24 Oct 2019

On October 22, Biogen stunned the Alzheimer’s field by announcing that aducanumab—presumed dead last March after failing a futility analysis—appears to have worked in one of its two Phase 3 trials, after all. Based on the results of a new analysis, and interactions with the Food and Drug Administration, Biogen will file for regulatory approval in early 2020.

Aducanumab rises from the dead based on analysis of more data from Phase 3.

In the larger dataset, the EMERGE trial was positive, ENGAGE was not.

Citing feedback from the FDA, Biogen believes the data support a regulatory filing.

Why the revival? In a quarterly investor phone call, Biogen CEO Michel Vounatsos said the interim futility analysis was flawed and did not adequately take into account the effect of two late protocol amendments that boosted the number of people receiving the highest dose of this biologic drug. A new analysis conducted since March 2019 included three more months of data, as well as data from the participants who did not complete the full course of treatment. It showed that one of the two trials, called EMERGE, in fact met its primary and secondary endpoints. Oddly, the identical ENGAGE trial, which started one month earlier, was a tad larger, yet had slightly fewer people who took an uninterrupted course of the maximum dose, remained negative. However, an exploratory subgroup analysis of ENGAGE participants who received 10 or more consecutive high doses did show a slowing of cognitive decline similar to that seen in EMERGE, Biogen researchers said.

“We were surprised when we learned about the potential implications of these additional data,” Vounatsos acknowledged. “The path to developing breakthrough treatments is not always direct and straightforward.”

Alzheimer’s researchers largely hailed the news. “These results breathe new life into this therapeutic strategy,” Colin Masters at the University of Melbourne, Australia, wrote to Alzforum. Paul Aisen at the University of Southern California, San Diego, agreed. “Overall, this is enormously encouraging for the field. While we need to fully digest these complex data, the results seem to support the amyloid hypothesis—very good news for multiple drug development programs underway—and may even indicate that disease-modifying therapy for AD is nearing the clinic,” Aisen wrote. “This is an injection of optimism for the research field and patients,” wrote Kaj Blennow of the University of Gothenburg. “I missed the original resurrection, so I am glad to be around for this one,” quipped Stephen Salloway of Brown University, Providence, Rhode Island, adding, “This is a great development.”

At the same time, the researchers struck a note of caution, saying they would reserve judgment until they see a fuller dataset. “There is not enough information here to assess the validity of the analysis,” Lon Schneider of USC, Los Angeles, told Alzforum. Nearly 20 researchers contacted by Alzforum echoed Schneider’s sentiment, though many spoke only off the record. Additional data will be presented at the 12th Clinical Trials on Alzheimer’s Disease conference, scheduled for December 4–7 in San Diego.

Aducanumab initially excited the field when it appeared to remove brain amyloid and slow cognitive decline in the Phase 1b PRIME trial (Mar 2015 conference news). Some researchers raised concern about the underpowered cognitive findings (Sep 2016 news). The data appeared in the journal Nature (Sevigny et al., 2016), and Biogen launched a Phase 3 program. In March 2019, Biogen stopped both those trials after a futility analysis predicted they would miss their primary endpoints (Mar 2019 news).

This futility analysis was based only on data from the 803 participants in EMERGE and 945 participants in ENGAGE who had completed the full 18-month course of treatment as of December 2018, representing about half the enrollment of each trial. By March 2019, when the trials were stopped, an additional 179 EMERGE participants and 139 ENGAGE participants had completed treatment. Biogen’s subsequent analysis of the larger dataset included these additional completers, as well as data from the rest of the participants who had not finished the intended course of treatment. EMERGE enrolled 1,638 people; ENGAGE, 1,647. A third of the participants received placebo, the remainder drug.

In each trial, about half the participants on aducanumab were randomly assigned to titrate up to a low dose of drug—3 mg/kg for ApoE4 carriers, 6 mg/kg for noncarriers. This difference was because ApoE4 carriers are more susceptible to ARIA, the fluid retention in the brain that accompanies treatment with many amyloid-removing therapies. In the high-dose group, ApoE4 carriers initially titrated up to 6 mg/kg; noncarriers to 10 mg/kg. However, in March 2017, about 18 months into the trial, the protocol was amended to allow ApoE4 carriers to titrate up to 10 mg/kg, as well. This was based on accumulating data from several studies suggesting that ARIA is a manageable side effect that usually resolves without harm.

For the same reason, the researchers had already made a prior protocol adjustment. Initially, participants who developed ARIA would stop dosing for a few weeks until it resolved, then resume at a lower dose. In July 2016, about a year into the study, participants with ARIA were allowed to resume dosing at their original level. Both of these protocol adjustments increased the number of participants receiving the highest dose. However, the futility analysis proceeded as originally conceived, and was not adjusted to incorporate the effect of these amendments on dosing.

