Is there a difference in the rates of neutralizing antibody formation with biosimilar rituximab compared to "originator" rituximab (Rituxan) in different patient populations/indications (ex: neurology, oncology, etc.)? Particularly interested in any published data on rates of neutralizing antibody formation in multiple sclerosis.

Comment by InpharmD Researcher

Comparative immunogenicity of reference rituximab (Rituxan®) and its biosimilars in patients suffering from multiple sclerosis has not been assessed. However, originator rituximab and biosimilar products have been studied in other conditions such as rheumatoid arthritis and non-Hodgkin's lymphoma. These studies have consistently found no difference between antibody formation between the reference and biosimilar products. Generally, these studies are limited by small sample sizes and were not statistically powered for immunogenicity outcomes; clinically relevant differences may exist if larger populations were examined. Additionally, these findings may not extend to multiple sclerosis patients.
Background

A 2019 meta-analysis evaluated randomized-controlled studies (RCTs) between rituximab originator and biosimilars for treatment of rheumatoid arthritis and non-Hodgkin's lymphoma. One of the primary outcomes was development of anti-drug antibodies as a safety outcome. From 11 head-to-head RCTs (N= 3,163), the pooled risk ratio (RR) of neutralizing antibody formation at week 24 to 28 was 1.16 (95% confidence interval [CI] 0.38 to 3.57; p= 0.79). The overall binding antibody formation at week 24 to 28 was 0.86 (95% CI 0.68 to 1.08; p= 0.20). No significant differences in adverse events were reported. While the overall results report similar efficacy and safety, studies of patients with multiple sclerosis were not evaluated. [1]

One randomized controlled trial compared biosimilar rituximab (Truxima®) and originator rituximab (MabThera®) in patients with multiple sclerosis; however, immunogenicity was not assessed. [2]

References:

[1] Lee S, Lee H, Kim E. Comparative Efficacy and Safety of Biosimilar Rituximab and Originator Rituximab in Rheumatoid Arthritis and Non-Hodgkin's Lymphoma: A Systematic Review and Meta-analysis. BioDrugs. 2019;33(5):469-483. doi:10.1007/s40259-019-00376-z
[2] Perez T, Rico A, Boutière C, et al. Comparison of rituximab originator (MabThera®) to biosimilar (Truxima®) in patients with multiple sclerosis. Mult Scler. 2021;27(4):585-592. doi:10.1177/1352458520912170

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

Is there a difference in the rates of neutralizing antibody formation with biosimilar rituximab compared to "originator" rituximab (Rituxan) in different patient populations/indications (ex: neurology, oncology, etc.)? Particularly interested in any published data on rates of neutralizing antibody formation in multiple sclerosis.

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-7 for your response.


Comparison of Biosimilar CT-P10 and Innovator Rituximab in Patients with Rheumatoid Arthritis: A Randomized Controlled Phase 3 Trial

Design

Multinational, randomized, double-blind, parallel-group, active-controlled phase 3 trial

Part 1: N= 189

Part 2: N= 372

Objective

To demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA)

Study Groups

Part 1:

CT-P10 (n= 64)

US-RTX (n= 65)

EU-RTX (n= 60)

Part 2:

CT-P10 (n= 161)

RTX (n= 211)

Inclusion Criteria

Aged 18–75 years; active RA diagnosed per revised 1987 ACR classification criteria ≥6 months before randomization

Exclusion Criteria

Had taken more than two biologic agents; previously administered rituximab; allergies or hypersensitivity to murine, chimeric, human, or humanized proteins; current or past history of chronic infection with hepatitis B, hepatitis C, or infection with human immunodeficiency virus (HIV)-1 or -2, or had a positive result to the screening test for these infections; infection requiring oral antibiotics 2 weeks before randomization; past or current diagnosis of tuberculosis (TB); previous treatment within 6 months of IV gamma globulin; any surgical procedure; current or past history of drug or alcohol abuse within 6 months of randomization; currently pregnant or breastfeeding

Methods

Part 1: pharmacokinetic (PK) evaluation

Patients were randomly assigned (1:1:1) to CT-P10, US-RTX, or EU-RTX for the PK evaluation.

Part 2: efficacy, pharmacodynamic (PD), and safety evaluation

All patients in Part 1 were also included in Part 2 of the study. Newly enrolled patients were randomly assigned (1:1) to either CT-P10 or US-RTX. 

Patients received two intravenous (IV) infusions of 1,000 mg CT- P10, US-RTX, or EU-RTX separated by a 2-week interval. Methotrexate 7.5–25 mg orally or parenterally and folic acid ≥ 5 mg orally were co-administered weekly with the study drug. Methylprednisolone (100 mg IV), acetaminophen 500–1,000 mg, and chlorpheniramine 2–4 mg or equivalent were administered orally 30–60 minutes before each infusion of the study drug.

