With several anti-amyloid antibodies now proven to clear plaque from the human brain, researchers are turning their attention to fine-tuning immunotherapy for Alzheimer’s disease. At the 16th International Conference on Alzheimer’s and Parkinson’s Diseases held March 15-20 in Barcelona, Spain, speakers showed how analyses from the lecanemab program are helping them model antibody efficacy and figure out which maintenance dose might keep plaques from coming back. Technical improvements in measuring plasma biomarkers are enabling some of these advances. “The science has converged,” Michael Irizarry of Eisai said during a panel discussion, noting advancements in both biomarkers and therapies. He expects upcoming trials to provide even more information on dosing, safety, and efficacy.

  • Scientists are testing maintenance dosing after plaques are gone.
  • Pharmacodynamic models help to predict antibody effects.
  • Lowering antibody dosing peaks might keep ARIA in check.

Immunotherapy can banish plaque, but what happens next? The lecanemab Phase 2 trials offer some clues. At the high dose of 10 mg/kg biweekly, four in five participants were deemed amyloid-negative after 18 months (Jul 2018 conference news), and their stored plasma samples subsequently revealed that their Aβ42/40 rose and p-tau181 fell in tandem with plaque removal (Nov 2021 conference news). 

At AD/PD, Eric McDade of Washington University in St. Louis added new data from this analysis. He tied plasma marker changes to clinical outcome. McDade found that larger changes in Aβ42/40 and p-tau181 correlated with slower slippage on the CDR-SB at the group level. For Aβ and p-tau181 the correlations were 0.57 and 0.47, respectively. The data hint that plasma markers could help monitor treatment response, McDade noted.

Between the end of Phase 2 and the start of the open-label extension study, there was a roughly two-year treatment gap, hence these data offer a glimpse of the long-term effects of amyloid removal. Previous reports had noted sustained improvement on biomarkers (Aug 2021 conference news) and in Barcelona, McDade put specific numbers to this. He reported that following 18 months of treatment at 10 mg/kg biweekly, plaque load and plasma p-tau181 both crept back up by about a quarter during this gap, while the plasma Aβ42/40 shifted halfway back to where it had started. These data suggest that staying on lecanemab might be necessary to maintain benefits, McDade said. This is quite different from the approach being taken by Eli Lilly with donanemab, where treatment is stopped once plaques are gone. Lilly scientists predict that it would take three to four years for amyloid to creep back into positive territory, and as long as 14 years to return to baseline levels (Nov 2021 conference news).

Feeding Phase 2 and gap period lecanemab data into a model of what such long-term treatment might look like led to a prediction that a maintenance dose of 10 mg/kg quarterly would prevent plaque growth, but that plasma markers would gradually worsen. A dose of 10 mg/kg monthly, however, would keep plasma markers flat, as well. McDade believes this prediction could change if the initial treatment more aggressively drove markers further into the normal range with higher dosage or longer duration.

Walking the Line. Modeling data predicts that without maintenance dosing (black), all AD biomarkers will rise after treatment stops at 18 months. A quarterly maintenance dose (blue) would keep plaque down (left) but not plasma p-tau181 (middle) or plasma Aβ42/40 (right), while a monthly dose (turquoise) would keep all biomarkers flat. Continued biweekly dosing (pink) would drive all lower still. [Courtesy of Eric McDade.]

Why is maintenance dosing required once plaque is gone? At AD/PD, Eisai’s Antonio Cabal suggested that protofibrils and oligomers that remain in interstitial fluid after plaque removal might be behind the worsening of plasma markers during the gap. These small soluble species are believed to be the most toxic forms of Aβ. If only there were good estimates of their concentration, doctors might be able to adjust dosing to mop them up, too, and prevent further damage to synapses and neurons, Cabal said.

Alas, such ISF markers do not exist. Meanwhile, McDade believes plasma biomarkers will be a sensitive tool for tracking drug effects. “These peripheral measures become critical when we think about monitoring chronic therapy and reaching maximal effect,” McDade said.

