Findings
From December 2014 to April 2016, Bristol-Myers Squibb ran a single-center, single-ascending-dose study in 65 healthy volunteers in Texas and California. This first human trial assessed safety parameters for up to eight months after administration of a single infusion of BIIB092. According to published results, there were no serious or severe adverse events, and all participants completed the treatment (Qureshi et al., 2018). Infusion caused a dose-dependent increase in blood and CSF BIIB092, and a 67 to 97 percent decrease in CSF unbound eTau after four weeks. Doses of 210 mg and higher led to sustained eTau reduction for up to 12 weeks.
In 2015, both the EMA and FDA assigned orphan drug status to this biologic.
In September 2015, a multicenter, multiple-ascending-dose Phase 1b trial in the U.S. began evaluating BIIB092 in 48 patients with progressive supranuclear palsy (PSP). Participants received doses of up to 2,100 mg, infused once every four weeks for 12 weeks, and were assessed for safety, pharmacology, and immunogenicity. The trial ran until October 2016, and offered participants an 18-month, open-label extension study, to run until 2020. At 2017 CTAD, BIIB092 was presented as having been safe and well-tolerated in this trial (Dec 2017 conference news). The antibody showed a dose-dependent accumulation in serum and CSF. There was a marked reduction in CSF free eTau, which exceeded 90 percent for all doses. Reductions averaged 90-96 percent after 29 days of treatment, and 91-97 percent after 85 days. CSF Total tau and phosphorylated tau were unchanged. Results were subsequently published (May 2019 news on Boxer et al., 2019).
In April 2017, Biogen started PASSPORT, a 52-week, 86-site Phase 2 efficacy study comparing 2,000 mg BIIB092 every four weeks to placebo in 490 people with PSP. This trial was to run through September 2019. Primary outcomes include change on the PSP rating scale, which measures movement problems, and safety.
From May 2018 to summer 2019, TANGO, a 105-center global Phase 2 trial in Alzheimer’s disease, enrolled 654 participants with mild cognitive impairment due to AD or mild AD, who had a positive amyloid PET scan. The trial did not require tau PET at screening. The trial compared monthly infusions of three different doses of BIIB092 to placebo for roughly 1.5 years, followed by three years of extended dosing. The primary outcome was the number of adverse events; secondary outcomes included change on the CDR-SB after 1.5 years of treatment, and whether participants develop anti-BIIB092 antibodies. The placebo-controlled phase was to run through 2021, with the long-term extension expected to end in 2024.
In September 2018, investigators at the University of California, San Francisco, began a Phase 1b placebo-controlled "basket" trial of BIIB092 in four different primary tauopathies: corticobasal degeneration, frontotemporal lobar degeneration with MAPT mutations, traumatic encephalopathy, and non-fluent primary progressive aphasia. This trial planned to enroll eight participants with each condition, randomized 3:1 to drug:placebo, for up to six monthly infusions of 2,000 mg antibody or placebo. The primary outcome was safety; secondary outcomes include serum and CSF PK, pharmacodynamic measures of CSF tau, exploratory MRI and CSF biomarkers, and cognitive and functional measures. During recruitment, the CBS and nfvPPA cohorts were increased to 12, and a one-year open label extension added.
On December 13, 2019, Biogen announced that BIIB092 showed no efficacy in the PASSPORT trial. The primary outcome, change on the PSP rating scale, was not significantly different between treatment and placebo after one year, nor were there any significant differences in key secondary endpoints. Biogen ended development of the antibody for PSP and other primary tauopathies in the "basket" trial, but continued the TANGO trial in people with mild cognitive impairment due to AD (Dec 2019 news). Full trial results, published after peer review, confirmed that gosuranemab reduced CSF unbound N-terminal tau fragments by 98 percent, but did not change other exploratory biomarkers, or primary or secondary outcomes (Dam et al., 2021). A subsequent paper on postmortem examination of three PSP patients treated in the Phase 1 or 2 trials reported treatment-related glial responses, including tau accumulation in lysosomes of perivascular astrocytes, but no clearance of neuropathologic tau inclusions compared to unimmunized controls (Kim et al., 2021).
In November 2020, results of the primary tauopathy trial were presented at the CTAD conference. At the time of termination, 25 participants had been randomized; 13 had completed six months of dosing. There were no adverse events attributed to the treatment, which led to a 100 percent decrease in unbound N-terminal tau fragments in CSF. There were no effects on exploratory measures of disease severity.
On June 16, 2021, Biogen announced negative topline results of TANGO (press release; Jun 2021 news and commentary). The antibody failed to change the CDR-SB primary endpoint, and gave no benefit on any of the secondary endpoints, or tau-PET compared to placebo after 1.5 years of treatment. The company terminated both TANGO and development of gosuranemab. At the November 2021 CTAD conference, additional data indicated that treatment led to worsening on the ADAS-Cog13 secondary endpoint. All three dose groups declined more on the cognitive measure than the placebo group. The difference reached statistical significance for those on the highest dose at 18 months (Nov 2021 conference news).
For all clinical trials, see clinicaltrials.gov.
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