Duration

August 2014 through January 2016

Follow up: 24 weeks

Outcome Measures

Part 1:

Co-primary pharmacokinetic: area under the serum concentration-time curve (AUC) from time zero to last measurable concentration (AUC0–last); AUC from time zero to infinity (AUC0–∞); maximum concentration (Cmax) after two infusions

Part 2:

Primary: change from baseline to week 24 in Disease Activity Score

Secondary: immunogenicity (anti-drug antibodies), safety 

Baseline Characteristics

 

Part 1

Part 2

 

CT-P10 (n= 64)

US-RTX (n= 65)

EU-RTX (n= 60) CT-P10 (n= 161) RTX (n= 211)
Age, years

52.4 ± 10.58

52.8 ± 11.84 50.8 ± 10.86  51.5 ± 11.54 51.8 ± 11.14

Female

54 (84.4%) 

51 (78.5%)

50 (83.3%)

138 (85.7%) 

180 (85.3%)

White

48 (75.0%)

53 (81.5%)

41 (68.3%)

91 (56.5%)

138 (65.4%)

RF or anti-CCP status

RF positive

Anti-CCP positive

 

53 (82.8%)

53 (82.8%) 

 

55 (84.6%)

55 (84.6%)

 

49 (81.7%)

53 (88.3%)

 

127 (78.9%)

131 (81.4%)

 

174 (82.5%)

178 (84.4%)

Joint status at baseline

Swollen

Tender

 

16.3 (7.84)

24.2 (14.06)

 

14.4 ± 6.87

23.4 ± 13.80

 

15.2 ± 10.42

22.0 ± 12.89

 

15.3 ± 7.99

22.4 ± 12.84

 

14.3 ± 8.11

21.8 ± 12.77

Prior anti-TNF blocker status

Inadequate response

Intolerant case

 

55 (85.9%)

9 (14.1%)

 

55 (84.6%)

10 (15.4%)

 

55 (91.7%)

5 (8.3%)

 

137 (85.1%)

22 (13.7%)

 

187 (88.6%)

24 (11.4%)

CRP, mg/dL

ESR, mm/h

2.2 ± 3.56

54.1 ± 26.35

2.1 ± 2.79

53.2 ± 25.38

3.4 ± 4.99

51.5 ± 20.54

2.2 ± 3.22

54.7 ± 27.89

2.6 ± 3.91

54.9 ± 26.67

DAS28-CRP

DAS28-ESR

5.8 ± 0.86

6.8 ± 0.76

5.8 ± 0.82

6.7 ± 0.77

6.0 ± 0.86

6.8 ± 0.74

5.8 ± 0.89

6.7 ± 0.82

5.8 ± 0.91

6.7 ± 0.81

Anti-drug antibodies

--

-- -- 19 (11.8%)  20 (9.5%)

CCP, cyclic citrullinated peptide; CRP, C-reactive protein; DAS28, Disease Activity Score using 28 joints; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; TNF, tumor necrosis factor

Results

Endpoint

Part 1  

 

 

 

CT-P10 (n= 161) RTX (n= 211) Difference, 95% Confidence Interval (CI)    

DAS28-CRP change at week 24 

−2.13 ± 0.175

−2.09 ± 0.176 −0.04 (−0.29 to 0.21)    

Anti-drug antibodies at week 24

24 (14.9%) 

49 (23.2%) --     

Part 1:Analysis of the co-primary PK endpoints showed that, for all comparisons, the 90% CI of the ratio of geometric means for the area under the serum concentration-time curve (AUC) for AUC0–last, AUC0–∞, and Cmax were entirely contained within the margin of 80–125%, indicating PK equivalence between CT-P10, US- RTX, and EU-RTX.

Part 2: Mean decreases from baseline in DAS28-CRP over time were similar in the CT-P10 and RTX groups.

Adverse Events

Common Adverse Events: Infusion-related reactions (14.3% CT-P10 vs. 4.6% US-RTX vs. 20.0% EU-RTX)

Serious Adverse Events: treatment-related (5 RTX combined vs. 0 CT-P10)

Percentage that Discontinued due to Adverse Events: 3 (1.9%) RTX combined vs. 5 (2.4%) CT-P10

Study Author Conclusions

This study demonstrated the PK and efficacy equivalence of CT-P10 and RTX in patients with RA. Pharmacodynamic and immunogenicity findings were also comparable between groups, and no unexpected safety concerns were raised.

InpharmD Researcher Critique

One strength is the high patient retention rates and the three-way comparison of PK in the study. However, since patients were randomized 1:1:1 for Part 1, and then 1:1 in Part 2, an overall 1:1 distribution of CT-P10- and RTX-treated patients was not created in the efficacy analysis.

References:

Park W, Božić-Majstorović L, Milakovic D. et al. Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase III trial. MAbs 2018;10:934–43.

