About Alymsys

Alymsys® from Amneal Biosciences

Alymsys® (bevacizumab-maly) injection is similar to Avastin® (bevacizumab) based on the totality of evidence, with no clinically meaningful differences in efficacy, safety and immunogenicity1-6.

Bevacizumab is an antineoplastic agent, inhibiting angiogenesis by specifically binding to the vascular endothelial growth factor (VEGF)1,2.

Product Info & Dosing
Alymsys® from Amneal Biosciences

Indications

The FDA has approved Alymsys® for the below listed Avastin indications through extrapolation.

This is an abbreviated summary of the approved indications. Please see Alymsys full Prescribing Information for patient restrictions.
Metastatic Colorectal Cancer (mCRC)
In combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment of patients with metastatic colorectal cancer (mCRC), and in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen.

Limitations of Use: Alymsys® is not indicated for adjuvant treatment of colon cancer
First-Line Non-Squamous Non small Cell Lung Cancer (NSCLC)
Alymsys®, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).
Recurrent Glioblastoma (GBM)
Alymsys® is indicated for the treatment of recurrent glioblastoma (GBM) in adults.
Metastatic Renal Cell Cancer (mRCC)
Alymsys®, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC).
Persistent, Recurrent, or Metastatic Cervical Cancer
Alymsys®, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.
Epithelial Ovarian, Fallopian tube, or Primary Peritoneal Cancer
Alymsys®, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

Over 60,000 Patients have been treated with Alymsys® with no new findings related to safety found from post-marketing and clinical development phase data.7

Evidence1-6

Multiple in vitro analytical similarity studies using state-of-the-art orthogonal analytical methods demonstrated similarity between Alymsys® and Avastin® in key features such as: primary structure, molecular conformation, glycosylation, charge variants, protein content, purity and biological activity.1

Comparative stability studies between Alymsys® and Avastin® under accelerated and forced degradation conditions have demonstrated similar behavior and degradation pathways for the two products.1

Alymsys® clinical comparability includes data from more than 1,000 subjects evaluated in different clinical trials2-6

      1. Strong comparability PK package in HV clinical trials in Caucasian and Japanese populations showed the PK similarity of both products.4,5

      • Statistical analysis of the PK parameters demonstrated similarity between Alymsys® and Avastin® (EU + US).4
      • Alymsys® was generally well tolerated by healthy subjects and the safety and immunogenicity profile of Alymsys® and Avastin® (EU + US) was determined to be similar.4

      2. Comparative clinical trial in a relevant and approved indication:2,3,6

      • A randomized clinical comparability phase III study, the Stella study was conducted in the Non- Squamous non-small Cell Lung Cancer (NSCLC). 2,3
      • The Stella study, confirms the clinical similarity in terms of efficacy, safety and immunogenicity of Alymsys® and Avastin®, supporting the clinical activity of Alymsys® treatment. Alymsys® was well tolerated with manageable adverse events (AEs) in patients with stage IIIB/IV NSCLC.2,3

      3. Supportive comparative clinical trial conducted in Metastatic Colorectal Cancer (mCRC). 7

      • Has shown similar safety results in both Alymsys (mAbxience bevacizumab biosimilar/Alymsys) and Avastin® groups, with no relevant differences in the nature, severity, or frequency of AEs. 2,6

Analytical, preclinical and clinical studies have demonstrated Alymsys® is similar to Avastin®1-6
Alymsys® ~ Avastin®

References:
1. Ruppen I, Beydon ME, Solís C, Sacristán D, et al. Similarity demonstrated between isolated charge variants of MB02 , a biosimilar of bevacizumab, and Avastin® following extended physicochemical and functional characterization. Biologicals. 2021 Sep;73:41-56. doi: 10.1016/j.biologicals.2021.09.001
2. FDA Summary Basis of Approval of MB02 (SBoA). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761231Orig1s000TOC.cfm.
3. Trukhin D, Poddubskaya E, Andric Z, et al.. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. doi: 10.1007/s40259-021-00483-w
4. Sinn, A, García-Alvarado, F, Gonzalez, V, Huerga, C, Bullo, F. A randomized, double blind, single dose, comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and reference bevacizumab in healthy male volunteers. Br J Clin Pharmacol. 2022; 88( 3): 1063- 1073. doi:10.1111/bcp.15032
5. Eto T, Karasuyama Y, González V, Del Campo García A. A randomized, single-dose, pharmacokinetic equivalence study comparing MB02 (proposed biosimilar) and reference bevacizumab in healthy Japanese male volunteers. Cancer Chemother Pharmacol. 2021;88(4):713-722. doi:10.1007/s00280-021-04324-z
6. Romera, A. et al. Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial. The Lancet Gastroenterology and Hepatology, volume 3, issue 12. 2018.
7. Periodic Safety Update Report (PSUR) For MB02 (Bevacizumab-maly), 22 April 2022