The amendments affected more EMERGE than ENGAGE participants, because the latter trial started enrolling a month earlier and remained ahead throughout the trials, said Samantha Budd Haeberlein, who leads late-stage clinical development at Biogen. Overall, more than 10 percent fewer ENGAGE than EMERGE participants received 10 consecutive high doses, which Biogen set as the benchmark for sufficient exposure to drug. Budd Haeberlein did not provide precise numbers for how many participants in each trial reached this benchmark, promising to show those data at CTAD. Nor did she explain by what rationale Biogen selected this benchmark.

Analysis of the more recent, larger dataset suggested that duration of treatment at the high dose was the key factor. In addition, Budd Haeberlein said, interruption of treatment played a role. In EMERGE, participants on the low dose had a trend of declining more slowly than those on placebo on the primary outcome, the CDR Sum of Boxes, but this was well shy of statistical significance. Participants on the high dose declined 23 percent more slowly than those on placebo, with a significant p value of 0.01. Secondary endpoints were similar. The high-dose group declined about a quarter less on the ADAS-Cog13, a cognitive battery, and up to 46 percent more slowly on the ADCS Activities of Daily Living, a caregiver assessment. Both results were statistically significant for both the intention-to-treat group, i.e., all participants who received some doses of aducanumab, and for those who finished the 18-month course. Decline on the MMSE reached significance in the high-dose completers, but not the whole cohort.

In ENGAGE, on the other hand, decline on the CDR-SB slowed a tad only in the low-dose group, missing statistical significance. The three secondary outcomes were similar, with some slowing of decline on each that missed significance. The high-dose group posted a slight trend toward worsening on the primary endpoint and the MMSE, and a slight benefit on the ADAS-Cog13 and the ADCS-ADL, which fell short of significance. Budd Haeberlein noted that these two measures are more sensitive indicators of change than the CDR and MMSE. Analysts on the investor call questioned why the low-dose group appeared to reap more benefit than the high-dose group in this study. Budd Haeberlein replied that the high-dose group had more interruptions due to ARIA and also more dose changes due to the protocol amendments, making dosing less consistent for these participants.

An exploratory analysis of just ENGAGE participants who received 10 or more doses of 10 mg/kg without interruption—97 people on aducanumab compared with the 336 on placebo by 78 weeks—hinted at a slowing of decline on the CDR-SB similar to that seen in EMERGE.

“This shows us that we have to get to a high dose to have an effect. Intermediate dosing, at least in an 18-month trial, is not enough,” Al Sandrock, who heads research and development at Biogen, said in the investor call. Sandrock noted that the Phase 1b PRIME study had shown some slowing of decline at 3 mg/kg and 10 mg/kg, but not at 6 mg/kg. At the time, the 6 mg/kg dose was believed to be an outlier. Now, Biogen researchers believe that the 3 mg/kg dose was the outlier in that study. “We believe 10 mg/kg is the correct dose for efficacy,” Budd Haeberlein said.

Biomarker findings, as presented, seem to support this. On amyloid PET, the researchers reported a decline of about 0.16 SUVR in those on low doses of aducanumab, 0.24 in the high-dose ENGAGE group, and 0.27 in the high-dose EMERGE group. The placebo group held steady. “We do believe the difference in amyloid reduction between groups is significant,” Budd Haeberlein said. “PET measurement of amyloid reduction is a very sensitive indicator of dose.” Notably, the ENGAGE subgroup with high exposure to aducanumab cleared as much amyloid as the EMERGE high-dose group.

Researchers wanted more data on this point. “It would be helpful to know how effectively lower doses led to changes in amyloid PET over time compared with the 10 mg/kg subset,” Douglas Galasko at the University of California, San Diego, wrote to Alzforum. He was a site investigator for the aducanumab Phase 3 trials. Others expressed some reservation about white-matter binding in the amyloid PET scans.

In the call, Biogen showed some data on CSF tau in subgroups of 15 to 29 people. P-tau nudged downward in both EMERGE and ENGAGE, in both low- and high-dose groups, by up to 19 picograms/ml and with statistical significance. Total tau dropped by up to 160 picograms/ml in EMERGE, though curiously not on the high dose in ENGAGE; these changes missed statistical significance. “The CSF p-tau data are quite encouraging, supporting the idea that reducing amyloid has a beneficial effect on downstream neurodegeneration,” Aisen noted. Other biomarker researchers called the numbers hard to evaluate without baseline levels given. Several commentators told Alzforum they would like to see spaghetti plots of how individuals fared on CSF tau, amyloid PET, and CDR-SB, saying that this way of showing the data would help make sense of this heterogeneous dataset.

