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13-12-2017 | Biosimilars | Feature | Article

Biosimilars: The story so far

medwireNews Hot Topic Reviews provide up-to-date overviews of fast-moving areas of research in order to help healthcare providers keep abreast of the latest developments that may influence patient care. 

The past few years have seen the approval of the first biosimilar agents for the treatment of rheumatic diseases, with biosimilars of biologic DMARDs including infliximab, adalimumab, etanercept, and rituximab now approved for use in countries including the USA, Europe, and Japan [1].

In this hot topic review, medwireNews provides an overview of the evidence supporting the equivalence of biosimilars and their reference products, takes a look at the current consensus recommendations, and answers some questions about the use of biosimilars in rheumatology.

What is a biosimilar?

A biosimilar medicine is a biologic agent that is highly similar to another biologic medicine already licensed for use.

Biologic medicines, including biosimilars, are derived from living organisms through a complex manufacturing process. Therefore, there is slight variation between batches, and between biosimilars and their reference products. These inconsistencies are tightly controlled, however, and biosimilars do not have clinically meaningful differences in quality, efficacy, and safety from their originator products [2].

How do biosimilars differ from generic medicines?

Unlike biosimilars, which are not an exact replication of their reference products, generic medicines and their originators have identical molecular structures [3]. As such, there is a shortened and simplified process for the approval of generic medicines, whereas the regulatory processes are much stricter for biosimilars [2]. Table 1 outlines the main differences between biosimilar and generic medicines.


Biosimilar medicine
Generic medicine
Typical production method
Obtained from a biologic source and produced using complex manufacturing processes
Chemical synthesis
Degree of similarity
Highly similar, but with some minor differences that are not clinically meaningful
An exact replica of the originator product
Preclinical studies required

Data on pharmaceutical quality, plus:

  • EMA: Target binding, signal transduction, and cell viability studies. Animal studies may be required
  • FDA: Structural analyses and functional assays. Animal toxicity, pharmacokinetic, and pharmacodynamic studies needed
Data on pharmaceutical quality
Clinical studies required

Comprehensive head-to-head comparisons of biosimilar with originator product to show high degree of similarity in structure, function, efficacy, safety and immunogenicity

Demonstration of bioequivalence (generic and reference product release active substance at the same rate and concentration under the same conditions)
Extrapolation

Efficacy and safety must be justified for each indication. Extrapolation to different indications possible if available scientific evidence addresses all aspects of the indications

All indications already approved for the originator medicine can be extrapolated based on bioequivalence without the need for further clinical studies

Table 1. Comparison of biosimilar and generic medicines. Information from [2,3,4]. EMA, European Medicines Agency; FDA, US Food & Drug Administration

Why are biosimilars needed in rheumatology?

Treatment with biologics has “dramatically improved” outcomes for patients with inflammatory diseases, but the high cost of these therapies means that many patients do not have access to them, say the authors of consensus-based recommendations for the use of biosimilars, led by Jonathan Kay from the University of Massachusetts Medical School in Worcester, USA [1].

“To make effective biologics more widely available, biosimilars of products that no longer are protected by patent have been developed and have been made available to patients at costs lower than those of the bio-originator,” they explain.

In a review article [5], Thomas Dörner (Charité Universitätsmedizin Berlin, Germany) and colleagues note that biosimilars offer the potential to reduce acquisition costs for biologic DMARDs, thus “removing current inequity in their use between countries with high and low [gross domestic products].”

In addition to the cost benefits, competition between different biologic treatments – including biosimilars – also creates more choice for patients and physicians, as well as increasing the sources of supply [2].

“Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases,” summarize Dörner et al [5].

Which biosimilar drugs are currently approved for use?

As shown in figure 1, the first biosimilar drug to be approved for the treatment of a rheumatologic condition was the infliximab biosimilar CT-P13. In September 2013, the European Commission granted a marketing authorization for the use of CT-P13 to treat rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis, in addition to other immune-mediated diseases including ulcerative colitis and Crohn’s disease [6]. CT-P13 was subsequently approved by the US FDA in April 2016 [7].

The first etanercept biosimilar, SB4, was approved in Europe for the treatment of RA, spondyloarthritis, juvenile arthritis, and PsA in January 2016 [8], and European approvals for adalimumab and rituximab biosimilars have been issued in 2017. Table 2 provides an overview of the biosimilar drugs that have been approved to date for the treatment of rheumatic diseases in the USA and Europe.

