What Factors Make Amyloid Immunotherapy Successful?

Series - Alzheimer's Association International Conference (AAIC) - 2023:

With three positive and three negative Phase 3 trials of second-generation anti-amyloid antibodies to draw upon, Alzheimerologists now have more data to mine for what works and what does not. At last month’s Alzheimer’s Association International Conference in Amsterdam, scientists pored over gantenerumab and lecanemab data, hunting for clues of which parameters might predict success. And clues they found.

  • Slow titration and high baseline plaque load may have doomed gantenerumab trials.
  • Subgroups with the highest drug exposure fared best.
  • Fast clearance led to better outcomes.

Some take-homes: Clinical benefit was linked to higher drug exposure and faster clearance, perhaps because people need to be amyloid-negative for some period of time before cognitive decline slows. Certain patient characteristics, such as age, APOE genotype, and tangle load, affected drug response, as well. Researchers also debated the still-murky relationship between biomarker change and subsequent cognitive response (see Part 12 of this series).

Overall, scientists in Amsterdam were optimistic that these analyses will enable them to improve treatment regimens. “We’re learning exponentially now,” said Jeffrey Cummings of the University of Nevada, Las Vegas.

Late Clearance. Spaghetti plots from the negative Graduate 1 (left) and 2 (right) trials show that plaque load rose on placebo (gray) and fell on drug (blue). Clearance was slow, however, with only a quarter of participants dipping below the threshold for amyloid negativity (red dotted line), and only by the end of the trial. [Courtesy of Roche.]

Gantenerumab’s Near Miss: Need to Get Lower For Longer?
In Amsterdam, researchers chewed over the Phase 3 Graduate results. Roche scientists had previously reported that gantenerumab cleared half as much plaque as they had expected, and that trends toward less decline on cognitive tests fell short of statistical significance (Dec 2022 conference news). In Amsterdam, researchers debated what caused the disappointing result.

First, one factor that did not explain it: Pharmacokinetic analysis of plasma samples showed the same peripheral drug exposure as had been achieved in the earlier open-label extension trials, said Christopher Lane of Roche. Likewise, the binding affinity of the gantenerumab formulation used in Phase 3 was the same as that of earlier formulations, Lane added in response to an audience question. So the problem did not lie in the antibody itself, nor in dosage or administration.

Then what does account for the weak effect? Partly, titration was slow, taking up nine of the 27 months of the trial. This was done to keep ARIA low, but also resulted in delayed plaque clearance. Spaghetti plots revealed that not only did three-quarters of the cohort stay above the threshold of 24 centiloids set for brain-wide amyloid negativity, but those who did cross it did so only by the end of the trial (see image above). Given that cognitive benefits lag behind amyloid removal, there may have been too little time left in the trial to detect a clinical change in most participants, noted Rachelle Doody of Roche. “We got the exposures we were expecting, but it took us longer to get there,” Doody said in Amsterdam.

Compounding the effect of slow clearance, the baseline amyloid load started high in this group, at around 95 centiloids, compared with 76 centiloids in the Phase 3 Clarity trial of lecanemab. This meant fewer people became amyloid-negative, with the group’s average final centiloid value being 43. Why did plaque load start so high? An audience member noted that use of the free and cued selective reminding test (FCSRT) as an inclusion criteria may have selected for people with more advanced disease, and thus higher plaque load. In particular, because women tend to do better than men on this test at the same disease stage, it might explain a previously observed sex difference in this trial, where women started with a higher tangle load than did men (Apr 2023 conference news). Doody called this a great observation. She noted the FCSRT was used to select for people whose disease would progress during the trial.

In panel discussions at AAIC, other researchers agreed that delayed clearance might be important. “Perhaps plaque did not get low enough for long enough,” said Nick Fox of University College London. Kaj Blennow of the University of Gothenburg, Sweden, pointed out that although fluid biomarkers showed improvement, no one knows how soon they changed. CSF biomarkers, which most directly reflect what happens in brain, were measured only at the beginning and end of the trial. Improvement may have come too late. “We are learning for how long we need to touch this pathway to get a clinical benefit,” Doody said.

Negativity is Key. In the gantenerumab trial, the majority of East Asian participants became amyloid-negative (right); they had a larger cognitive benefit than the rest of the cohort (left). [Courtesy of Roche.]

All About Exposure Other data pointed to the importance of high drug exposure. Graduate participants received a fixed dose of gantenerumab, i.e., 510 mg given subcutaneously every two weeks. Other antibody trials have calculated a person’s dose by weight, in mg/kg. This meant that in the Graduate trials, lighter people received a higher effective dose than did heavier people. In Amsterdam, Angeliki Thanasopoulou of Roche showed subgroup analyses that suggested this could have made a difference.

