A Cleveland Clinic researcher anticipates that the FDA’s definition of strength of formulation could impair acceptance of Boehringer Ingelheim’s biosimilar to Humira (adalimumab), even though the FDA has approved the biosimilar as “interchangeable” to Humira.
Boehringer Ingelheim’s Cyltezo, a biosimilar to Humira (adalimumab), is equivalent in all major respects to Humira except that the amount of active drug by volume is different, according to a recently published retrospective review of pharmacologic and clinical evidence.
Shubha Bhat, Pharm.D., M.S., a clinical pharmacist at the Cleveland Clinic, and her co-researchers, said the difference in formulation is the result of Boehringer Ingelheim changing the concentration of drug content in order to avoid infringing on patents for Humira. The change, they wrote, could “pose a barrier to the adoption and use” of the biosimilar because it is not strictly interchangeable according to the FDA’s definition of strength of formulation.
Even so, Bhat and her colleagues said results of clinical trials of Cyltezo show that it will be safe for patients to switch from Humira to the biosimilar.
Their findings were published in the Annals of Pharmacotherapy in early April.
In apetition in December 2020, Boehringer Ingelheim formally asked the FDA to change its definition of strength “to account for total drug content regardless of drug concentration” but has yet to receive an official decision.
Regardless of active drug content versus volume, Cyltezo in October 2021 became the first biosimilar approved as an interchangeable for the treatment of certain inflammatory diseases.Interchangeable biosimilars may be substituted for reference biologics (such as Humira) at the pharmacy counter without the need for physician authorization, although state-level pharmacy laws can add steps and interfere with swapping out the original biologic for the biosimilar in other ways.
Many observers of the biologics and biosimilars industry see relatively hassle-free interchangeability as being crucial to adoption of biosimilars, which are supposed to lower the cost of biologics in the same way that genetics have lowered the cost of small-molecule drugs, such as statin.
Cyltezo is scheduled to come on the market in July 2023. The biosimilar was originally approved as a treatment of rheumatoid arthritis and subsequently approved, via extrapolation based on evidence, approved as a treatment for Crohn’s disease, ulcerative colitis, ankylosing spondylitis and chronic plaque psoriasis.
The product will be available in a “painless” citrate-free formulation in 40 mg/0.8 mL and 20 mg/0.4 mL concentrations, versus the comparable-but-slightly-different 40 mg/0.8 mL and 40 mg/0.4 mL formulations for Humira. Humira is also available in a higher-concentration formulation.
Pharmacokinetic equivalence of Cyltezo was demonstrated in VOLTAIRE-PK, a phase 1, randomized three-arm trial (N = 327). Bhat wrote that functional potency assays revealed no significant differences between lots of the biosimilar and reference product, and drug concentration and clearance patterns were equivalent.
Cyltezo was originally approved for treatment of rheumatoid arthritis and via extrapolation based on evidence, the biosimilar also was approved for Crohn’s disease, ulcerative colitis, ankylosing spondylitis, and chronic plaque psoriasis.
The phase 3 VOLTAIRE-RA and VOLTAIRE-RAext randomized trials demonstrated equivalence in patients with moderate to severe active rheumatoid arthritis who were stable on methotrexate. In VOLTAIRE-RA (N = 479), response rates at week 24 were 69% and 64.5% for Cyltezo and Humira, respectively (95% CI, -3.4 to 12.5).
VOLTAIRE-RAext (N = 430) evaluated the long-term safety, efficacy, and immunogenicity of Cyltezo. Roughly 20.2% of patients experienced a drug-related adverse event (AE), and rates were similar across trial cohorts.
Response rates throughout the extension trial were sustained during the 48-week term of additional treatment with Cyltezo. “Thus, VOLTAIRE-RAext further supports the clinical acceptability of switching participants from (Humira) to (Cyltezo),” Bhat and her colleagues wrote.
Separate randomized studies of Cyltezo versus Humira in Crohn's disease and chronic plaque psoriasis demonstrated high similarity in terms of safety, efficacy, and immunogenicity, Bhat and her co-investigators wrote.
Finally, VOLTAIRE-X was a phase 3 randomized control trial that provided key evidence on switching that supported the FDA’s determination of interchangeability. The trial enrolled patients with chronic plaque psoriasis. “Overall, the efficacy, safety, and immunogenicity findings of VOLTAIRE-X highlighted the safety of multiple switches between (Cyltezo) and (Humira),” Bhat wrote.
“(Cyltezo) represents an important advance in the continued expansion of biosimilars,” Bhat and her colleagues concluded. They wrote that although the biosimilar won’t be available for another year, pharmacists can facilitate uptake by working now to educate patients and providers “about biosimilars and the process for interchangeability status designation.”