At the time their review was published, Dörner and colleagues noted that in addition to the approved agents, “[m]ore than 40 biosimilar candidates are in development for use in rheumatic diseases.”

Reference product
Biosimilar
US approval
European approval
Infliximab
CT-P13 (infliximab-dyyb/Remsima®/Inflectra®)
April 2016 [7]

September 2013 [6]


SB2 (infliximab-abda/Flixabi®/RenflexisTM)
April 2017 [9]

May 2016 [10]


PF-06438179 (infliximab-qbtx/GP1111/ IxifiTM)
December 2017 [11]

Etanercept
SB4 (Benepali®)

January 2016 [8]

GP2015 (etanercept-szzs/Erelzi®)
August 2016 [12]
June 2017 [13]
Adalimumab
ABP 501
(Adalimumab-atto/AmjevitaTM/AmgevitaTM/Solymbic*)

September 2016 [14]

March 2017 [15,16]

BI 695501 (adalimumab-adbm/CytelzoTM)
August 2017 [17]
November 2017 [18]

SB5 (Imraldi®)

August 2017 [19]
Rituximab
CT-P10 (TruximaTM)

February 2017 [20]

GP2013 (Rixathon®)

June 2017 [21]

Table 2. Biosimilar drugs approved for the treatment of rheumatic diseases by the US FDA and the EMA.
*Two brand names of ABP 501, Amgevita and Solymbic, were approved for use in Europe in March 2017.

What are the data supporting similar efficacy and safety profiles of biosimilars and their reference products?

As per regulatory criteria, all biosimilar agents that have been approved for use in rheumatology in the USA and the European Union have demonstrated equivalent efficacy, safety, and immunogenicity profiles to their reference products in randomized trials, the majority of which have been carried out in patients with rheumatic diseases and published in peer-reviewed journals. Table 3 outlines the main data supporting the similarity of these agents from randomized trials that have been conducted in patients with rheumatic diseases.

Biosimilar

Trial design and population

Key results

Main conclusions

Infliximab CT-P13

Phase IV NORSWITCH trial [22]

Related news story: Support for switching from infliximab to biosimilar CT-P13

 

  • 482 patients with SpA, RA, PsA, Crohn’s disease, ulcerative colitis, and chronic plaque psoriasis
  • Infliximab-treated patients randomly assigned to continue with originator or switch to CT-P13
  • Disease worsening occurred in a comparable 26% of patients receiving originator infliximab and 30% of those who switched to CT-P13 over 1 year of follow-up
  • TEAEs occurred in 70% of infliximab- versus 68% of CT-P13-treated patients; serious TEAEs occurred in 10% versus 9% of patients

 

  • Switching to CT-P13 noninferior to continuing treatment with infliximab originator

Phase III PLANETRA study and extension [23,24]

  • 455 patients with active RA randomly assigned to receive 52 weeks of treatment with infliximab originator or CT-P13
  • Comparable ACR20 response rates between infliximab and CT-P13 groups (71.3 vs 74.7%)
  • Comparable radiographic progression scores in the two groups
  • Similar proportion of patients in reference and CT-P13 groups had antidrug antibodies (36.0 vs 41.1%); safety profiles were comparable
  • PLANETRA extension study demonstrated sustained equivalence of the two agents for up to 2 years
  • CT-P13 and reference infliximab are comparable in terms of efficacy, safety, and immunogenicity profiles

Infliximab SB2

Phase III trial and extension study [25,26]

Related news story: Sustained equivalence of SB2 and infliximab in patients with RA

 

  • 584 patients with moderate-to-severe RA despite methotrexate treatment randomly assigned to receive infliximab or SB2
  • ACR20 response at week 30 was 66.0% for infliximab-treated patients versus 64.1% for those given SB2; adjusted rate difference of –1.88% within prespecified noninferiority margin
  • Comparable incidence of TEAEs and antidrug antibodies in infliximab and SB2 groups at week 30 (58.0 vs 57.6% and 49.7 vs 55.1%, respectively)
  • Extension results demonstrated sustained efficacy and tolerability up to 1 year
  • SB2 has comparable efficacy, safety, and immunogenicity as infliximab reference product and is well tolerated

