Researchers got a fuller view of the data coming out of the Phase 2b trial of the anti-Aβ BAN2401 antibody at the 11th Clinical Trials on Alzheimer Disease conference, which convened in Barcelona, Spain, from October 24–27. Eisai’s Chad Swanson presented a preplanned subgroup analysis in response to criticism that arose in the wake of a regulator-induced hiccup in this Bayesian adaptive trial, which had led to an imbalance in the number of APOE4 carriers between treatment and placebo arms. According to the new analysis, the imbalance was not the reason for the treatment benefit on cognition that was first reported last July. On the contrary, Swanson said, it may have led the trial to underestimate the antibody’s effect on the cognitive endpoints. Changes in cerebrospinal fluid biomarkers of tau, synaptic function, and neurodegeneration also moved in a positive direction in the treatment groups, suggesting the antibody may moderate underlying pathology. Ditto for amyloid PET.
- Randomization debate clouds Phase 2b results of BAN2401.
- A subgroup analysis clears APOE4 imbalance.
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Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, told the audience that the subgroup analysis should allay worries that the drug effect was driven by the uneven allocation of APOE4 carriers. To Cummings’ mind, the finding that results were consistent across all clinical measures and biomarkers supports the conclusion that the treatment effect is real. Some members of the audience shared his optimism. Others did not, noting that the highest dose group of 161 participants included just 48 APOE4 carriers, of whom only 10 completed the study. Only a truly randomized trial will properly test BAN2401, they maintained.
According to data presented this past summer at AAIC, at the highest doses tested, this anti-Aβ protofibril antibody being jointly developed by BioArctic, Eisai, and Biogen slashed brain amyloid and slowed cognitive decline in people with MCI due to Alzheimer’s disease or mild Alzheimer’s dementia (Jul 2018 conference news). There was a fly in the ointment, however. Because of a change in study design midway through the trial, the high-dose treatment group had far fewer APOE4 carriers than the placebo group, rendering the comparison suspect. At AAIC, commenters asked for the data broken down by APOE genotype, and at CTAD, Swanson delivered.
The trial enrolled 856 participants, who were randomized into one of five dose groups or placebo using a Bayesian adaptive randomization algorithm. As the trial proceeded, frequent analyses of blinded study data steered new participants into dose arms most likely to be effective. Early on, that looked to be the top two doses, of 10 mg/kg monthly and 10 mg/kg every two weeks, hence nearly half the participants ended up in these groups.
But partway through, the European Medicines Agency requested that APOE4 carriers not be put on the highest dose, and also that all APOE4 carriers who had been on that dose for less than six months discontinue. The regulators’ concern was ARIA-E, a temporary inflammatory reaction seen in the first few months of Aβ immunotherapy, which appears more commonly in APOE4 carriers receiving higher doses of antibody. The investigators complied, but the EMA request left APOE4 carriers underrepresented in the highest group. By the end of the trial, they made up only 30 percent of that arm, compared with 71 percent of the placebo group and 89 percent of the next-lower-dose group, who received 10 mg/kg monthly.
As reported at AAIC, the highest dose performed the best, registering a statistically significant 30 percent less decline on the ADCOMS compared with the decline in the placebo group. They also declined 47 percent less on the ADAS-COG, and 26 percent less on the CDR-SB. In the 10 mg/kg monthly group—the one with the highest percentage of APOE4 carriers—there was a trend toward slower cognitive decline on all three measures, but none was statistically significant.
According to new data presented at CTAD, APOE4 status did not affect the rate of cognitive decline in the placebo group. In untreated participants, the downward trajectories in ADCOMS, ADAS-COG, and CDR-SB scores, measured every three months, were virtually the same for carriers and noncarriers. The factors that did contribute to placebo participants’ progression included their clinical stage, whether they were taking medication for AD, and their baseline ADCOMS score—not their APOE4 status.
Did APOE4 affect response to treatment? The subgroup analysis said yes, Swanson reported. Carriers on the highest dose had less cognitive decline at 18 months than the noncarriers or the group overall. On the ADCOMS, for example, where the highest dose group declined 30 percent less than placebo, APOE4 carriers declined 63 percent less and noncarriers only 7 percent less. This result indicates that the treatment effect on the high dose was likely not due to the lack of APOE4 carriers, Swanson said. In fact, he thinks the imbalance may have led the trial to underestimate BAN2401’s effect. However, the trial was not powered to show statistical significance in the subgroup analysis, and the groups were small. The high-dose cohort was left with only 10 APOE4 carriers among the 79 people who completed the 18-month regimen—and those 10 had been on that dose for six months or longer before the EMA intervened, and did not drop out due to ARIA-E.
