First Hit on Aggregated Tau: Antisense Oligonucleotide Lowers Tangles

Series - International Conference on Alzheimer's and Parkinson's Diseases 2023:

With amyloid-lowering treatments in hand, the field's next wish is for a way to clean up tau tangles, the pathological hallmark that correlates more closely with cognitive decline. So far, tau antibodies and aggregation inhibitors have struck out in clinical trials. At the International Conference on Alzheimer’s and Parkinson’s Diseases, held March 28 to April 1 in Gothenburg, Sweden, Biogen researchers debuted the first data showing clearance of tau tangles in the brains of people with AD.

  • Tau antisense oligomer slashes soluble tau by 60 percent in Phase 1.
  • A year of treatment lowered tau tangles across the cortex.
  • A Phase 2 trial will test cognitive and neurodegeneration outcomes.

The drug, BIIB080, is an antisense oligonucleotide that suppresses production of all forms of tau. In a small Phase 1 study, a year of treatment lowered the tau PET signal below baseline in all six cortical brain regions examined. “Reducing tau ameliorates tau aggregates,” Dominic Walsh, who leads neurodegeneration research at Biogen, told Alzforum. “That’s good news for tauopathies.”

The findings traveled quickly through AD/PD’s hallway and bar conversations. The word “phenomenal” was uttered. “Some people might have doubted that reducing soluble tau would reduce the aggregated tau seen on PET,” said Adam Fleisher at Eli Lilly, Indianapolis, adding, “These are groundbreaking findings.” At the same time, researchers cautioned that the number of participants was small, and pointed to questions about effect size and long-term consequences. As was the case with anti-Aβ drugs, whether a slowing of neurodegeneration or cognitive decline will follow this biomarker result remains to be shown.

Bye Bye Tangles. In two people with mild AD (left), tangles (red) worsened over six months on placebo (middle), but cleared up during a year of tau ASO treatment (right). [Courtesy of Dominic Walsh, Biogen.]

This research started at Washington University in St. Louis, where scientists led by Timothy Miller, David Holtzman, and John Cirrito found that in tau transgenic mice, the ASO suppressed seizures, tangles, and neurodegeneration and, in monkeys, lowered tau protein in the hippocampus (Aug 2013 news; Jan 2017 news).

Biogen is trialing the therapy in partnership with Ionis Pharmaceuticals, Carlsbad, California, which makes ASOs for a range of neurodegenerative diseases. Biogen began its Phase 1b trial in 2017, and previously reported that BIIB080 lowered tau in cerebrospinal fluid (Aug 2021 conference news).

Four Regimens. The Phase 1 trial tested four doses, with the lower two featuring a longer gap before the beginning of the open-label extension (top row), and the highest dose testing quarterly administration (bottom row). [Courtesy of Dominic Walsh, Biogen.]

In Gothenburg, Biogen’s Jessica Collins discussed these biomarker data, adding results from the long-term extension and tau PET. The trial enrolled 46 people with mild AD from 12 sites in Canada and Europe. Participants were split into four dose cohorts, receiving either 10, 30, 60, or 115 mg BIIB080 or placebo via injection into the spinal cord. One-quarter of each cohort received placebo. Collins said the participants tolerated treatment well, with all completing dosing and no serious adverse events in treated participants during the placebo-controlled portion of the trial.

In the lower-dose cohorts, of eight people each, participants had their first dose at baseline and then monthly thereafter for three months, i.e., four injections total. After about a six-month gap period, they entered an open-label long-term extension, where all participants received 60 mg quarterly for a year. In these cohorts, CSF p-tau181 and total tau dropped rapidly, and rebounded during the gap. In the 10 mg group, tau biomarkers fell about 30 percent, and rapidly returned to the levels seen in placebo controls. On 30 mg, tau markers dropped further, about 40 percent, and rose only halfway back to control levels during the gap, suggesting a dose-dependent suppression of tau production. These data had been reported before; new at AD/PD were the long-term extension findings. During that year, tau markers fell again, bottoming out at six months of treatment around 60 percent suppressed. These two cohorts did not include tau PET data.

The higher-dose cohorts received either four doses of 60 mg, or two of 115 mg, over three months. In them, effects were slightly stronger. On either regimen, CSF p-tau181 and t-tau fell by 60 percent, and remained flat during a three-month gap period. During the LTE, the cohorts received either 60 or 115 mg quarterly for a year, but their tau markers fell no further, suggesting this represents maximal suppression with this treatment.