Infliximab PF-06438179

Phase III randomized trial (unpublished): results presented at the 2017 ACR/ARHP Annual Meeting in San Diego, California, USA [27]

 

  • 650 patients with moderate-to-severe RA and an inadequate response to methotrexate and up to 2 doses of non-infliximab biologic randomly assigned to receive infliximab or PF‑06438179
  • Week 14 ACR20 response rates were a comparable 64.1% in the infliximab group and 62.7% in the PF‑06438179 group
  • Similar changes in DAS28-CRP scores and ACR50/70 response rates between groups
  • Comparable rates of TEAEs (54.0 vs 57.3%) and antidrug antibodies (51.2 vs 48.6%) between the originator and biosimilar groups
  • Infliximab and PF‑06438179 have comparable efficacy, safety, and immunogenicity in the patient population studied

Etanercept SB4

 

Phase III trial and extension studies [28,29,30]

Related news story: Further evidence for equivalence of SB4 and etanercept

 

  • 596 patients with moderate-to-severe RA despite methotrexate treatment randomly assigned to receive etanercept or SB4 for up to 52 weeks
  • After week 52 patients were given open-label SB4 for an additional 48 weeks
  • Week 24 ACR20 response rate was 80.3% for the etanercept group and 78.1% for the SB4 group
  • Incidence of TEAEs was comparable in the etanercept and SB4 groups at week 24 (58.2 vs 55.2%); a higher proportion of patients receiving the reference product had antidrug antibodies (13.1 vs 0.7%)
  • Follow-up results at weeks 52 and 100 indicated comparable efficacy, safety, and immunogenicity of the two drugs
  • SB4 is effective and well tolerated for up to 2 years
  • Comparable efficacy, safety, and immunogenicity between SB4 and etanercept; “no risk” associated with switching

Adalimumab ABP 501

 

Phase III trial in RA patients [31]

Related news story: Equivalence of adalimumab biosimilar demonstrated in RA

 

  • 494 patients with moderate-to-severe RA despite methotrexate treatment randomly assigned to receive adalimumab reference product or ABP 501
  • A comparable proportion of patients in the adalimumab originator and ABP 501 groups experienced an ACR20 response at week 24 (72.4 vs 74.6%)
  • No “clinically meaningful differences” in AEs and laboratory abnormalities between the two groups
  • ABP 501 is similar to adalimumab in clinical efficacy, safety, and immunogenicity

Adalimumab
BI 695501

Phase III randomized trial (unpublished): results presented at the 2017 ACR/ARHP Annual Meeting in San Diego, California, USA [32]

 

  • 645 adalimumab-naïve, methotrexate-treated patients with moderate-to-severe RA treated with methotrexate randomly assigned to receive adalimumab or BI 695501 until week 24 
  • Adalimumab-treated patients were randomly assigned to continue the same treatment or switch to BI 695501 at week 24
  • Patients in all groups had comparable changes from baseline in DAS28-ESR scores at week 48
  • Infections and infestations were the most common AE. Similar safety and immunogenicity profiles in all groups
  • Adalimumab and BI 695501 have similar efficacy, safety, and immunogenicity in RA patients

Adalimumab SB5

Phase III randomized trial [33]

Related news story: Equivalence of SB5 and adalimumab established in patients with RA

 

  • 542 methotrexate-treated patients with moderate-to-severe RA randomly assigned to receive adalimumab or SB5
  • Equivalent ACR20 response rates among adalimumab- and SB5-treated patients at week 24 (72.2 vs 72.4%)
  • Comparable ACR50 and ACR70 response rates and DAS28-ESR scores between the two groups
  • Similar incidence of antidrug antibodies and AEs among patients receiving adalimumab and SB5
  • Adalimumab and SB5 were well tolerated, and had comparable efficacy and safety profiles in RA patients

Rituximab CT-P10

Phase I randomized trial [34]*

 

  • 154 patients randomly assigned to receive rituximab or CT-P10
  • 137 received one course of treatment from week 1 to 2, and 83 patients completed a second treatment course between week 24 and 48
  • Improvements in DAS28-ESR and DAS28-CRP were “highly similar” over both treatment courses
  • A comparable proportion of patients receiving rituximab versus CT-P10 had antidrug antibodies at week 24 (21.7 vs 20.0%)
  • Both drugs had a similar safety profile
  • Rituximab and CT-P10 have comparable efficacy and safety profiles through two courses of treatment

