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A Phase I Single Ascending Dose Study of RO7126209 in Healthy Japanese Subjects

A Phase I Single Ascending Dose Study of RO7126209 in Healthy Japanese Subjects

32

32 healthy male volunteers (HVs)

Cohort 1: 6 subjects on 0.4 mg/kg RO7126209, 2 subjects on placebo Cohort 2: 6 subjects on 1.2 mg/kg RO7126209, 2 subjects on placebo Cohort 3: 6 subjects on 3.6 mg/kg RO7126209, 2 subjects on placebo Cohort 4: 6 subjects on 7.2 mg/kg RO7126209, 2 subjects on placebo

Out of the 32 HVs, 7 of 8 subjects who received placebo experienced at least one adverse event (AE), 20 of 24 subjects who received RO7126209 experienced at least one AE. Among the subjects who received placebo, reported AEs were post lumbar puncture syndrome (6 subjects), rash (2 subjects), blood triglycerides increased and C-reactive protein increased (1 subject each). Among the subjects who received 0.4 mg/kg RO7126209, reported AEs were post lumbar puncture syndrome (4 subjects) and otitis externa (1 subject). Among the subjects who received 1.2 mg/kg RO7126209, reported AEs were infusion-related reaction (IRR) (3 subjects), post lumbar puncture syndrome (2 subjects) and back pain (1 subject). Among the subjects who received 3.6 mg/kg RO7126209, reported AEs were IRR (6 subjects), post lumbar puncture syndrome (2 subjects), back pain, blood creatine phosphokinase increased and headache (1 subject each). Among the subjects who received 7.2 mg/kg RO7126209, reported AEs were IRR (5 subjects), post lumbar puncture syndrome, alanine aminotransferase increased, aspartate aminotransferase increased, CSF white blood cell count increased, iron binding capacity unsaturated decreased and abnormal sensation in eye (1 subject each). Among the 24 RO7126209-treated subjects, the RO7126209-related AE which was reported by two or more subjects was IRR (14 subjects). Among the 8 placebo-treated subjects, 1 subject experienced one AE related to study treatment (rash). All AEs were Grade 1 or 2. The Grade 2 AEs were post lumbar puncture syndrome [placebo (n=6), 0.4 mg/kg RO7126209 (n=4), 1.2 mg/kg and 3.6 mg/kg RO7126209 (n=2 each) and 7.2 mg/kg RO7126209 (n=1)], IRR [7.2 mg/kg RO7126209 (n=1)], back pain [1.2 mg/kg RO7126209 (n=1)], otitis externa [0.4 mg/kg RO7126209 (n=1)]. There were no deaths, serious adverse events (SAEs), AEs of severe intensity, or AEs leading to study discontinuation. RO7126209 had an acceptable safety profile.

Primary outcome measures: Safety and tolerability Refer to "Adverse events" Secondary outcome measures: Plasma concentration and PK parameters of RO7126209 Following IV infusion of RO7126209 at doses ranging from 0.4 to 7.2 mg/kg, the geometric mean Cmax was 6.50 mcg/mL (0.4 mg/kg RO7126209), 25.2 mcg/mL (1.2 mg/kg RO7126209), 76.1 mcg/mL (3.6 mg/kg RO7126209), and 160 mcg/mL (7.2 mg/kg RO7126209) each. The geometric mean AUC0-inf was 369 mcg- hr/mL (0.4 mg/kg RO7126209), 1210 mcg- hr/mL (1.2 mg/kg RO7126209), 3560 mcg- hr/mL (3.6 mg/kg RO7126209), and 7980 mcg- hr/mL (7.2 mg/kg RO7126209) each. RO7126209 exposures after single doses increased with increasing doses in a dose-proportional manner in terms of AUC0-inf and Cmax in the dose range tested (0.4 mg - 7.2 mg/kg). Cerebrospinal fluid (CSF) concentration of RO7126209 CSF pharmacokinetic samples were taken either on Day 3 or on Day 6 for the measurement of RO7126209 CSF concentrations. The mean RO7126209 CSF/plasma ratios appeared to be dose-independent with the mean ratios ranging from 0.524% to 1.71% (from 0.524% to 0.681% on Day 3 and from 0.823% to 1.71% on Day 6). Inter-subject variability (CV% geometric mean) was generally low to moderate for the RO7126209 CSF/plasma ratios, 19.7% on Day 3 and ranging from 24.1% to 34.0% on Day 6. Incidence of anti-RO7126209 antibodies Of the 24 subjects who received RO7126209 at any of the doses investigated and had a post-baseline ADA assay result, 15 subjects (62.5%) [0.4 mg/kg RO7126209 (n=3), 1.2 mg/kg RO7126209 (n=5), 3.6 mg/kg RO7126209 (n=4) and 7.2 mg/kg RO7126209 (n=3)] showed positive results in confirmatory test of ADA. Although one subject received 3.6 mg/kg RO7126209 showed the detectable value of >100 titer, there was no effect on pharmacokinetics.

A single IV dose of RO7126209 (0.4, 1.2, 3.6, 7.2 mg/kg) had an acceptable safety profile in healthy Japanese subjects. In addition, RO7126209 exposures after single doses increased with increasing doses in a dose-proportional manner in terms of plasma AUC0-inf and Cmax in the dose range tested (0.4 mg - 7.2 mg/kg).

Yes

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https://jrct.mhlw.go.jp/latest-detail/jRCT2031210091

Nanki Toshihiro

Division of Rheumatology, Department of internal Medicine, Toho University School of Medicine

1-1 NIHONBASHI-MUROMACHI 2-CHOME, CHUO-KU, Tokyo

clinical-trials@chugai-pharm.co.jp

Clinical trials information

Chugai Pharmaceutical Co., Ltd.

1-1 NIHONBASHI-MUROMACHI 2-CHOME, CHUO-KU, Tokyo

+81-120-189-706

clinical-trials@chugai-pharm.co.jp

Complete

July. 07, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Written informed consent.
2. Healthy Japanese man who is 20 to 40 years of age at the time of informed consent.
3. Individuals who are judged to be healthy based on their medical, history surgical history, or physical examination.
4. Body mass index (weight [kg]/[height [m]2) of 18.5 to 25.0 kg/m2 at screening.
5. Individuals who have agreed to abstinence or to use contraception methods and to refrain from sperm donation during the study treatment period and for a certain period after administration of the investigational drug.

1. Individuals with cardiovascular, renal, hepatic, gastrointestinal, immunological, neurological, endocrine, metabolic, cerebrovascular, or bronchopulmonary diseases and individuals with a history of these diseases and disorder kidney, liver, or cardiorespiratory function.
2. Individuals affected by hypersensitivity to biological products or excipients in pharmaceutical products.
3. Subjects who participated in any clinical trial within 4 months before administration of the investigational product and who received the investigational product (including placebo).
4. Individuals who have received or have taken prescription drugs within 1 month before administration of the investigational product.

Male

Alzheimer's disease

RO7126209 (trontinemab) : RO7126209 will be administered once intravenously at designated dose

safety
Observation

safety
Measurement

+81-3-5213-0028

May. 27, 2021

none