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Hospital-Compounded Birabresib Capsules for NUT Carcinoma: A Quality- and Risk-Based CMC Strategy
Maxime Annereau1,2, François-Xavier Legrand3, Maria Virginia Sánchez-Becerra4,5
1Département de Pharmacie Clinique, Gustave Roussy, 94805, Villejuif, France. maxime.annereau@gustaveroussy.fr.
Purpose:
NUT carcinoma is an ultra-rare and highly aggressive malignancy lacking authorised systemic therapies. Birabresib, a bromodomain and extra-terminal (BET) inhibitor, has shown preliminary clinical activity; however, its development was discontinued and no GMP-grade active pharmaceutical ingredient or finished product is available. This work describes the hospital-based pharmaceutical development enabling authorised therapeutic use of birabresib in France.
Methods:
Within the French ANSM temporary usage protocol (PUT), a quality- and risk-based Chemistry, Manufacturing and Controls (CMC) strategy inspired by ICH Q8-Q10 was implemented to convert a research-grade material into a qualified drug substance for compounding. An initial batch of birabresib dihydrate underwent comprehensive CMC-like characterisation, including purity, identity, structural confirmation, solid-state properties, residual solvents, and forced degradation to establish a primary chemical reference substance and a stability-indicating analytical method.
Results:
The generated data supported acceptance criteria for subsequent batches and for 20-mg capsules compounded under Good Preparation Practice in a centralised hospital pharmacy. Finished product controls complied with pharmacopoeial and ICH requirements, and capsules were enrolled in a prospective stability programme under PUT-defined storage conditions.
Conclusions:
This risk-proportionate, CMC-oriented hospital framework enabled the first authorised therapeutic use of birabresib in NUT carcinoma and may be extended to other discontinued small molecules used in regulated access programmes for ultra-rare diseases.
Insights
Hospital pharmacists developed a framework to enable the authorized use of birabresib, a bromodomain and extra-terminal (BET) inhibitor, for treating NUT carcinoma. This approach qualifies discontinued drugs for rare cancer patients.
Area of Science:
- Pharmaceutical Sciences
- Oncology
- Drug Development
Background:
- NUT carcinoma is an aggressive cancer with no approved systemic treatments.
- Birabresib (a BET inhibitor) showed early promise but its development was halted, leaving no available GMP-grade drug.
- Access to birabresib was limited due to the lack of an authorized product.
Purpose of the Study:
- To describe the pharmaceutical development of birabresib for authorized therapeutic use in France.
- To establish a hospital-based framework for qualifying a discontinued drug for a rare malignancy.
- To enable patient access to birabresib under a temporary usage protocol.
Main Methods:
- A quality- and risk-based Chemistry, Manufacturing, and Controls (CMC) strategy was applied, inspired by ICH Q8-Q10 guidelines.
- Research-grade birabresib was characterized to establish a reference substance and stability-indicating analytical methods.
- Compounding of 20-mg capsules was performed under Good Preparation Practice in a hospital pharmacy.
Main Results:
- Characterization data supported acceptance criteria for drug substance and finished product batches.
- Finished product controls met pharmacopoeial and ICH requirements.
- Capsules were entered into a stability program under defined storage conditions.
Conclusions:
- A risk-proportionate, CMC-focused hospital framework facilitated the first authorized use of birabresib for NUT carcinoma.
- This model can be adapted for other discontinued small molecules in rare disease access programs.
- Hospital pharmaceutical development is crucial for enabling access to investigational therapies for ultra-rare diseases.
