31 May 2019

As anti-tau antibodies move through clinical trials, Biogen researchers led by Tien Dam publish results from the Phase 1b trial of their antibody BIIB092 in the June Lancet Neurology. This antibody recognizes N-terminal fragments of tau, which are abundant in cerebrospinal fluid. At the 2017 CTAD conference, the company had reported that BIIB092 was safe and well-tolerated in 48 participants with progressive supranuclear palsy (Dec 2017 conference news). In the paper, first author Adam Boxer of the University of California, San Francisco, and colleagues add detail on safety, pharmacokinetics, and target engagement.

Six participants received 150 mg of drug, six received 700, 24 received 1,200 mg, and 12 placebo. All underwent three infusions spaced a month apart. Participants reported some adverse events such as falls, headaches, and urinary tract infections, but none appeared related to treatment. All participants completed the study. BIIB092 accumulated in CSF and serum, with its concentration roughly doubling between the one- and three-month timepoints. The researchers calculated its half-life at 28 days. About 0.5 percent of the antibody ended up in CSF.

All doses of BIIB092 mopped up CSF N-terminal tau, suppressing it by 90 percent or more. There was no dose response. However, a post hoc analysis comparing N-terminal tau to plasma drug exposure teased out a modest correlation, with the lowest exposure squelching N-terminal tau by 91 percent and the highest, 96 percent. The researchers noted that this is the first anti-tau therapy shown to hit its target in PSP patients. They saw no change in exploratory clinical endpoints and biomarkers, including MRI scans and CSF levels of total tau, ptau181, Aβ42, or neurofilament light. This was expected given that treatment lasted only three months. The participants are enrolled in an ongoing extension study. 

Boxer and colleagues cautioned that it remains unclear what form of tau causes toxicity and propagates disease. Recent in vitro studies suggest that antibodies targeting the mid-region of tau may be most effective in slowing disease spread (Apr 2018 conference news). In this study, BIIB092 did not alter levels of mid-domain tau in CSF or serum. Researchers could not measure whether tau tangles in the brain dropped, because current tau tracers do not detect the type of deposit found in PSP (Sep 2016 conference news). Commenting in Lancet Neurology, Jean-Christophe Corvol at Sorbonne University, Paris, and Luc Buée at University of Lille, France, noted that CSF tau levels typically remain low in people with PSP. “Whether tau concentration in CSF is a relevant marker in progressive supranuclear palsy remains to be confirmed,” they wrote.

BIIB092 is now being tested in a one-year Phase 2 trial enrolling 459 people with PSP. The primary outcome will be change on the PSP Rating Scale, which measures movement problems. Biogen is also recruiting for a Phase 1 study in four primary tauopathies: corticobasal degeneration, frontotemporal lobar degeneration with MAPT mutations, traumatic encephalopathy, and nonfluent primary progressive aphasia. This trial will enroll eight participants with each condition, randomized 3:1 to drug:placebo, who will receive six infusions total over 20 weeks.

Finally, an ongoing 18-month Phase 2 trial of BIIB092 in 528 AD patients will measure safety and change on the CDR-SB.—Madolyn Bowman Rogers

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References

Therapeutics Citations

1. Gosuranemab

News Citations

1. In the Running: Trial Results from CTAD Conference 14 Dec 2017
2. To Block Tau’s Proteopathic Spread, Antibody Must Attack its Mid-Region 5 Apr 2018
3. Fluid NfL Shines, Tau PET Dims, in the Hunt for FTD Biomarkers 29 Sep 2016

External Citations

1. extension study
2. Phase 2
3. Phase 1
4. Phase 2

Further Reading

News

1. Can Clinical Trials and Longitudinal Studies Crack Rare Tauopathies? 8 Nov 2018
2. New Antibody Binds to Mid-Region, and Aggregates, of Tau 22 Oct 2018
3. High-Dose Aβ and Tau Immunotherapies Complete Initial Safety Tests 27 Aug 2017
4. SfN: Tau Toxicity in the Limelight 30 Nov 2012
5. Truncated Tau Triggers Tangles, Transmits Pathology 4 Feb 2013
6. Tau Biomarkers—More Informative Fragments in Spinal Fluid? 1 Nov 2013