Skip to main content
. 2017 Dec;23(12):10.18553/jmcp.2017.23.12.1234. doi: 10.18553/jmcp.2017.23.12.1234

TABLE 3.

Efficacy, Safety/Immunogenicity, PK/PD, and Analytical/Functional Evidence for Biosimilars37-40

Biosimilar Efficacy Safety/Immunogenicity PK/PD Analytical/Functional
Zarxio [filgrastim-sndz] 1 efficacy trial:
R, DB, AC (n = 204) in breast cancer patients undergoing 6 cycles of TAC comparing 5 mcg/kg, SC, multiple dose filgrastim-sndz to U.S.-filgrastim. Primary endpoint and result: difference in DSN in cycle 1 (90% CI) = 0.04 days (-0.21, 0.28).		 Same key efficacy clinical trial (n = 214 for safety and immunogenicity).
Safety endpoints and results: descriptive statistics were similar in major safety events (TEAEs, related TEAEs, SAEs, related SAEs, fatal TEAEs, related fatal TEAEs); common AEs (musculoskeletal pain, injection site reaction); and hypersensitivity (anaphylactic reaction, hypersensitivity).
Immunogenicity endpoint and result: No patients developed ADA.
Other clinical studies also demonstrated similar safety and immunogenicity results.		 5 clinical studies:

  1. Substudy from key efficacy clinical trial (n = 54).

  2. R, DB, 2WC trial (n = 28) in HS comparing 10 mcg/kg SC single dose filgrastim-sndz to U.S.-filgrastim.

  3. R, DB, 2WC trial (n = 28/dose) in HS with 2 dose groups, comparing 2.5 and 5 mcg/kg SC single and multiple (7-day) dose filgrastim-sndz to EU-filgrastim.

  4. R, DB, 2WC trial (n = 24) in HS, comparing 1 mcg/kg SC single dose filgrastim-sndz to EU-filgrastim.

  5. R, DB, 2WC trial (n = 32) in HS, comparing 10 mcg/kg SC single and multiple dose filgrastim-sndz to EU-filgrastim.


PK endpoints and results: similar AUC and Cmax.
PD endpoints and results: similar ANC and CD34+.		 The following quality attributes were deemed highly similar between filgrastim-sndz, U.S.-filgrastim, and EU-filgrastim:
primary structure, bioactivity, protein content, receptor binding, clarity, subvisible particles, secondary and tertiary structure, high molecular weight variants/aggregates, oxidized species, covalent dimers, partially reduced species, formyl methionine 1 species, sequence variants: histidine → glutamine, aspartate → glutamate, threonine → aspartate, succinimide species, phosphoglucunoylation, acetylated species, N-terminal truncated variants, norleucine species, deamidated species, and stability profiles.
Inflectra [infliximab-dyyb] 2 efficacy trials:

  1. R, DB, PG 54-week clinical study (n=606) of patients with active RA despite MTX use to receive infliximab-dyyb and EU-infliximab. Primary endpoint and result: estimated difference in ACR20 response at week 30 (90% CI) = 2% (-5%, +9%)

  2. R, DB, PG 54-week clinical study (n=250) of patients with active AS. Primary endpoint was PK. Secondary endpoint and result: estimated difference in ASAS20 response at week 30 (95% CI) =-4% (-16%, +8%)

 803 subjects (patients and HS) exposed to at least 1 dose of infliximab-dyyb. Descriptive statistics were similar in TEAEs, SAEs, and AEs leading to discontinuation. The most common TEAEs were infections.
Immunogenicity endpoints and results:
4 deaths: 2 on infliximab-dyyb and 2 on EU-infliximab
7 cases of anaphylaxis on infliximab-dyyb vs. 7 on EU-infliximab; did not increase following transition from EU-infliximab to infliximab-dyyb
Incidence of ADA similar between infliximab-dyyb and EU-infliximab. ADA incidence remained unchanged following transition from EU-infliximab to infliximab-dyyb		 3 clinical studies:

  1. 3-way PK bridging/similarity study in HS: R, DB, 3-arm, PG single dose study (N=71/arm).

