Eds. note, 25 Jun 2021: In the three days since this series posted, Senators Elizabeth Warren (D, Massachusetts) and Bill Cassidy (R, Louisiana) have requested the Senate Finance Committee examine how Aduhelm will affect the Medicare budget. Private insurer Point32Health, a merger of Tufts Health Plan and Harvard Pilgrim Health Care that insures some two million people in New England, said it may not cover Aduhelm unless the cost comes down. Meanwhile, the FDA granted breakthrough therapy status to Biogen’s lecanemab and Eli Lilly’s donanemab, and Lilly applied for accelerated approval. Gantenerumab developer Roche has said it will continue its Phase 3 program unchanged.
In the two weeks since the Food and Drug Administration approved a license for Biogen’s Alzheimer’s antibody aducanumab, marketed as Aduhelm, controversy over the decision has continued to build. Industry analysts have written numerous scathing editorials. Critical debate reached the U.S. Congress. A watchdog group called for heads to roll at the FDA, and three members of the agency’s advisory committee quit in protest. On the other side, advocacy groups continue to laud the decision, but even they note qualms about the treatment’s price tag (see Part 2 of this series). Among Alzheimer’s researchers and clinicians, reaction remains mixed. Privately, many express unhappiness with the decision and lament a possible chilling effect on other therapeutic research, as well as the logistical challenge of integrating monthly infusions into clinical practice (see Part 3 of this series). Others view it as a first, if faltering, step toward more disease-modifying treatments. They see a bright future ahead. The debate will likely continue as the field grapples with this disruptive change to Alzheimer’s practice.
- Three AdComs members resigned in protest of the FDA’s decision.
- Critics question the use of plaque reduction as a surrogate of meaningful benefit.
- Plaques may have an indirect effect on cognition, possibly acting through tangles.
Recriminations Swirl in Wake of FDA Decision
The approval process for aducanumab has been fraught from the beginning. After skipping Phase 2, Biogen halted its two Phase 3 trials when they failed a futility analysis, but later announced that additional data rendered one of them positive (Mar 2019 news; Dec 2019 news). None of the members of the FDA’s advisory committee considered these conflicting data sufficient for approval (Nov 2020 news; Nov 2020 news).
In its June 7 ruling, the FDA acknowledged uncertainties in the efficacy data but based its decision on aducanumab’s robust clearance of amyloid plaques, noting their expectation that this will lead to a clinical benefit. The agency granted a marketing license using its accelerated approval program, which accepts change on a surrogate biomarker as likely evidence of efficacy but requires a post-market study to prove clinical benefit. Biogen has nine years to conduct such a trial (Jun 2021 news), a time span that sparked outrage for its length.
In the industry press, the decision ignited a firestorm of criticism. Observers lamented the lowering of standards and the precedent this might set for other drug approvals (Bloomberg news; AAAS blog). In a poll of 1,400 biopharma executives and staff, 80 percent thought the FDA should not have approved aducanumab, and 70 percent disagreed with the use of the accelerated approval pathway (Endpoints news).
The FDA’s move led Joel Perlmutter at Washington University in St. Louis, David Knopman at the Mayo Clinic in Rochester, Minnesota, and Aaron Kesselheim at Brigham and Women’s Hospital, Boston, to resign from AdComs (STAT news). Kesselheim later penned a New York Times editorial lambasting the agency. A fourth member, Madhav Thambisetty of the National Institute on Aging in Bethesda, Maryland, felt the need to explain why he was staying on the committee (STAT news).
The Washington, D.C.-based watchdog group Public Citizen, which had earlier criticized the close collaboration between Biogen and the FDA, went so far as to call for the removal of acting FDA commissioner Janet Woodcock, drug evaluation director Patrizia Cavazzoni, and neuroscience director Billy Dunn (Jan 2021 news; Endpoints news). The issue even reached the halls of the U.S. Congress, where Senator Joe Manchin (D, West Virginia) cited the aducanumab approval in his June 17 letter urging President Biden not to appoint Woodcock commissioner of the FDA. The decision also prompted criticism of the agency in the general media (e.g., The Washington Post editorial).
Plaque Removal A Surrogate Marker?
In particular, the FDA’s use of the accelerated approval mechanism raised eyebrows. At the AdComs meeting last November 6, FDA officials explicitly said this pathway was not on the table (Endpoints news). The advisory committee was asked to evaluate the drug based on the efficacy data. After receiving a “no,” the agency pivoted to make its decision on a different basis not discussed by the committee. The FDA never consulted the AdComs about the different pathway it had switched to since the meeting.
Lon Schneider at the University of Southern California, Los Angeles, noted that by using this pathway, the FDA in effect declared that amyloid PET functions as a surrogate marker of efficacy in AD treatment. “This perhaps is the most stunning outcome,” he wrote to Alzforum. Normally, the FDA follows a methodical qualification process, whereby it first establishes the validity of a surrogate marker and issues guidance to the whole field, before using the marker as the basis for approving a specific drug. That did not happen here, giving the de facto validation of plaque removal as a surrogate a sense of sleight of hand.
