Clinical Review

Biosimilars in Psoriasis: The Future or Not?

Cutis. 2017 February;99(2):116-120

As patents for the biologic agents reach their expiration dates, dermatologists must prepare for the coming of biosimilars. These agents have been deemed “highly similar” to their reference products in a process outlined by the US Food and Drug Administration (FDA). In 2016, the FDA approved 3 biosimilars for various indications including plaque psoriasis and psoriatic arthritis. However, biosimilars are not the same as small-molecule generics because they have a complex manufacturing process that makes it impossible to produce identical products to their reference products. Therefore, should biosimilars be granted FDA approval for the same indications as their reference products? Furthermore, can biosimilars automatically be substituted for the branded drug at the pharmacy level? Putting aside these technical concerns, physicians must focus on the impact of biosimilars on patient care. These agents will have to be integrated into a complex health care system comprised of drug developers, employers, payers, and drug formularies.

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Practice Points

Three biosimilars have been approved by the US Food and Drug Administration to treat adult patients with plaque psoriasis and psoriatic arthritis.
By virtue of their production, biosimilars are not identical to their reference products, and we must ensure that their safety is comparable.

References

Information on biosimilars. US Food and Drug Administration website. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/. Updated May 10, 2016. Accessed July 5, 2016.
US Department of Health and Human Services. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry. Silver Spring, MD: US Food and Drug Administration; 2015.
McKeage K. A review of CT-P13: an infliximab biosimilar. BioDrugs. 2014;28:313-321.
FDA approves Inflectra, a biosimilar to Remicade [news release]. Silver Spring, MD: US Food and Drug Administration; April 5, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm. Updated April 20, 2016. Accessed January 23, 2017.
FDA approves Erelzi, a biosimilar to Enbrel [news release]. Silver Spring, MD: US Food and Drug Administration; August 30, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm. Accessed January 23, 2017.
FDA approves Amjevita, a biosimilar to Humira [news release]. Silver Spring, MD: US Food and Drug Administration; September 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm. Accessed January 23, 2017.
Scott BJ, Klein AV, Wang J. Biosimilar monoclonal antibodies: a Canadian regulatory perspective on the assessment of clinically relevant differences and indication extrapolation [published online June 26, 2014]. J Clin Pharmacol. 2015;55(suppl 3):S123-S132.
Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars [published online September 14, 2007]. Ann Oncol. 2008;19:411-419.
Puig L. Biosimilars and reference biologics: decisions on biosimilar interchangeability require the involvement of dermatologists [published online October 2, 2013]. Actas Dermosifiliogr. 2014;105:435-437.
Strober BE, Armour K, Romiti R, et al. Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know. J Am Acad Dermatol. 2012;66:317-322.
Falit BP, Singh SC, Brennan TA. Biosimilar competition in the United States: statutory incentives, payers, and pharmacy benefit managers. Health Aff (Millwood). 2015;34:294-301.
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;72:1605-1612.
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;72:1613-1620.
Carretero Hernandez G, Puig L. The use of biosimilar drugs in psoriasis: a position paper. Actas Dermosifiliogr. 2015;106:249-251.
Regulation of Biological Products, 42 USC §262 (2013).
Ventola CL. Evaluation of biosimilars for formulary inclusion: factors for consideration by P&T committees. P T. 2015;40:680-689.
Park W, Yoo DH, Jaworski J, et al. Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther. 2016;18:25.
Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther. 2015;18:82.
Strober B, Foley P, Philipp S, et al. Evaluation of efficacy and safety of ABP 501 in a phase 3 study in subjects with moderate to severe plaque psoriasis: 52-week results. J Am Acad Dermatol. 2016;74(5, suppl 1):AB249.
Momenta Pharmaceuticals announces positive top-line phase 3 results for M923, a proposed Humira (adalimumab) biosimilar [news release]. Cambridge, MA: Momenta Pharmaceuticals, Inc; November 29, 2016. http://ir.momentapharma.com/releasedetail.cfm?ReleaseID=1001255. Accessed January 25, 2017.
Griffiths CE, Thaci D, Gerdes S, et al. The EGALITY study: a confirmatory, randomised, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, versus the originator product in patients with moderate to severe chronic plaque-type psoriasis [published online October 27, 2016]. Br J Dermatol. doi:10.1111/bjd.15152.
Vanderpuye-Orgle J, Zhao Y, Lu J, et al. Evaluating the economic burden of psoriasis in the United States [published online April 14, 2015]. J Am Acad Dermatol. 2015;72:961-967.
Brezinski EA, Dhillon JS, Armstrong AW. Economic burden of psoriasis in the United States: a systematic review. JAMA Dermatol. 2015;151:651-658.
Menter MA, Griffiths CE. Psoriasis: the future. Dermatol Clin. 2015;33:161-166.
Hackbarth GM, Crosson FJ, Miller ME. Report to the Congress: improving incentives in the Medicare program. Medicare Payment Advisory Commission, Washington, DC; 2009.
Lovenworth SJ. The new biosimilar era: the basics, the landscape, and the future. Bloomberg website. http://about.bloomberglaw.com/practitioner-contributions/the-new-biosimilar-era-the-basics-the-landscape-and-the-future. Published September 21, 2012. Accessed July 6, 2016.
Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6:469-478.
Calvo B, Zuniga L. The US approach to biosimilars: the long-awaited FDA approval pathway. BioDrugs. 2012;26:357-361.
Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health-system pharmacists. Am J Health Syst Pharm. 2013;70:2004-2017.
Barriers to access attributed to formulary changes. Manag Care. 2012;21:41.