In Gothenburg, Collins offered a first peek at tau PET data from the two higher-dose cohorts. Imaging with the MK6240 tracer was done at baseline and six months; it comprised six composite regions that together encompassed the whole cerebral cortex. For participants on placebo, during the initial three-month treatment period, the tau PET signal rose in medial temporal, parietal, cingulate, frontal, and occipital cortices, and was unchanged in temporal cortex. For people who received two 115 mg doses of BIIB080, tangle accumulation slowed in the parietal, cingulate, frontal, and occipital cortices, and dropped slightly in the medial temporal lobe. For those who received four 60 mg doses, the tau PET signal dropped from baseline in all six regions. The effect was small, amounting to 0.2 SUVR in the medial temporal lobe, the region with the greatest effect.

Across The Cortex. A year of open-label treatment cleaned up tangles in most cortical regions examined, regardless of the dose a person had received initially. [Courtesy of Dominic Walsh, Biogen.]

During the year-long LTE, effects were more dramatic, though the cohort was tiny. Only 12 people in the LTE underwent PET. Two who had been on placebo caught up to those in the treatment groups, with similar results across the dozen. The PET signal dropped about 0.6 SUVR in medial temporal and temporal lobes, 0.4 in parietal and occipital lobes, 0.3 in cingulate, and 0.2 in frontal. Importantly, the change in tau PET was associated with total drug exposure in CSF, with the correlation around 0.60 in parietal, medial temporal, and cingulate cortex, 0.50 in frontal, and 0.40 or lower in temporal and occipital.

The findings suggest that tau monomers and aggregates are in equilibrium, such that suppressing monomer production triggers dissociation of aggregates, Walsh said. He added that as aggregates dissolve, tau may be disposed of by normal cellular clearance mechanisms such as the proteasome. A similar dynamic was seen in tau mice in the WashU study (DeVos et al., 2017).

Adam Boxer at the University of California, San Francisco, agreed this is plausible. He noted that the largest changes in tau PET signal occurred in earlier Braak stage regions, where there would be a heavier tangle load. “That makes the data more believable,” he told Alzforum. In future data, he suggested showing baseline tau PET values, as well, to give an idea of the relative reduction in tangles.

But does clearing tangles slow neurodegeneration? This is unknown. Walsh noted that the trial included CSF markers of inflammation and degeneration such as neurogranin, YKL40, and NfL. During the placebo-controlled portion, no dose-responsive differences from baseline were seen, and LTE data are still being analyzed. Likewise with the clinical measures, CDR and CDR-SB, no consistent trends were observed in the initial study, and LTE analysis is ongoing.

The researchers also included MRI to monitor safety issues such as enlarged ventricles, which were seen in a trial of the Huntington’s ASO tominersen; on this measure, too, there were no robust differences. Data from the placebo-controlled portion of the Phase 1 trial is in press at Nature Medicine, and a second paper detailing the LTE CSF and PET tau findings will follow shortly thereafter, Walsh said.

These questions will be better addressed in the Phase 2 trial enrolling now in the United States and Canada. It aims to enroll 735 participants with MCI or mild AD, and will compare two doses of BIIB080 over 72 weeks against a placebo control. The lower dose will be given biannually, the higher both biannually and quarterly. Researchers are testing biannual dosing because that would be less burdensome for clinical use, Collins said in Gothenburg. The primary outcome measure is the dose response on the CDR-SB, but the trial will include numerous other cognitive and biomarker outcomes.

Boxer believes that drugs lowering tau might be most efficacious in pure tauopathies, such as progressive supranuclear palsy or some forms of frontotemporal dementia, where there are no other pathologies to complicate the clinical picture. “We’re interested in testing drugs like this in these populations, where there is arguably an even greater unmet medical need,” he told Alzforum.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. BIIB080

News Citations

  1. In Adult Mice, Reduced Tau Quiets Agitated Neurons
  2. Antisense Oligos Tango with Tau Transcripts to Reverse Tauopathy
  3. Antisense Therapy Stifles CSF Tau in Mild Alzheimer’s Disease

Paper Citations

  1. DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017 Jan 25;9(374) PubMed.

External Citations

  1. tominersen

Further Reading

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