Tony Hagen is senior managing editor for The Center for Biosimilars®.
Product differentiation by concentration is a threat to the multiple adalimumab biosimilars approved but not yet launched.
Multiple biosimilar developers have obtained FDA approval for biosimilar versions of adalimumab, an immunosuppressive drug for rheumatologic and gastrointestinal disorders, but won’t be able to bring these products to market until 2023, based on deals struck with AbbVie, which markets Humira, the blockbuster adalimumab innovator product. One question is whether these approved biosimilars will still be relevant 2 years from now.
Not only has AbbVie introduced new products to take over market share from Humira (risankizumab, Skyrizi; upadacitinib, Rinvoq), it also has introduced high-concentration versions of Humira that, according to Boehringer Ingelheim, a rival producer, are capturing market share. Humira products had global net revenues exceeding $19 billion in 2019.
“A majority of all Humira prescriptions are now for the high concentration as opposed to the original formulation,” according to Boehringer Ingelheim, which developed the yet-unmarketed original concentration adalimumab biosimilar Cyltezo. “Additionally, 2 dosage forms of the original formulation of Humira have been discontinued by AbbVie since the high-concentration version was launched in July 2018,” Boehringer Ingelheim noted in a statement issued to The Center for Biosimilars®. AbbVie began marketing its citrate-free, higher-concentration formulation of Humira in July 2018.
That’s a problem for the producers with approved adalimumab biosimilars in the original concentration that have yet to launch. In the United States, 6 biosimilar adalimumab products have been licensed by the FDA for use only in a 50-mg/mL concentration formulation. Those include Boehringer Ingelheim’s Cyltezo, which is approved for 2 strengths: 20 mg and 40 mg.
Original vs High Concentration
Humira was originally approved in the 40-mg strength with a 50-mg/mL concentration, but later in 10-mg and 20-mg strengths for the same concentration. It is currently approved in citrate-free, high-concentration form for all 3 strengths plus 80 mg, all in a 100-mg/mL formulation. Citrate-free adalimumab is considered to cause less pain on injection, and the higher-concentration injections can involve smaller amounts.
AbbVie’s ability to distinguish its adalimumab offerings by concentration has created competitive obstacles for companies that now must match these high-concentration formulations in order to move in the direction that the adalimumab market appears to be going.
Celltrion of Incheon, Republic of Korea, has sought European Union marketing approval for CT-P17, a high-concentration formulation of adalimumab and in December 2020 reported a positive recommendation for approval from the Committee for Medicinal Products for Human Use. The company is poised to be the first to bring a high-concentration, citrate-free adalimumab biosimilar to market, albeit in Europe. In November 2020, Alvotech, of Reykjavik, Iceland, announced that its high-concentration 100-mg/mL dose (AVT02) adaliumumab biosimilar candidate had been accepted for review by the FDA and European Medicines Agency.
Interpretation of Strength
Recently, Boehringer Ingelheim has engaged with the FDA over its interpretation of product strength in an attempt to mitigate what the company considers a too-restrictive emphasis on concentration of formulation that it says allows “evergreening” of originator products to the disadvantage of biosimilar competition.
In a citizen’s petition, the company has requested that the FDA reinterpret the term “strength” in section 351(k) of the Public Health Service Act to mean “total drug content” regardless of concentration.
Boehringer Ingelheim’s original concentration adalimumab biosimilar (Cyltezo) was approved in August 2017 but can’t debut until July 2023, under the agreement with AbbVie.
“Under the FDA’s current interpretation of ‘strength,’ no biological product can be considered biosimilar and/or interchangeable if there has been any variation in the inactive drug volume as compared to the reference product. [The] FDA’s current definition encourages, or at least permits, manufacturers to use minor concentration changes as an anticompetitive tactic, depriving patients [of] more affordable biological products contrary to the goal of the [Biologics Price Competition and Innovation Act (BPCIA)],” the company said in its statement.
Boehringer Ingelheim said it wants its Cyltezo biosimilar to be considered to have the same strength as both the original-concentration and high-concentration versions of Humira “because they contain the same total drug content per container.”
Recent draft guidance from the FDA suggests that the agency is willing to consider a reinterpretation of “strength.” However, Boehringer Ingelheim said that bringing the issue to prominence through its citizen petition helps to provide impetus for a change. “We are hopeful that by working closely with industry peers, payors, health care providers, and patient advocates, and engaging in a transparent and public discussion of the issues we have raised, the FDA will take a positive action on our petition.”
In making its case for a reinterpretation of “strength,” Boehringer Ingelheim maintains that dropping the concentration emphasis would be more in line with the nurturing environment for biosimilars that Congress intended when it created the BPCIA, which incorporates the biosimilar approval pathway.
Asked whether the scientific decision of how “strength” should be defined should be left up to the FDA, not Congress, the company responded, “Boehringer Ingelheim believes that [the] FDA should be able to assess the clinical effects of concentration differences, if any, via the usual analytical and clinical studies required to demonstrate biosimilarity and interchangeability.
“This approach would distinguish between products that, despite minor concentration differences, have no clinically meaningful differences from the reference product and/or may be substituted for the reference product without the intervention of the prescribing physician, and those that cannot. [The] FDA can adequately address the clinical effect of concentration differences through BPCIA mechanisms other than ‘strength.' [The] FDA’s interpretation of ‘strength’ is incorrect as a matter of law,” the company said.