Riding the Wave of Adalimumab Biosimilars: Considerations for Pediatric Gastroenterologists

In January of 2023, the first adalimumab biosimilar became available in the United States for treatment of inflammatory bowel disease (IBD). Seven more adalimumab biosimilars are set to become available over the summer and fall of the same year, with more likely to follow. Based on our previous experiences with infliximab biosimilars that identified a number of challenges, pediatric gastroenterologists should be aware of several similarities and differences when prescribing an adalimumab biosimilar.

What are biosimilars:

The Federal Drug Administration (FDA) defines a biosimilar as a biologic that is highly similar, but not structurally identical, to an existing FDA-approved biologic with no meaningful differences in efficacy, safety, or purity. Another important FDA designation is the interchangeable biosimilar, which allows substitution of the reference product with the interchangeable biosimilar according to each state’s law. To meet the interchangeable designation, a biosimilar must demonstrate that it produces the same clinical effect as the reference product and can be switched with no additional safety risks or diminished efficacy. Meeting these criteria requires evidence from trials in which patients are switched from the reference product to the biosimilar, but a head-to-head clinical trial is not a requirement for interchangeability. While the interchangeability designation is on a federal level, substitution of drugs at a pharmacy is governed by the state and may vary. In addition, while a pharmacy in these states can substitute without the consent of a physician, this does not imply the payer will cover the interchangeable biosimilar.

Biologics are distinct from small molecules, and understanding the concept of biosimilarity requires an understanding of this uniqueness. Most therapeutic medications are small molecules synthesized through chemical reactions. Biologics are significantly larger and more complex and are derived from living organisms. Even so, variety exists among biologics, and these can be further categorized into peptide hormones (i.e. insulin, growth hormone), cytokines (i.e. epoetin alfa, filgrastim), fusion proteins (i.e. immunoglobulins), blood products, vaccines, and monoclonal antibodies. Monoclonal antibodies, and tumor necrosis factor (TNF) inhibitors in particular, are a mainstay of therapy in moderate to severe IBD.

While FDA approval of a novel biologic, also referred to as a reference product, is heavily based on safety and efficacy in clinical trials, biosimilar approval is primarily based on characterization of protein structure and function, pharmacokinetics and pharmacodynamics, and immunogenicity through pre-clinical studies. By definition, biosimilars have the same amino acid sequence as the reference product, but because of the complex, living organism-based synthesis of biologics, subtle differences in these processes may lead to differences in post-translational modifications including glycosylation, phosphorylation, and/or hydroxylation. Additionally, there may be differences in concentration, inactive ingredients or buffers, and delivery device. These are particularly important considerations for adalimumab due to volume-related injection site pain, pain related to citrate-containing formulations, and differences in pen auto-injectors and pre-filled syringes. However, sufficient evidence must exist for approval that these differences are not clinically meaningful.

How does a biosimilar get approval:

Approval of biosimilars typically requires only one clinical trial in patients with a condition in which the reference product is FDA-approved. Extrapolation often allows for approval of biosimilars for all the same indications as the reference product without extensive clinical trials, as long as the mechanism of action under review is similar across indications. For example, approval of infliximab-dyyb (Inflectra^®) was based on a Phase I trial in rheumatoid arthritis patients and a Phase III trial in ankylosing spondylitis patients, but extrapolation of its clinical efficacy and mechanism of action ultimately led to its approval for Crohn’s disease and ulcerative colitis. The concept of extrapolation significantly decreases time and costs associated with approval of novel monoclonal antibodies, and thus may reduce barriers and improve access to these high-cost medications for patients. However, extrapolation does not take differences in disease processes and differences in the pediatric population as opposed to the adult populations into account. Once accepted for use, third-party payers then develop their biologic formularies, which rarely include all the biosimilars, as is the case with infliximab. Each third-party payer decides what their preferred biosimilar is, thus increasing the complexity of obtaining prior authorization. In addition, each third-party payer can choose a different biosimilar, and formularies may change every year. Thus, there is no protection from frequent non-medical switching, which has yet to be shown as safe in the pediatric population. There are theoretical and physiologic concerns that may confer immunogenicity due to the subtle structural differences of biosimilars.

The first biosimilar agent was FDA-approved in 2015, which was filgrastim-sndz (Zarxio^®), followed in 2016 by infliximab-dyyb (Inflectra^®). Since then, over thirty additional biosimilar agents have been approved, with many more in the pipeline. As of December 2022, there are eight adalimumab (Humira^®) biosimilars that have been FDA-approved, all of which are anticipated to be commercially available in 2023, though litigation between drug manufacturers often leads to delays. Several others are in phase III clinical trials or pending FDA approval. Of the currently approved adalimumab biosimilar products, only adalimumab-adbm (Cyltezo^®) has been designated as interchangeable, though others are pursuing this designation.

