P123: Regulatory CMC Trends in Bispecific Antibody Development
Poster Presenter
Jessica Miller
1st-Year Fellow, Global Regulatory Affairs CMC
GlaxoSmithKline United States
Objectives
To review the regulatory CMC trends associated with developing and manufacturing bispecific antibody (bsAb), inform sponsors of factors that should be considered in their own bsAb development programs, and identify where additional guidance is needed from agencies.
Method
Data were collected via review of relevant literature, FDA-approval documents, Drugs@FDA database, and EMA approval documents (EPAR) from the EMA website.
Results
T-cell engagers (TCEs) are gaining favor for use in cancer treatment as they exert anti-tumor effects despite some of the common methods of tumor evasion. The mechanism of action of TCEs facilitates high-potency tumor cell killing, resulting in the need for lower doses when used as treatment. Seven of the nine (78%) currently approved bsAbs are TCEs: blinatumomab, amivantamab, tebentafusp, mosunetuzumab, teclistamab, epcoritamab, and glofitamab. All TCEs listed here are approved in both the US and EU. Six of the seven (86%) currently approved TCEs received approval via an expedited development program (including fast track designation, accelerated approval, breakthrough therapy designation, and priority review) in the US and/or EU. Five of the seven (71%) currently approved TCEs are granted Orphan Drug Designation in the US and/or EU. Common US and EU CMC Post-Marketing Commitments include development and/or validation of analytical assays, provision of data from container closure leachable studies, reevaluation of drug substance (DS) and drug product (DP) specifications after a certain number of commercial batches have been manufactured, and development and implementation of additional endotoxin risk mitigation measures. US FDA Type B pre-BLA meetings were requested and mid/late marketing application review cycle meetings with health authorities were utilized by sponsors to obtain feedback on CMC contents of the BLA/MAA. Questions from sponsors to the agencies primarily focused on the following topics: use of clinical batches or commercial batches for submission of stability data; submission of additional stability data during the review period; clarification regarding items to be included in the DS and DP comparability package; how to set specifications for subvisible particles to be compliant with pharmacopeial requirements; and timing of site inspections.
Conclusion
The advantages of TCEs make these bsAbs ideal candidates for drug development, particularly through expedited development programs and/or Orphan Drug Designation. As a result, TCEs are the most common type of bsAb developed thus far. Additional analytical assays, above the standard assays for traditional mAbs, may need to be developed to demonstrate control due to the unique structure and attributes of bsAbs. Questions asked to regulators for TCEs in preparation of marketing applications were very similar to those typically asked for traditional mAbs, indicating that bispecific technical issues were not a major obstacle at the stage of commercial filing or were resolved with the health authority earlier in development. Additionally, with the increasing number of TCEs both on the market and in development, and thus a greater precedence for the basis of new approvals, this type of bsAb may become a more attractive venture for sponsors and sponsors may be encouraged to pursue their development in a wider range of markets.