Many others expressed similar surprise. “This [decision] implies that brain amyloid has achieved the status of blood cholesterol for heart disease, and I don’t believe it has,” John Hardy at University College London wrote to Alzforum (full comment below). AdComs member Thambisetty warned that the aducanumab approval could make it easier for other amyloid-lowering drugs to reach the market without proving efficacy. Jörg Schulz, who chairs the neurology department at RWTH University Medical School in Aachen, Germany, asked if a slew of amyloid-reducing agents from the past will now be re-evaluated under the accelerated approval pathway (see full comment from June 14). In a public defense of her agency’s decision on June 22, Woodcock said future approvals under this pathway would be possible if the magnitude of plaque reduction was great enough.
Marsel Mesulam at Northwestern University, Chicago, believes the agency stepped outside of its purview by declaring amyloid reduction a surrogate marker. “Many of us have wondered whether regulators should be in the business of deciding on hope rather than fact, and whether they should be adjudicating on theories of pathogenesis,” Mesulam wrote (comment below). Jason Karlawish at the University of Pennsylvania, Philadelphia, said, “It raises real concerns about what’s going on at FDA and how they are using their regulatory authority.”
Plaque and Cognition, a Hazy Relationship
One reason for some scientists’ reservations about plaque removal as a surrogate marker is that small reductions in amyloid have not led to cognitive benefit in trials of several different drugs. In a recent meta-analysis, researchers led by Edo Richard at Radboud University Medical Center, Nijmegen, the Netherlands, evaluated data from trials of solanezumab, bapineuzumab, and low-dose gantenerumab, the latter two of which nudged plaque load but not ADAS-Cog scores (Richard et al., 2021).
Researchers led by Maria Glymour at the University of California, San Francisco, cast a wider net, including published studies of all drugs purported to lower amyloid plaque, regardless of their mechanism of action. In addition to the trials studied by Richard et al., Glymour et al. analyzed data from bexarotene, semagacestat, verubecestat, lecanemab Phase 1, and aducanumab Phase 1 trials. Their meta-analysis found no correlation between MMSE score and the small amyloid reduction in these studies (Ackley et al., 2021).
“The idea that we would approve medications on the basis of a biomarker change, i.e., amyloid reduction, when we know that reducing amyloid does not equate to definite benefit for improving people’s lives, i.e., memory and functioning improvements, sets a bad precedent,” Glymour wrote to Alzforum (full comment below).
The connection between amyloid removal and cognitive benefit remains possible, however. These meta-analyses included small trials, e.g. lecanemab; low-dose trials, e.g., gantenerumab; and drugs not primarily designed to lower plaques, e.g., BACE inhibitors, bexarotene. Much more drastic amyloid plaque reduction is being reported for three other anti-amyloid antibodies besides aducanumab. Two of them—donanemab and lecanemab—did tap the brakes on cognitive decline by 20 to 30 percent in well-designed Phase 2 trials, while Phase 3 data on high-dose gantenerumab are expected next year. This renders the agency’s assumption that near-complete amyloid removal may foretell a subsequent cognitive benefit not formally proven but plausible.
And indeed, many scientists focus on the bigger scientific picture in their qualified welcome of the agency’s decision. Bart De Strooper, who leads the U.K. Dementia Research Institute at UCL, thinks it is misleading to set up a dichotomous choice whereby amyloid plaques are seen as either a driver of cognitive decline, or irrelevant to the disease process. “A simplistic cause-consequence relationship between accumulating amyloid and neurodegeneration should have been abandoned more than a decade ago,” he wrote to Alzforum (full comment below). “Amyloid pathology [is] a trigger of a series of disease processes.” In this scheme, often referred to as the amyloid cascade hypothesis, amyloid buildup unleashes tau tangles, which then lead to neurodegeneration and memory problems. Inflammation is an important player, too.
And How About the Tangles?
Takeshi Iwatsubo at the University of Tokyo noted that aducanumab’s effect on tangles may be the key to its apparent slowing of cognitive decline in Biogen’s one positive Phase 3 trial. “The FDA statement emphasized amyloid reduction as a surrogate biomarker, but they should rather have valued the CSF p-tau and tau PET data,” he wrote to Alzforum (full comment below). Biogen ran only tiny substudies on these tau markers; the data they did show indicated normalization in people on high-dose aducanumab.
All four of the anti-amyloid antibodies that clear plaques to below the threshold of brain-wide positivity also seem to dampen tau pathology, as seen by CSF or tau PET. These data often come from substudies and effect sizes are typically small (Mar 2021 conference news; Nov 2018 conference news; Apr 2020 conference news).
For more reaction from Alzheimer’s researchers, see Part 2 of this series.—Madolyn Bowman Rogers
- A New Era of Alzheimer’s Treatment
- Biogen/Eisai Halt Phase 3 Aducanumab Trials
- Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case
- FDA Advisory Committee Throws Cold Water on Aducanumab Filing
- Aducanumab Still Needs to Prove Itself, Researchers Say
- Aducanumab Approved to Treat Alzheimer’s Disease
- Begone 2020: Despite COVID, Alzheimer’s Research Advanced
- Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
- Second Look at BAN2401 Data Still Positive, Despite Snafu
- In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned
- Richard E, den Brok MG, van Gool WA. Bayes analysis supports null hypothesis of anti-amyloid beta therapy in Alzheimer's disease. Alzheimers Dement. 2021 Jun;17(6):1051-1055. Epub 2021 May 31 PubMed.
- Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, Mayeda ER, Filshtein TJ, Power MC, Elahi FM, Brickman AM, Glymour MM. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372:n156. PubMed.