LB-011 - BIIB091, A NONCOVALENT BRUTON'S TYROSINE KINASE (BTK) INHIBITOR IN DEVELOPMENT FOR TREATMENT OF MULTILE SCLEROSIS (MS): MASS BALANCE, ELIMINATION ROUTE, AND METABOLISM IN HEALTHY MALE PARTICIPANTS.

M. Sheikhy¹, Y. Gu², C. Gu², H. Tsai¹, A. Traube-Childs³, Y. Xu¹; ¹Biogen, Biogen - Cambridge, MA, United States, ²Biogen, Biogen, Cambridge, MA, United States, ³Biogen, Biogen - Maidenhead, England, United Kingdom.

Background: BIIB091 is an oral, potent, selective, noncovalent small molecule BTK inhibitor in development for the treatment of MS. Early clinical studies in healthy participants have shownBIIB091 is safe and well-tolerated. This phase 1 open label study (NCT06311786) was to characterize the absorption, metabolism, and excretion of BIIB091 using radiolabeled drug in healthy male participants, to detect any previously unknown BIIB091 metabolites, and to characterize the pharmacokinetic of one of BIIB091’s metabolites, M23.

Methods: 8 male participants were administered a single 250 mg (100 μCi) dose of [14C]-BIIB091 following overnight fasting. Blood, plasma, urine and feces were collected throughout confinement and analyzed by liquid scintillation counting. Concentrations of BIIB091 and M23 in plasma and BIIB091 in urine were quantified using liquid chromatography with tandem mass spectrometry (LC-MS). Metabolite profiles were evaluated using LC with radioactivity detection, and metabolite identification assessed by LC-MS.

Results: The mean total radioactivity recovered was 76.9% with 8.4% recovery in urine and 68.5% in feces. The total cumulative recovery increased to 82.4% by excluding 1 participant who had anomalous low feces recovery with no fecal samples provided on 2 consecutive days. M23 had a plasma exposure significantly lower than BIIB091 at ~5%. BIIB091 minimally distributed into red blood cells with the mean blood:plasma ratio of 0.575. The metabolism of BIIB91 is not extensive; over 50% of total excreted radioactivity in urine and feces combined recovered as unchanged BIIB091. Individual metabolites detected in urine and feces accounted for less than 10% of dosed radioactivity, including azepane N-dealkylation (M23), methylpyrazole oxidation (M06), oxetane hydrolysis (M09), and several other minor metabolites. Predominant drug-related material in human systemic circulation was parent. No new human circulating metabolite was identified when compared to previous multiple dose studies.

Conclusion: BIIB091 was not extensively metabolized and largely excreted unchanged, with fecal elimination as the major route. Plasma exposure for M23 was significantly lower compared to BIIB091, and no new human circulating metabolites were identified.