Several researchers Alzforum spoke with were troubled by the difference in the EMERGE and ENGAGE outcomes, questioning if the slightly higher number of people on the highest dose in EMERGE was enough to account for it. Several said they wanted to see an analysis of ApoE4 carriers versus noncarriers, and the rates of ARIA in each group. ApoE4 carriers would be expected to have more ARIA and more dosing interruptions. Howard Feldman at the University of California, San Diego, noted the importance of knowing the standardized effect size, so that aducanumab can be compared with other interventions.

Overall, most researchers cautiously agreed that what they can see so far of the new analysis appears sound, and that the futility analysis was likely wrong. “This is not the first time I’ve seen a company get burned by futility analysis,” said Marwan Sabbagh, who leads the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. Roche’s gantenerumab failed futility analysis in the Phase 3 SCarlet RoAD trial (Dec 2014 news). That nearly derailed the program, before a deeper data analysis indicated that differences between fast and slow progressors in the trial might have masked a possible treatment benefit among a subgroup of participants with the highest exposure (Nov 2015 news). “We learned from our early studies with low doses of gantenerumab that exposure is what drives amyloid lowering as well as clinical signals,” Rachelle Doody of Roche wrote to Alzforum (full comment below).

“I do think such analyses can be risky, and result in a loss of statistical power. This is particularly true when treatment protocols are amended midstream, so that early data may not be representative of later data,” Aisen wrote. Salloway noted, “With a futility analysis, you can end up killing a promising drug by mistake.”

Some commentators recommended that futility analyses be applied with more nuance. Galasko noted that the timing of a cognitive and clinical response to amyloid removal is still so poorly understood that it might be better to base futility analyses on biomarker change, not on cognitive/clinical outcome measures. Along a similar vein, Randy Bateman at Washington University in St. Louis wrote to Alzforum, “After taking years for a program to get to Phase 3 trials, I prefer to see more adaptive actions based on a futility, rather than complete shutdown of a program.” Off the record, others noted soul-searching at Biogen on the futility methods.

Sandrock touched on the issue himself, saying that in AD trials, the clinical benefit may lag behind amyloid removal. In PRIME, amyloid removal became significant at six months but a clinical signal did not appear until 12 months, he noted. Sabbagh said this makes sense, given that the removal of amyloid may gradually halt inflammation or tangle production, and this secondary effect may be what benefits cognition.

Many researchers lamented that the stoppage of these trials rendered the available aducanumab dataset messy and incomplete, with a mixed result of one positive and one negative trial. “That’s the biggest problem with futility analyses—unless the signal to stop is very clear, you never know what might have happened had you done the trial as originally planned,” Andrew Satlin at Intra-Cellular Therapies in New York City told Alzforum. Others called it upsetting that the sites put in tremendous work to launch these trials, recruit the participants, and then did not get to the end and a full dataset.

Biogen plans to call back participants in EMERGE, ENGAGE, and PRIME to resume dosing. Will they return? “Absolutely. People are clamoring to go back on aducanumab,” said Salloway. Experienced trialists develop a gut sense of whether a trial drug is “doing something.” While they do not talk up such anecdotal observations, some site clinicians privately expressed shock at the end of EMERGE and ENGAGE because in their minds, aducanumab was in this category. They were dismayed at having to stop, and are now pleased to be able to invite the participants back.

Biogen believes the current data support a regulatory filing. Sandrock noted that the full dataset was shown to the FDA, and the agency indicated that submitting an application was reasonable based on the data. He said Biogen is just beginning discussions with regulators in Europe and Japan.

Noting that the data from EMERGE show target engagement and slowing of disease progression, Sabbagh believes it might just be enough for approval. “I think the FDA has been looking for any shot on goal,” he said. If aducanumab were to be approved, it could transform the practice of Alzheimer’s medicine within a year or two, Sabbagh predicted. He believes the existence of an approved drug to remove amyloid would lead Medicare to approve coverage for amyloid PET scans. “This would be a game changer,” Sabbagh said.

With or without regulatory approval next year, this week’s news will intensify the field’s focus on developing blood and CSF biomarkers for screening, diagnosis, and monitoring treatment effects, said Blennow, who co-leads the Neurotoolkit and other initiatives to validate such markers (August 2019 conference news). Cheaper markers than PET are sorely needed.

Antibody therapies will be expensive, and regulatory approval may be a smaller hurdle to clear than insurance coverage in the U.S. and especially in countries with national health care systems. “Biologics, and also anti-sense oligonucleotides, will not be available to the masses. Prevention with small molecules is key,” Joachim Herz at the University of Texas Southwestern Medical Center in Dallas wrote to Alzforum.

Biogen scientists were unavailable to answer follow-up questions before this story was published. The slides of this presentation are available on the company website.

Biogen’s quarterly presentation led to a spike in its stock price by day’s end, while commentators talked over each other pumping up the story in the usual build-’em-up-tear-’em-down play cycle of TV analysts.—Madolyn Bowman Rogers