Hospital-Compounded Birabresib Capsules for NUT Carcinoma: A Quality- and Risk-Based CMC Strategy

  • Pharm Res. 2026 May;43(5):1455-1470. doi: 10.1007/s11095-026-04081-9.
Maxime Annereau  #  1  2 ,  François-Xavier Legrand  #  3 ,  Maria Virginia Sánchez-Becerra  4  5 ,  Stéphanie Ramos  6  7 ,  Françoise Duperray  8 ,  Lucas Denis  6  3 ,  Christina Sizun  9 ,  Sylvère Durand  10 ,  Valérie Salomon  8 ,  Benjamin Besse  4  5 ,  Bernard Do  6  7
Affiliations
  • 1. Département de Pharmacie Clinique, Gustave Roussy, 94805, Villejuif, France. [email protected].
  • 2. Inserm U1360 - Oncogenesis, Resistance and Therapeutic Targets of Pediatric Cancers, Villejuif, France. [email protected].
  • 3. Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91400, Orsay, France.
  • 4. Département de Médecine Oncologique, Gustave Roussy, 94805, Villejuif, France.
  • 5. Gustave Roussy, Inserm, Prédicteurs moléculaires et nouvelles cibles en oncologie, Université Paris-Saclay, 94800, Villejuif, France.
  • 6. Département de Pharmacie Clinique, Gustave Roussy, 94805, Villejuif, France.
  • 7. Institut Des Sciences Moléculaires d'Orsay, Université Paris-Saclay, CNRS, 91405, Orsay, France.
  • 8. Agence Nationale de Sécurité du Médicament Et Des Produits de Santé, 93200, Saint-Denis, France.
  • 9. CNRS, Institut de Chimie Des Substances Naturelles, Université Paris-Saclay, UPR 2301, 91198, Gif-Sur-Yvette, France.
  • 10. Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Université Paris-Saclay, 94805, Villejuif, France.
  • # Contributed equally.
PMID: 41882454 DOI: 10.1007/s11095-026-04081-9
Abstract

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.

Keywords
Capsule compounding; Non-GMP material qualification; Quality & risk-based CMC framework; Stability program.
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