What Clinicians Need to Know About Using Biosimilars to Treat IBD

A review article in Current Gastroenterology Reports summarized the available infliximab and adalimumab biosimilars for treating inflammatory bowel disease (IBD) and those in the pipeline. The review, intended as a guide for clinicians, provided resources to help clinicians navigate biosimilar use with their patients and stay up to date on the biosimilar landscape.

Despite availability of these lower-cost alternatives to the originator drugs they reference, the authors said that uptake “remains low” because of concerns about efficacy and safety and delayed market entry of biosimilars. However, they suggested clinicians “can effectively address some of these barriers.”

The authors included a table of biosimilar product characteristics with links to training videos and patient programs, plus a checklist for biosimilar adoption and utilization in practice which outlined recommended educational, workflow, and monitoring steps.

IBD includes Crohn disease (CD) and ulcerative colitis (UC), chronic conditions characterized by inflammation of the gastrointestinal tract. The authors noted that the incidence of IBD has doubled in recent years. Although there have been, ”significant advances made with IBD treatment to prevent disease progression and improve quality of life,” the cost of biologics is high due to the complexity of the development and manufacturing processes, they said. They added that financial burden on patients and health care systems “is anticipated to worsen given the growing population of patients with IBD needing effective biologic treatment.”

The reviewers began by explaining the concepts of biosimilarity, extrapolation, and the US FDA’s interchangeability designation. For example, biosimilars are not generics, because biologics are manufactured in living cells and producing an identical copy is not possible. There is inherent variability both between manufacturing lots of the reference product and between the reference product and biosimilars. The approval process for biosimilars involves demonstrating similarity to the originator molecule in structure, function, pharmacokinetics, and clinical efficacy and safety. The approval of a biosimilar can be extrapolated based on a comparative clinical efficacy and safety study in one condition to other conditions based on the same mechanism of action.

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The reviewers noted the nocebo effect is a major barrier to biosimilar adoption and persistence, but that physician influence can mitigate the nocebo effect, citing previous research suggesting that over 80% of biosimilar discontinuations are due to the nocebo effect. Since patients with negative perceptions of biosimilars are at risk of the nocebo effect, and “many patients turn to their healthcare providers as the best source of medical information,” those perceptions can be influenced by their clinicians, the reviewers wrote. They provided strategies for clinicians to address the nocebo effect, such as “providing proactive biosimilar education and incorporating a shared decision-making process that addresses patients’ concerns while empowering them in their care.”

Infliximab biosimilars

The authors discussed 3 available infliximab biosimilars, infliximab-dyyb (Inflectra), the first

approved by the FDA for treating IBD in 2016, as well as infliximab-abda (Renflexis) and infliximab-axxq (Avsola). They added that an unbranded infliximab product produced by Janssen using the same cell line as the reference product is also available. Additionally, although most infliximab biosimilars are delivered intravenously, the first subcutaneous formulation of infliximab-dyyb (Zymfentra; Celltrion) was approved in October 2023.

Although infliximab biosimilars initially achieved approval for IBD by extrapolation from other conditions, “numerous studies have since then been conducted, providing reassuring data that infliximab biosimilars are effective, safe, and comparable to reference infliximab in IBD,” the authors said. They cited survey data showing that gastroenterologists have become more comfortable with infliximab biosimilars since they were first introduced in 2016 and that most gastroenterologists reported they have prescribed infliximab biosimilars.

Adalimumab biosimilars

As of April 2024, there are 10 adalimumab biosimilars approved by the FDA. Despite the first approval occurring in 2016, market entry was delayed by patent litigation until 2023. The reviewers noted that “adalimumab is one of the costliest biologics,” and the entry of adalimumab biosimilars to the market is expected to promote price competition and cost savings.

However, they noted, adalimumab biosimilars have “several layers of complexity” clinicians should be aware of. Product characteristics such as concentration, stability at room temperature, formulation, and inclusion of citrate and latex vary among adalimumab biosimilars. For example, citrate-free formulations and higher concentration, lower injection volume formulations aim to reduce injection site pain. Also, 3 adalimumab biosimilars have received the interchangeability designation: adalimumab-adbm (Cyltezo; Boehringer Ingelheim), adalimumab-ryvk (Simlandi; Alvotech/Teva) and adalimumab-afzb (Abrilada; Pfizer). The authors provided a table outlining these characteristics, saying “familiarity with each product will be important as this could drive patient preference and/or biosimilar product selection.”

Ustekinumab and other biosimilars

The first ustekinumab biosimilar (ustekinumab-auub, Wezlana; Amgen) with an interchangeability designation was approved by the FDA in November 2023, and it is indicated for moderate to severe CD or UC. Unfortunately, the authors wrote, ustekinumab-auub will not enter the market until 2025, “due to the settlement terms set by the manufacturer of reference ustekinumab.”

They added that several other ustekinumab biosimilars are currently in the pipeline, as are biosimilars to golimumab and natalizumab, whose patents are expected to expire in the next few years.

The future of biosimilars in IBD

According to the authors, although clinical research on biosimilars “objectively shows there is no decrease in safety or efficacy when compared to the respective reference products,” biosimilar integration into IBD care “has been hindered by several barriers.” As more biosimilars enter the market, they said, “clinicians continue to be important stakeholders and can significantly help improve biosimilar utilization in IBD in numerous ways.”

Reference

Angyal A, Bhat S. Biosimilars in IBD: What every clinician needs to know. Curr Gastroenterol Rep. 2024;26(3):77-85. doi:10.1007/s11894-023-00913-5