As there are significant differences between the biosimilars including their delivery systems, contents, and concentration, we provide a summary of these adalimumab and biosimilar product differences (Table 1) to improve understanding and provide gastroenterologists the opportunity to make an informed choice. Of note, product brand names, formulations, induction kit availability, and approved indications may vary outside of the United States. The adalimumab reference product and biosimilar products are FDA-approved for the treatment of adult and pediatric patients aged six and older with Crohn’s disease. However, the biosimilar products are only approved for treatment of adult patients (≥18 years of age) with ulcerative colitis. This may be due to the recent change in pediatric ulcerative colitis Humira^® FDA-approved dosing.

Table 1:

Adalimumab reference and biosimilar product characteristics. ^¥ Interchangeability is a designation demonstrating that a biosimilar produces the same clinical effect as the reference product and can be switched with no additional safety risks or diminished efficacy. * Humira^® is available as a citrate-free, latex-free, high concentration formulation and also has a citrate-containing, latex-containing, low concentration formulation. The latter formulation is still FDA-approved but may not be readily available in dispensing pharmacies due to limited usage. Doses and formulations shown in Table 1 are limited to those recommended for the treatment of IBD.

	Humira® adalimumab	Abrilada® adalimumab -afzb	Amjevita® adalimumab -atto	Cyltezo® adalimumab -abdm	Hadlima® adalimumab -bwwd	Hulio® adalimumab- fkjp	Hyrimoz® adalimumab- adaz	Idacio® adalimumab- aacf	Yusimry® adalimumab- aqvh
Interchangeable with Humira®? ¥	Reference product	No	No	Yes	No	No	No	No	No
Crohn’s disease FDA approval	≥6 years of age
Ulcerative colitis FDA approval	≥5 years of age	≥18 years of age
Citrate-free?	Yes *	Yes	Yes	Yes	No	Yes	No	Yes	Yes
Latex-free?	Yes *	Yes	No	No	Yes	Yes	No	Yes	Yes
Available concentration	80mg/0.8 mL 40mg/0.4 mL 20mg/0.2 mL	40mg/0.8 mL 20mg/0.4 mL	40mg/0.8 mL 20mg/0.4 mL	40mg/0.8 mL 20mg/0.4 mL	40mg/0.8 mL 40mg/0.4 mL	40mg/0.8 mL 20mg/0.4 mL	40mg/0.8 mL	40 mg/0.8 mL	40mg/0.8 mL
High concentration available?	Yes *	No	No	No	Yes	No	No	No	No
Needle size	29G	29G	Pen: 27G Syringe: 29G	27G	29G	29G	27G	29G	29 G
Induction formulations available?	Yes	No	No	No	No	No	Yes	Yes	No
Maintenance formulations	Pen: 80 mg, 40 mg Syringe: 40mg, 20 mg	Pen: 40 mg Syringe: 40mg, 20 mg	Pen: 40 mg Syringe: 40mg, 20 mg	Pen: None Syringe: 40mg, 20 mg	Pen: 40 mg Syringe: 40mg	Pen: 40 mg Syringe: 40mg	Pen: 40 mg Syringe: 40mg	Pen: 40 mg Syringe: 40mg	Pen: None Syringe: 40mg

One major challenge unique to the treatment of IBD may be the lack of induction kits with biosimilar products. While Humira^® is available in a wide variety of induction kits for all indications and ages, only Hyrimoz^® and Idacio^® are available as an induction kit, though additional induction kits will likely need to be made commercially available when biosimilars are FDA-approved for pediatric ulcerative colitis. Specific challenges that may be unique to pediatric patients include the presence of citrate in two of the biosimilars as a preservative as well as the larger injection volume for biosimilar products, both of which may be associated with more injection site pain compared to the citrate-free and high concentration reference product. In addition, the presence of latex in three of the biosimilars may be a concern for those patients that are latex allergic and is a relative contraindication for use of these adalimumab biosimilars in latex allergic patients. The fourteen-day excursion time (stability out of refrigeration) of the adalimumab biosimilar products match that of Humira^®, except for Abrilada^®, which has a 30-day excursion time and Idacio^®, which has a 28-day excursion time. It is important to note that specific pen and syringe device mechanisms differ between products. Thus, patients and clinical staff alike will require training on new injection techniques. Lastly, there may be differences in copay assistance programs, patient assistance programs, ambassador programs, and injection training resources for each adalimumab biosimilar. It will be important to ensure that all patients on the reference product or a biosimilar have access to the same financial and injection resources.

As we have seen with infliximab and other biosimilars, there is little to no difference in effect between the biosimilars and their references. In the United States, these biosimilars can provide savings for third-party payers, and one would hope that these savings would be passed on to the patients. The issues that arise with adalimumab biosimilars and interchangeable biosimilars are the differences in the formulations and delivery devices that will significantly affect our pediatric population and will need to be considered as shown in Table 1. The challenge in the United States will be that third-party payers will mandate the use of specific adalimumab biosimilars by limiting their formularies. If recent history is any indication, these decisions will not likely consider the issues described above and how they relate to pediatric patients. In conclusion, the adalimumab biosimilars will likely provide a clinically effective, cost saving option for our patients, but consideration of a number of factors will be key when selecting between the new wave of these options.