Safety and Immunogenicity of Rituximab Biosimilar GP2013 After Switch from Reference Rituximab in Patients with Active Rheumatoid Arthritis

Design

Multinational, randomized, double-blind, parallel-group, controlled, safety study

N= 107 

Objective

To provide a comparison with regard to safety and immunogenicity between either continuation of reference rituximab (RTX) or a switch from reference rituximab to GP2013 in patients with rheumatoid arthritis (RA)

Study Groups

GP2013 (switch; n= 53)

RTX (reference; n= 54)

Inclusion Criteria

Patients with RA; had previously received any duration of treatment with reference RTX as part of routine practice; required a continuation of treatment

Exclusion Criteria

Not specified

Methods

Eligible patients were randomized (1:1) to receive 2 x 1,000 mg intravenous (IV) infusions of either GP2013 (Rixathon®) or reference RTX as received prior to the study enrollment (either Rituxan® or MabThera®). Two IV infusions of study medication were administered on two consecutive visits 2 weeks apart, premeditated with IV methylprednisolone, antipyretic, and antihistamine prior to each infusion. All patients received a stable dose of methotrexate (7.5‒25 mg/week) and folic acid during the study.

Duration

Safety follow-up: 24 weeks

Outcome Measures

Incidence of hypersensitivity, infusion-related and anaphylactic reactions, immunogenicity (anti-drug antibodies [ADA])

Baseline Characteristics

 

GP2013 (n= 53)

RTX (n= 54)

 

Age, years

56.8 ± 9.9

57.1 ± 12.1

 

Female

46 (86.8%)

39 (72.2%)

 

Body mass index, kg/m2

29.58 ± 7.4

29.19 ± 7.6

 

Duration of RA, years

13.5 ± 9.4

14.0 ± 8.5

 

Number of previous treatments

Biologics other than rituximab

Prior treatments courses with rituximab

 

1.2 ± 1.0

4.1 ± 3.3

 

1.4 ± 1.0

5.0 ± 3.8

 

Time since last rituximab treatment, weeks

35.8 ± 13.2

39.85 ± 15.0

 

Results

Endpoint

GP2013 (n= 53)

RTX (n= 54)

Difference % (95% Confidence Interval)

Hypersensitivity reactions

After first and before second infusion

After second infusion up to the end of the study

Overall from first infusion up to the end of the study

Severe

 

3/53 (5.7%)

2/51 (3.9%)

5/53 (9.4%)

1/53 (1.9%)

 

4/54 (7.4%)

3/54 (5.6%)

6/54 (11.1%)

0

 

-1.7 (-20.6 to 16.9)

-1.6 (-20.9 to 17.3)

-1.7 (-20.6 to 16.9)

--

Anaphylactic reactions

Within 24 hours of either infusion

 

0/53

 

1/54 (1.9%)

 

-1.9 (-20.6 to 16.9)

Infusion-related reactions

First infusion

Second infusion

Overall

Severe

 

4/53 (7.5%)

2/51 (3.9%)

6/53 (11.3%)

1/53 (1.9%)

 

7/54 (13.0%)

5/54 (9.3%)

10/54 (18.5%)

0

 

-5.4 (-24.2 to 13.3)

-5.3 (-24.5 to 13.6)

-7.2 (-26.0 to 11.4)

--

Anti-drug antibodies

ADA+ post-treatment

 

0/51

 

1/53 (1.9%)

 

-1.9 (-21.2 to 17.6)

Adverse Events

  

Common Adverse Events: Arthralgia 3 (5.7%) vs. 0; osteoarthritis 2 (3.8%) vs. 0; infections and infestations 10 (18.9% vs. 13 (24.1%); nausea/vomiting 2 (3.8%) vs. 10 (18.5%)

Serious Adverse Events: 0 vs. 3 (5.6%)

Adverse Events Leading to Discontinuation: 1 (1.9) vs. 0

Study Author Conclusions

No safety risks were detected when patients switched from reference RTX to GP2013. The safety profiles of patients in both treatment groups were similar, although the study was not powered for statistical safety equivalence testing.

InpharmD Researcher Critique

There were no additional safety risks in patients who switched from reference RTX to GP2013 in this study; however, given the relatively small sample size, only descriptive statistics were used for all safety endpoints.

References:

Tony HP, Krüger K, Cohen SB, et al. Brief report: safety and immunogenicity of rituximab biosimilar GP2013 after switch from reference rituximab in patients with active rheumatoid arthritis. Arthritis Care Res (Hoboken). 2019;71(1):88-94. doi:10.1002/acr.23771

Long-Term Efficacy and Safety of Biosimilar CT-P10 Versus Innovator Rituximab in Rheumatoid Arthritis: 48-Week Results from a Randomized Phase III Trial

Design

Randomized, multinational, double-blind, active-controlled, parallel-group, phase III study

N= 372

Objective

To investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks

Study Groups

CT-P10 (n= 161)

US-RTX (n= 151)

EU-RTX (n= 60)

Inclusion Criteria

Aged 18–75 years with active RA diagnosed ≥ 6 months before randomization (active disease was defined by the presence of six or more swollen joints and six or more tender joints, and serum C-reactive protein (CRP) ≥ 1.5 mg/dL or an erythrocyte sedimentation rate (ESR) ≥ 28 mm/h); inadequate response or intolerance to anti-TNF agents; recipient of oral or parenteral methotrexate 7.5–25 mg/week for at least the past 12 weeks, with a stable dose over the 4 weeks immediately before screening

Exclusion Criteria

Patients with a history of any inflammatory or rheumatic disease other than RA 

Methods

Eligible patients received up to two courses of intravenous (IV) CT-P10, US-RTX, or EU-RTX 1,000 mg given 2 weeks apart (at weeks 0 and 2) alongside oral or parenteral methotrexate 7.5–25 mg/week and folic acid ≥ 5 mg/week. As long as predefined safety criteria were met, a second course (at weeks 24 and 26) was given irrespective of the patient's clinical response to the first course. Premedications (methylprednisolone, antipyretic, antihistamine) were administered 30–60 minutes prior to each infusion.

