A Review of the Totality of Evidence in the Development of ABP 798, A Rituximab Biosimilar

Figures & data

Figure 1. Mechanisms of rituximab-mediated cell death.

Rituximab-coated B cells are killed by at least four different mechanisms. Binding of rituximab to CD20 on the B-cell surface causes activation of the complement cascade, which generates the membrane attack complex that can directly induce B-cell lysis by complement-dependent cytotoxicity. Binding of rituximab allows interaction with NK cells via Fc receptors III (FcRIII), which leads to antibody-dependent cell-mediated cytotoxicity. The Fc portion of rituximab and the deposited complement fragments allow for recognition by both FcR and complement receptors on macrophages, which lead to antibody-dependent cell-mediated phagocytosis and antibody-dependent cell-mediated cytotoxicity. The crosslinking of several molecules of rituximab and CD20 in the lipid raft determines the interaction of these complexes with elements of a signaling pathway involving Src kinases that mediate direct apoptosis.

ADCC: Antibody-dependent cell-mediated cytotoxicity; ADCP: Antibody-dependent cell-mediated phagocytosis; CDC: Complement-dependent cytotoxicity; MAC: Membrane attack complex.

Reproduced with permission from [24], © Elsevier (2010) on behalf of The American Society of Hematology.

Figure 2. Functional data supporting mechanism of action.

(A) NK92 ADCC activity. (B) CDC potency. (C) Apoptosis activity. (D) ADCP activity.

ADCC: Antibody-dependent cell-mediated cytotoxicity; ADCP: Antibody-dependent cell-mediated phagocytosis; CDC: Complement-dependent cytotoxicity.

Reproduced with permission from [18], © Elsevier (2021) on behalf of the International Alliance for Biological Standardization.

Figure 3. Mean ± standard deviation of serum concentrations in rheumatoid arthritis patients over time by treatment through week 12.

Reproduced with permission from [21] under the terms of the Creative Commons CC BY license.

Figure 4. Disease Activity Score-28 for Rheumatoid Arthritis with CRP: change from baseline at week 24 (primary end point).

RP: Reference product.

Reproduced with permission from [22] under the terms of the Creative Commons CC BY license.

Table 1. Overall safety results: rheumatoid arthritis.

	ABP 798/ABP 798 (n = 104)	Rituximab (EU)/Rituximab (EU) (n = 104)	Rituximab (US)/ABP 798 (n = 103)
Day 1 until first or second infusion
Any adverse event, n (%)	52 (50.0)	44 (42.3)	44 (42.7)
Any ≥grade 3 adverse event, n (%)	4 (3.8)	6 (5.8)	4 (3.9)
Any fatal adverse event, n (%)	0 (0.0)	0 (0.0)	0 (0.0)
Any serious adverse event, n (%)	4 (3.8)	5 (4.8)	5 (4.9)
Any adverse event leading to discontinuation of IP/study, n (%)	3 (2.9)	1 (1.0)	4 (3.9)
Adverse events of interest, n (%)	19 (18.3)	11 (10.6)	18 (17.5)
Infusion reactions including hypersensitivity	12 (11.5)	7 (6.7)	12 (11.7)
Hematological reactions	4 (3.8)	2 (1.9)	3 (2.9)
Serious infections	2 (1.9)	3 (2.9)	1 (1.0)
Cardiac disorders	2 (1.9)	2 (1.9)	2 (1.9)
Opportunistic infection	1 (1.0)	0 (0.0)	1 (1.0)
Day 1 through end of study
Any adverse event, n (%)	67 (64.4)	54 (51.9)	56 (54.4)
Any ≥grade 3 adverse event, n (%)	5 (4.8)	9 (8.7)	9 (8.7)
Any fatal adverse event, n (%)	0 (0.0)	0 (0.0)	0 (0.0)
Any serious adverse event, n (%)	8 (7.7)	8 (7.7)	8 (7.8)
Any adverse event leading to discontinuation of IP/study, n (%)	3 (2.9)	2 (1.9)	7 (6.8)
Adverse events of interest, n (%)	25 (24.0)	15 (14.4)	23 (22.3)
Infusion reactions including hypersensitivity	16 (15.4)	9 (8.7)	16 (15.5)
Hematological reactions	5 (4.8)	2 (1.9)	7 (6.8)
Serious infections	4 (3.8)	4 (3.8)	1 (1.0)
Cardiac disorders	4 (3.8)	3 (2.9)	2 (1.9)
Opportunistic infection	1 (1.0)	2 (1.9)	1 (1.0)

IP: Investigational product.

