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A phase I, open-label, single-dose, randomized, cross-over study to evaluate BLZ945 granule for suspension in healthy participants: relative bioavailability in comparison to BLZ945 capsule and food effect (CBLZ945C12102)

A study to evaluate the relative bioavailability of drug substance and formulation variants of BLZ945 and food effect in healthy participants (CBLZ945C12102)

36

Out of 36 randomized participants, 34 participants (94.4%) completed the study, while 2 participants (5.6%) discontinued the study. The primary reasons for study discontinuations were protocol deviation (1 participant, 2.8%) and withdrawal by participant (1 participant, 2.8%). The median age of the participants was 34.5 years. All the 36 participants (100%) were male, Asians and belonging to the ethnicity, not Hispanic or Latino. The study population had a median weight of 64.45 kg (SD: 8.54) and a mean body mass index (BMI) of 22.05 kg/m2 (SD: 2.04).

A total of approximately 54 participants (36 participants for Part 1 and 18 participants for Part 2) were planned to be included in the study. Due to early termination only Part 1 was conducted with 36 participants. Part 1 (400 mg dose level): Approximately 18 participants randomized in a 1:1:1 ratio to one of 3 sequences. Treatment sequences consisted of 3 treatment periods. BLZ945 granules were administered under fasted or fed conditions and BLZ945 capsule under fasted conditions. Part 1 (800 mg dose level): Approximately 18 participants randomized in a 1:1 ratio to one of 2 sequences. Treatment sequences consisted of 2 treatment periods. BLZ945 granules and BLZ945 capsules were administered under fasted conditions.

- The single doses of BLZ945 in healthy participants was poorly tolerated. Of the 36 participants randomized, the majority (31 participants (86.1%)) was reported to have at least one TEAE during the study. - TEAEs with Grade >=3 was reported in 10 participants, considered probably related to the study medication. - Two participants randomized to the Treatment Sequence- BLZ945 granule 800 mg fasted/BLZ945 capsule 800 mg fasted experienced SAEs. One had ALT increase, and the other developed jaundice and drug-induced liver injury. - ALT, AST, amylase, bilirubin, lipase, CRP, creatinine, lactate dehydrogenase were the biochemistry parameters most frequently reported outside the normal range. Aside from these, no clinically relevant changes in other clinical laboratory evaluations, vital signs, ECG intervals, and physical examinations were observed after dosing. - Eight participants experienced Grade >= 3 liver enzyme elevations, including increases in ALT and/or AST. One out of the eight participants were reported to have Grade 4 clinical chemistry parameters shifts, which included increases in ALT and AST, accompanied by a Grade 3 increase in bilirubin, resulting in jaundice and drug-induced liver injury. For this participant, the elevations in transaminases and bilirubin met the Hy's law criteria. - There was no death or discontinuation of participants due to TEAEs.

Primary outcome measures - The peak (Cmax) and overall exposures (AUClast and AUCinf) were lower with BLZ945 granules than with BLZ945 capsule at single doses in fasted state in healthy participants. - An overall increase in peak and overall exposure was observed in the fed state when compared to the fasted state following the single dose administration of BLZ945 granules 400 mg (GMR of 1.26, 1.26 and 1.08 for AUCinf, AUClast and Cmax, respectively). Secondary outcome measures - The single doses of BLZ945 in healthy participants was poorly tolerated. Of the 36 participants randomized, the majority (31 participants (86.1%)) was reported to have at least one TEAE during the study. - TEAEs with Grade >=3 was reported in 10 participants, considered probably related to the study medication. - Two participants randomized to the Treatment Sequence- BLZ945 granule 800 mg fasted/BLZ945 capsule 800 mg fasted experienced SAEs. One had ALT increase, and the other developed jaundice and drug-induced liver injury. - ALT, AST, amylase, bilirubin, lipase, CRP, creatinine, lactate dehydrogenase were the biochemistry parameters most frequently reported outside the normal range. Aside from these, no clinically relevant changes in other clinical laboratory evaluations, vital signs, ECG intervals, and physical examinations were observed after dosing. - Eight participants experienced Grade >= 3 liver enzyme elevations, including increases in ALT and/or AST. One out of the eight participants were reported to have Grade 4 clinical chemistry parameters shifts, which included increases in ALT and AST, accompanied by a Grade 3 increase in bilirubin, resulting in jaundice and drug-induced liver injury. For this participant, the elevations in transaminases and bilirubin met the Hy's law criteria. - There was no death or discontinuation of participants due to TEAEs.

The relative bioavailability of two BLZ945 formulations was evaluated in healthy participants. Peak and overall exposure were lower with granule, compared to capsule under the fasted state. In the fed state, granules 400 mg showed higher peak and overall exposure than in the fasted state. Single doses of BLZ945 were poorly tolerated, with most participants experiencing Grade 1-4 TEAEs related to abnormal biochemistry. One participant had jaundice and drug-induced liver injury, considered related to BLZ945.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031230272

Maruyama Hideki

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

rinshoshiken.toroku@novartis.com

Maruyama Hideki

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

+81-120-003-293

rinshoshiken.toroku@novartis.com

Complete

Aug. 14, 2023

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

other

Japanese healthy male and female 18 to 55 years of age, inclusive, and in good health as determined by past medical history, physical examination, vital signs, 12-lead ECG, and laboratory tests at screening and initial baseline.
- Participants must weigh at least 40.0 kg to participate in the study and must have a Body Mass Index (BMI) within the range of 18-30 kg/m2 at screening.
- At screening and initial baseline, vital signs (body temperature, systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the participant has rested at least 3 minutes. Sitting vital signs should be within the following ranges:
- Axillary body temperature, 35.0-37.5 degree
- Systolic blood pressure, 90-139 mm Hg
- Diastolic blood pressure, 50-89 mm Hg
- Pulse rate, 40-90 bpm

- Use of any prescription drugs or herbal supplements within 4 weeks prior to initial dosing, and/or over-the-counter (OTC) medication or dietary supplements (vitamins included) within 2 weeks prior to initial dosing.
- Significant illness, including infectious diseases that has not resolved within 30 days prior to baseline, or positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test results at screening or baseline, or contact with a known case of Coronavirus Disease 2019 (COVID-19) infection in the 2 weeks prior to baseline.
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 14 days after stopping study treatment.
- Sexually active males unwilling to use a condom during intercourse during the study and for 14 days after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.
- Participants unwilling to comply with lifestyle restrictions during the study period.

Both

Healthy participants

- Regimen 1 for Arm 1: BLZ945 will be randomized in a 1:1:1 ratio to one of 3 sequences.
- Regimen 2 for Arm 2: BLZ945 will be randomized in a 1:1 ratio to one of 2 sequences.
- Arm 3: BLZ945 granule will be administered under fasted condition

Primary PK parameters in plasma: AUClast, AUCinf, Cmax

+81-3-6665-0572

July. 28, 2023

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