23 Nov 2021

As Aβ-targeted therapeutic antibodies set their sights on regulatory approval, tau-targeted antibodies still toil near the starting line of clinical development, while some have fallen by the wayside already. At the Clinical Trials on Alzheimer’s Disease meeting, held November 9-12 in Boston, researchers debated a lone positive sign—a slowing of decline on one cognitive battery in the Phase 2 semorinemab trial—and presented the results of two failed trials. Save for that, no antibodies directed against tau’s N-terminus have benefited trial participants with AD or other tauopathies, and one, gosuranemab, may have made things worse.

Adam Boxer, University of California, San Francisco, said he is undeterred, because while anti-Aβ drugs have been tested for decades, it is early days for tau, a big, complex protein. Different ways of taking shots at tau are only beginning to come into their own. Scientists are learning which of tau’s many forms to target, in which diseases they are active, and when. As a new crop of antibodies aimed at tau’s midsection enters the fray, Boxer is hoping to build a tau platform trial that can test different tau drugs by themselves or in combination with amyloid drugs. The emergence of a clinical effect for four separate anti-Aβ therapies and the arrival of informative plasma biomarkers make for exciting days in AD clinical trials, Boxer believes. “Even though we haven’t seen a clear benefit of a tau therapy, progress is being made, and we shouldn’t give up,” he said.

Semorinemab: Blip, or Beginning of a Benefit?
At CTAD, Cecilia Monteiro of Genentech presented top-line data from LAURIET, a Phase 2 trial of semorinemab in people with mild to moderate AD. Alzforum covered the upshot when Genentech and co-sponsor AC Immune announced it (Sep 2021 news). LAURIET enrolled 272 people with brain amyloid whose MMSE scores were between 16 and 21, then randomized them to monthly infusions of placebo or semorinemab for 48 weeks. A subset who had to skip infusions due to the pandemic stuck with the trial for an additional 12 weeks. As announced previously by Genentech and AC Immune, semorinemab slowed decline on the ADAS-Cog11, one of two primary endpoints, by 42 percent at week 49 of the trial. At CTAD, Monteiro presented the data, which showed a crack open up between semorinemab and placebo groups at 25 weeks, hold steady at 37 weeks, and widen by 49 weeks, at which point the semorinemab group appeared stable. This benefit was driven primarily by the memory domain of the composite test, Monteiro said.

This was LAURIET’s lone positive result. Monteiro reported no difference between groups for the trial’s co-primary endpoint, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), a measure of functional decline. Semorinemab did not budge scores on the MMSE or the CDR-SB, either. It had no effect on tangle accumulation as measured by uptake of Genentech's GTP1 tau tracer on PET scans.

In a panel discussion, chaired by Rachelle Doody of Roche/Genentech, clinicians attempted to make sense of this. What might be the reason for an effect on the ADAS-Cog11, but not other cognitive or functional measures, Doody asked Stephen Salloway of Brown University in Providence, Rhode Island, a site investigator for LAURIET. “When we get a single result like this, we have to be concerned about the reliability of the finding,” Salloway responded. This is especially true given the negative result of the TAURIEL trial of semorinemab in prodromal to mild AD. Urging further study, Salloway cautioned that even if the ADAS-Cog11 benefit is reproducible, it alone would not constitute a meaningful benefit at this stage of AD. Semorinemab would have to do more.

Randall Bateman, Washington University, St. Louis, is not convinced either. He noted that lack of benefit on the CDR-SB and MMSE, which also contain memory components, imply the ADAS-Cog effect may not be robust. “Patients at this stage need an impact on function, not just cognition,” he added. He thinks the most useful data will come from the ongoing open-label extension trial of semorinemab in people with mild to moderate AD.  "Once the cognitive and clinical durability is known, then the robustness of the effect can better be determined," he said.

To the eyes of Gil Rabinovici, University of California, San Francisco, the leveling off of the ADAS-Cog11 decline in the treatment group in the final weeks of the trial looked unusual. Alireza Atri of Banner Sun Health Research Institute in Phoenix said that it’s possible the ADAS-Cog11 benefits appeared slowly, and CDR-SB and ADCS-ADL might show change only later. Monteiro said the ongoing open-label extension will at least show whether the ADAS-Cog11 is durable or a blip, and whether functional benefits, which tend to follow cognitive ones, might still emerge.

“While it is always exciting to see a positive result on a clinical outcome in an AD drug trial, replication will be essential for determining the robustness of the semorinemab effect on cognition observed in the LAURIET trial,” Rabinovici wrote in a comment to Alzforum. “The lack of consistency between the clinical (ADAS-Cog11) and functional (ADCS-ADL) outcomes in the trial, as well as the lack of a signal for slowing of tau spread by PET, do not paint a picture that is clearly indicative of disease slowing.”