Duration

August 6, 2014 (first patient recruited)

July 5, 2016 (last 48-week visit)

Outcome Measures

Primary: change in DAS28 score from baseline at week 24 between CT-P10 and rituximab groups

Secondary: American College of Rheumatology (ACR) response rates, pharmacokinetics, pharmacodynamics, immunogenicity, and safety 

Baseline Characteristics

 

CT-P10 (n= 161)

US-RTX (n= 151)

EU-RTX (n= 60)

Combined RTX (n= 211)

Age (range), years

53.0 (18 to 74) 53.0 (21 to 74) 51.5 (20 to 74) 53.0 (20 to74)

Female

138 (85.7%) 130 (86.1%) 50 (83.3%) 180 (85.3%)

BMI, kg/m2

26.8 ± 5.9 27.0 ± 5.6 26.5 ± 6.1 26.9 ± 5.7

Race

White

Asian

Other

 

91 (56.5%)

12 (7.5%)

58 (36.0%)

 

97 (64.2%)

7 (4.6%)

47 (31.1%)

 

41 (68.3%)

5 (8.3%)

14 (23.3%)

 

138 (65.4%)

12 (5.7%)

61 (28.9%)

Duration of RA, years

10.7 ± 8.0

8.8 ± 7.4 9.9 ± 7.4 9.1 ± 7.4 

Prior anti-TNF status

Inadequate response

Intolerant case

 

137 (85.1%)

22 (13.7%)

 

132 (87.4%)

19 (12.6%)

 

55 (91.7%)

5 (8.3%)

 

187 (88.6%)

24 (11.4%)

RF or anti-CCP status

RF positive

Anti-CCP positive

 

127 (78.9%)

131 (81.4%) 

 

125 (82.8%)

125 (82.8%)

 

49 (81.7%)

53 (88.3%)

 

174 (82.5%)

178 (84.4%)

DAS28-CRP score

5.8 ± 0.9 5.8 ± 0.9 6.0 ± 0.9 5.8 ± 0.9

DAS28-ESR score

6.7 ± 0.8 6.7 ± 0.8 6.8 ± 0.7 6.7 ± 0.8

SJC at baseline

15.3 ± 8.0 13.9 ± 7.0 15.2 ± 10.2 14.3 ± 8.1

TJC at baseline

22.4 ± 12.8 21.7 ± 12.8 22.0 ± 12.9 21.8 ± 12.9

HAQ-DI at baseline

1.7 ± 0.6 1.7 ± 0.6 1.7 ± 0.5  1.7 ± 0.6

SF-36 at baseline

Physical functioning

Mental health

Van der Hijde modified total sharp score

 

27.5 ± 8.9

35.3 ± 10.7

78.7 ± 59.0

 

28.0 ± 8.8

36.0 ± 10.7

82.7 ± 66.7

 

26.6 ± 8.1

35.8 ± 10.4

90.1 ± 77.6

 

27.6 ± 8.6

35.8 ± 10.4

84.9 ± 70.0

Baseline CRP, mg/dL

2.2 ± 3.2

2.3 ± 3.4 3.4 ± 5.0 2.6 ± 3.9

Baseline ESR, mm/h

54.7 ± 27.9 56.2 ± 28.7 51.5 ± 20.5 54.9 ± 26.7

MTX dose, mg/week

14.6 ± 4.3 14.8 ± 4.5 15.6 ± 5.0 15.0 ± 4.7

Data are presented as n (%), mean ± standard deviation or median (range).

BMI body mass index, CCP cyclic citrullinated peptide, CRP C-reactive protein, DAS28 Disease Activity Score 28-Joint Count, ESR erythrocyte sedimentation rate, FcγR Fc gamma receptor, HAQ-DI Health Assessment Questionnaire Disability Index, MTX methotrexate, RA rheumatoid arthritis, RF rheumatoid factor, RTX rituximab, SF-36 Short Form 36-Item Health Survey, SJC swollen joint count, TJC tender joint count, TNF tumor necrosis factor

Results

Endpoint

CT-P10 (n= 155)

US-RTX (n= 144)

EU-RTX (n= 59)

Combined RTX (n= 211)

