A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers.

Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of >18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time- or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.).

Lim JJ ，Derby MA ，Zhang Y ，Deng R ，Larouche R ，Anderson M ，Maia M ，Carrier S ，Pelletier I ，Girard J ，Kulkarni P ，Newton E ，Tavel JA ... -  《-》

Two Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Studies To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza A Virus Monoclonal Antibody, MHAA4549A, in Healthy Volunteers.

Hospitalized patients with severe influenza are at significant risk for morbidity and mortality. MHAA4549A is a human monoclonal immunoglobulin (Ig) G1 antibody that binds to a highly conserved stalk region of the influenza A virus hemagglutinin protein and neutralizes all tested seasonal human influenza A virus strains. Two phase 1 trials examined the safety, tolerability, and pharmacokinetics of MHAA4549A in healthy volunteers. Both single ascending-dose trials were randomized, double blinded, and placebo controlled. Trial 1 randomized 21 healthy adults into four cohorts receiving a single intravenous dose of 1.5, 5, 15, or 45 mg/kg MHAA4549A or placebo. Trial 2 randomized 14 healthy adults into two cohorts receiving a single intravenous fixed dose of 8,400 mg or 10,800 mg of MHAA4549A or placebo. Subjects were followed for 120 days after dosing. No subject was discontinued in either trial, and no serious adverse events were reported. The most common adverse event in both studies was mild headache (trial 1, 4/16 subjects receiving MHAA4549A and 1/5 receiving placebo; trial 2, 4/8 subjects receiving MHAA4549A and 2/6 receiving placebo). MHAA4549A produced no relevant time- or dose-related changes in laboratory values or vital signs compared to those with placebo. No subjects developed an antitherapeutic antibody response following MHAA4549A administration. MHAA4549A showed linear serum pharmacokinetics, with a mean half-life of 22.5 to 23.7 days. MHAA4549A is safe and well tolerated in healthy volunteers up to a single intravenous dose of 10,800 mg and demonstrates linear serum pharmacokinetics consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (These trials have been registered at ClinicalTrials.gov under registration no. NCT01877785 and NCT02284607).

Lim JJ ，Deng R ，Derby MA ，Larouche R ，Horn P ，Anderson M ，Maia M ，Carrier S ，Pelletier I ，Burgess T ，Kulkarni P ，Newton E ，Tavel JA ... -  《-》

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies.

SHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects. Two randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18-45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55-80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg). Sixty-two (part 1/2, n = 50/12; age range, 18-42/55-63 years) and 30 subjects (age range, 18-42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2-60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed. A single intravenous dose of SHR-1707 at 2-60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development. NCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

Yang Y ，Qiu H ，Fan Y ，Zhang Q ，Qin H ，Wu J ，Zhang X ，Liu Y ，Zhou R ，Zhang Q ，Ye Z ，Ma J ，Xu Y ，Feng S ，Fei Y ，Li N ，Cui X ，Dong F ，Wang Q ，Shen K ，Shakib S ，Williams J ，Hu W ... -  《Alzheimers Research & Therapy》

Safety and tolerability of a humanized rabbit monoclonal antibody (SSS07) in healthy adults: Randomized double-blind placebo-controlled single ascending dose trial.

SSS07, a humanized rabbit monoclonal antibody, can selectively block human tumor necrosis factor-α (TNF-α). The objective of this study was to assess the safety, tolerability, and relative immunogenicity of SSS07 after multiple single subcutaneous (SC) doses in healthy volunteers. A total of 71 healthy volunteers were randomized to six sequential ascending-dose groups (5, 15, 30, 50, 75, and 100 mg), and except for the 100 mg group that only had one subject who received a placebo, all of the other groups included two placebo-control subjects. Safety, tolerability, and immunogenicity were assessed by physical examinations, vital signs, electrocardiography (ECG), clinical laboratory tests, and plasma anti-drug antibody (ADA) over 28 days for each group. Their concentrations of TNF-α were also analyzed. Only after safety and tolerance were determined in the lower-dose groups was the next dose group initiated. The dose increments did not exceed 100 mg. No serious adverse events or dose-limited toxicity (DLT) were observed, so 100 mg was defined as the maximum tolerated dose (MTD). Overall, 71 AEs and 59 treatment-related adverse events (TRAEs) were reported in 36 (60.0%) and 30 (50.0%) volunteers, respectively, who received SSS07. All AEs and TRAEs were mild or moderate and expected based on previous results with similar types of drugs, without new safety concerns. Except for infections and administration site reactions, the frequency and intensity of the other TRAEs were similar for SSS07 and placebo. No severe acute immune reactions occurred. The lower dose's immunogenicity was stronger than the higher doses. The highest ADA titer was observed 3 to 6 months after administration. SSS07 was generally safe and well tolerated in healthy Chinese volunteers. Higher immunogenicity was observed at low SSS07 concentration levels. The infections and administration site conditions might have been related to the immunogenicity and the degree of inhibition of TNF-α. However, the existence of ADA did not appear to affect the safety of the subjects throughout the follow-up period. These findings could support further investigations of treatments with humanized monoclonal antibodies.

Liu C ，Dong W ，Xia L ，Lv J ，Jiang D ，Wang Q ，Wang M ，Wu M ，Miao J ，Tao T ，Wang D ，Zheng L ，Su S ，Liu L ，Fang Y ... -  《-》

Pharmacokinetics of MHAA4549A, an Anti-Influenza A Monoclonal Antibody, in Healthy Subjects Challenged with Influenza A Virus in a Phase IIa Randomized Trial.

Deng R ，Lee AP ，Maia M ，Lim JJ ，Burgess T ，Horn P ，Derby MA ，Newton E ，Tavel JA ，Hanley WD ... -  《-》