Therapeutics

BIIB076

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Overview

Name: BIIB076
Synonyms: NI-105, 6C5 huIgG1/l
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Biogen, Eisai Co., Ltd., Neurimmune

Background

BIIB076 is a human recombinant, monoclonal anti-tau IgG1 antibody generated by Neurimmune's reverse translational medicine platform. Biogen acquired it in 2010. 

Initially called 6C5, this antibody targets the mid-domain of tau. It was reported to block tau aggregation in vitro and also to block neuron-to-neuron propagation of tau (Nobuhara et al., 2017). At the 2017 AD/PD and AAIC conferences, Biogen reported that BIIB076 binds with subnanomolar affinity to human and cynomolgus monkey recombinant tau. It recognizes monomeric and fibrillar forms, as well as tau isolated from healthy human and Alzheimer's disease brains.

In young monkeys, a single 100 mg/kg dose of BIIB076 had a half-life in blood of eight to 11 days. It reached maximum CSF concentration in 24 to 48 hours, but its CSF concentration was 1,000 times lower than in plasma. Using ultrasensitive single-molecule array (Simoa) assays to measure tau concentration in blood and CSF, Biogen reported that after BIIB076 administration, plasma total tau rose; CSF total tau stayed unchanged but free tau unbound to BIIB076 dropped 75 percent after 24 hours, returning to baseline after three weeks. This was taken to indicate CNS target engagement (April 2017 conference news). 

A separate toxicity study evaluated three doses of up to 16 times the highest predicted efficacious dose, given intravenously or subcutaneously over the course of a month to 48 young cynomolgus monkeys, and compared to vehicle. Blood and CSF were sampled to measure BIIB076 and tau levels. This study reported no toxicology or pathology findings related to BIIB076, but did report dose-dependent increases in serum BIIB076 levels as well as exposure with subcutaneous delivery. CSF total and free tau were reported to be reduced at the highest doses used (Czerkowizc et al., 2017).

Findings

In February 2017, Biogen started a six-center Phase 1 trial in the U.S., aiming to enroll 56 healthy volunteers and people whose mild or probable AD was ascertained by CSF Aβ42, t-tau, and p-tau levels. This is an ascending-dose study giving a single intravenous infusion; healthy volunteers will be grouped into five successive dosing cohorts, AD patients into two. Primary outcomes were adverse events, clinical labs, vital signs, neurological exam, EKG, and MRI; secondary outcomes include eight pharmacokinetic parameters of exposure and clearance, as well as BIIB076 immunogenicity, all in blood.

In June 2019, the company modified the trial protocol, reducing participant number to 48, dropping the more advanced AD cohort, and adopting adverse events as the sole primary outcome. The trial was completed in March 2020, and results were presented at the 2021 CTAD conference. Twenty-four healthy controls received five doses, six people with AD received one, 12 controls and two AD patients got placebo. Safety issues appeared in the next-to-highest dose, so the investigators backed off for the fifth group, to a dose midway between the third and fourth. The same dose was tested in the AD patients. Most adverse events were mild to moderate, and more common at higher doses. They included headaches, dizziness, nausea, vomiting, and decreased blood pressure. BIIB076 engaged its target, reducing by half the amount of mid-region-bearing tau in the cerebrospinal fluid one week after infusion. The reduction persisted up to three weeks (Nov 2021 conference news).

In July 2022, Biogen announced it had ended development of BIIB076 for business reasons (Q2 earnings call transcript).

For all trials of BIIB076, see clinicaltrials.gov.

Last Updated: 28 Jul 2022

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References

News Citations

  1. More Tau Antibodies Bid Adieu; Semorinemab Keeps Foot in Door
  2. Treating Tau: Finally, Clinical Candidates Are Stepping into the Ring

Paper Citations

  1. Nobuhara CK, DeVos SL, Commins C, Wegmann S, Moore BD, Roe AD, Costantino I, Frosch MP, Pitstick R, Carlson GA, Hock C, Nitsch RM, Montrasio F, Grimm J, Cheung AE, Dunah AW, Wittmann M, Bussiere T, Weinreb PH, Hyman BT, Takeda S. Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro. Am J Pathol. 2017 Jun;187(6):1399-1412. Epub 2017 Apr 11 PubMed.
  2. Czerkowicz J, Chen W, Wang Q, Shen C, Wager C, Stone I, Stebbins C, Lamb M, Setser J, Cantone G, Graham D. Pan-Tau Antibody Biib076 Exhibits Promising Safety and Biomarker Profile in Cynomolgus Monkey Toxicity Study. Alzheimer's & Dementia, July 2017, Volume 13, Issue 7S, Part 26, p1271 Alzheimers Dement.

External Citations

  1. earnings call transcript
  2. clinicaltrials.gov

Further Reading

No Available Further Reading