Change in DAS28-ESR from baseline at week 24

Change in DAS28-ESR from baseline at week 48

− 2.3 ± 1.1

− 2.9 ± 1.3

− 2.5 ± 1.1 

− 2.8 ± 1.4

− 2.3 ± 1.3

− 2.9 ± 1.3

− 2.5 ± 1.2 

− 2.8 ± 1.4

Change in DAS28-CRP from baseline at week 24

Change in DAS28-CRP from baseline at week 48

− 2.3 ± 1.1

− 2.7 ± 1.2

− 2.3 ± 1.1

− 2.6 ± 1.3

− 2.3 ± 1.3

− 2.7 ± 1.3

− 2.3 ± 1.2

− 2.6 ± 1.3 

ACR response rates at week 48

ACR20

ACR50

ACR70

 

80.6%

55.4%

31.7% 

 

-

-

-

 

-

-

-

 

79.8%

53.9%

33.7%

 

CT-P10 (n= 161)

US-RTX (n= 151) EU-RTX (n= 60)

Combined RTX (n= 211)

Adverse event (AE)

Treatment-related

 Treatment-related ≥ grade 3

125 (77.6%)

74 (46.0%)

3 (1.9%)

97 (64.2%)

47 (31.1%)

4 (2.6%)

39 (65.0%)

25 (41.7%)

1 (1.7%)

136 (64.5%)

72 (34.1%)

5 (2.4%)

Serious AE

Treatment-related

13 (8.1%)

0

14 (9.3%)

5 (3.3%)

4 (6.7%)

1 (1.7%)

18 (8.5%)

6 (2.8%) 

Discontinuation due to AEs

3 (1.9%)  7 (4.6%) 3 (5.0%) 10 (4.7%)

Infection

Upper respiratory tract infection

Urinary tract infection

Lower respiratory tract infection

Rhinitis

62 (38.5%) 

24 (14.9%)

15 (9.3%)

10 (6.2%)

3 (1.9%)

54 (35.8%)

30 (19.9%)

8 (5.3%)

8 (5.3%)

6 (4.0%)

17 (28.3%)

9 (15.0%)

2 (3.3%)

3 (5.0%)

1 (1.7%)

71 (33.6%)

39 (18.5%)

10 (4.7%)

11 (5.2%)

7 (3.3%)

Infusion-related reaction

33 (20.5%) 12 (7.9%) 13 (21.7%)  25 (11.8%)

Malignancy

0 2 (1.3%) 2 (3.3%) 4 (1.9%)

Death

1 (0.6%) 0

Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, anti-drug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic and pharmacodynamic profiles.

Adverse Events

See Results

Study Author Conclusions

This phase III RCT demonstrated the long-term similarity of CT-P10 and two approved rituximab reference products (RPs) in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety for up to 48 weeks. These results provide further support for the recent approval of CT-P10 for the treatment of RA and other CD20+ B-cell-related diseases.

InpharmD Researcher Critique

This study demonstrates the long-term equivalence of a rituximab biosimilar to its RP. The study allowed for a three-way comparison of CT-P10 and the two licensed rituximab RPs in a randomized design with a high level of patient retention at 48 weeks. 

References:

Suh CH, Yoo DH, Berrocal Kasay A, et al. Long-term efficacy and safety of biosimilar CT-P10 versus innovator rituximab in rheumatoid arthritis: 48-week results from a randomized phase III trial. BioDrugs. 2019;33(1):79-91. doi:10.1007/s40259-018-00331-4

 

Efficacy and Safety of ABP 798 (Riabni): Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product

Design

Randomized, double-blind, comparative clinical study; N= 256

Objective

To evaluate the efficacy and safety of ABP 798 compared with rituximab reference product

Study Groups

ABP 798 (n= 128)

Reference product (n= 128)

Inclusion Criteria

Adults≥ 18 years of age with histologically confirmed grade 1, 2, or 3a follicular B-cell lymphoma expressing CD20 within 12 months before randomization. Disease was classified as stage II, III, or IV based on Cotswold’s modification of the Ann Arbor Staging System, with measurable disease and low tumor burden (and Eastern Cooperative Oncology Group performance status score of 0 or 1). 

Exclusion Criteria

History or known presence of central nervous system metastases; had used either commercially available or investigational chemotherapy, biological therapy, or immunological therapy for non-Hodgkin lymphoma (NHL) (including rituximab RP or biosimilar rituximab or other anti-CD20 treatments)

Methods

Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab reference product once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28.

Blood samples for anti-drug antibody (ADA) assessments were collected at baseline/week 1, week 12, 20, and 28/EOS. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. Patients who tested positive for neutralizing antibodies to ABP 798 or rituximab RP at the final scheduled study visit were asked to return for additional follow-up testing.

Duration

28 weeks

Outcome Measures

The primary endpoint was risk difference (RD) of overall response rate (ORR) from the central, independent, blinded tumor assessments by week 28.