Reproduced with permission from [22] under the terms of the Creative Commons CC BY license.

Table 2. Summary of overall response rate by week 28: primary efficacy based on independent central assessment of disease.

	ABP 798 (n = 123)	Rituximab RP (n = 124)
ORR^†, n (%)	96 (78.0)	87 (70.2)
95% CI of ORR (%)	(70.7–85.4)	(62.1–78.2)
RD (ABP 798 vs rituximab RP)^‡ (%)		7.7
One-sided 95% lower confidence limit (%)		-1.4
One-sided 95% upper confidence limit (%)		16.8
Two-sided 95% CI (%)		(-3.2–18.6)
Best overall response, n (%)
Complete response	29 (23.6)	32 (25.8)
Unconfirmed complete response	0 (0.0)	3 (2.4)
Partial response	67 (54.5)	52 (41.9)
Stable disease	23 (18.7)	35 (28.2)
Relapsed disease	0 (0.0)	0 (0.0)
Progressive disease	1 (0.8)	0 (0.0)
Missing	2 (1.6)	2 (1.6)
Unknown	1 (0.8)	0 (0.0)

† ORR is defined as the percentage of patients with a best overall response of complete response, partial response or unconfirmed complete response, defined per IWG-NHL criteria [16].

‡ Point estimate and CIs were estimated using a generalized linear model adjusted for the randomization stratification factors geographic region and age group.

Data are based on the modified full analysis set.

IWG: International Working Group; NHL: Non-Hodgkin lymphoma; ORR: Overall response rate; PP: Per-protocol; RD: Risk difference; RP: Reference product.

Reproduced with permission from [19] under the terms of the Creative Commons CC BY-NC license.

Table 3. Overall summary of adverse events: non-Hodgkin lymphoma.

	ABP 798 N = 128 n (%)	Rituximab RP N = 126 n (%)
Any adverse event	107 (83.6)	95 (75.4)
Treatment-emergent events in ≥5% of patients
Abdominal pain	4 (3.1)	10 (7.9)
Asthenia	12 (9.4)	6 (4.8)
Diarrhea	3 (2.3)	9 (7.1)
Fatigue	13 (10.2)	12 (9.5)
Headache	15 (11.7)	12 (9.5)
Nausea	6 (4.7)	14 (11.1)
Pruritus	6 (4.7)	12 (9.5)
Pyrexia	8 (6.3)	8 (6.3)
Rash	9 (7.0)	6 (4.8)
Throat irritation	9 (7.0)	8 (6.3)
Upper respiratory tract infection	7 (5.5)	1 (0.8)
Urticaria	7 (5.5)	2 (1.6)
Grade ≥3 adverse events	14 (10.9)	13 (10.3)
Any AEOI	63 (49.2)	57 (45.2)
Infusion reactions including hypersensitivity^†	55 (43.0)	54 (42.9)
Hematological reactions	7 (5.5)	6 (4.8)
Cardiac disorders	3 (2.3)	2 (1.6)
Serious infections	2 (1.6)	0 (0.0)
Severe mucocutaneous reactions	1 (0.8)	0 (0.0)
Gastrointestinal perforation, hepatitis B reactivation, opportunistic infection, progressive multifocal leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, tumor lysis syndrome	0 (0.0)	0 (0.0)

† Infusion reactions including hypersensitivity AEOIs must have start date the same as, or 1 day after, an IP product administration start date.

Only treatment-emergent adverse events were summarized (by actual treatment received). For each category, patients were included only once, even if they experienced multiple adverse events in that category.

AEOI: Adverse event of interest; IP: Investigational product; RP: Reference product.

Reproduced with permission from [19] under the terms of the Creative Commons CC BY-NC license.

Figure 5. Serum concentrations over time by treatment (weeks 4–12) in the subset of non-Hodgkin lymphoma patients who agreed to the optional pharmacokinetic testing.

Note: This graph represents pharmacokinetic results from the 45 patients treated with ABP 798 and the 41 patients treated with rituximab reference product who agreed to the optional pharmacokinetic sampling. The sample sizes for each visit (ABP 798 vs rituximab) were as follows: week 4 predose (44 vs 39), week 4 post-dose (36 vs 32), week 5 (38 vs 37) and week 12 predose (44 vs 41).

Reproduced with permission from [19] under the terms of the Creative Commons CC BY-NC license.

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