Irizarry described how Eisai is testing these ideas. Each participant in the Phase 2 OLE starts below the threshold for amyloid positivity, and will go on a maintenance dose of 10 mg/kg either monthly or quarterly. Researchers will track their changes in amyloid PET, plasma Aβ42/40, and plasma p-tau181 to find the minimum dose that maintains treatment gains.

This type of long-term treatment could become onerous if it requires monthly trips to a clinic for intravenous infusions for years or decades. To establish a more convenient route of administration, Eisai will use the open-label extension of its ongoing Clarity Phase 3 trial to explore subcutaneous injection. As each participant reaches the end of the blinded study period, they can switch from monthly IV to weekly subcutaneous, which can be done at home. All major anti-amyloid antibody companies are currently testing subcutaneous dosing.

Some safety benefits might be had this way, as well, Irizarry said. Plaque clearance correlates with the average plasma concentration of lecanemab, while the brain edema known as ARIA-E correlates with lecanamab’s maximum concentration. Because antibody makes its way into the plasma more slowly following a subcutaneous bolus, and it reaches a lower maximal concentration, Irizarry hopes this route of administration may produce less ARIA, perhaps half that seen with IV dosing.

Predicting Antibody Effects
How might the dynamics of plaque clearance and soluble species change when other antibodies are used? Each antibody currently in trials has its own distinct characteristics, recognizing different species of Aβ with varying affinities. In Barcelona, Cabal presented a quantitative systems pharmacology (QSP) model of Aβ aggregation kinetics that takes into account these affinities and the effect of age and APOE genotype on slowing clearance. Cabal then plugged different antibodies into this model, assuming 1.5 years of treatment followed by 2.5 years of follow-up. The idea was to link each antibody's distinct binding characteristics to their clinical effects.

The model showed that solanezumab and crenezumab, which bind Aβ monomers and oligomers, respectively, would halt plaque growth but not reduce existing plaque. Bapineuzumab, gantenerumab, and lecanemab, which bind fibrils, would remove plaque, with lecanemab having the strongest effect according to the Eisai model and gantenerumab the next. For protofibrils, the model forecast lecanemab to mop up the most, with crenezumab next, and the other antibodies doing little. Cabal said these predictions match observed pharmacologic and pharmacodynamic data for each antibody.

Cabal did not model donanemab or aducanumab treatment. Donanemab, which recognizes a pyroglutamated form of Aβ, cleared plaque rapidly in Phase 2, in many cases banishing deposits by six months (Mar 2021 conference news).

The QSP model also offered insight into ARIA-E. Researchers believe this condition arises when antibodies bind to Aβ at blood vessels, disrupting their walls and allowing fluid to leak into the brain. But do fibrils or protofibrils do this? Cabal modeled for both, and found that fibril binding produced the best fit to actual data. Fibrillar amyloid in the perivascular space, aka cerebral amyloid angiopathy, present at the start of treatment may explain differing rates of ARIA, Cabal concluded.

While researchers now have enough data to model what happens during immunotherapy, they still know little about what the AD brain looks like once plaque is gone. How does its biochemistry change? How do microglia respond? Autopsy data from immunotherapy trial participants will be crucial for determining this. “These are fascinating open questions,” Irizarry said.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Leqembi
  2. Donanemab
  3. Solanezumab
  4. Crenezumab
  5. Bapineuzumab
  6. Gantenerumab
  7. Aduhelm

News Citations

  1. BAN2401 Removes Brain Amyloid, Possibly Slows Cognitive Decline
  2. Lecanemab Sweeps Up Toxic Aβ Protofibrils, Catches Eyes of Trialists
  3. Lecanemab Post Hoc: Is Continual Treatment Required for Cognitive Benefit?
  4. Donanemab Phase 3 Puts Plasma p-Tau, Remote Assessments to the Test
  5. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit

Further Reading