufacturers take the current nonproprietary name (such as infliximab or adalimumab) and combine it with a four-letter suffix, such as infliximab-dyyb or adalimumab-atto. According to Dr. Loftus, the FDA designates a biosimilar as interchangeable if it is anticipated to produce the same clinical result in any given patient, and if administered more than once, the risk of alternating or switching is not greater than using the reference alone.
The threshold of evidence for designation as interchangeable is more rigorous, and will involve studies where patients are switched between the originator and the biosimilar multiple times within the study. Thus far, neither infliximab-dyyb nor adalimumab-atto has been designated as being interchangeable. To further complicate matters, beyond the federal interchangeability designation, each state's pharmacy board will govern whether pharmacists may dispense the biosimilar rather than the branded version (or vice versa) without intervention by the prescriber.
To address these issues, the Crohn's and Colitis Foundation issued a position statement and principles to enhance and safeguard shared decision-making between providers and patients. That statement includes the following guidelines:
- All biologics and biosimilars should undergo thorough human testing and meet the highest safety standards
- The risk of immunogenicity should be included in prescribing information
- For interchangeability, reasonable proof must be provided that switching from the originator to the biosimilar would not incur immunogenicity or loss of response to the originator (and vice versa)
- Each biosimilar should have a unique identification number and name or use international nonpropriety names
- Substitution should be tracked and provided to the prescriber
While the potential cost savings associated with the use of biosimilars could be substantial, the true impact on cost for patients in the U.S. may not be as great as those seen in other countries, cautions Dr. Loftus. The largest discounts seen thus far have been in countries with single-payer systems. In Norway, for example, the government has agreed to replace the originator with the biosimilar, resulting in a 60 percent discount in cost.
Clinical trials for IBD using biosimilars
At this time, there are at least 13 studies involving IBD patients who were switched from infliximab to the biosimilar known as CT-P13 (infliximab-dyyb). Study findings published in the Journal of Crohn's and Colitis in 2017 indicate that treatment persistence in these patients ranged from 57 to 88 percent at the end of follow-up, with an expected incidence of adverse events. Results from a prospective trial conducted in Italy involving 548 patients and published in 2017 in Inflammatory Bowel Disease suggest that CT-P13 offers promising clinical response, safety and loss-of-response rates.
"These studies and the resulting data are encouraging, as they suggest that the efficacy and safety of biosimilars for IBD are comparable to those seen with the brand-name original product," notes Dr. Loftus. "Hopefully, with time, the reduction in costs of biosimilars will be substantial enough to translate into improved access to these life-altering therapies for our patients with Crohn's disease and ulcerative colitis."
For more information
Danese S, et al. ECCO position statement on the use of biosimilars for inflammatory bowel disease — An update. Journal of Crohn's and Colitis. 2017;11:26.
Fiorino G, et al. The PROSIT-BIO cohort: A prospective observational study of patients with inflammatory bowel disease treated with infliximab biosimilar. Inflammatory Bowel Diseases. 2017;23:233.