Clinical Overview: Cyletzo, a Biosimilar Version of Adalimumab

Indications for adalimumab include ankylosing spondylitis, Crohn disease, chronic plaque psoriasis, juvenile idiopathic arthritis, moderate to severe rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

Adalimumab-adbm (Cyltezo) is an interchangeable biologic that can serve as a substitute for the originator product, adalimumab (Humira). Its indications include ankylosing spondylitis, Crohn disease, chronic plaque psoriasis, juvenile idiopathic arthritis, moderate to severe rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.1 The FDA approved adalimumab-adbm on October 15, 2022.2

Mechanism of Action3

Adalimumab-adbm, a recombinant IgG1 monoclonal antibody, is a tumor necrosis factor inhibitor (TNFi). It binds to TNF alpha and blocks the interaction with p55 and p75.

Dosage and Administration4

  • Rheumatoid arthritis, psoriatic arthritis, and active ankylosing spondylitis: 40 mg subcutaneously every other week.
  • Crohn disease and ulcerative colitis: 160 mg subcutaneously on day 1, followed by 80 mg day 15, and 40 mg every other week starting on day 29.
  • Plaque psoriasis: Initial dose of 80 mg subcutaneously followed by 40 mg every other week starting 1 week after the initial dose.

Pediatric Dosing4

Juvenile idiopathic arthritis

Crohn Disease

Storage4

The manufacturer supplies adalimumab-adbm as a pre-filled syringe to be stored in the refrigerator between 36oF and 46oF. It cannot be frozen. If traveling, patients can store adalimumab-adbm at room temperature up to 77oF for up to 14 days.

Administration4

  • Step 1: Gather supplies (sharps container, cotton balls, alcohol swabs).
  • Step 2: Take adalimumab-adbm out of refrigerator 30 minutes prior to injection.
  • Step 3: Make sure medication is clear to cloudy and colorless to slightly yellow. Check expiration date and make sure syringe is not damaged.
  • Step 4: Wash hands.
  • Step 5: Choose injection site such as the upper thighs or abdomen. Injection site must be at least 1 inch from previous injection sites.
  • Step 6: Clean the injection site with alcohol swabs.
  • Step 7: Remove the cap by holding the syringe with 1 hand while using the other hand pull the cap off. Do not touch the needle.
  • Step 8: Squeeze the skin and hold firmly.
  • Step 9: Insert the needle into the skin at a 45-degree angle and using a thumb push down on the plunger to release the medication.
  • Step 10: Remove the needle and dispose into an FDA-cleared sharps container. Do not touch the needle at any time.

VOLITARE-RA Trial

The VOLITARE-RA trial found that adalimumab-abdm is a bioequivalent to adalimumab. The 24-week VOLITARE-RA trial randomized 645 patients to be administered 40 mg of adalimumab-abdm or adalimumab. The study used the College of Rheumatology 20% response criteria (ACR 20) required by the FDA and the European Medicines Agency (EMA).

The FDA's asymmetric margin suggests that the difference in ACR29 between adalimumab-abdm and adalimumab must be within -12% and 15% at week 12. The EMA's asymmetric margin suggests that adalimumab-abdm and adalimumab must be within -15% and 15% at week 24.5

At week 12, the ACR associated with adalimumab-abdm was 67% compared to adalimumab's ACR of 61.1%. The ACR results in a 5.9% (95% Cl: -0.9 to 12.7) difference in proportions between the 2 biologics.

At week 24, the ACR of adalimumab-abdm was 69% compared to adalimumab's ACR of 64.5%. The ACR resultsin a 4.5% (95% Cl: -3.4 to 12.5) difference in proportions between the 2 biologics.

The values fall within the range of the FDA and EMA’s asymmetric margin. Adalimumab-abdm and adalimumab are therapeutically equivalent and are biosimilar medications.5

Adverse Events (AEs)

Patients taking adalimumab-abdm are at risk of developing anti-drug antibodies (ADAs) that can neutralize the drug and decrease clinical efficacy. At week 24, 47.4% of adalimumab-abdm patents were ADA-positive compared to 53% of adalimumab-treated patients.5

The most common AEs include injection site pain, headache, and rash.4 Other AEs include serious infections; therefore, patients should not start treatment during an active infection.

Patients are at an increased risk of malignancies and heart failure. Cytopenia may occur, for which patients must stop treatment.4

Warnings and Precautions4

Adalimumab-adbm's boxed warning states that patients are at an increased risk for infections, which can be serious and can result in hospitalization or death. Patients taking concurrent azathioprine or 6-mercaptopurine are at a higher risk of lymphoma.

Pregnancy

Previous studies show that adalimumab is actively transported across the placenta by FcRn. Levels range from 4.28 ug/mL to 17.1 ug/mL.6

Adalimumab is actively transported across the placenta during the third trimester and affects the immune response of the infant.4 Prescribers must weigh the benefits and risks of using adalimumab-adbm. Untreated rheumatoid arthritis or irritable bowel disease results in preterm delivery, low birth weight, and low gestational age at birth.4

Lactation

In studies, the maximum concentration of breast milk in adalimumab was 0.71 mcg/mL and is not associated with any AEs. Adalimumab-adbm should be associated with similar effects on pregnancy and lactation as adalimumab.7

About the Author

Ryan Kurschner is a 2024 PharmD/MPH candidate at the UConn School of Pharmacy.

References

  1. Cyletzo FDA information. October 2021. Accessed May 25, 2022 https://www.fda.gov/news-events/press-announcements/fda-approves-cyltezo-first-interchangeable-biosimilar-humira
  2. Cyletzo FDA Approval. October 2021. Accessed May 25, 2022https://www.fda.gov/news-events/press-announcements/fda-approves-cyltezo-first-interchangeable-biosimilar-humira#:~:text=The%20FDA%20granted%20approval%20of,a%20variety%20of%20health%20conditions.
  3. Zhao S, Chadwick L, Mysler E, Moots RJ. Review of Biosimilar Trials and Data on Adalimumab in Rheumatoid Arthritis. Curr Rheumatol Rep. 2018;20(10):57. Published 2018 Aug 9. doi:10.1007/s11926-018-0769-6
  4. Medication Guide of Adalimumab-adbm. October 2021. Accessed May 25, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761058s008lbl.pdf
  5. Cohen SB, Alonso-Ruiz A, Klimiuk PA, et al. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomized VOLTAIRE-RA equivalence study. Ann Rheum Dis. 2018;77(6):914-921. doi:10.1136/annrheumdis-2017-212245
  6. Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure Concentrations of Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and Development. Gastroenterology. 2018;155(3):696-704. doi:10.1053/j.gastro.2018.05.040
  7. Seow CH, Leung Y, Vande Casteele N, et al. The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45(10):1329-1338. doi:10.1111/apt.14040