According to the US Food and Drug Administration (FDA), a biosimilar is “highly similar to an FDA-approved biological product, . . . and has no clinically meaningful differences in terms of safety and effectiveness.”¹ The Biologics Price Competition and Innovation (BPCI) Act of 2009 created an expedited pathway for the approval of products shown to be biosimilar to FDA-licensed reference products.² In 2013, the European Medicines Agency approved the first biosimilar modeled on infliximab (Remsima [formerly known as CT-P13], Celltrion Healthcare Co, Ltd) for the same indications as its reference product.³ In 2016, the FDA approved Inflectra (Hospira, a Pfizer Company), an infliximab biosimilar; Erelzi (Sandoz, a Novartis Division), an etanercept biosimilar; and Amjevita (Amgen Inc), an adalimumab biosimilar, all for numerous clinical indications including plaque psoriasis and psoriatic arthritis.^4-6

There has been a substantial amount of distrust surrounding the biosimilars; however, as the patents for the biologic agents expire, new biosimilars will undoubtedly flood the market. In this article, we provide information that will help dermatologists understand the need for and use of these agents.

Biosimilars Versus Generic Drugs

Small-molecule generics can be made in a process that is relatively inexpensive, reproducible, and able to yield identical products with each lot.⁷ In contrast, biosimilars are large complex proteins made in living cells. They differ from their reference product because of changes that occur during manufacturing (eg, purification system, posttranslational modifications).^7-9 Glycosylation is particularly sensitive to manufacturing and can affect the immunogenicity of the product.⁹ The impact of manufacturing can be substantial; for example, during phase 3 trials for efalizumab, a change in the manufacturing facility affected pharmacokinetic properties to such a degree that the FDA required a repeat of the trials.¹⁰

FDA Guidelines on Biosimilarity

The FDA outlines the following approach to demonstrate biosimilarity.² The first step is structural characterization to evaluate the primary, secondary, tertiary, and quaternary structures and posttranslational modifications. The next step utilizes in vivo and/or in vitro functional assays to compare the biosimilar and reference product. The third step is a focus on toxicity and immunogenicity. The fourth step involves clinical studies to study pharmacokinetic and pharmacodynamic data, immunogenicity, safety, and efficacy. After the biosimilar has been approved, there must be a system in place to monitor postmarketing safety. If a biosimilar is tested in one patient population (eg, patients with plaque psoriasis), a request can be made to approve the drug for all the conditions that the reference product was approved for, such as plaque psoriasis, rheumatoid arthritis, and inflammatory bowel disease, even though clinical trials were not performed in all of these patient populations.² The BPCI Act leaves it up to the FDA to determine how much and what type of data (eg, in vitro, in vivo, clinical) are required.¹¹

Extrapolation and Interchangeability

Once a biosimilar has been approved, 2 questions must be answered: First, can its use be extrapolated to all indications for the reference product? The infliximab biosimilar approved by the European Medicines Agency and the FDA had only been studied in patients with ankylosing spondylitis¹² and rheumatoid arthritis,¹³ yet it was granted all the indications for infliximab, including severe plaque psoriasis.¹⁴ As of now, the various regulatory agencies differ on their policies regarding extrapolation. Extrapolation is not automatically bestowed on a biosimilar in the United States but can be requested by the manufacturer.²

Second, can the biosimilar be seamlessly switched with its reference product at the pharmacy level? The BPCI Act allows for the substitution of biosimilars that are deemed interchangeable without notifying the provider, yet individual states ultimately can pass laws regarding this issue.^15,16 An interchangeable agent would “produce the same clinical result as the reference product,” and “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product.”¹⁵ Generic drugs are allowed to be substituted without notifying the patient or prescriber¹⁶; however, biosimilars that are not deemed interchangeable would require permission from the prescriber before substitution.¹¹