Like semorinemab, gosuranemab binds tau's N-terminus, but unlike semorinemab, it appears to hasten decline on the same test battery. Biogen shelved gosuranemab after it failed to curb decline in progressive nuclear palsy and in early AD (Jun 2021 news). At CTAD, Biogen’s Melanie Shulman showed the top-line results of the latter study. It had enrolled 654 people who had early AD and evidence of amyloid for monthly infusions of placebo, or low, medium, or high doses of the drug over 18 months.

As reported, the trial missed its primary endpoint of change on the CDR-SB and conferred no benefit on any exploratory measure, including the ADAS-Cog13, ADCS-ADL, MMSE, and the Functional Assessment Questionnaire (FAQ). While this was expected, one result came as a surprise. All three gosuranemab dose groups declined more on the ADAS-Cog13 than placebo. A gap between the treatment and placebo groups opened at 12 months and widened by 18 months. The effect was not dose-dependent, Shulman reported, but only the highest dose group had a statistically significant difference from placebo on ADAS-Cog13 change by 18 months.

Gosuranemab bound its target, dramatically lowering N-terminal tau in the cerebrospinal fluid at all doses. Still, it did not budge tangles as per tau PET.

How might two N-terminal antibodies exert opposite effects? Afterall, both latch onto similar tau epitopes and are of the same IgG4 antibody ilk. While the answer is unknown, one difference between the two trials is the degree of impairment of enrolled participants. While semorinemab was given to people with mild to moderate AD in the LAURIET trial, gosuranemab flowed into participants with early AD. Notably, semorinemab had previously failed in people with early AD as well, though it did not make people worse. Boxer and other scientists suspect that different forms of tau may have different effects at different stages of the disease and that the N-terminal species targeted by these antibodies may only wreak havoc later on. Boxer noted that studies from Lennart Mucke’s lab at UCSF suggest extracellular tau messes with synaptic firing. Perhaps this effect differs by disease stage, and electrophysiological recordings such as EEG or MEG could possibly monitor that in future trials, he said.

Tilavonemab, also directed against N-terminal tau, sang its swan song at CTAD also. Hana Florian of AbbVie reported data from a Phase 2 trial in 453 people with early AD who had evidence of amyloid. They, too, received monthly infusions of placebo or one of three doses of tilavonemab for two years. The drug did nothing to CDR-SB scores—the primary endpoint—which worsened similarly between groups throughout the trial. Ditto for all cognitive and functional measures, including the ADAS-Cog14, RBANS, MMSE, FAQ, and ADCS-ADL. Tilavonemab curbed neither brain atrophy nor plasma neurofilament light (NfL), suggesting it did nothing to assuage neurodegeneration. Like semorinemab and gosuranemab, tilavonemab was safe and well-tolerated. AbbVie has canned tilavonemab, which had also flopped in a PSP trial (Jul 2019 news). 

With the exception of semorinemab, which clings by a thread to a single signal, all tau antibodies thus far have come up short. They engaged their target in CSF and even in brain autopsy studies, but did not budge tangle accumulation as gauged by tau PET. What gives? Maybe the antibodies target the wrong form of tau, one that is not involved in the downstream formation of aggregates, Boxer said. In support of this idea, previous studies led by Bateman found that in the AD brain, N-terminal forms of tau are secreted, while full-length tau remains inside the cell (Mar 2018 news). If antibodies are latching onto these fragments, they may be doing little to halt the aggregation of tau inside cells.

It could also be that tau progression is not driven by transcellular spread of tau, which these antibodies aim to intercept. In keeping with this idea, a recent kinetics study concluded that after Braak stage III, the lion’s share of tau accumulation occurs via local replication, as opposed to dissemination from one region to another (Nov 2021 news). In his keynote talk, Boxer emphasized the need for the field to stay open to alternate hypotheses about how tauopathy progresses in different diseases, and how best to stop it.

“I continue to view tau immunotherapy as an important therapeutic strategy that should be further pursued, and I think we are still on the steep end of the learning curve,” Rabinovici wrote in a comment to Alzforum. “As we learned from anti-Aβ monoclonals, treatment approaches require a lot of fine-tuning before we see consistent results within a class.” In that vein, the field’s optimism has swung toward second-generation tau antibodies that take aim at tau’s midsection—particularly the microtubule binding repeats that drive aggregation (Mar 2021 conference news). 