Secondary endpoints included PK, PD, safety, and immunogenicity

Baseline Characteristics

 

ABP 798 (n=128)

Rituximab RP (n=128)

Age, mean years (standard deviation) 

 57.6 (12.72)  58.2 (12.20)

Female

 68 (53.1%)   62 (48.4%)

White

 102 (79.7%)  101 (78.9%)

ECOG performance status

0

1

 

107 (83.6%)

21 (16.4%)

 

110 (85.9%)

18 (14.1%)

 

Results

Endpoint

ABP 798 (n=128)

Rituximab RP (n=128)

ORR [n (%)]

95% CI of ORR (as a %)

96 (78.0)

[70.7, 85.4]

87 (70.2)

[62.1, 78.2]

Patients with a binding antibody negative
or no result at baseline and a post-baseline result

126 123

Developing antibody incidence, n (%)

Binding antibody positive post-baseline

Transient*

Neutralizing antibody positive anytime

Transient*

 

3 (2.4)

2 (1.6)

1 (0.8)

1 (0.8)

 

1 (0.8)

0

1 (0.8)

0

CI confidence interval, CR complete response, CRu unconfirmed complete response,  ORR overall response rate, PR partial response, RD risk difference

ORR is defined as the percentage of patients with a best overall response of CR, PR, or CRu, defined per IWG-NHL criteria

*negative result at the subject’s last time point tested within the study period

Adverse Events

Common Adverse Events: Any adverse event 83.6% ABP 798 vs 75.4% ref product

Serious Adverse Events: Grade≥ 3 adverse events 10.9% ABP 798 vs 10.3% ref product

Percentage that Discontinued due to Adverse Events: 3.1% ABP 798 vs 0.8% ref product (infusion reactions)

Study Author Conclusions

Overall, the results of this study support a conclusion of similarity in efficacy and safety/tolerability with regard to ABP 798 and rituximab reference product in patients with CD20+ follicular B-cell NHL.

InpharmD Researcher Critique

Comparative statistics between groups were limited. Due to small sample size, this study may not have been sufficiently powered to detect clinically relevant differences, including antibody development.  



References:

Niederwieser D, Hamm C, Cobb P, et al. Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product [published correction appears in Target Oncol. 2020 Dec;15(6):807]. Target Oncol. 2020;15(5):599-611. doi:10.1007/s11523-020-00748-4

 

A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a Rituximab Biosimilar) Compared with Rituximab Reference Product (MabThera®) in Subjects with Previously Untreated CD20-Positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL)

Design

Randomized, double-blind, comparative clinical study

N= 394

Objective

To evaluate the efficacy, safety, immunogenicity, PK, and pharmacodynamics (PD) of PF-05280586 compared with rituximab-EU in subjects with previously untreated CD20-positive LTB-FL

Study Groups

PF-05280586 (Ruxience; rituximab-pvvr) (n= 196)

Rituximab-EU (n= 198)

Inclusion Criteria

Age 18 years or older, presence of low-tumor-burden follicular lymphoma (LTB-FL) without lymphoma-related B symptoms

Exclusion Criteria

Ineligible for rituximab monotherapy; high-grade or diffuse large B-cell lymphoma; previous history of T-cell lymphoma, ≥ 5000/mm3 circulating lymphoma cells; prior treatment with rituximab or other systemic therapy for B-cell Non-Hodgkin Lymphoma; severe, acute, or chronic conditions

Methods

Patients were randomized (1:1) to receive either PF-05280586 or rituximab-EU 375 mg/m2 intravenous (IV) once weekly for 4 weeks (days 1, 8, 15, and 22). Concomitant medications were allowed except for cancer therapy, radiotherapy, or immunotherapy agents. Additional doses of rituximab beyond 4 weeks were also not permitted.

Duration

Follow-up: 52 weeks

Outcome Measures

Primary: overall response rate (ORR) at week 26 defined as the percentage of subjects to achieve complete response (CR) or partial response (PR) for malignant lymphoma based on the revised response criteria

Secondary: ORR in the per-protocol population, positive anti-drug antibody (ADA)

Baseline Characteristics

 

PF-05280586 (n= 196)

Rituximab-EU (n= 198)

 

Age, years

58.7 ± 12.1 58.3 ± 12.8  

Female

110 (56.1%) 106 (53.5%)  

Body mass index, kg/m2

26.7 26.3  

Race

White

Black

Asian

Other

 

80.6%

0.5%

15.3%

3.6%

 

73.7%

0%

22.2%

4.0%

 

Ann Arbor stage

I

II

III

IV

 

0

26.5%

45.4%

28.1%

 

0

27.3%

42.9%

29.8%

 

ECOG performance status

0

1

 

87.2%

12.8%

 

85.4%

14.1%

 

Results

Endpoint

PF-05280586 (n= 196)

Rituximab-EU (n= 198)

Difference

Intent-to-treat population

ORR

95% confidence interval (CI)

 

75.5%

68.9% to 81.4%

 

70.7%

63.8% to 76.9%

 

4.66

-4.16 to 13.47

Per-protocol population

ORR

95% CI

n= 166

86.1%

79.9% to 91.0%

n= 176

78.4%

71.6% to 84.2%

 