Rituximab GP2013

Phase III randomized trial [35]

Related news story: Similarity of GP2013 and rituximab demonstrated in patients with RA

 

  • 312 patients with active RA despite prior TNFi therapy randomly assigned to receive either the US or European rituximab reference product or GP2013 alongside methotrexate
  • DAS28-CRP scores decreased from baseline to week 24 by a comparable 2.11 points in the rituximab group and 2.07 points in the GP2013 group
  • Similar incidence of TEAEs, SAEs, and antidrug antibodies in the two groups
  • The two drugs were “similar in terms of efficacy, safety and immunogenicity”

Table 3. Randomized trial data supporting the equivalence of biosimilar agents approved for use in rheumatology compared with their reference products. ACR20/50/70, proportion of patients achieving at least a 20%, 50%, or 70% improvement in ACR criteria; AEs, adverse events; DAS28-CRP, Disease Activity Score at 28 joints based on C-reactive protein; DAS28-ESR, Disease Activity Score at 28 joints based on erythrocyte sedimentation rate; TEAEs, treatment-emergent adverse events; PsA, psoriatic arthritis; PASI, Psoriasis Area and Severity Index; PASI50/75/90/100 response, more than a 50%/75%/90%/100% improvement in PASI score; RA, rheumatoid arthritis; SAE, serious adverse event; SpA, spondyloarthritis; TNFi, tumor necrosis factor inhibitor. *Phase III trial was conducted in follicular lymphoma patients [36]

How do clinical trials and label information for biosimilars differ from those for originator drugs?

Discussing the clinical data in a review article, Joseph Markenson (Hospital for Special Surgery, New York, USA) and colleagues note that the “clinical benefit of a biosimilar is expected, by definition, to be the same as that of the originator,” meaning that trials evaluating the efficacy of a biosimilar versus placebo are not carried out [4].

“Instead, clinical trials are specifically designed as a final comparative evaluation step(s) and to confirm whether the product can be considered a biosimilar, as well as to address remaining residual uncertainty,” they explain.

“Health care providers should expect to see different types of (and likely less) clinical data than what they usually see for originator products,” summarize Markenson et al.

Because approved biosimilars have demonstrated comparable efficacy and safety profiles to their reference products, drug labels for biosimilar agents are currently the same as those for the originators. EMA guidance specifies that biosimilarity “only refers to the medicine’s development route and is not related to the use of the medicine,” and Dörner and colleagues note that the only way for healthcare providers to obtain specific information about biosimilars is via regulatory agency documentation or publications [3,5].

Is there agreement about whether biosimilars should be recommended to patients?

Whether or not biosimilar agents should be prescribed for patients with rheumatic diseases is currently a topic of much controversy. At the “Great Debate” session of the 2017 ACR/ARHP Annual Meeting in San Diego, California, USA, Jonathan Kay discussed the subject with Roy Fleischmann (University of Texas Southwestern Medical Center, Dallas, USA).

As outlined previously by medwireNews, Kay argued that the current data support “that it is safe and effective and cost-effective to switch to a biosimilar” in most settings, whereas Fleischmann highlighted that there are insufficient data to support equivalent efficacy profiles, and that it is not currently cost-effective for patients to switch to biosimilars in the USA.

In their consensus recommendations, Kay and colleagues propose that the decision to use a biosimilar should be based on shared decision-making between patients and rheumatologists, and that financial differences in healthcare systems across different settings must be considered when choosing an appropriate therapy [1]. They highlight the importance of education to avoid the “misconception” that biosimilars are of lesser quality than their originator products given that they are usually marketed at a lower price.

The recommendations specify that biosimilars “can be used to treat appropriate patients in the same way as their bio-originators,” and endorse a single switch to a biosimilar product, provided that the patient and healthcare provider are both aware of the change.

The European Commission has also issued information on biosimilars in a Q&A format for patients [37].

Are there any real-world data on the use of biosimilars?

Studies on the use of biosimilars in everyday clinical practice are emerging. One such investigation used the DANBIO registry to compare disease activity before and after a nationwide nonmedical switch from infliximab to CT-P13 among patients with inflammatory arthritis in Denmark [38].

