Telomere related genes (TRG) pathogenic variants are detected in ?30% of familial pulmonary fibrosis (PF). Retrospective cohorts suggested a rapid decline of forced vital capacity (FVC) compared to sporadic IPF despite anti-fibrotic treatment. Danazol, a synthetic sex hormone with androgenic properties, has been associated with telomere elongation and hematological response in TRG mutation carriers. The objective of the phase II ANDROTELO trial (NCT03710356) was to evaluate the efficacy and safety of danazol in TRG mutation carriers with PF and/or bone marrow failure.

ANDROTELO was a multicenter, prospective, phase II open label clinical trial. Patients with pulmonary fibrosis had to be carrier of a pathogenic or likely pathogenic TRG variant and to present a parenchymal involvement ?10% on the CT scan. Patients were planned to receive danazol 400 mg twice a day for a total scheduled treatment period of 12 months.

We included 25 PF patients (16 males) with TERT (n=12), TERC (n=5), PARN (n=2) or RTEL1 (n=6) variant. At inclusion the median age was 62 [36-80], median FVC 69% [40-120] and DLCO 44% [29-84]. Ten patients only achieved the 12 months treatment period. Causes of premature arrest were side effects (=9), death (n=3), lung transplantation (n=1), progression (n=1), withdrew consent (n=1). Fourteen patients were evaluated at M12: the relative decline of FVC was 2 % [1.7;15.6] and of DLCO was 7.4% [0.5;13.0]. The analysis of the other endpoints (telomere length, quality of life, CT scan, hematological response) is in progress.

The ANDROTELO study showed poor tolerance of danazol in this population. Analyzes are ongoing to identify which population may benefit from androgen therapy.