13 Dec 2019

There was a new feeling in the air at the 12th Clinical Trials on Alzheimer’s Disease conference. It felt good: After decades of failure, the field might finally be turning a corner. The renewed optimism at the meeting, held December 4–7 in San Diego, was driven largely by Biogen’s shocking announcement last October that one of its two Phase 3 aducanumab trials, after a prior declaration of futility, was looking positive, after all. At CTAD, scientists got a look at some more of the data. It mostly opened a window on how protocol amendments midway through the trial slowly raised exposure among subsets of participants, and tried to link exposure to drug effect.

Aducanumab exposure said to be tied to cognitive benefit in Phase 3.

In a tiny tau PET sub-study, drug exposure correlated with fewer tangles.

Anyone’s guess: Will FDA statisticians give thumbs-up on this dataset?

The audience wanted to see more data still. Even so, they found much to dissect in hallway conversations afterward, with many privately questioning whether the dataset is clean enough to garner marketing approval from the Food and Drug Administration. Nonetheless, the consensus was that the drug probably works. Why? It robustly removes amyloid, possibly clears tau tangles as well, and, at sustained high doses, may modestly slow decline. “All the data suggest this is a disease modification,” Paul Aisen of the University of Southern California, San Diego, noted in a panel discussion, though the panel was criticized as being too one-sided.

It wasn’t only aducanumab that fueled the hopeful mood. Presentations on gantenerumab, donanemab, and BAN2401 all described dramatic amyloid clearance that was sustained over time, although none discussed cognitive outcomes. Other talks also reported positive findings, with researchers getting their first look at detailed Phase 3 data of the anti-agitation drug pimavanserin in AD (Sep 2019 news). Ditto for AMBAR, whose sponsor, Grifols, had previously reported slowing of cognitive and functional decline in AD dementia (Nov 2018 conference news), and in San Diego added cerebrospinal fluid and FDG PET biomarker data, as well as additional statistical analyses.

“For the first time in my 25-year career, we had a conference with not one, but several positive readouts,” said Marwan Sabbagh of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. “We’re starting to make progress. This has reignited enthusiasm in the field.”

Cynthia Lemere of Brigham and Women’s Hospital in Boston, who investigates anti-amyloid therapies, noted that Biogen’s previous announcement of futility had discouraged her (Mar 2019 news). “These new data have restored my faith in this approach,” she told Alzforum.

So what were the data? In October, Biogen had reported that 10 mg/kg aducanumab slowed cognitive decline by a quarter, and functional decline by 40 percent, in the EMERGE trial. By contrast, the biologic appeared to have no benefit in the identical ENGAGE trial, with placebo and treatment groups performing similarly, and the high-dose group, if anything, trending a tad worse on the primary outcome. The company ascribed the difference to mid-study protocol amendments that raised dosing and disproportionately benefitted EMERGE participants (Oct 2019 news).

In San Diego, Samantha Budd Haeberlein of Biogen elaborated on this point. The key amendment, protocol version 4 (PV4), allowed ApoE4 carriers to be titrated up to the 10 mg/kg dose. About two-thirds of study participants carried an E4 allele, and their dose had been previously capped at 6 mg/kg because of worries over ARIA. To examine the consequences of this dosing change, Budd Haeberlein divided the pooled EMERGE and ENGAGE cohort into people who had enrolled before PV4 was adopted in March 2017, and those who enrolled after. Eighteen percent of pre-PV4 participants received the full possible course of treatment—14 doses of 10 mg/kg—compared with 49 percent of post-PV4 participants. Overall, the amendment boosted the cumulative aducanumab exposure by a third, with the pre-PV4 group reaching a median cumulative dose of 116 mg/kg by the end of the study, and the post-PV4 group, 153 mg/kg. “Protocol 4 had a real impact on dosing,” Budd Haeberlein said.

ENGAGE had begun enrolling before EMERGE, hence fewer of its participants were affected by this protocol change. When PV4 was adopted, ENGAGE had 200 more participants than EMERGE. Each participant had to consent to the protocol change, and PV4 took 18 months to fully implement, Budd Haeberlein noted. As a result, by the end of the trial, 22 percent of ENGAGE patients had received the full course of 14 doses of 10 mg/kg, compared with 29 percent of EMERGE patients. To represent this, Budd Haeberlein showed exposure “heat maps” for ENGAGE and EMERGE of the dose each patient received at each visit. Dark blue indicated maximum dosage, and yellow no dose, providing a visual representation of dosing changes and interruptions. The EMERGE map showed a slightly thicker slice of solid blue than ENGAGE (see image below).

