Brain Shuttle Could Halve Amount of Gantenerumab Needed

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2021 (Hybrid In-Person/Virtual):

Of the four anti-amyloid antibodies that abolish plaque, gantenerumab is the only one not yet applying for accelerated approval. Because its Phase 2 trials used too low a dose to dislodge plaque, this program does not yet have placebo-controlled data showing a slowing of cognitive decline. Even so, its Phase 3 program is advanced, with its two GRADUATE trials expected to read out late next year. At the Clinical Trials on Alzheimer’s Disease conference, held in Boston and online November 9-12, Roche’s Chris Lane presented their baseline data. Meanwhile, other Roche talks touted the company’s “brain shuttle” program, which ferries large molecules such as antibodies across the blood-brain barrier. New data suggest this strategy could double the plaque clearance a given dose of antibody achieves.

  • GRADUATE trials expanded diversity, brain imaging over past trials.
  • Roche’s brain shuttle technology is being tested in AD patients.
  • Preliminary data suggests it could move twice as much antibody into the brain as expected.

After the negative result of the Phase 2 SCarlet RoAD and Marguerite RoAD trials, Roche scientists explored different doses in open-label extension trials (Dec 2014 news). They found that fivefold higher dosing robustly removed plaque, such that participants became amyloid-negative within two or three years (Dec 2017 conference news; Dec 2019 conference news). Armed with these data, they picked a 1,020 mg monthly subcutaneous dose for Phase 3.

At CTAD, Lane described the scheme. Unlike in the aducanumab Phase 3 trials, all participants are being titrated up to the maximum dosage on the same schedule, regardless of their APOE genotype. Titration takes nine months, with the first three doses at 120 mg, the next three at 255, and the final three at 510. Because gantenerumab is injected subcutaneously, participants have the option of administering it at home, thus easing their time commitment and the burden of participating in a long trial.

The two GRADUATE trials are identical, but mostly run in different countries. GRADUATE I consists of 985 participants from 15 countries; GRADUATE II, 981 participants from 19 countries. Only the U.S. and Spain host both studies. The trials will take 27 months, having been extended for three months due to pandemic-related disruptions. Participants’ average age is 72, and their mean MMSE 24. Fifty-five percent of them have mild cognitive impairment, the remainder mild AD dementia. The population is somewhat more diverse than those of past trials, about 17 percent Hispanic, 12 percent Asian, and 3 percent Native American. However, like many other trials, there are almost no black participants. In part, this may be because diversity was largely driven by the countries participating, Lane noted. The study includes several Asian and South American countries, but none in Africa.

Unlike past trials, GRADUATE I and II will include hefty imaging substudies, Lane reported. About three-quarters of participants were screened for amyloid positivity by PET, and all of them continue to undergo longitudinal scans. All participants were invited into the tau PET substudy, as well, although Lane did not say how many joined.

While a subcutaneous jab has the advantage of being simple, scientists at Roche and elsewhere have been developing an alternative option for years. In this approach, gantenerumab is conjugated to an antibody fragment that recognizes the transferrin receptor, a major entry point through the blood-brain barrier. This is currently given as an infusion, and Roche declined to speculate whether it might eventually be a jab under the skin, as well. At AAIC 2021, Roche’s Luka Kulic had presented single ascending dose (SAD) results from a first-in-human study of this hybrid molecule, RG6102 (Mar 2021 conference news). 

At CTAD, Kulic laid out the ongoing multiple ascending dose (MAD) phase of the study. It comprises four dose cohorts, with eight people on drug and two on placebo in each. Doses are 0.2, 0.6, 1.8, and 3.6 mg/kg, infused every four weeks. Participants will receive seven doses over the 28 weeks of the study, and then be followed for another 28 weeks. Unlike the healthy volunteers in the SAD phase, all MAD participants have either prodromal, mild, or moderate AD.

Besides measuring pharmacokinetics, -dynamics, and whether the conjugate provokes host antibodies, researchers will explore brain imaging by way of structural MRI, functional MRI, ASL-MRI to measure cerebral perfusion, and DTI-MRI to check the integrity of axonal tracts. They will also measure plasma and cerebrospinal fluid biomarkers including Aβ42, total tau, p-tau, NfL, neurogranin, and sTREM2.

Better Uptake? Preliminary human data on gantenerumab’s brain shuttle version (solid lines) indicates that it is cleared from plasma (blue) faster than a typical IgG (dotted lines), but reaches a higher concentration in cerebrospinal fluid (green) and could clear plaque faster (orange). [Courtesy of Roche/Genentech.]

How much might the brain shuttle boost delivery? Roche’s João Abrantes addressed this question by analyzing data from the human SAD study. To his surprise, he found the drug disappeared from blood at a rate of 2.0 L/day, almost twice as fast as expected based on prior data from monkeys, and much faster than typical monoclonal antibodies, which tend to top out at 0.5 L/day. Why might this be? Perhaps because more drug is moving from blood to brain in people. In support of this, the CSF/plasma ratio of RG6102 was 2.5-fold higher in people than in monkeys. These data suggest RG6102 has a higher affinity for the human transferrin receptor, increasing brain uptake, Abrantes speculated.

Based on these data, he estimated that 28 weeks of 3.6 mg/kg RG6102 treatment could lower plaque load about one-quarter from baseline. Alternatively, if the greater CSF exposure does not reflect greater brain uptake, and uptake is instead similar to that in monkeys, then plaque load would drop only by 12 percent in the same time period. This would be similar to the 15 percent clearance achieved by 10 mg/kg aducanumab in that time frame, Abrantes said. Results from the MAD phase will show which of these scenarios is true, he noted. This study is still enrolling and expected to end in the second half of 2024.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Gantenerumab

News Citations

  1. End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s Trial Futile
  2. High-Dose Gantenerumab Lowers Plaque Load
  3. Amyloid Clearance: Check. Cognitive Benefit: Um … Maybe.
  4. Shuttle Unloads More Gantenerumab Into the Brain

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