Immunogenicity


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All biologics are inherently immunogenic, which means they are capable of provoking an immune response that stimulates the production of anti-drug antibodies (ADAs).24 The formation of ADAs over time compromises the effectiveness of biologic DMARDs, ultimately leading to treatment failure.24 Factors that affect immunogenicity include the molecular composition of the drug, patient factors, and possibly disease pathology. For example, a comparison of the CT-P13 arms of the PLANETRA and PLANETAS studies shows that a higher percentage of RA patients developed ADAs than AS patients.9 This is one example of why some experts have voiced concerns about extrapolating findings of biosimilarity from a study in one patient population to another patiednt population when approving the drug.22 In his February testimony before the ADAC, Dr Worthing advised the FDA to use caution when “considering approving extrapolation of biosimilar products for indications where the reference biologic has already been approved in the absence of safety data specific to the biosimilar agent and the patient population in question.”18

Dr Kay pointed out that the clinical trials of biosimilars for RA and ankylosing spondylitis found no increase in immunogenicity with the biosimilar. “In fact, the etanercept biosimilar manufactured by Samsung Bioepis induced ADAs in a smaller proportion of patients than did the reference etanercept,” he said. Another concern some have expressed is that switching between the biosimilar and reference drug could increase immunogenicity. “There are data from clinical trials that show no significant loss of efficacy or increase in immunogenicity or other safety concerns after patients have been transitioned from the reference product to the biosimilar,” Dr Kay said.

Summary and Clinical Applicability

The growing use of expensive biologics has led public and private insurers in the United States to impose cost-sharing burdens that place these drugs out of reach for many patients. To date, the FDA has approved only 1 biosimilar. However, the FDA is anticipating a marked increase in the biosimilar market as more patents expire for brand-name biologics. Many biosimilars for chronic inflammatory illnesses like RA are in development, and recently the ADAC has voted to back an infliximab biosimilar (Remicade). 

Thus far, data from studies of promising biosimilars in RA have established that these drugs, which have the same primary amino acid structure as the reference drug, also have similar mechanisms of action, pharmacokinetics, efficacy, safety, and immunogenicity to the reference drug. Many states will allow clinicians who have concerns about the interchangeability of a biosimilar to request no substitutions for a brand-name biologic.


Figure. Comparison of the standard development process for a new drug and the development process for a biosimilar. Image courtesy of the FDA.4

References

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2.       Kay J, Smolen JS. Biosimilars to treat inflammatory arthritis: the challenge of proving identity. Ann Rheum Dis. 2013;72(10):1589-1593.

3.       US Food and Drug Administration. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product: guidance for industry.Source link. Published April 2015. Accessed February 12, 2016.

4.       Christl L. Overview of the regulatory pathway and FDA’s guidance for the development and approval of biosimilar products in the US. US Food and Drug Administration. Source link. Published February 9, 2016. Accessed February 12, 2016.

5.       World Health Organization Expert Committee on Biological Standardization. Guidelines on evaluation of similar biotherapeutic products (SBPs). Source link. Published October 2009. Accessed February 15, 2016.

6.       Generics and Biosimilars Initiative. Biosimilars approved in Europe. Source link. Updated February 5, 2016. Accessed February 10, 2016.

7.       Woodcock J; US Food and Drug Administration. Testimony on biosimilars implementation before the Committee on Energy and Commerce, Subcommittee on Health, United States House of Representatives. Source link. Published February 4, 2016. Accessed February 11, 2016.

8.       Reinisch W, Smolen J. Biosimilar safety factors in clinical practice. Semin Arthritis Rheum. 2015;44(6 Suppl):S9-S15.  doi: 10.1016/j.semarthrit.2015.04.005.

9.       Dörner T, Kay J. Biosimilars in rheumatology: current perspectives and lessons learnt. Nat Rev Rheumatol. 2015;11(12):713.

10.   Carnegie TC, Hawana J, Smith SB, Sternfield E. Emerging state biosimilar laws – reference chart and five issues to watch. Health Law & Policy Matters website. Source link. Published July 28, 2015. Accessed February 15, 2016.

11.   Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Source link. Published 2014. Accessed February 12, 2016.

12.   Ryan C. The new frontier of pharmaceuticals: biosimilars. American Action Forum website. Source link. Published September 10, 2015. Accessed February 10, 2016.

13.   Richardson E. Biosimilars. To encourage competition, the health care law directs the FDA to develop an accelerated approval pathway for follow-on versions of original biologic products. Health Affairs. Source link. Published October 10, 2013. Accessed February 7, 2016.

14.   US Food and Drug Administration. Nonproprietary naming of biological products: guidance for industry (draft). Source link. Published August 2015. Accessed February 5, 2016.

15.   World Health Organization. Biological qualifier: an INN proposal. Source link. Published January 26, 2016. Accessed February 17, 2016.

16.   Biosimilars Council joins pharmacies, payers, and others in message to FDA & HHS: require same names for biologics and biosimilars to ensure patient safety [press release].  Source link. Published June 30, 2015. Accessed February 6, 2016.

17.   Liang B. Biosimilars Council statement regarding the World Health Organization’s biosimilar naming proposal [press release]. Source link. Published February 11, 2016. Accessed February 14, 2016.

18.   American College of Rheumatology encourages safe adoption of biosimilars during FDA public hearing on CT-P13, a proposed biosimilar for infliximab (Remicade) [press release]. Source link. Published February 10, 2016. Accessed February 11, 2016.

19.   FDA’s Arthritis Advisory Committee recommends approval of Celltrion’s CT-P13, a proposed biosimilar infliximab, for all indications [press release]. Source link. Published February 9, 2016. Accessed February 11, 2016.

20.   Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with  methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613-1620.  

21.   Park W, Hrycaj P, Jeka S, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72(10):1605-1612.

22.   Pitts PJ. Biosimilar sins of omission. The Hill. Source link. Published February 15, 2016. Accessed February 16, 2016.

23.   Emery P, Vencovský J, Sylwestrzak A, et al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2015 Jul 6. pii: annrheumdis-2015-207588. [Epub ahead of print]

24.   Solomon G. Immunogenicity – implications for rheumatoid arthritis treatment. Source link. Bull Hosp Jt Dis. 2013;71(3):200-203.