7.49

-0.67 to 15.80

Positive ADA (titer ≥ 1.88)

Day 1 prior to treatment (baseline)

Post-dose

 

7.2%

22.1%

 

8.7%

19.8%

 

Adverse Events

Common Adverse Events: PF-05280586 vs rituximab-EU

Infusion-related reactions: 25.0% vs 29.9%

Pruritus: 6.6% vs 11.2%

Headache: 8.2% vs 9.6%

Serious Adverse Events: PF-05280586 vs rituximab-EU (8.7% vs 7.6%)

Treatment-emergent adverse event grade 3 or higher: 14.3% vs 13.2%

Percentage that Discontinued due to Adverse Events: PF-05280586 vs rituximab-EU (13.7% vs 14.1%)

Study Author Conclusions

The efficacy, safety, immunogenicity, PK, and PD of PF-05280586 and rituximab-EU were similar up to week 52 in subjects with previously untreated CD20-positive LTB-FL.

InpharmD Researcher Critique

Typically, lymphoma is treated with eight doses of rituximab (possibly even greater). The current treatment protocol may be inadequate in identifying the true immunogenicity.



References:

Sharman JP, Liberati AM, Ishizawa K, et al. A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a Rituximab Biosimilar) Compared with Rituximab Reference Product (MabThera®) in Subjects with Previously Untreated CD20-Positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL). BioDrugs. 2020;34(2):171-181. doi:10.1007/s40259-019-00398-7

 

Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis

Design

Extension analysis of a randomized, parallel‐group, 3‐arm clinical pharmacokinetic (PK) study

N= 185

Objective

To evaluate overall pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of PF‐05280586 (Ruxience) after the transition from rituximab reference products to PF‐05280586, and follow‐up of biomarker and efficacy assessments

Study Groups

Parent study (PS): PF‐05280586, Extension study (ES): PPP (n= 59)

PS: rituximab‐EU, ES: EPP (n= 33)

PS: rituximab‐EU, ES: PPP (n= 33)

PS: rituximab‐US, ES: UPP (n= 30)

PS: rituximab‐US, ES: PPP (n= 30)

Inclusion Criteria

Active rheumatoid arthritis (RA) who received background therapy with methotrexate, an inadequate response to at least 1 tumor necrosis factor antagonist therapy; completion of ≥ 16 weeks of a pharmacokinetic similarity study of PF‐05280586 (parent study)

Exclusion Criteria

Treatment with prohibited concomitant medications during the study, including live attenuated vaccines, cytotoxic drugs, prednisone >10 mg/day or equivalent, disease‐modifying antirheumatic drugs (other than stable dose of methotrexate up to 25 mg weekly), plasma exchange therapy, or immunoglobulin; severe reaction to rituximab reference products or PF‐05280586, or a serious adverse event (SAE) that was deemed to be related to the study drug in the parent study; absolute neutrophil count ≤ 1,500 cells/mm3 or immunoglobulin G levels <300 mg/dL 

Methods

The parent study had subjects with active RA randomized (1:1:1) to receive PF‐05280586, rituximab‐EU (MabThera), or rituximab‐US (Rituxan), each administered as 2 intravenous (IV) 1,000‐mg doses on study days 1 and 15. In the extension study, eligible subjects were offered ≤ 3 additional courses of treatment of PF‐05280586, with or without a single transition from rituximab‐EU or rituximab‐US to PF‐05280586. Each course comprised 2 IV infusions (1,000 mg on days 1 and 15, separated by 24 weeks [± 8 weeks]).

The first course of this extension study randomized subjects as follows: those who received rituximab‐EU in the parent study were blindly randomized (1:1) to either continue on rituximab‐EU (E‐E) or receive PF‐05280586 (E‐P), and subjects who received rituximab‐US were blindly randomized (1:1) to either continue rituximab‐US (U‐U) or receive PF‐05280586 (U‐P). All subjects who continued after the end of course 1 received PF‐05280586 for courses 2 and 3 in this study (E‐EPP and E‐PPP, or U‐UPP and U‐PPP, respectively). Subjects who received PF‐05280586 in the parent study continued blind randomization to receive PF‐05280586 for courses 1, 2, and 3 (P‐P, P‐PP, P‐PPP, respectively).

Duration

Up to 96 week

Outcome Measures

Immunogenicity (ADA test results), safety, and tolerability of PF‐05280586

Baseline Characteristics

 

PS: PF‐05280586, ES: PPP (n= 59)

PS: rituximab‐EU, ES: EPP (n= 33)

PS: rituximab‐EU, ES: PPP (n= 33) PS: rituximab‐US, ES: UPP (n= 30) PS: rituximab‐US, ES: PPP (n= 30)

Age, years

55.4 ± 1.91 56.3 ± 1.82 56.7 ± 9.35 52.6 ± 3.73 55.8 ± 0.35

Female

50 (84.7%) 30 (90.9%) 23 (69.7%) 20 (66.7%) 25 (83.3%) 

Race

White

Black

Asian

Other

 

44 (74.6%)

1 (1.7%)