At CTAD, Biogen’s Hua Carroll talked about the first human study of one such newbie, BIIB076. Carroll did not say exactly where BIIB076’s target epitope is on tau, but did say the antibody is specific for extracellular forms that contain tau's mid-region. Carroll showed data of a single ascending dose study that tracked BIIB076's safety and pharmacokinetics in healthy controls and in people with AD. Five doses went into 24 healthy controls, and one into six people with AD who had evidence of amyloid. Twelve controls and two people with AD got placebo.

As doses were ramped up, safety concerns cropped up at the fourth-highest dose. Rather than proceed to a higher dose for the fifth group of controls, the researchers treated them with a dose midway between the third and fourth doses, and chose this for the AD cohort as well. A majority of adverse events—headaches, dizziness, nausea, vomiting, decreased blood pressure—were mild to moderate, but were more frequent in the higher-dose groups. One control fainted after infusion with the highest dose, accounting for the lone serious adverse event. Carroll called the safety profile of BIIB076 acceptable, and consistent with an older population.

BIIB076 engaged its target, halving the concentration of unbound mid-region-bearing tau in the cerebrospinal fluid of people with AD within one week of infusion. Three weeks later, the reduction persisted.

Can the tau immunotherapy field avoid the seemingly endless trail of failures that beset Aβ-targeted antibodies before things turned around? One way to speed things up is to go from sequential to parallel—i.e., platform trials. Oncologists use them, so does DIAN-TU, and at CTAD, Boxer unveiled his own plan. With Keith Johnson at Massachusetts General Hospital in Boston, and others, Boxer designed the Alzheimer’s Clinical Trial Consortium (ACTC) Tau platform trial, aka, ATP. It aims to test two tau-targeted therapies alone or in combination with an amyloid-lowering drug in a 2 x 3 factorial design that will share a placebo group.

The ATP proposal is currently under review at the National Institutes on Aging. The drugs have not yet been picked.

Tau Platform Trial. The proposed platform trial will test two tau immunotherapies alone or in combination with an anti-Aβ immunotherapy, in 900 people with preclinical or prodromal AD. One group, or about 17 percent of the trial’s participants, will receive placebo. [Courtesy of Adam Boxer, University of California, San Francisco.]

Participants with preclinical or prodromal AD will be prescreened for elevated amyloid using a blood test that measures the ratio of Aβ42 to Aβ40 and have amyloid and tau pathology confirmed via PET scan (Nov 2021 conference news). The trial aims to enroll 900 participants. It will run for two years and use change in tau PET as a primary endpoint. In essence, it aims to prevent the so-called “ca-tau-strophe.” Coined by Johnson, the term refers to the mushrooming of tau pathology that happens around the time symptoms emerge.

Why include anti-Aβ arms in a tau trial? For one, FDA approval of aducanumab, and perhaps others before long, means participants with early AD may want to take an anti-amyloid antibody rather than commit years to a tau drug they do not know will help them. Including several anti-Aβ arms, but only one placebo arm, offers participants a greater chance of receiving one or two therapies. Second, including both Aβ- and tau-targeted drugs in the trial will test whether two drugs given concurrently is better than either drug alone. Finally, inclusion of anti-Aβ drugs can serve as a positive control for biomarkers, Boxer said, because all of the anti-Aβ front-runners have been shown to influence tau PET as well as plasma biomarkers.

Rabinovici agreed that tau biomarkers will play a key part in moving the field forward. “I am optimistic that we will make rapid progress in evaluating the utility of tau immunotherapy, especially with our growing and maturing armamentarium of tau biomarkers,” he said.—Jessica Shugart

Comments

1. • Emory Hill
     Screen, Inc.
   • Posted: 06 Dec 2021

   It is probably too elementary a consideration, but the true blindness of a live neuropsychology technician to whether or not a subject is in active versus placebo status might be revealing. Just asking technicians to guess at the end of testing whether or not the subject is in active treatment might be justified. Disclosure: I am affiliated with a computer-administered test battery (CANS-MCI).

   View all comments by Emory Hill

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References

Therapeutics Citations

1. Semorinemab
2. Gosuranemab
3. Tilavonemab
4. BIIB076

News Citations

1. First Cognitive Signal that Tau Immunotherapy Works? 2 Sep 2021
2. Biogen Shelves Gosuranemab After Negative Alzheimer’s Trial 18 Jun 2021
3. AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy 26 Jul 2019
4. Isotope Labeling Links Tau Production to Aβ Burden 28 Mar 2018
5. Doubling of Tau Seeds, Not Spread, Sets Pace of Tauopathy in Alzheimer's 3 Nov 2021
6. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore 27 Mar 2021
7. Plasma Aβ—First Sign of AD, But Tough to Measure Prospectively? 21 Nov 2021

Further Reading

News

1. Gosuranemab, Biogen’s Anti-Tau Immunotherapy, Does Not Fly for PSP 13 Dec 2019