14 Nov 2024

The fifth time may be the charm for antibodies targeting tau. At the 16th Clinical Trials on Alzheimer’s Disease conference, held October 29 to November 1 in Madrid, Brussels-based UCB Pharma presented the first signal that a monoclonal antibody might be slowing the progression of tau pathology in the brain, at least in some people. Its drug, bepranemab, did not improve symptoms in the full trial population, but it did offer a signal of clinical benefit in people with low baseline tau levels and no ApoE4. On balance, researchers at CTAD were hopeful that bepranemab, or similar candidates, could mark the beginning of a new Alzheimer's treatment strategy.

“It’s an important milestone for the field,” Adam Boxer, University of California San Francisco, told Alzforum. Not only are tau antibodies promising as treatments, Boxer said, but the results also suggest that tau seeding and propagation through the brain plays an important role in driving Alzheimer's clinical symptoms. This would open the door to better understanding the disease mechanism. “There is now clear experimental evidence–not just in animals or cell culture—that tau transmission extracellularly is doing something,” Boxer said.

“I think it’s really promising finally to see an antibody against tau moving the needle,” Rakez Kayed, University of Texas Medical Branch, Galveston, told Alzforum.

Immunotherapy against tau, given either alone or in combination with anti-amyloid antibodies, has been a goal of many companies for years. That said, four earlier antibodies showed no effect on either tau clearance or symptoms in clinical trials. They all targeted the protein’s N-terminal region, which may have been the reason they failed, said bepranemab developer Martin Citron of UCB, Brussels. While they engaged their targets well, later data suggested that this end of tau is cleaved off before tau aggregates, and likely irrelevant to the disease process.

Most of the current generation of investigational tau antibodies, including bepranemab, bind at or near a central part of the protein known as the microtubule binding region. The MTBR is important for tau aggregation, and some scientists think it may be the source material of tau seeding in the brain (Mar 2021 conference news; Apr 2018 conference news).

Most discontinued anti-tau antibodies (red) targeted tau’s N-terminus. Of the antibodies currently in trials (green), bepranemab and E2814 presented results at CTAD, while JJ-63733657/posdinemab and PRX005/BMS0986446 presented trial designs. Active vaccines in blue. [Courtesy of Translational Neurodegeneration.]

In their October 31 talks at CTAD, Citron and Matthew Barton, UCB, presented the first data from the company’s Phase 2 TOGETHER trial in 466 people with prodromal to mild Alzheimer's disease. The trial missed its primary endpoint of improving cognition and function as measured by the CDR-sum of boxes in the full trial population.

Randall Bateman, Washington University, St. Louis, welcomed the results in the low-tau group. He noted that anti-amyloid antibodies also tend to work best at this stage of disease. “It may be now a question of can you find the right population to treat with this kind of antibody, and get the right timing so that you can prevent the growth and spread of tau pathology?” he told Alzforum.

Citron told Alzforum that UCB is still deciding whether it will evaluate bepranemab in another Phase 2 trial specifically in an early tau population before moving to a pivotal Phase 3 study.

Michelle Farrell, Massachusetts General Hospital, Boston, said that the discrepancy in the bepranemab trial between the high and low tau groups support Keith Johnson’s hypothesis of a “cataustrophe,” whereby tangles accumulate in the medial temporal lobe before symptom onset, then, somehow in conjunction with amyloid plaques, suddenly spread more quickly across the cortex and trigger a cascade of subsequent pathologies (Apr 2022 news; Johnson et al., 2020).

Treating people before this happens might be key, Farrell told Alzforum. “There may be an element where once things get moving, it’s hard to stop.” She added that low tau pathology burden does not always correspond with mild symptoms, hence PET or fluid biomarkers might be more useful than clinical measures in determining whether a person is likely to benefit from immunotherapy. “That is an important component when we’re thinking about who we should be targeting for these trials,” Farrell said.

While bepranemab’s results in the low tau subgroup made sense to scientists at CTAD, the trial’s finding that the drug had no measurable effect in people with the ApoE4 genotype mystified them. Scientists still debate whether ApoE4 affects tau propagation or tau’s role in driving clinical symptoms. Mouse and some human experimental data suggest that the isoform accelerates tau seeding and tau-mediated neurodegeneration independent of Aβ pathology. (e.g., Shi et al. 2017; Koutsodendris et al., 2023). ApoE4 carriers also start depositing amyloid plaques up to a decade earlier than noncarriers, hence their AD pathogenesis might have been more advanced. Barton did not relate participants’ outcomes to their baseline amyloid load, but Citron said these analyses would be done.

Other drug developers are trying to get a handle on the proposed cataustrophe as well. Monitoring tau spread is a distinctive ambition of the ongoing Autonomy Phase 2 trial for posdinemab. This antibody targets phosphorylated tau near the p217 site in tau’s proline-rich mid-domain region just upstream of the MTBR. At CTAD, David Henley, Janssen, Titusville, New Jersey, reported that this trial, which began in 2021, has enrolled 523 people with intermediate levels of tau pathology in their temporal lobes. The trial randomized participants into high dose, low dose, and placebo groups and will treat each person once a month for two to four years. Using tau PET, the study is tracking how each participant’s tau spreads into regions of their brain where it previously had not been seen, rather than only measuring the overall tau burden in a participant’s brain. The hope is that tangles will spread less in people receiving antibody than placebo. The trial will also assess clinical measures.

