Bryxta™ is a recombinant humanized monoclonal antibody (containing 1337 amino acids) produced in Chinese Hamster Ovary cell line. VEGF is a signal protein which stimulates vasculogenesis and angiogenesis. Bevacizumab binds to VEGF and inhibits its interactions with VEGF receptors (VEGFRs), Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. This results in regression of tumour vasculature and inhibition of new tumour vessel growth.

Bryxta™ is contraindicated in patients with hypersensitivity to Bevacizumab (active ingredient), excipients, Chinese Hamster Ovary (CHO) cell products, recombinant human or humanized antibodies and pregnancy.

Gastrointestinal (GI) perforations and Fistulae, GI-vaginal Fistulae, Non-GI Fistulae, Wound healing and Surgery complications, Hypertension, Posterior Reversible Encephalopathy Syndrome (PRES), Proteinuria, Arterial Thromboembolis, Venous thromboembolism, Hemorrhage, Pulmonary hemorrhage/hemoptysis, Congestive heart failure (CHF), Neutropenia and infections, Hypersensitivity reactions/infusion reactions, Systemic effects following intravitreal use, Eye Disorder, Osteonecrosis of the jaw (ONJ) AND Ovarian failure/fertility.

Women of childbearing potential: Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Bryxta™ is contraindicated in pregnancy. Women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of Bryxta™.

If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate.

Severe migraine if dose ≥ 20mg/kg, IV every 2 weeks

Total 248 subjects randomized in this trial; 169 subjects in Bryxta™ and 79 subjects in Bevacizumab (Originator). Total 52 subjects were enrolled in pharmacokinetic assessment; 28 subjects in Bryxta™ and 24 subjects in Bevacizumab (Originator) to have 20 completed subjects in each group for pharmacokinetic assessment after cycle 1. Of which 13 subjects from Bryxta™ and 16 subjects in Bevacizumab (Originator) completed pharmacokinetic assessment after Cycle 6. The primary endpoint was to compare ORR, the sum of complete response (CR) and partial response (PR) at end of study (Cycle 6, day 127) in Bryxta™ with Bevacizumab (Originator), as assessed by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). The tumor response evaluation for target lesion and non-target lesion in Bryxta™ group was comparable to Bevacizumab (Originator). Majority of subjects had PR (60.00% vs 64.58%) followed by stable disease (30.59% vs 31.25%) at the end of Cycle 6 (Day 127). Summary of best overall response by treatment for per protocol population in Bryxta™ group and Bevacizumab (Originator) group was comparable and majority of subjects showed partial response (62.35% vs 70.83%) followed by stable disease (32.94% vs 29.17%). There was no statistical significant difference (p>0.05) observed between test group and reference group. Bryxta™ and Bevacizumab (Originator) were well tolerated by subjects and comparable in safety profiles. The immunogenicity of Bevacizumab following intravenous infusion of Bryxta™ and Bevacizumab (Originator) in Non-Small Cell Lung Cancer (NSCLC) subjects was assessed. The incidences of immunogenicity in test product treated group were marginally lower compared to the reference drug product treated subjects (59% vs. 73%). The Secondary efficacy variable was to evaluate pharmacokinetics (Cmax and AUC0-t) following IV infusions of Bryxta™ and Bevacizumab (Originator) till Day 22 before the administration of second dose with Bevacizumab in subjects with non-small cell lung cancer (NSCLC) after single dose. The pharmacokinetic assessment of the Ln-transformed Bevacizumab Cycle-1 data showed the 90% confidence intervals for the ratio of the Test geometric least square mean to Reference geometric least square mean are within the 80.00% to 125.00% limits for Cmax (87.99%;120.41%) and AUC0-t (90.70%;122.03%).

Preclinical studies for Bryxta™ were performed as per GLP standards. In acute toxicity studies, Bryxta™ revealed a good safety margin in terms of mortality over the acute dose of 625 mg/kg in mice & 500 mg/kg in rats by intravenous route and were approximately 5X (in mice) and 8X (in rats) of the human equivalent dose. No mortality, apparent signs of toxicity, adverse changes in body weights and gross pathological lesions were noticed in both mice and rats when compared to vehicle control groups. Bryxta™ did not induce any dermal sensitization in guinea pigs. No adverse local tolerance effects were noticed at the site of injection in both rats and rabbits. Comparative studies with repeated biweekly intravenous administration with Bryxta™ was conducted in rats and rabbits over a period of four weeks at dose levels which was 1X, 2.5X & 5X of the human equivalent dose. No differences were noticed in these studies in comparison to reference medicinal product, in both rats and rabbits. No delayed toxicity was noticed during treatment of recovery period of two weeks. The immunogenic response in Bryxta™ treated groups was comparable to that of reference medicinal product treated group. The no observed adverse effect level (NOAEL) of similar biologic of Bevacizumab was considered to be more than 5X of human equivalent dose (310 mg/kg in rats and 155 mg/kg in rabbits) by intravenous administration.

The active Ingredient is bevacizumab and it contains excipients viz; α, α-Trehalose dihydrate, Sodium phosphate monobasic monohydrate, Sodium phosphate dibasic anhydrous, Polysorbate 20 and Water for injections.

Dextrose (5%) solution should not be used since it causes aggregation of the protein.

Its shelf life is 24 months. It should be stored at 2 °C - 8 °C and protect from light. The infusion solution is physically and chemically stable for 72 hrs. (Do not store above 30°C).

Aseptic techniques should be used. Prior to administration, Bryxta™ should be inspected visually for particulate matter and discolouration. The necessary amount of bevacizumab should be withdrawn and diluted to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution for injection. The final concentration should be kept within the range of 1.4 mg/ml to 16.5 mg/ml. Bryxta™ can be diluted with 0.9% sodium chloride solution for injection to a total volume of 100 ml. Any unused medicinal product should be disposed off