ALYMSYS (bevacizumab-maly) injection is similar to Avastin® (bevacizumab) based on the totality of evidence, with no clinically meaningful differences in efficacy, safety and immunogenicity.1-6
Pre-clinical findings from in vitro and animal models
Based on findings from in vitro models in animal studies, it is believed that bevacizumab may inhibit angiogenesis by specifically binding to the vascular endothelial growth factor (VEGF).1,7
ALYMSYS is a biosimilar to bevacizumab which has been developed in comparison with Avastin® as the Reference Product (RP). Over 50 analytical methods were applied to evaluate >90 quality attributes and confirm analytical similarity between ALYMSYS and Avastin®.1,2
Primary Structure
The same amino acid composition is confirmed in ALYMSYS and Avastin®.
Each peak observed corresponds to a part of the monoclonal antibody (peptide) after its digestion by trypsin. The detection of the same peptides by mass spectrometry confirms the identical AA sequence between ALYMSYS and Avastin®. Orthogonal mass spectrometry methods confirm the same primary structure for ALYMSYS and Avastin®.1,2
Molecular Conformation
Highly similar molecular conformation between ALYMSYS and Avastin®.
Multiple structural characterization assays confirmed similar molecular conformation between ALYMSYS and Avastin®. Superimposed circular dichroism (CD) and fluorescence spectra confirm similar secondary and tertiary structure between ALYMSYS and Avastin®.1,2
Glycosylation Profile
Similar N-glycans identity and distribution.
Protein glycosylation is an important quality attribute which may impact the product’s immunogenicity, PK, safety and efficacy. ALYMSYS and Avastin® glycosylation profiles have been characterized by multiple assays including chromatography and mass spectrometry methods which have confirmed minor differences which are not clinically meaningful. Variability in glycosylation depends on the cell line and manufacturing process which are specific to each product.3 The ALYMSYS manufacturing process was designed to achieve a quality profile close to the RP and the small differences observed are not clinically meaningful based on bevacizumab mechanism of action (MoA).1,2,4
Charge Variants
Similar post-translational modifications
Large proteins exist as multiple charged species, with presence of positively and negatively charged AA and negatively charged glycans (sialic acids). Protein degradation during their shelf life can also create new charges e.g. by oxidation or deamidation of the AA forming the primary sequence. Charge variants must be controlled since they may affect the efficacy and safety of the molecule.5
The distribution of charge variants is similar in ALYMSYS and Avastin® when considering the age of the samples, as demonstrated by such techniques as cation exchange chromatography and capillary isoelectric focusing.1,2
Protein Content and Purity
ALYMSYS and RP have a similar protein concentration and purity profile.
Biotherapeutic monoclonal antibodies are highly pure molecules, but aggregates and fragments may affect the biological activity and safety.5
Both ALYMSYS and Avastin® are highly pure products with >90% purity measured by size exclusion chromatography. Low levels of aggregates are present in both products with slightly lower amounts in ALYMSYS (higher purity) as confirmed by multiple orthogonal methods.1,2
Biological Activity
Biological activity in vitro reflects the mechanisms of action in vivo.
Bevacizumab, the active ingredient, is a recombinant humanized monoclonal antibody that selectively binds to all human vascular endothelial growth factor A (VEGF A) isoforms with high affinity. It neutralizes VEGF A by sterically disrupting the ability of VEGF to bind its receptors on the surface of endothelial cells to promote angiogenesis.6
Comparative Stability
Comparative accelerated and forced degradation studies have shown a similar behavior and degradation profile of ALYMSYS and Avastin®.1,2
A randomized, multicenter, multinational, double-blind study in combination with carboplatin and paclitaxel for the treatment of subjects with stage IIIB/IV Non-squamous Non-Small Cell Lung Cancer (NSCLC) was conducted to assess the efficacy and safety of ALYMSYS versus Avastin®.1
The primary objective was achieved for the clinical similarity of ALYMSYS versus Avastin® at Week 18 and confirmed at Week 52. The Objective Response Rate (ORR) to measure the clinical efficacy was comparable and demonstrated in both arms1:
In addition to key efficacy results for the Stella study, further sensitive secondary endpoints to detect differences in the clinical setting base were included, such as Progression Free Survival (PFS) and Overall Survival (OS) supporting the similarity between the 2 treatment groups.1
| Adverse events of interest grade | ALYMSYS (n=311) | Avastin® (n= 310) |
|---|---|---|
| At least 1 AESI Grade 3 - 4 | 49 (15.8) | 55 (17.7) |
| Neutropenia | 16 (5.1) | 21 (6.8) |
| Hypertension | 7 (2.3) | 7 (2.3) |
| Deep vein thrombosis | 1 (0.3) | 1 (0.3) |
| Embolism | 2 (0.6) | 0 |
| Pulmonary haemorrhage | 0 | 0 |
| Pulmonary embolism | 6 (1.9) | 3 (1.0) |
| Hemoptysis | 0 | 1 (0.3) |
| Epistaxis | 0 | 1 (0.3) |
| Proteinuria | 1 (0.3) | 4 (1.3) |
| Diverticular perforation | 0 | 1 (0.3) |
| Intestinal perforation | 1 (0.3) | 0 |
| Gastric ulcer perforation | 0 | 1 (0.3) |
| Left ventricular dysfunction | 1 (0.3) | 0 |
| Myocardial infarction | 0 | 1 (0.3) |
| Ischemic stroke | 0 | 1 (0.3) |
| Purpura | 1 (0.3) | 0 |
| Infusion related reaction | 0 | 0 |
A phase I, double-blind, randomized, parallel-group, single dose 3-treatment arms healthy male volunteers study was conducted to investigate and compare the PK profiles of ALYMSYS and Avastin® (EU + US) and confirmed bioequivalence between the 3 treatments1:
