HPE Biosimilars: Where are we and what is next? - Page 11

rationale to reject the possibility of substitution . If substitution is widely accepted for generic drugs , even sometimes with reticence , why reject it for biosimilars , which are more studied than generics ? The main contentions are the complexity of the biologics , the specificity , or the patients and immunogenicity ; however , these arguments are not applicable , and possibly controversial . Why ?
The complexity is a truism which is verified for all biological drugs regardless of its origin ( that is , originator or biosimilar ). Indeed , the variability between batches is the rule because differences in composition and variability are inherent of all biological substances . For proteins , post-translational modifications are of crucial importance , and for monoclonal antibodies ( mAbs ), several isoforms are produced by the transfected host cells , which correspond to subtle differences such as different glycosylation patterns or the formation of protein chains with or without lysine in the carboxylic terminal ( C terminal ). These differences mainly result from small and uncontrollable modifications in the culture conditions ( pH , pO2 , use of different batches of nutrients , etc ). For example , infliximab naturally contains seven different isoforms , which can be separated by ionic chromatography , and the percentages of which vary from 2.26 ± 0.16 % ( minor component ) to 38.47 ± 1.03 % ( main component without lysine in the C terminal ), the variability corresponding to three different batches . The component in the second highest percentage is an isoform with a lysine at the C terminal ( 23.02 ± 0.49 %). 15 This suggests that each time a different batch is administered to a patient following a renewed prescription , the patient will not receive the same product but a highly comparable one . One might say that for a biologic drug from the same manufacturer , a specific batch is the ‘ biosimilar ’ to another batch , but that prescriber and patient are not aware of this . Thus , because a biosimilar must fall in the batch to batch range of variability of the originator , both biologics will be fully comparable in their composition regardless of the complexity .
The specificity of the patient is not particularly relevant in terms of comparison between biosimilar and originator . Obviously , strong differences might exist between patients in terms of age , sex , pathologies , metabolism , sensitivity to specific drugs , or polymedication . However , in cases of switching , only the drug will be different and not the patient characteristics , and the influence of these individual parameters will be identical . Because both biosimilar and its originator are fully comparable in their structures and thus their properties , there is no reason that differences be observed for the patient if a switch occurs .
Immunogenicity is considered the main problem in switching between originator and biosimilar . Indeed , for many people , when analytics demonstrate that the active moieties in two products are ‘ highly similar ’, then the only ‘ unknown ’ – or residual uncertainty – is immunogenicity . However , the basis of immunogenicity of a drug is often poorly understood . Indeed , for a biologic which is a foreign substance , immunogenicity can differ dramatically from one biologic to another and from one patient to another . The immunogenic response to a foreign protein is related to three main causes : the drug ; the patient ; and , the disease . The drug-related causes are due to :
• The primary structure of the protein and its glycosylation pattern
• The route of administration
• The presence of impurities such as aggregates and remaining protein contaminants ( the so-called host cell proteins ( HCPs )). 16
The primary structure determines why a mAb may be more antigenic than another due to the presence of specific immunogenic sequences . Infliximab is itself more immunogenic than rituximab in the same rheumatic diseases , as demonstrated by the high level of neutralising antibodies directed against infliximab compared with the levels directed against rituximab . But , because a biosimilar has exactly the same primary structure as its originator , the related immunogenic potential will be identical .
For glycosylation , it is well established that the nature of the sugars can play a crucial role in the immunogenicity of glycoproteins . However , for a biosimilar , it is also mandatory to demonstrate that the glycan profiles are comparable to the originator ( through methods including glycan mapping or the determination of sialic acid and fucose residues ). Because these parameters do not differ between the originator and the biosimilar , their related incidences will be the same .
The same conclusion may be reached for the way of administration . It is well known that immunogenicity depends on the route of administration ( the subcutaneous ( SC ) route being more immunogenic than the intravenous ( IV ) route for a same molecule ). In the HannaH pivotal clinical trial for SC trastuzumab registration , the rates of anti-drug antibodies ( ADAs ) against trastuzumab were 7.1 % for the IV route and 14.6 % for the SC route . Moreover , more patients had serious adverse events in the SC group ( 62 of 297 patients ( 21 %)) than in the IV group ( 37 of 298 ( 12 %)). Interestingly , no correlation in terms of efficacy and pharmacokinetics was detected between the two routes of administration . 17 Nonetheless , because the biosimilar is administered by the same route as the originator , the related immunogenicity will be identical .
Thus , the only parameters that can theoretically differ between a biosimilar and its originator would be the aggregate levels and the HCPs , both of which depend on the manufacturing process . However , these parameters must be carefully tested during the development process of a biosimilar and , as for any another characteristic , they must fall in the range of variability of the originator .
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