References

Information on biosimilars. US Food and Drug Administration website. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/. Updated May 10, 2016. Accessed July 5, 2016.
US Department of Health and Human Services. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry. Silver Spring, MD: US Food and Drug Administration; 2015.
McKeage K. A review of CT-P13: an infliximab biosimilar. BioDrugs. 2014;28:313-321.
FDA approves Inflectra, a biosimilar to Remicade [news release]. Silver Spring, MD: US Food and Drug Administration; April 5, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm. Updated April 20, 2016. Accessed January 23, 2017.
FDA approves Erelzi, a biosimilar to Enbrel [news release]. Silver Spring, MD: US Food and Drug Administration; August 30, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm. Accessed January 23, 2017.
FDA approves Amjevita, a biosimilar to Humira [news release]. Silver Spring, MD: US Food and Drug Administration; September 23, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm. Accessed January 23, 2017.
Scott BJ, Klein AV, Wang J. Biosimilar monoclonal antibodies: a Canadian regulatory perspective on the assessment of clinically relevant differences and indication extrapolation [published online June 26, 2014]. J Clin Pharmacol. 2015;55(suppl 3):S123-S132.
Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars [published online September 14, 2007]. Ann Oncol. 2008;19:411-419.
Puig L. Biosimilars and reference biologics: decisions on biosimilar interchangeability require the involvement of dermatologists [published online October 2, 2013]. Actas Dermosifiliogr. 2014;105:435-437.
Strober BE, Armour K, Romiti R, et al. Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know. J Am Acad Dermatol. 2012;66:317-322.
Falit BP, Singh SC, Brennan TA. Biosimilar competition in the United States: statutory incentives, payers, and pharmacy benefit managers. Health Aff (Millwood). 2015;34:294-301.
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;72:1605-1612.
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;72:1613-1620.
Carretero Hernandez G, Puig L. The use of biosimilar drugs in psoriasis: a position paper. Actas Dermosifiliogr. 2015;106:249-251.
Regulation of Biological Products, 42 USC §262 (2013).
Ventola CL. Evaluation of biosimilars for formulary inclusion: factors for consideration by P&T committees. P T. 2015;40:680-689.
Park W, Yoo DH, Jaworski J, et al. Comparable long-term efficacy, as assessed by patient-reported outcomes, safety and pharmacokinetics, of CT-P13 and reference infliximab in patients with ankylosing spondylitis: 54-week results from the randomized, parallel-group PLANETAS study. Arthritis Res Ther. 2016;18:25.
Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther. 2015;18:82.
Strober B, Foley P, Philipp S, et al. Evaluation of efficacy and safety of ABP 501 in a phase 3 study in subjects with moderate to severe plaque psoriasis: 52-week results. J Am Acad Dermatol. 2016;74(5, suppl 1):AB249.
Momenta Pharmaceuticals announces positive top-line phase 3 results for M923, a proposed Humira (adalimumab) biosimilar [news release]. Cambridge, MA: Momenta Pharmaceuticals, Inc; November 29, 2016. http://ir.momentapharma.com/releasedetail.cfm?ReleaseID=1001255. Accessed January 25, 2017.
Griffiths CE, Thaci D, Gerdes S, et al. The EGALITY study: a confirmatory, randomised, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, versus the originator product in patients with moderate to severe chronic plaque-type psoriasis [published online October 27, 2016]. Br J Dermatol. doi:10.1111/bjd.15152.
Vanderpuye-Orgle J, Zhao Y, Lu J, et al. Evaluating the economic burden of psoriasis in the United States [published online April 14, 2015]. J Am Acad Dermatol. 2015;72:961-967.
Brezinski EA, Dhillon JS, Armstrong AW. Economic burden of psoriasis in the United States: a systematic review. JAMA Dermatol. 2015;151:651-658.
Menter MA, Griffiths CE. Psoriasis: the future. Dermatol Clin. 2015;33:161-166.
Hackbarth GM, Crosson FJ, Miller ME. Report to the Congress: improving incentives in the Medicare program. Medicare Payment Advisory Commission, Washington, DC; 2009.
Lovenworth SJ. The new biosimilar era: the basics, the landscape, and the future. Bloomberg website. http://about.bloomberglaw.com/practitioner-contributions/the-new-biosimilar-era-the-basics-the-landscape-and-the-future. Published September 21, 2012. Accessed July 6, 2016.
Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6:469-478.
Calvo B, Zuniga L. The US approach to biosimilars: the long-awaited FDA approval pathway. BioDrugs. 2012;26:357-361.
Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health-system pharmacists. Am J Health Syst Pharm. 2013;70:2004-2017.
Barriers to access attributed to formulary changes. Manag Care. 2012;21:41.

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Biosimilars in Psoriasis: The Future or Not?

References

Biosimilars Versus Generic Drugs

FDA Guidelines on Biosimilarity

Extrapolation and Interchangeability

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