Background

This is an anti-tau IgG4 antibody that grew out of a research collaboration between AC Immune and Genentech, part of the Roche Group. The collaboration focused on approaches that target extracellular, not intracellular, tau. The aim was to explore antibodies with reduced effector function in an effort to limit microglial activation leading to inflammatory responses (Lee et al., 2016). At the 2017 AD/PD conference, Genentech reported that RO7105705 binds the N-terminus of all six isoforms of human tau, both monomeric and oligomeric, regardless of phosphorylation status, and that 13 weeks of treatment with either 3, 10, or 30 mg/kg of the antibody dose-dependently reduced brain pathology while raising plasma tau levels in P301L mice. Chronic dosing was safe in mice or cynomolgus monkeys, Genentech also reported (Apr 2017 conference news). 

Findings

From June 2016 to June 2017, Genentech ran a Phase 1 study of 74 volunteers comprising both healthy controls and people with mild to moderate Alzheimer's disease. Conducted in Tennessee, this trial compared the antibody to placebo on safety, tolerability, pharmacokinetics, and preliminary activity outcomes. It combined single doses, dose escalation, and multiple dosing, given both intravenously and subcutaneously. At the 2017 AD/PD and AAIC conferences, Genentech reported that single doses in healthy volunteers went as high as 16,800 mg, with a 15-day window observed between a given dose and the next-higher dose, and that 70 percent of the subcutaneous doses were bioavailable. Results remained blinded at this point in time, but the trial had not generated serious adverse events; minor AEs related to the drug included bruising and pain at the injection site. RO7105705 plasma half-life was 32 days, and plasma and CSF concentration increased with dose (Apr 2017 conference news; Aug 2017 conference news).

In October 2017, Genentech started TAURIEL, a Phase 2 study in 457 people with prodromal or probable AD ascertained by a positive amyloid PET or CSF Aβ42 finding, and mild symptoms. Participants were randomized to an 18-month course of monthly infusions of placebo or 1,500, 4,500, or 8,100 mg of RO7105705, with a 96-week open-label extension option for those who completed the blinded portion of the trial. This trial used Genentech's tau PET tracer GTP1 at baseline and to measure treatment response at week 73. Primary outcomes are change on the CDR sum of boxes and safety; secondary measures include the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), the new Amsterdam Instrumental Activity of Daily Living questionnaire, the ADAS-Cog13 and ADCS-ADL Inventory, as well as serum drug concentration and anti-drug antibodies. This trial ran at more than 100 locations in North America, Australia, and various European countries.

The placebo-controlled phase completed in July 2020 and in September, Genentech reported top-line results. Semorinemab missed the primary efficacy endpoint of reducing decline on the CDR sum of boxes, and missed on both of two secondary endpoints, the ADAS-Cog13 and ADCS-ADL (press release). According to results presented at the 2020 CTAD virtual conference, there was no change in any other secondary clinical endpoint, either, nor did the antibody slow tangle accumulation in brain relative to placebo. Tau-PET showed a significant increase from baseline in all groups by 12 months, and continued accumulation out to 18 months. Antibody pharmacokinetics were dose-proportional, and the two highest doses elicited maximal increases in plasma tau. The drug was safe. Additional unfavorable biomarker data were presented at AD/PD 2021 (Mar 2021 conference news).

In February 2019, Roche started LAURIET, another Phase 2 study in 272 people with a diagnosis of probable AD confirmed by amyloid positivity via PET or CSF testing, and with moderate dementia. The study comprises a screening, double-blind treatment, optional open-label extension period, and a safety follow-up period. The study was to have up to three cohorts, receiving treatment for 48, 60, or 72 weeks, though the last cohort was never enrolled. Co-primary endpoints are change from baseline on both ADAS-Cog11 and ADCS-ADL; secondary endpoints include CDR-SB, MMSE, adverse events, serum concentration of RO7105705, and anti-drug antibodies to RO7105705. This trial uses GTP1 to monitor tauopathy. It is being run at 50 sites across the United States, France, Poland and Spain. The placebo-controlled part of the study is set to run until May 2021; it has completed enrollment and is continuing despite the TAURIEL result.

On August 31, 2021, the sponsors announced topline results indicating a 43.6% slowing of decline on the ADAS-Cog11 co-primary, though no benefit of the other cognitive or functional outcomes (see Sep 2021 news). A Phase 3 decision is pending additional data from LAURIET's ongoing long-term extension study and biomarker measurements. In November at CTAD, the company showed this trial's data, and reported the treatment did not change tangle accumulation measured by GTP1 PET (conference news).

For all trials with this antibody, see clinicaltrials.gov.