Learn FDA’s Review of Bio-similar from ABP215

ABP215 is a biosimilar drug developed by Amgen and Allergan, using Avastin (bevacizumab) as a prototype drug. Amgen filed a drug application to the FDA in November 2016. The FDA Oncologic Drugs Advisory Committee (ODAC) met on July 13, 2017, and the members voted in favor of approving the ABP215 drug application. The ABP215 is expected to become America's first Avastin bio-similar drug. Liu Shining, the research manager in TrendForce, pointed out that, in the process of FDA review biosimilar, we can see it’s quite different from the review of new drug. Biosimilar focuses more on the similarities among physical and chemical characteristics, biological functional characteristics, and pharmacokinetics/efficacy, then comes to preclinical and clinical trial data. This is quite different with the innovative drug review which pay more attention on the data in clinical phase II to clinical phase III. In order to confirm the similarity between ABP215 and Avastin, it can be seen from Figure 1 that the two drugs compare ranges of items, and each item involves more than one subdivision analysis items. For example, the primary structure item uses 17 analytical subdivision to confirm the similarity of the amino acid sequence homogeneity and the glycosylation performance. In addition, from the secondary to quaternary structure, VEGFA binding affinity and many other biological function characteristics, also show similarity between the two drugs through a variety of analysis. Overall, although there are some qualitative difference between the two drugs, the subsequent clinical trial data do not show that these differences could lead to differences in clinical efficacy and safety.

Fig1. Comparison of structural and biological function between ABP215 and Avastin

In the clinical trial section, Amgen performed two clinical trials, Study 20110216 (Trial 216) and Study20120265 (referred to as Test 265), as shown in Table 1. The objective of Trial 216 is to observe the pharmacokinetics, safety, immunogenicity of ABP215 and Avastin. Test 265 targets non-small cell lung cancer patients and adds an evaluation assay of efficacy performance.

Table 1. ABP215 Clinical Trial

Test name	Object	Test type	Test design	Number of subjects	Time	clinical trial endpoint
Study20110216	Healthy male	Pharmacokinetics, safety, Immunogenicity	Randomly assigned, single-blind, three-arm, parallel-group	202	85 days	Cmax, AUClet
Study20120265NCT01966003	Non-small cell lung cancer	Efficacy, safety, Immunogenicity	Randomly assigned, double-blind, two-arm, parallel-group	642(ITT)	18 weeks	ORR

The results of the trial 216 show that the pharmacokinetic performance of ABP215, United States approved Avastin and the EU approved bevacizumab, as shown in Figure 2, are all in the 90% confidence interval. The difference between the area average of concentration in blood on the time under the curve of (AUC0-∞, AUC0-t) and the average of maximum concentrations in the blood (CMax) ranged from 80% to 125%, which concluded the similarity of pharmacokinetic performance between the biosimilar and prototype.

Fig 2. Pharmacokinetics of ABP and Avastin

In test 265, the immunogenicity, safety, and efficacy similarity were verified. Immunogenicity data showed that ABP215 did not show a significant increase in the performance of anti-drug antibodies (ADA) compared with Avastin. Clinical data on safety also shows that ABP215 and Avastin are similar in proportion to the occurrence and severity of adverse events. The objective response rate (ORR) is the main clinical trial endpoint, so the risk ratio (RR) of ORR is tested. In order to determine the similarity threshold of RR, the FDA obtained four other randomized data of Avastin. Using meta-analysis analyzed these data and obtained the set of confidence interval of 0.73-1.36. As it can be seen from Table 2, in the intention-to-treat (ITT), the ORR of ABP215 was 39%, while the ORR of the EU approved Avastin was 41.7% and the RR was 0.93 (90% CI: 0.8- 1.09). In fact, the FDA also compared the ORR differences of the per-protocol (PR) (n = 555) ethnic group, whose RR was 0.94 (90% CI: 0.8-1.1); no matter the ITT or PR group, the 90% confidence interval for RR are both within 0.73-1.36. Compared the performance of the progression free survival (PFS) (figure 3), the median PFS of ABP215 was 6.6 months, and the median PFS of Avastin was 7.9 months, the hazard ratio (HR) was 1.03 (90% CI: 0.8-1.34). US FDA integrated ORR, including sensitivity analysis and PFS and other clinical data, and concluded that ABP215 and Avastin clinical manifestations have no significant difference.

Table 2 Comparison of ABP215 with EU approved Avastin in clinical efficacy

Clinical indicators	ABP215 (n=328) N (%)	EU-Avastin (n=314) N (%)
ORR	128 (39.0)	131 (41.7)
Risk ratio (90% CI)	0.93 (0.8-1.09)
CR	2 (0.6)	2 (0.6)
PR	126 (38.4)	129 (41.1)
SD	144 (43.9)	137 (43.6)
PD	21 (6.4)	18 (5.7)

Fig3. Comparison of ABP215 with EU approval of Avastin at PFS

In the ABP215 drug application, although the subject efficacy of clinical trials only tested on non-small cell lung cancer, Amgen applied approval for indications included metastatic colorectal cancer (and with different chemotherapy drugs in the first, second line treatment), non-small cell lung cancer, pleomorphic glioblastoma, metastatic renal cell carcinoma and cervical cancer. Considering: 1. Similarities between ABP215 and Avastin in the structure, biological function and clinical manifestations; 2. Avastin function mechanism (MoA) has no difference in the indications; 3. The pharmacokinetic of Avastin has been shown consistent in each indication; 4. Avastin's toxicity is known and the cause of the side effects is same in all indications, and the data of ABP215 and Avastin's for adverse events are similar. Thus, the Tumor Drugs Advisory Board voted ABP215 to be approved based on scientifically justification and extend to other indications. It is expected that ABP215 may be able to acquire US Biosimilar Certificate on or before September 2017, which means that the entry to the market is permitted. But the challenges are still huge, including patent disputes and market share and other aspects are still waiting for overcome.