To boost those numbers, the investigators combined the 10 mg/kg biweekly and 10 mg/kg monthly groups. The merged cohort comprised 273 APOE4 carriers and 141 noncarriers, a similar makeup to the placebo group. This combined group declined 21 percent less than placebo. Once again, the APOE4 carriers had a better response, declining 25 percent less than placebo, whereas noncarriers declined just 6 percent less.
In other subgroup analyses, BAN2401 appeared to reduce progression in both the MCI and mild AD groups, and regardless of whether participants took AD medications. BAN2401 treatment substantially reduced brain amyloid, by as much as 93 percent in the high-dose group, and was similar across all subgroups.
Analysis of CSF biomarkers in a substudy of participants hinted at treatment effects on pathology. Previously, the investigators had shown that Aβ concentrations in cerebrospinal fluid increased 300-fold after treatment, while total tau levels trended downward over the course of the study. New data on neurogranin, a marker of synaptic damage, and phosphoTau181, a marker of tau pathology downstream of amyloid, revealed that their median concentrations dipped by 11 and 13 percent, respectively, after 18 months of treatment. The placebo group showed less or no change. Neurofilament, a marker of axonal damage, rose in all groups, but its rise was halved in the treatment group. These results are exploratory because they included only 23 people from the two high-dose arms and 16 from the placebo group.
Swanson showed additional analyses supporting the idea that the antibody slows disease progression. Calculating change on ADCOMS over time, investigators found that treatment reduced the slope of decline from 0.0083 to 0.0060 points per month, a statistically significant difference. This indicates that the changes at 18 months might produce larger clinical benefits when treatment continues longer, Swanson said. According to a joint press release, Biogen and Eisai are planning an open-label extension for participants in this study, with enrollment expected to begin this year.
Reisa Sperling, Brigham and Women's Hospital, Boston, called it “very encouraging,” that APOE status did not affect decline in the placebo group, and appeared to increase a person’s benefit from treatment. However, she noted that anyone who developed ARIA-E was removed from the study. APOE4 carriers have higher rates of ARIA-E, which could have led to more of them discontinuing the study, further confounding the results. Swanson said the team had not specifically looked at this, but would.
Robert Vassar, Northwestern University in Chicago, said he was struck that, despite the dramatic reduction in amyloid on the high dose, clinical progression continued, albeit at a lower rate. Was the decline independent of Aβ? Could this be related to the tau reduction that was observed in CSF? Swanson reiterated that they did see a correlation between clinical measures and amyloid PET across the dose range, but that other factors could be involved, too.
Swanson said Eisai and Biogen are discussing next steps with regulators. Meanwhile, slides of the CTAD presentation are posted on Eisai’s website.
Samantha Budd Haeberlein of Biogen presented data on the company’s other anti-amyloid antibody, aducanumab. By now, aducanumab has reached 48 months of continuous dosing in its open-label extension of the Phase 1b PRIME trial in prodromal or mild Alzheimer’s disease. Continuing on from the 24- and 36-month data (May 2018 conference news), aducanumab still clears amyloid at 48 months. Removal seems to bottom out at a reduction of 75 centiloid units, which brings people below the 1.1 cutoff on the SUVR scale for brain-wide amyloid positivity. The highest aducanumab dose group of 10 mg/kg reached that cutoff by 24 months of treatment, and stayed there. By 48 months, the next-highest dose of 6 mg/kg group joined them.
At 48 months, the 10 mg/kg group continued to show slower decline in MMSE and CDR-SB compared with lower doses, including the 6 mg/kg group. ApoE4 status does not seem to affect disease progression or treatment effects in this study, Budd said. The safety profile of aducanumab remains unchanged, according to 48-month data presented by Philipp von Rosenstiel, also of Biogen. Biogen is testing aducanumab in two large Phase 3 studies. Both are now fully enrolled, with a total of just over 3,200 participants, said Budd.—Pat McCaffrey
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