Janssen screened participants using a Ptau217 blood test (see upcoming story in CTAD series), which Henley said halved the number of required PET scans.

Companies besides UCB and Janssen are also going after tau. Kristin Wildsmith, Eisai, Nutley, New Jersey, presented results for an open-label, ascending-dose trial of E2814, an antibody that has two separate binding sites in the MTBR. Completed in May 2024, this study was conducted in eight people with autosomal-dominant Alzheimer's who already had mild to moderate symptoms at the study’s start.

In her CTAD presentation, Wildsmith added further data to an earlier presentation by Jin Zhou of Eisai on this trial, which was designed to assess safety and target engagement (Aug 2023 conference news) The participants received the drug for up to 26 months, though five of them dropped out along the way. Comparing their course to the disease progression seen in otherwise matched participants in the DIAN observational study (DIAN-OBS), Wildsmith estimated that E2814 cut the CSF pTau217 concentration in half over the course of two years of treatment. Three people remained in the trial long enough to undergo brain scans, which trended toward a reduction in tau PET, though Wildsmith noted that some of this may be due to atrophy.

Bateman, who leads the DIAN initiative, acknowledged that the numbers are too small to be conclusive, and an Eisai spokesperson confirmed that the data largely serve to inform current E2814 trials. The Phase 2/3 NexGen trial run by the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) has finished enrolling its 197 participants; results are expected in 2028. Another Phase 2 study in 90 participants with sporadic MCI due to AD started up in September 2024 and is currently enrolling.

Last but not least, CTAD saw mention of another Phase 2 trial of a tau antibody. Similar to E2814, BMS-986446 binds to tau’s MTBR, regardless of whether the protein is phosphorylated. The 18-month TargetTau-1 started enrolling people with mild cognitive impairment or mild Alzheimer's pathology in March 2024, Chris Van Dyck, Yale University, told the audience.

Thus far, all of the tau antibodies seem to be safer than anti-amyloid antibodies, which can cause ARIA. Bepranemab is an IgG4 that doesn’t fully activate the immune system; posdinemab, E2814 and BMS-986446 are IgG1s that have full effector function, i.e. activate microglia in hopes of more protein clearing.

Citron, and many others, believe that it is time to test tau antibodies in combination with amyloid antibodies. “We've been hammering away at amyloid for 30 years, and one thing we understand pretty well now is that, with amyloid clearance, we are maxing out slowing of disease progression at about 30 percent,” he said. At CTAD, a panel discussion featured debate about the promise and design challenges of combination trials. Notably, DIAN-TU’s NextGen trial and the new E2814 trial are already testing this tau antibody concurrently with lecanemab.

For his part, Boxer has been planning for some years to launch the Alzheimer’s Clinical Trial Consortium tau platform trial, aka ATP, to test two tau therapies alone or in combination with amyloid drugs (Aisen et al., 2021; Nov 2021 conference news). He hopes ATP will start up in 2025. In Madrid, Boxer said that ATP will initially enroll 750 people with late preclinical to prodromal Alzheimer's, with a primary endpoint of slowing tau accumulation as per PET over two years. The researchers will also look at blood and CSF biomarkers and clinical decline, and will add another 150 participants when they begin testing a second tau therapy. Boxer declined to say which drugs will be tested.

Kayez said that for all tau antibody development, researchers may want to look at postmortem brains to determine whether the antibody at hand is targeting all forms of aggregated tau or only those that can be seen on PET imaging. “Despite all the positives, I think important questions still need to be addressed,” he said.—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

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References

Therapeutics Citations

1. Bepranemab
2. Posdinemab
3. BMS-986446

News Citations

1. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore 27 Mar 2021
2. To Block Tau’s Proteopathic Spread, Antibody Must Attack its Mid-Region 5 Apr 2018
3. From Near and Far, Aβ Beckons Tau to Tangle in the Cortex 28 Apr 2022
4. CSF MTBR-tau-243 Tracks Tangles, Plummets in Response to Antibody 31 Jul 2023
5. More Tau Antibodies Bid Adieu; Semorinemab Keeps Foot in Door 23 Nov 2021

Paper Citations

1. Johnson K et al. Critical threshold of elevated amyloid associated with rapid tau accumulation: a ca-tau-strophe in the making. HAI Book 2020/#346. HAI Book 2020
2. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.
3. Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, Yip O, Rao A, Nelson MR, Hao Y, Thomas R, Yoon SY, Arriola P, Huang Y. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging 2023 Nature Aging
4. Aisen PS, Bateman RJ, Carrillo M, Doody R, Johnson K, Sims JR, Sperling R, Vellas B. Platform Trials to Expedite Drug Development in Alzheimer's Disease: A Report from the EU/US CTAD Task Force. J Prev Alzheimers Dis. 2021;8(3):306-312. PubMed.

Further Reading

News

1. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore 27 Mar 2021
2. Anti-Tau Antibody Data Leave Best Isotype Unclear 14 May 2021
3. Aiming at the Tangle’s Heart? DIAN-TU Trial to Torpedo Tau’s Core 18 Mar 2021
4. To Block Tau’s Proteopathic Spread, Antibody Must Attack its Mid-Region 5 Apr 2018