Biogen Shelves Gosuranemab After Negative Alzheimer’s Trial

Biogen has halted development of gosuranemab, the company’s first anti-tau antibody. The company announced as much in a June 16 release of top-line results of TANGO, a Phase 2 trial that evaluated the immunotherapy in people who had either mild cognitive impairment due to AD, or mild AD dementia. The treatment failed to slow cognitive decline on the clinical dementia rating-sum of boxes (CDR-SB), the trial’s primary efficacy endpoint. It also came up short on all exploratory cognitive measures.

  • Phase 2 TANGO trial missed primary endpoint, i.e., slowing of cognitive decline.
  • The immunotherapy lowered N-terminal tau fragments in CSF.
  • No change in tau accumulation as measured by PET.

The results of the AD trial are the latest in a string of failures for gosuranemab, which also flopped in trials for the primary tauopathy progressive supranuclear palsy (Dec 2019 news). The antibody is trained to tau’s N-terminus, and joins other N-terminal antibodies, including Roche’s semorinemab, in showing no signs of efficacy. The field has since shifted focus to antibodies against tau’s midsection, which houses the aggregation-coaxing microtubule binding domains (Mar 2021 conference news). 

TANGO enrolled 654 people who had evidence of amyloid accumulation. The participants, who ranged from 50 to 80 years of age, were randomized to receive monthly infusions of placebo or low, medium, or high doses of gosuranemab for 18 months. 

The drug was safe and well-tolerated at all doses, but at 18 months had failed on the CDR-SB. None of the treatment groups benefitted on exploratory cognitive measures, either, slipping just as much as the placebo group on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog 13), the Alzheimer Disease Cooperative Study Activity of Daily Living (ADCS-ADL), the Mini-Mental State Examination (MMSE), and the Functional Assessment Questionnaire (FAQ).

Consistent with prior studies, gosuranemab did appear to engage its target, because N-terminal tau fragments dropped in the cerebrospinal fluid of those in the treatment groups. However, the antibody had no effect on tau accumulation as measured by tau-PET scans over 78 weeks.

Biogen terminated the trial, which was previously slated to include a long-term extension. The company also announced that it would discontinue clinical development of gosuranemab.—Jessica Shugart

Comments

  1. In our view, for a tau antibody to work, there are four major hurdles to overcome:

    (i) the blood-brain barrier, given that only an estimated 0.1 percent of peripherally administered therapeutic antibodies enter the brain;

    (ii) the plasma membrane of neurons bearing pathological tau;

    (iii) engagement of an antibody with intraneuronal tau; and

    (iv) clearance of pathological tau (with which the therapeutic antibody has engaged), e.g., via the proteasomal or lysosomal route.

    Evidently, the question is which species of tau to target. This is reflected by the field (uniformly) shifting from phospho- to N-terminal to mid-domain antibodies. Another question is whether (as the above would suggest) intra- rather than extracellular tau should be targeted. We believe that intraneuronal tau should be the target for three reasons: Firstly, extracellular tau is not easily accessible, as it may either be contained in exosomes and other extracellular vesicles, or it may be confined within the synaptic space or shielded by extracellular matrix. Secondly, by the time a treatment is given, tau may already have spread quite significantly. Thirdly, secreted tau is likely truncated and the epitopes of antibody therapeutics are potentially lost. So even when one assumes that tau is spreading via extracellular routes, most of the pathogenic process has become cell-autonomous by the time of diagnosis or better treatment and hence, intraneuronal tau should be preferentially targeted.

    To overcome hurdles (i) and (ii) we are advocating techniques such as therapeutic ultrasound as shown by us and others (references).

    References:

    Leinenga G, Koh WK, Götz J. A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease. Alzheimers Res Ther. 2021 Apr 9;13(1):76. PubMed.

    Janowicz PW, Leinenga G, Götz J, Nisbet RM. Ultrasound-mediated blood-brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody. Sci Rep. 2019 Jun 25;9(1):9255. PubMed.

    Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Götz J. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017 Mar 4; PubMed.

    Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J, Hynynen K, Aubert I. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease. PLoS One. 2010;5(5):e10549. PubMed.

    View all comments by Jürgen Götz View all comments by Rebecca Nisbet

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References

Therapeutics Citations

  1. Gosuranemab

News Citations

  1. Gosuranemab, Biogen’s Anti-Tau Immunotherapy, Does Not Fly for PSP
  2. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore

External Citations

  1. release
  2. TANGO

Further Reading

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