Proven Similarity with Avastin®

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 Alymsy® 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 > 95% 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. Its 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

References:
1. Ruppen I, Beydon ME, Solís C, Sacristán D, et al. Similarity demonstrated between isolated charge variants of MB02 , a biosimilar of bevacizumab, and Avastin® following extended physicochemical and functional characterization. Biologicals. 2021 Sep;73:41-56. doi: 10.1016/j.biologicals.2021.09.001
2. FDA Summary Basis of Approval of MB02 (SBoA). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761231Orig1s000TOC.cfm.
3. Liu, L. Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. 2015.
4. Trukhin D, Poddubskaya E, Andric Z, et al. STELLA Investigators. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. doi: 9. 1007/s40259-021-00483-w.
5. Ambrogelly, A., et al. (2018). “Analytical comparability study of recombinant monoclonal antibody therapeutics.” MAbs 10(4): 513-538.
6. FDA Summary Basis of Approval of Avastin (SBoA). August 2004 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/STN-125085_Avastin.cfm

Efficacy

Similar efficacy shown with Avastin®

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 arms:1

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.1,2

Stella Study Design

Alymsys® was approved based on a totality of evidence, including a comparative study1

References:
1. Trukhin D, Poddubskaya E, Andric Z, et al.. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. doi: 10.1007/s40259-021-00483-w
2. FDA Summary Basis of Approval of MB02 (SBoA). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761231Orig1s000TOC.cfm.

Similar Safety and Immunogenicity
to Avastin® Demonstrated

  • Alymsys® demonstrated similar safety and immunogenicity to Avastin®.1-5
  • There were no new or unexpected safety signals for Alymsys® compared with Avastin®.1-5

Summary of global adverse events of special interest (AESI) grade

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
  • The immunogenicity data showed a comparable incidence between treatment groups supporting the similarity between Alymsys® and Avastin®, with no apparent impact on evaluated efficacy or safety concern.1-4
  • Anti-Drug Antibody (ADA) positive subjects were not associated with serious infusion-related reactions or anaphylactic reactions.1-4
References:
1. FDA Summary Basis of Approval of MB02 (SBoA). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761231Orig1s000TOC.cfm.
2. Trukhin D, Poddubskaya E, Andric Z, et al.. Efficacy, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study (STELLA). BioDrugs. 2021 Jul;35(4):429-444. doi: 10.1007/s40259-021-00483-w
3. Sinn, A, García-Alvarado, F, Gonzalez, V, Huerga, C, Bullo, F. A randomized, double blind, single dose, comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and reference bevacizumab in healthy male volunteers. Br J Clin Pharmacol. 2022; 88( 3): 1063- 1073. doi:10.1111/bcp.15032
4. Eto T, Karasuyama Y, González V, Del Campo García A. A randomized, single-dose, pharmacokinetic equivalence study comparing MB02 (proposed biosimilar) and reference bevacizumab in healthy Japanese male volunteers. Cancer Chemother Pharmacol. 2021;88(4):713-722. doi:10.1007/s00280-021-04324-z
5. Romera, A. et al. Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial. The Lancet Gastroenterology and Hepatology, volume 3, issue 12. 2018.
6. Periodic Safety Update Report (PSUR) For MB02 (Bevacizumab-maly), 22 April 2022

Clinical data

Pharmacokinetics demonstrate bioequivalence to Avastin®

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 treatments1,2:

References:
1. FDA Summary Basis of Approval of MB02 (SBoA). April 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761231Orig1s000TOC.cfm.
2. Sinn, A, García-Alvarado, F, Gonzalez, V, Huerga, C, Bullo, F. A randomized, double blind, single dose, comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and reference bevacizumab in healthy male volunteers. Br J Clin Pharmacol. 2022; 88( 3): 1063- 1073. doi:10.1111/bcp.15032
Avastin® is a registered trademark of Genentech USA, Inc. Alymsys® and Amneal Pathways® are registered trademarks of Amneal Pharmaceuticals LLC.