As the proteopathic drivers of Alzheimer's disease, Aβ and tau have for decades kept scientists trying to understand which of their isoforms and fragments are most to blame for the memory-robbing pathogenic cascade—and which ones might be the best therapeutic targets. Two oligonucleotide therapies circumvent these thorny questions by taking aim at the transcripts encoding each troublemaking protein. At the Clinical Trials on Alzheimer’s Disease conference, held October 24-27 in Boston, exploratory findings from a trial testing an antisense oligonucleotide aimed at tau suggested that not only did the drug dock tangles, it may also have stemmed cognitive decline. A small interfering RNA that douses APP expression markedly reduced cerebrospinal fluid levels of APP cleavage products, including Aβ40 and Aβ42.

  • Tau antisense oligonucleotide BIIB080 shows tiny trend toward clinical benefit.
  • Small interfering RNA ALN-APP lowered APP fragments, including Aβ, in CSF.
  • Both RNA-targeted therapies seem safe and well-tolerated thus far.

Both drugs were safe and well-tolerated. Both studies were far too small to draw conclusions, but they support the idea of starting larger ones.

Biogen’s latest glimmer of hope on its tau ASO, called BIIB080, follows a splashier reveal a few months ago, when the company reported that the drug reduced parenchymal tangle accumulation, as gauged by tau-PET (Apr 2023 conference news). That the drug reduced existing aggregates, as opposed to merely slowing their accumulation, was both exciting and unexpected to many in the field.

At CTAD, Biogen’s Melanie Shulman reported exploratory clinical outcomes in the same Phase 1b trial and its long-term extension (LTE). The trial's placebo-controlled portion enrolled 46 participants with mild AD. Four ascending doses of BIIB080 or placebo were administered in sequential cohorts via intrathecal injection over a three-month period. The two low-dose groups got 10 and 30 mg of BIIB080 every four weeks, respectively, while the two high-dose groups got 60 mg every four weeks or 115 mg every 12 weeks. Shulman noted an important protocol change: Midway through enrollment of one of the low-dose groups, Biogen changed the trial inclusion criteria from CDR 1 to now also enroll less-impaired people with a CDR of 0.5. Therefore, baseline CDR scores were lower for the two high-dose groups relative to the low-dose groups. Participants were tracked with three clinical tests—the MMSE, FAQ, and RBANS—for an additional six months.

For all three measures, Shulman reported a positive trend: At weeks 25 and 37, participants in the two high-dose groups had declined less than those who received one of the lower doses or placebo.

In the LTE, all participants received either 60 mg every four weeks or 115 mg every 12 weeks for a year, and were then monitored for an additional five months. Thirty-three participants enrolled in the LTE, but only 22 had available cognitive outcome data, including 16 who had transitioned from a high dose and six from one of the low-dose groups. While the high-dose participants transitioned seamlessly into the LTE, those who switched from the low-dose groups had a lag of five to 19 months. These low-dose switchers started the LTE with an average CDR of 4.9 sum of boxes, and their performance on cognitive tests was compared between the start and finish of the LTE. In contrast, cognitive changes in participants who had transitioned from one of the high-dose groups were compared across the entire two-phase study—from MAD baseline, when their CDR-SB scores averaged 3.1, to week 100.

To gauge potential drug effects in this open-label phase of the study, the scientists selected external placebo controls from TANGO, Biogen’s previous trial of gosuranemab (Jun 2021 news). Relative to matched TANGO participants, people who received a high dose of BIIB080 throughout both phases of the trial trended toward slower decline on the CDR-SB, MMSE, and FAQ between baseline and week 100 of the extension (image below). The researchers saw similar trends when they used matched ADNI volunteers as external controls, Shulman reported.

Tantalizing Trends. Volunteers in two high-dose BIIB080 groups (top and bottom) appear to have declined less on the CDR-SB (left), MMSE (middle), and FAQ (right) than external controls. [Courtesy of Biogen.]

Even among the six participants who switched from the low to the high dose in the LTE after a delay, Shulman still observed a whiff of benefit on the CDR-SB and MMSE, but not on the FAQ.

BIIB080 was safe and well-tolerated at the doses tested. Most adverse events, such as headache, back pain, and extremity pain, were deemed related to lumbar puncture, Shulman said.

