Background

SHR-1707 is a humanized anti-Aβ IgG1 monoclonal antibody that, according to Hengrui Pharmaceuticals, binds to Aβ fibrils and monomers.

No preclinical data is published on this antibody, but Hengrui has claimed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice (e.g. see Yang et al., 2024).

Findings

Two Phase 1 studies, in China and Australia, assessed safety and pharmacokinetics of SHR-1701 in healthy participants (Yang et al., 2024). In China, 50 young adults in five cohorts received 2, 6, 20, 40, or 60 mg/kg SHR-1701 or placebo as an intravenous injection. Twelve elderly participants received 20 mg/kg or placebo.

In Australia, 30 young adults were enrolled in three cohorts receiving 2, 20, or 60 mg/kg. A planned escalation to 80 mg/kg was cancelled after pharmacokinetic analysis revealed a higher drug exposure than anticipated at 60 mg/kg. In both trials, treatment-related adverse events were mainly mild, and mostly similar across antibody and placebo groups. In Australia, one moderate adverse event each was reported with SHR-1707 and placebo. The most common adverse events attributed to the antibody were a bad taste in the mouth and fatigue. Pharmacokinetics were slightly greater than dose-proportional, and similar in young or elderly people. Antibody half-life in blood ranged from six to 10 days depending on dose; CSF levels were not measured. The antibody caused a dose-dependent increase in plasma monomer Aβ42 concentration. Other forms of Aβ were not assessed. No ethnic difference in safety or pharmacokinetics of SHR-1707 was observed. Of 72 people treated, three tested positive for anti-drug antibodies.

Phase 1, multiple-ascending-dose studies are underway. One began In February 2023 at one center in China. The placebo-controlled study will test up to four different doses of SHR-1707 in 41 participants with mild cognitive impairment due to AD or mild AD. The primary outcome is safety up to six months, including MRI imaging. Secondary measures include change in brain amyloid out to 18 months, and anti-drug antibodies.

A Phase 1 of similar design began in Australia in April 2024. It plans to enroll 12 AD patients for a six-month course of SHR-1707 at one dose, or placebo. Outcomes are the same as the China study. Both trials are planned to finish in the second half of 2025.

In February 2024, the company began a Phase 2 study in patients with mild cognitive impairment or mild dementia due to AD. At one site in China, the study plans to enroll 45 patients in four cohorts at 5, 10, 20, or 40 mg/kg SHR-1707, or placebo, every two weeks for six months, followed by a one-year open-label extension (Shi et al., 2023). The primary outcome is safety. Secondary outcomes include change in amyloid PET at six months, and after the long-term extension. Other secondary and exploratory endpoints span serum and CSF pharmacokinetics, antidrug antibodies, biomarkers, and measures of cognition. Completion is slated for June 2026.

For details on SHR-1707 trials, see clinicaltrials.gov