The Blues. More participants achieved 14 treatments at maximum dosage (dark blue) in EMERGE than ENGAGE, with fewer dosing interruptions (yellow). [Courtesy of Biogen.]

Budd Haeberlein showed a slide illustrating marked differences in how fast sites in the countries of these global trials consented their participants to PV4. Biogen issued PV4 in March 2017, and the majority of participants at U.S. sites were on it by December of that year, but participants in Italy and Poland only started signing on by then; in Portugal, signing started in spring of 2018. This implies differences by country, but Budd Haeberlein did not show exposure/efficacy data by country, and declined to answer questions about country or site effects.

Was Exposure the Key? A post hoc subgroup analysis of participants enrolled after maximum dosing was raised suggests a cognitive benefit in both trials (gray, placebo; purple, high dose). [Courtesy of Biogen.]

Biogen contends that participants need to reach this 14 x 10 mg/kg exposure to have a cognitive benefit. Budd Haeberlein showed a comparison of post-PV4 subgroups in ENGAGE and EMERGE, amounting to 886 participants in the former and 790 in the latter, roughly half of each cohort. In this post hoc subgroup analysis, 10 mg/kg aducanumab treatment appeared to slow CDR-SB decline by a similar amount in both trials, 27 percent in ENGAGE and 30 percent in EMERGE. Numerically, CDR-SB worsened by 1.76 points in EMERGE, with treatment reducing this by 0.53. CDR-SB worsened by 1.79 points in ENGAGE, with treatment cutting this by 0.48. In the whole ENGAGE cohort, the placebo group had declined more slowly, by 1.55 points.

Curiously, people who enrolled post-PV4 but were titrated to only 6 mg/kg fared nearly as well as the high-dose group, with a slowing of decline of 20 percent in ENGAGE and 24 percent in EMERGE. On graphs, both treatment groups tracked together (see image above).

The secondary outcome measures followed a similar pattern in this post hoc subgroup, Budd Haeberlein said, but she did not show those data, nor any further characteristics of those subgroups. She declined to address subsequent questions about these subgroups, except to say that their ApoE genotype distribution was as in the ITT population. Biogen believes the findings support the idea that sufficient exposure to drug slowed disease progression in both trials.

Conference attendees had a mixed reaction to this, with most wanting to see more detailed data. Dennis Selkoe at Brigham and Women’s Hospital said that the explanation makes sense to him, but he would like to see the secondary outcomes as well. “If they look similar, it would be compelling,” Selkoe told Alzforum. Henrik Zetterberg, University of Gothenberg, Sweden, essentially concurred, as did other leading researchers at CTAD. At the same time, they noted that other factors could have affected the results. Many wanted to see the percentage of ApoE4 carriers, as well as baseline values and demographic information of each subgroup, and suggested that imbalances there could have skewed the post hoc findings. Howard Feldman of the University of California, San Diego, Bruno Imbimbo of Chiesi Pharmaceuticals in Parma, Italy, and others suggested that a higher incidence of ARIA in treatment groups than controls could have effectively unblinded study participants and some study staff, leading to a placebo effect.

Lon Schneider of the University of Southern California, Los Angeles, said that researchers will need to see sensitivity analyses to know whether the drug effect is real (see full comment below). Others wanted to see spaghetti plots of the dose-response effect. In hallway talk, researchers grumbled that the presentation contained little new data beyond that released in October, and noted that Biogen is holding its cards close to the chest. Maria Teresa Ferretti of the University of Zurich spoke for many when she said, “I’m left with the same questions I had coming in.”

The biomarker data elicited more positive reactions. Budd Haeberlein reiterated amyloid PET findings, reporting consistent plaque removal that correlated with dose. At 6 mg/kg aducanumab, SUVR dropped by 0.17 in both studies. At 10 mg/kg, SUVR dropped by 0.24 in ENGAGE and 0.27 in EMERGE, with group sizes ranging from 74 to 203 people. As previously reported, CSF p-tau and t-tau dropped dose-dependently in EMERGE, though group sizes here were tiny, ranging from 14 to 29 people in a trial that enrolled 1,638 participants total. In ENGAGE, p-tau and t-tau reduction were not dose-dependent, with group sizes ranging from 16 to 21.

Tangle Cleanup? In a small tau PET sub-study, high-dose aducanumab lowered tracer uptake in medial temporal regions over 14 months. [Courtesy of Biogen.]