“The results seem promising and are in the expected direction, but they are too preliminary to draw any firm conclusions,” commented Adam Boxer of the University of California, San Francisco. “The results of the ongoing Phase 2 BIIB080 trial will provide important insights into the mechanistic role of tau pathology in Alzheimer’s disease.” Shulman said the Phase 2 CELIA trial will compare the 60 mg dose of BIIB080 to placebo in 735 people with MCI or mild AD.

Einar Sigurdsson of New York University called the exploratory findings promising. “Collectively, this data, in light of some of the failed tau antibody trials, supports our view that targeting intracellular tau is likely to be more efficacious than focusing solely on extracellular tau,” he wrote to Alzforum (comment below).

Another program is taking aim at APP. At CTAD, Catherine Mummery of University College London presented interim safety and biomarker findings from an ongoing single-ascending-dose (SAD) study of ALN-APP. Developed by Alnylam Pharmaceuticals in Cambridge, Massachusetts, and Regeneron Pharmaceuticals in Tarrytown, New York, this small interfering RNA binds to APP transcripts, relegating them to destruction.

Mummery presented interim data from the first three cohorts, together comprising 20 people with early onset MCI or mild AD. Participants in each cohort were randomized 3:1 to receive placebo or a single dose of 25, 50, or 75 mg ALN-APP, also by intrathecal infusion. Depending on the cohort, participants had so far been followed for six to 14 months with safety assessments and lumbar punctures to measure APP fragments and Aβ peptides.

Previously, the researchers had reported that, within two months of treatment with the two highest doses of ALN-APP, CSF concentrations of both APPα and APPβ—cleavage products of α- and β-secretases, respectively—had plummeted. At CTAD, Mummery extended those findings out to six to 10 months, reporting that although both fragments had started to creep upwards after two months, they remained more than 30 percent reduced relative to placebo.

Mummery also showed Aβ peptide findings. Two months after treatment, the 50 and 75 mg doses reduced CSF Aβ42 and Aβ40 by 50 and 70 percent, respectively. Mummery said that phospho-tau is also being measured to look for amyloid-accumulation-dependent changes in tau processing, but she did not yet have that data.

The treatment appeared safe and well-tolerated at the doses tested, with most of the mild to moderate adverse events attributable to lumbar puncture. Mummery said that analysis of safety biomarkers, routine lab assessments, and preliminary measurements of CSF NfL revealed no concerning or significant responses to treatment. While this study continues to the higher-dose cohorts, a multiple ascending dose study is newly underway.

Michael Weiner, University of California, San Francisco, called the findings exciting. Recalling the cognitive worsening that sank BACE inhibitor programs, he asked Mummery if participants were being monitored for that. Mummery replied that cognition is being closely monitored for safety reasons, and no troubling trends have emerged thus far.

Lon Schneider of the University of Southern California in Los Angeles noted that some scientists believe monomeric forms of Aβ could be neuroprotective. Might ALN-APP counteract those potential benefits? Mummery acknowledged that ALN-APP does reduce all products of APP processing, including Aβ monomers, and that the effects of such a broad reduction are not yet known in humans. APP and its metabolites do have physiological functions, she said, and the drug partially lowers the protein. Careful dosing studies will be essential to address this issue, she agreed.—Jessica Shugart


  1. These are promising exploratory findings that will hopefully be confirmed and extended in the larger ongoing trial. Collectively, this data, in light of some of the failed tau antibody trials, supports our view that targeting intracellular tau is likely to be more efficacious than focusing solely on extracellular tau. Since intraneuronal tau antibodies appear to mostly target tau in degradation pathways, tau ASOs may have an additive effect and perhaps even a synergistic effect with tau antibodies that get into neurons. It would be interesting to explore that possibility in future trials.

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Therapeutics Citations

  1. BIIB080
  2. Gosuranemab
  3. ALN-APP

News Citations

  1. First Hit on Aggregated Tau: Antisense Oligonucleotide Lowers Tangles
  2. Biogen Shelves Gosuranemab After Negative Alzheimer’s Trial

External Citations

  1. Biogen

Further Reading

No Available Further Reading