PB2200: FOOD AND ACID REDUCING AGENT EFFECTS ON PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF THE COVALENT BRUTON TYROSINE KINASE INHIBITOR (BTKI) TL-895 IN HEALTHY SUBJECTS

Abstract Topic: 16. Myeloproliferative neoplasms - Clinical

Background: TL-895 is a highly potent, selective, orally available, covalent inhibitor of Bruton tyrosine kinase (BTK) and bone marrow tyrosine kinase X-linked (BMX), under development for treatment of myelofibrosis and chronic lymphocytic leukemia.

Aims: To (i) assess PK and BTK occupancy PD of TL-895 in fasted and fed states, and (ii) evaluate effect of acid reducing agents on TL-895 PK and PD in fed healthy subjects.

Methods: TL-895-204 is an open-label, 4 period study (N=26): Arm A (Reference) 150 mg TL-895 - low fat meal (LFM) (PK/PD); B - high fat meal (HFM) (PK); C - LFM and -10h, +2h staggered steady state (SS) famotidine (20 mg BID, PK); D - LFM and SS omeprazole (40 mg QD, PK/PD).

TL-895-207 is an open-label, crossover study (N=26): Arm E (Reference) 300 mg TL-895 fasted (PK/PD) vs. F: 300 mg with LFM (PK/PD).

Plasma concentrations were determined using validated plasma LC MS/MS assay. PD as % BTK target occupancy in peripheral blood mononuclear cells was measured over 7 days.

PD parameters in arms D vs A, and F vs E were: area under effect curve (AUEC_0-t as h*%), maximum occupancy (BTK%TO_max), time to maximum BTK%TO (TE_max, h), target coverage duration at BTK%TO >90% (TEGT₉₀, h), and BTK resynthesis t_1/2.

Results: TL-895 was well tolerated; no new safety signals were identified. PK with a LFM (A vs F) was dose-proportional for 150 and 300 mg TL-895 doses, with respective geomean (GM) AUC_0-t of 670 and 1213 ng*h/mL and C_max of 257 and 508 ng/mL (Table). Median T_max (2.0-2.5 h) and GM t_1/2 (2.2-2.3 h) were similar for each dose.

After the 300 mg dose of TL-895, AUC was higher and less variable when given with food. The GM ratio (GMR) AUC_0-12 for fed vs fasted (reference) administration (F vs E) was 149% (P=0.012) and for C_max was 111% (ns, P=0.62). T_max was 1 h later with a LFM. After a 150 mg TL-895 dose, meal type (HFM vs LFM, B vs A) did not affect TL-895 PK exposure.

Staggered famotidine (H2-receptor antagonist) did not affect TL-895 exposure (C vs A). TL-895 in combination with omeprazole (proton pump inhibitor [PPI]) (D vs A) had an impact on PK. With SS omeprazole, 150 mg TL-895 GMR AUC_0-t was decreased by ~half (46.8%, P<0.0001) and C_max by ~5-fold (20.9%, P<0.0001). Median T_max was delayed by ~1 h and GM t_1/2 increased from 2.3 to 9.2 h.

After a 300 mg dose, TL-895 AUEC_0-12, BTK%TO_max, TE_max and TEGT₉₀ were not significantly different with LFM vs fasted administration (F vs E). The BTK PD profile following 150 and 300 mg TL-895 doses given with a LFM (A vs F) had similar BTK occupancy, as measured by GM AUEC_0-12 (1008 and 1051 h*%), BTK resynthesis t_1/2 (56.6 and 58.4 h) and BTK%TOmax (95.8% and 97.9%) (Figure).

When administered with omeprazole and a LFM (D vs A), TL-895 GMR AUEC_0-12 and BTK%TO_max were 18% and 8% lower. All evaluable subjects (A) vs 14 of 26 (D) obtained GM BTK%TO_max >90%. Median TE_max increased by 2.0 h (P=0.003) and TEGT₉₀ decreased by 11.2 h (P=0.0002) with omeprazole.

Summary/Conclusion: TL-895 had appropriate PK for a covalent BTKI, with a short t_1/2, long PD effect, and dose-proportional PK. Food increased AUC and decreased PK variability, regardless of meal type, TL-895 is given with food. At 300 mg TL-895, BTK occupancy was similar in fed vs fasted states, with saturable maximum BTK occupancy only incrementally higher than 150 mg. Staggered H2 antagonist dosing at 150 mg TL-895 did not affect TL-895 PK. Omeprazole (PPI) administration with 150 mg TL-895 decreased exposure enough to delay and decrease maximum BTK occupancy, and to decrease the duration of target coverage TEGT_90.

Keywords: Healthy individuals, Pharmacokinetic, Drug interaction, Tyrosine kinase inhibitor