What’s in a name? Quite a lot actually when it comes to substances used in cell and gene therapies

By Jane Byrne contact

- Last updated on GMT

© GettyImages/Artur
© GettyImages/Artur

Related tags: cell and gene therapy, CAR T cell therapy, INN nomenclature

The World Health Organization (WHO), as part of its International Nonproprietary Names (INN) system, has recently made progress in developing and harmonizing the definition paragraphs that support the naming of cell-based substances.

Those efforts are reflected in a newly revised INN application form for cell therapy substances, which was officially approved during the 70th INN Consultation in April 2020.

That version is now mandatory for all new INN applications for gene therapy (GT), cell therapy (CT) and cell-based gene therapy (CGT) substances.

The work was initiated based on the increasing volumes of cell and gene therapy applications the WHO was seeing in relation to INN requests,”​ Massimo Dominici, medical oncology CGT developer and CDMO, scientific founder of Rigenerand, and a member of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations serving the INN Expert Group, told BioPharma-Reporter.

As the cell therapy market exhibits a tremendous growth potential, that will likely translate into a corresponding increase in INN applications, he said.

The INN nomenclature system was originally developed to assign INN mainly to chemically well-defined, homogeneous substances.  However, with the advent of large, complex biologics such as GT, CT and CGT substances, this has changed dramatically, noted Dominici in a landmark review​ of the work the INN CGT working group has undertaken.

He and Raffaella Balocco Mattavelli, head of the INN Team at the WHO, led a session with other colleagues and patient associations on this milestone development regarding nomenclature in advanced therapy medicinal products (ATMPs) during last month’s ISCT annual meeting​, held virtually. 

The challenge

While INN published in the WHO Drug Information​are largely substances conforming to International Union of Pure and Applied Chemistry (IUPAC) nomenclature rules, GT, CT and CGT substances cannot be defined in this way.

Instead, INN around CGT are published together with a textual definition to univocally describe their characteristics. These definitions are an integral part of the INN, and particular importance is therefore allocated to these descriptive paragraphs, as they are the basis for defining the uniqueness of a particular cell substance.

With the advent of new technologies, such as genome editing by, for example, as well as the arrival of personalized medicine, the field is rapidly becoming even more complex.

Data revision

Therefore, to adapt the INN nomenclature, including the definition paragraphs, to these new technologies, a revision of data required for CT/CGT INN requests became indispensable.

However, a precise definition of a substance can only be achieved if the information provided by the applicant is complete and comprehensive.

“Generally in the past, for cell and gene therapy, there was a name without an updated and deep characterization of the product. We have agreed that the companies now have to provide more information on the product from cell type, subset type, mechanism of action, and other forms of functional characterization,”​ said Dominici.

The text would include more precise information on the origin of the starting material. 

The INN experts also emphasize that key steps of the manufacturing process should be provided as well.

“Both the starting material and the manufacturing process become integral parts of the live cell component that constitute the active substance,”​ commented Dominici, when asked about the rationale for the inclusion of such data.

Moreover, the INN working group determined that it would also be important to assess the purity of the substance and to describe the proportion of all major cell populations that contribute to the final product. 

Dominici stressed the interactive nature of the INN process and how that can circumvent any misunderstandings: “It is collaborative, there is a lot of scope for interaction between the applicant and the INN experts if further clarification is sought by either party.”

Enhancing the CGT regulatory process

The precise characterization and naming of CT/CGT substances as part of the regulatory process are especially important, as many cell therapies are marketed directly to patients without appropriate regulatory control, claimed Dominici.

An INN together with a distinct descriptive paragraph helps stakeholders and patients clearly distinguish those unproven cell-based interventions from cell therapies that have undergone a regulatory process, he said.

CAR T-call evolution

CAR T-cell therapies now represent the most prevalent group and comprise half of all CGT related INN applications, according to the WHO.

The field is growing rapidly, and novel CAR T cell products are under development that aim to overcome current issues such as severe toxicity, limited use, and in particular, the lack of efficacy in solid tumors. Among these new technologies are CAR-engineered natural killer cells for cancer therapy and switchable adaptor CAR platforms, which are developed with the aim of improving the safety, flexibility, and controllability of conventional CAR T cells.

The evolution of CAR designs beyond their current conventional structure will mean the INN Program will have to adapt accordingly.

On that, Dominici noted: “We now have a solid foundation on which to move forward and can take account of such new developments as they arise.”

The road to marketing authorization

As INN applications are usually filed during early clinical development, not all of these substances will reach marketing authorization.

Out of around 70 cell therapy and 80 gene therapy substances that have been assigned INN, only six have been approved by the US Food and Drug Administration (FDA), and only 10 had received marketing authorization from the European Medicines Agency (EMA) at the end of 2020, as per the Cytotherapy ​paper.

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