  2. PK study in AS patients: R, DB, 2-arm, PG, multiple dose study (N=125/arm).

  3. Comparative clinical study in RA patients: R, DB, PG study (N=606).


PK endpoints and results: similar AUC and Cmax.		 The following quality attributes were deemed highly similar between infliximab-dyyb, U.S.-infliximab, and EU-infliximab: primary structure, bioactivity, (TNF-α binding and neutralization), purity, Fc receptor binding, protein content, subvisible particles, higher order structure (second structure), biologic analysis and MOA exploration, high molecular weight variants/aggregates, and physicochemical analysis.
Highly critical quality attributes include amino acid identity and in vitro TNF-α neutralization and binding.
Erelzi [etanercerpt-szzs] 2 efficacy trials:
R 52-week clinical trial (n = 531) in PsO patients comparing etanercept-szzs vs. EU-etanercept (50mg SC twice per week followed by 50 mg SC once per week)
2 treatment periods:
TP 1: week 0 to 12. Primary endpoint and results: estimated difference in PASI75 at week 12 (90% CI) = -2.3 (-8.63, 4.08)
TP 2: week 12 to 30, comparing efficacy of continued treatment arm vs. repeated switches between etanercerpt and etanercerpt-szzs. Comparable PASI response between continued etanercerpt and etanercerpt-szzs and no impact of switching on PASI response in patient pools that underwent multiple switches		 747 subjects (patients and HS) exposed to at least 1 dose of etanercept-szzs.
Descriptive statistics were similar in TEAEs, SAEs, and AE leading to discharge. Most common AEs were infection. There was 1 death in the EU-etanercept treatment group (cardiopulmonary death).
Immunogenicity endpoints and results:
No immunogenicity concerns for etanercept-szzs vs. etanercept. No cases of anaphylaxis. 5% of EU-etanercept treatment group were ADA positive but only transiently.		 4 clinical studies of up to 3 months each in healthy volunteers:

  1. Compare etanercept-szzs vs. U.S.-etanercept in 57 HS

  2. Compare etanercept-szzs vs. EU-etanercept in 54 HS

  3. Compare etanercept-szzs vs. EU-etanercept in 54 HS

  4. Compare etanercept-szzs administration autoinjection vs. prefilled syringes in 51 HS


Comparative clinical study in PsO subjects (n = 531) also demonstrated similar PK profile between etanercept-szzs and EU-etanercept.
PK endpoints: similar Cmax and AUC		 The following critical quality attributes were deemed highly similar between etanercept-szzs, U.S.-etanercept and EU-etanercept: primary structure; higher order structure (there are some incorrect disulfide bond variants present that are detectable in vitro; however, these will refold correctly under physiological condition); TNF-α neutralization; content; FcRn binding; product related impurities; and stability.
Amjevita [adalimumab-atto] 2 efficacy trials:

  1. R, DB, PG 26-week clinical trial (n = 526) in RA patients comparing 40 mg SC Q2W+MTX adalimumab-atto to U.S.-adalimumab. Primary endpoint and result: estimated difference in ACR20 at week 24 (90% CI) = -0.4% (-6.8%, 6.1%)

  2. R, DB, PG (weeks 1-16 of 48-week trial) clinical trial (n = 350) in PsO patients comparing 80 mg SC day 1 then 40 mg SC Q2W from week 2 adalimumab-atto to EU-adalimumab. Primary endpoint and result: difference in % improvement in PASI (90% CI) = -2.2% (-6.6%, 2.2%)

 1,076 subjects (patients and HS) exposed to at least 1 dose of adalimumab-atto. Descriptive statistics were similar in AEs, SAEs, withdrawal due to AEs, infections, malignancies, liver enzyme elevations, injection site reactions, anaphylaxis, and death. No increase in AEs after single transition from EU-adalimumab to adalimumab-atto.
Immunogenicity endpoints and results: descriptive statistics were similar in ADA and neutralizing antibodies.		 3 clinical studies:
1. Same as efficacy study in RA patients
2a. Same as efficacy study in PsO patients
2b. Continuation (week 16 to 48) of efficacy study in PsO patients. Patients on EU-adalimumab were re-randomized to adalimumab-atto so 3 treatment arms of 40 mg SC Q2W were compared: (a) adalimumab-atto → adalimumab-atto; (b) EU-adalimumab → adalimumab-atto; and (c) EU-adalimumab → EU-adalimumab
3. R, PG, single-dose, 3-way PK bridging study (n=203) in HS, comparing 40 mg SC in adalimumab-atto, U.S.-adalimumab, and EU-adalimumab
PK endpoints and results: similar Cmax and AUC		 The following quality attributes were deemed highly similar between adalimumab-atto, U.S.-adalimumab, and EU-adalimumab: primary structure, bioactivity, purity, Fc receptor binding, protein content, higher order structure, biologic analysis and MOA exploration, high molecular weight variants/aggregates, physicochemical analysis, and general properties.
High criticality quality attributes include primary sequence, apoptosis inhibition, and TNF-α binding.

2WC = 2-way crossover; AC = active-control; ACR20 = American College of Rheumatology scale that measures 20% improvement in RA; ADA = antidrug antibodies; AE = adverse event; ANC = absolute neutrophil count; AS = ankylosing spondylitis; ASAS 20 = Assessment in Ankylosing Spondylitis Response criteria, scale that measures 20% improvement in AS; AUC = area under curve; CD34+ = hematopoietic progenitor cell antigen; CI = confidence interval; Cmax = maximum concentration; DB = double-blinded; DSN = duration of severe neutropenia; EU = European Union; HS = healthy subjects; MOA = mechanism of action; MTX = methotrexate; PASI = Psoriasis Area Severity Index; PD = pharmacodynamics; PG = parallel group; PK = pharmacokinetics; PsO = plaque psoriasis; Q2W = every 2 weeks; R = randomized; RA = rheumatoid arthritis; SAE = serious adverse event; SC = subcutaneous; TAC = docetaxel, doxorubicin, and cyclophosphamide; TEAE = treatment-emergency adverse event; TNF-α = tumor necrosis factor-α; TP = treatment period.