A national guideline issued in May 2015 specified that “all patients treated with [infliximab] should switch to CT-P13 for economic reasons,” explain Bente Glintborg (Rigshospitalet, Glostrup, Denmark) and study co-authors.

They found that disease activity was “largely unchanged” in the majority of patients at 3 months before versus 3 months after the switch; the median Disease Activity Score at 28 joints based on C-reactive protein (DAS28-CRP) score was 2.5 points before the switch and 2.4 points after the switch for patients with PsA, and 2.2 points at both timepoints for patients with RA. The study authors concluded that the switch “had no negative impact on disease activity.”

However, during the debate at the 2017 ACR/ARHP meeting, Fleischmann noted that an appreciable proportion of CT-P13-treated patients discontinued treatment, with 16.6% of the 802 patients who switched to CT-P13 stopping treatment over 413 days of follow-up, indicating that “for many patients, you can do the switch, but not for every individual patient.”

Another real-world study explored reasons for discontinuation of CT-P13 following a switch from infliximab originator among 192 Dutch patients with RA, PsA, or ankylosing spondylitis, almost a quarter of whom discontinued treatment with the biosimilar over 6 months of follow-up [39].

The researchers, led by Lieke Tweehuysen (Sint Maartenskliniek, Nijmegen, the Netherlands), found that the main reasons for stopping treatment were subjective measures of disease activity, leading them to conclude that the “substantial discontinuation rate” may be explained by the “nocebo effect,” or misattribution of bodily symptoms to a drug.

“[C]ommunication seems to be the determining factor of the success of transitioning to a biosimilar in daily practice,” say Tweehuysen and team.

The results of more real-world studies on the use of biosimilar agents in clinical practice are expected to become available in the future. Dörner and colleagues note that “several efforts” are currently underway to collect real-world data on biosimilar use, and recommend that “it will be most important to establish pharmacovigilance databases across countries that are adequate to monitor long-term safety after marketing approval.”

What are the remaining gaps in knowledge?

Some unanswered questions regarding the use of biosimilars in rheumatology remain. Although the consensus guidelines recommend a single switch to a biosimilar product, Kay and colleagues caution that there are currently insufficient data to support multiple switching between biosimilars [1].

The taskforce believes that “there is no scientific rationale to expect that switching among biosimilars of the same biooriginator would result in a different clinical outcome,” but they note that “patient perspectives must be considered,” and call for a randomized trial “that incorporates multiple switches between the two biologics” to support the notion of interchangeability.

Other remaining gaps in knowledge include naming, traceability, and long-term safety of biosimilars, explain Dörner and Kay in a review article [40]. As shown in table 2, each biosimilar is known by at least two different names, with some having multiple brand names. For example, the adalimumab biosimilar ABP 501, also known as adalimumab-atto, has the brand name Amjevita in the USA, and two brand names (Amgevita and Solymbic) have been approved in Europe [14–16].

The US FDA issued guidance on the naming of biosimilars in early 2017 [41], but a number of concerns remain, including problems with ordering, prescribing, and record keeping, as well as inconsistencies between different countries [42,43].

“[A]n internationally standardized system of nomenclature for biosimilars is urgently needed,” say Dörner and Kay [40].

Finally, given that most biosimilars have only been approved in the rheumatologic setting in the past 1–2 years, there are limited data available on their long-term safety profiles.

 “At the time of regulatory approval of any drug, the data from clinical studies are usually too limited to identify all potential safety issues, particularly rare but potentially serious adverse events,” write Markenson and colleagues [4].

“Thus, as typically occurs with a novel biologic, ongoing postmarketing safety monitoring for an approved biosimilar will likely be needed to evaluate long-term safety,” they continue.

The authors of the consensus guidelines recommend that “[s]ystematic postmarketing pharmacovigilance should be carried out using biologics registries and by conducting long-term, observational cohort studies to which data are reported regularly by prescribing healthcare providers and patients who are treated with specific products.”

And they conclude: “Pertinent standardised data must be collected to address any remaining uncertainty regarding the safety of biosimilars.”

By Claire Barnard

medwireNews is an independent medical news service provided by Springer Healthcare. © 2017 Springer Healthcare part of the Springer Nature group


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