3 (5.1%)

11 (18.6%)

 

23 (69.7%)

3 (9.1%)

0 (0.0%)

7 (21.2%)

 

26 (78.8%)

3 (9.1%)

0 (0.0%)

4 (12.1%) 

 

25 (83.3%)

3 (10.0%)

0 (0.0%)

2 (6.7%)

 

21 (70.0%)

2 (6.7%)

0 (0.0%)

7 (23.3%)

BMI, kg/m2

31.81 ± 7.514 28.59 ± 6.833 31.46 ± 5.367 0.68 ± 6.420 27.12 ± 5.487

Results

Endpoint

PS: PF‐05280586, ES: PPP (n= 48)

PS: rituximab‐EU, ES: EPP (n= 30)

PS: rituximab‐EU, ES: PPP (n= 30)

PS: rituximab‐US, ES: UPP (n= 27) PS: rituximab‐US, ES: PPP (n= 29) 

Any treatment‐emergent adverse events (TEAEs)

34 (70.8%) 21 (70.0%) 23 (76.7%) 20 (74.1%) 21 (72.4%)

Serious TEAE

4 (8.3%) 1 (3.3%)  4 (13.3%) 1 (3.7%) 1 (3.4%)

TEAE resulting in withdrawal from study treatment

0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (3.4%) 
TEAE resulting in withdrawal from study 0 (0.0%)  0 (0.0%)  0 (0.0%)  0 (0.0%)  1 (3.4%) 
Treatment‐related TEAE 12 (25.0%) 5 (16.7%) 11 (36.7%) 11 (40.7%) 7 (24.1%)
TEAE grade ≥3 5 (10.4%) 2 (6.7%) 7 (23.3%) 2 (7.4%) 3 (10.3%)

The incidence of ADA response during the combined courses 1–3: 13.3% with the anti‐rituximab antibody assay vs.10.0% with the anti–PF‐05280586 antibody assay

Of the 27 subjects who were ADA+ at baseline in this study, 19 (70%) were also ADA+ in the parent study, 20 (74%) had cross‐reactive ADA with similar titers, and 23 (85%) reverted to ADA– by their last visit. The remaining 4 subjects  (1 randomized to the P‐PPP, 2 E-PPP, 1 U-UPP) were ADA+ at their last visit. 

Of the 146 subjects who were ADA– at pre‐dose, 1 (<1%) had tested positive in the parent study but remained ADA– throughout this study. Additionally, 17 of 146 subjects (12%) became ADA+ during this study, of which 15 of 17 (88%) were ADA– in the parent study. Finally, 5 of 146 subjects (3.4%) remained ADA+ at the last visit and did not report an IRR. In total, 11 of 17 subjects (65%) who were ADA+ had cross‐reactive ADAs with similar titers.

Adverse Events

See Results

Study Author Conclusions

This study demonstrated acceptable safety, tolerability, and immunogenicity, with or without a single transition from rituximab reference products to PF‐05280586, without increased immunogenicity on a single transition.

InpharmD Researcher Critique

The study had relatively small numbers of subjects who were ADA+. None of the samples that tested positive for ADAs tested positive for neutralizing activity in this study.



References:

Cohen SB, Burgos-Vargas R, Emery P, et al. Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2018;70(11):1598-1606. doi:10.1002/acr.23586

Summary of CT-P10 (Truxima®) Trials in Rheumatoid Arthritis

Phase

Comparator

Follow-up period

Immunogenicity

I

CT-P10 (n= 102) vs. EU-rituximab (n= 51)

24 weeks

ADA: 18 (17.6%) vs. 9 (17.6%)

Neutralizing antibodies: 2 (2%) vs. 1 (2%)

I (long-term)

CT-P10 (n= 60) vs. EU-rituximab (n= 23)

72 weeks

ADA: 12 (20%) vs. 5 (21.7%)

Neutralizing antibodies: 1 (1.7%) vs. 1 (4.3%)

Open-label extension

Maintenance (n= 38) vs. switching (n= 20) 56 weeks

ADA: 5 (13.2%) vs. 3 (15%)

Neutralizing antibodies: 1 (5%) vs. 0

III

CT-P10 (n= 161) vs. US- and EU-rituximab (n= 211) 24 weeks

ADA: 24 (14.9%) vs. 49 (23.2%)

Neutralizing antibodies: 0 vs. 0

Extension

CT-P10/CT-P10 (n= 120) vs. US-rituximab/US-rituximab (n= 64) vs. US- rituximab/CT-P10 (n= 60) vs. EU-rituximab/CT-P10 (n= 47) 72 weeks

ADA: 5 (4.1%) vs. 2 (3.1%) vs. 8 (12.9%) vs. 3 (6.4%)

Neutralizing antibodies: 1 patient (0.8%) in CT-P10/CT-P10

ADA: anti-drug antibody

References:

Jung JY, Kim JW, Kim HA, Suh CH. Rituximab biosimilar CT-P10 for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2019;19(10):979-986. doi:10.1080/14712598.2019.1665018