Dividing participants by geographical region, the East Asian subgroup, which comprised 225 people, fared much better than others. For them, cognitive decline on the CDR-SB slowed by 38 percent, similar to the benefit seen in positive antibody trials. This compared with a slowing of 5 percent for other Graduate participants. The East Asian subgroup also cleared more amyloid, with nearly two-thirds of them becoming amyloid-negative, again similar to the benefit in the lecanemab trial.

Demographically, the biggest difference between East Asians and other groups was weight. East Asians averaged 55 kilograms, meaning they received a dose of about 9 mg/kg, compared with 71 kilograms, or 7 mg/kg, for other groups. In addition, East Asians missed fewer doses than other groups (but had no less ARIA), and by the end of the trial had received a 20 percent higher cumulative dose of antibody.

Additional subgroup analyses strengthened the emphasis on exposure. Thanasopoulou showed that for Graduate participants who received 90 percent or more of their scheduled doses, cognitive decline on the CDR-SB slowed by 16 percent, twice as much as the 8 percent in the cohort overall.

Does Speed Matter? In an exploratory posthoc analysis, cognition (right) declined less in people on gantenerumab who cleared amyloid quickly (green, left) than in those who cleared amyloid more slowly (red, blue). [Courtesy of Roche.]

How Fast Does Amyloid Need to Fall?
Clearance speed might matter, as well. In a preliminary posthoc analysis, Roche scientists clustered participants in the amyloid PET subgroup by patterns of amyloid removal. They found three groups (see image above). In one, plaque resisted clearance, falling late; in another, it dropped steadily but slowly. Neither group notched a cognitive benefit compared with placebo. In the third group, however, plaque load dropped rapidly, ending lower than in the other groups, near the negativity threshold. In this group, cognitive decline slowed.

It is unclear if the speed of removal itself mattered, or the fact that these participants spent longer below the negativity threshold. The analysis is exploratory and the three groups were small, at about 25 people each. It is also unclear what caused these different patterns of plaque removal. At baseline, the fast-clearance group tended to be at an earlier disease stage, with three-quarters diagnosed with MCI compared with half of the other groups, Thanasopoulou said.

Data from other antibody programs further informed the speed question. In Amsterdam, Brian Willis of Eisai presented a pharmacokinetic model constructed with data from all lecanemab trials. Its predictions closely matched observed findings, Willis said. The model identified two participant characteristics that influenced the speed of plaque clearance: APOE genotype, and age. APOE4 carriers cleared plaque faster than did other genotypes, but because they started with about 20 centiloids more, they ended up in the same place after 18 months. Likewise, older participants cleared more plaque than younger ones. The difference could be substantial: for example, compared with a 73-year-old, an 83-year-old cleared 30 percent more plaque, and a 57-year-old cleared only half as much. Unlike genotype, age did not affect baseline plaque load.

Willis did not discuss potential explanations for these clearance differences. Previous research has found that the blood-brain barrier becomes leakier with age, and is leakier in E4 carriers, raising the possibility that in these groups, more antibody may enter the brain, resulting in more exposure (Feb 2015 webinar; Jan 2019 news; May 2020 news). Willis noted that in the aducanumab trials, older participants also cleared plaque faster than did younger ones.

Overall, a picture emerged in which small differences in a person’s drug exposure and plaque clearance determine the size of their clinical benefit. For gantenerumab, a high baseline plaque load and slow clearance meant it came up short in Phase 3. “This was a drug that almost worked,” Doody concluded. She noted that Roche is using publicly available anti-amyloid antibody data to model factors such as the amount of amyloid removed, the speed of removal, and the percentage of people who become amyloid negative, to determine which are most important for efficacy.—Madolyn Bowman Rogers

Comments

  1. This is even more evidence that the key step in anti-amyloid therapy is removal of the existing deposits. Immunotherapy is one of the few anti-amyloid approaches that remove existing deposits in animal models, instead of preventing additional deposits (as indicated for BACE inhibitors in multiple animal models). To reverse memory loss in mice, there needed to be 90 percent or greater reductions in parenchymal compacted plaques. No one "bothered" to test cognition with BACE inhibitors in mice with pre-existing amyloid deposition. The trade off between induction of ARIA and time to slowing of cognitive decline will continue until we find agents to reduce ARIA without blocking clearance. Roger Nitsch has shown that slowing impairment requires amyloid reductions below threshold CLs. The hope is if we treat earlier and monitor longer, we will find stabilization of cognitive decline.

    View all comments by Dave Morgan

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References

Therapeutics Citations

  1. Gantenerumab
  2. Leqembi
  3. Aduhelm

News Citations

  1. Biomarkers and Efficacy: Not (Yet?) a Perfect Union
  2. Gantenerumab Mystery: How Did It Lose Potency in Phase 3?
  3. What Happens After Amyloid Plaque Removal? Who Benefits Most?
  4. Absent Aβ, Blood-Brain Barrier Breakdown Predicts Cognitive Impairment
  5. Even Without Amyloid, ApoE4 Weakens Blood-Brain Barrier, Cognition

Webinar Citations

  1. Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?

Further Reading

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