New in San Diego were tau PET data, using the second-generation tracer MK6240. Examining a medial temporal composite made up of hippocampus, parahippocampus, entorhinal cortex, and other anterior medial and lateral temporal lobe regions, the researchers found that the SUVR increased among people on placebo by about 0.09 over 14 months. For those on drug, the SUVR dropped by about 0.05 (see image above). The PET sub-study comprised 11 participants on placebo, 14 people on 6 mg/kg, and 11 on 10 mg/kg. The change in tracer uptake correlated inversely with dose. No correlation analyses were shown for amyloid removal versus CDR change.

“The tau PET data were impressive,” Eric Siemers of Siemers Integration LLC in Zion, Indiana, told Alzforum in San Diego. Siemers elaborated in writing (see below). Sabbagh, and others, speculated that a reduction of tau pathology might underlie the cognitive benefit.

In trials of aducanumab, as well as other anti-amyloid antibodies like BAN2401 and solanezumab, the cognitive benefit seems to lag behind amyloid removal, hinting it could be due to a downstream effect. Defining the lag time between amyloid removal and a cognitive benefit is a priority for future anti-amyloid trials, researchers agreed. Stephen Salloway of Brown University, Providence, Rhode Island, who was the lead site investigator for the aducanumab trials, noted that although the cognitive benefit seen in the aducanumab trials was small, the data overall suggest an effect on disease progression. “We’re looking for a biological foothold we can build on,” he said.

Across the board, researchers lamented the early termination of these trials, which led to an incomplete, confusing dataset. “The futility decision was highly unfortunate, and puts us in this position of having to analyze a complex dataset,” Aisen said. Budd Haeberlein agreed, but presented no data on the futility analysis. She noted that although Biogen will call patients back to resume dosing, they will have been off drug for varying numbers of months, further complicating long-term efficacy and biomarker data. The dosing changes midway through the trial clouded the picture, but Budd Haeberlein believes amending the protocol was the right decision under the circumstances. “I would not recommend changing the dose in the middle of a Phase 3 trial, but it turned out to be important for this study. Had we not done so, we would not have the results we do today,” she said in San Diego.

Audience members questioned whether the small cognitive benefit, amounting to a 23 percent slowing of decline on the CDR-SB, was meaningful. In the panel discussion, Sharon Cohen of the Toronto Memory Program, a site leader for the aducanumab trials, urged them to focus instead on the 40 percent slowing of decline in activities of daily living (ADL). “Eighty percent of the participants were in the prodromal stage, meaning they are living independently. The ability to continue to work, travel, bank, and enjoy leisure activities matters more to patients than what score they get on a memory test. In this disease, patients lose themselves slice by slice. Anything they can do to hang on is a triumph,” she explained. ADL was a secondary outcome measure. Some in the audience noted that such comments increase public pressure on the FDA to approve the drug, regardless of the unanswered scientific questions, and efficacy data resting largely on one incomplete Phase 3 trial.

Will these data be enough for regulators to allow Biogen to market aducanumab? Many were skeptical. Feldman noted that the FDA might find the risk-benefit ratio insufficient. Although ARIA was manageable and the field in general is less acutely concerned about this phenomenon now than when ARIA first cropped up, its incidence was high. Altogether, 25.8 percent of participants on 6 mg/kg, and 35.1 percent of those on 10 mg/kg, developed ARIA-E, a form of brain swelling. This compared with 2.3 percent of the placebo group. Most ARIA occurred in ApoE4 carriers. For a large majority it was asymptomatic, but about a quarter of those with ARIA complained of headaches, dizziness, or nausea.

In addition, some participants developed ARIA-H, indicating microhemorrhages. These occurred in 17.5 percent of people on drug, versus 6.8 percent of controls. This incidence is higher than in other antibody trials; for example, the Marguerite RoAD extension study of high-dose gantenerumab reported 9 percent (Aug 2018 conference news). ARIA-H has received less attention in AD trials than ARIA-E, with clinicians saying this phenomenon worries them less. Like ARIA-E, it is usually asymptomatic. Seven people on aducanumab and four controls had more extensive brain bleeds. Overall, 31.7 percent of people on 6 mg/kg and 40.7 percent of those on 10 mg/kg experienced some form of ARIA, compared to 10 percent of controls.

Whether aducanumab will be approved is a huge question the FDA and international regulators will decide. That aside, though, most researchers at CTAD saw a deeper significance for the field in these new data. “Everyone I’ve talked to agrees that this validates amyloid as a target,” Selkoe said. Aisen went further. “The lesson here is that the amyloid hypothesis is going to yield effective therapies,” he predicted. Slides of Budd Haeberlein’s presentation are available on Biogen’s website.—Madolyn Bowman Rogers