Part 1 of a two-part story.

The Food and Drug Administration's approval of aducanumab based on plaque removal rather than clinical benefit has thrown open the gates for other anti-amyloid therapeutic antibodies to follow the same route to market. Eisai/Biogen are already on that path with lecanemab, having applied to the FDA for a marketing license on September 27. Unlike with aducanumab, the companies filed directly under the accelerated-approval pathway, using Phase 2b data that show drastic plaque reduction. Eli Lilly is expected to follow suit later this year with donanemab. Roche/Genentech have not disclosed plans for gantenerumab, but the FDA earlier this month granted this Phase 3 antibody breakthrough therapy status, expediting its regulatory review. This designation places gantenerumab in the same category as lecanemab and donanemab (Oct 8 Businesswire). 

  • Eisai/Biogen applied for accelerated approval of lecanemab.
  • Lilly expected to do the same with donanemab soon.
  • FDA grants gantenerumab breakthrough therapy status.

Meanwhile, Biogen is still facing headwinds in its effort to roll out aducanumab, trade name Aduhelm.  In a debate conducted via published editorial (e.g., Crosson et al., 2021; Gauthier and Rosa-Neto, 2021; Kallmyer et al., 2021; Scheltens and Vijverberg, 2021; Usman et al., 2021; Weiner et al., 2021), Alzheimer's researchers agree on little beyond saying that Alzheimer's treatment has entered a new era. “The recent accelerated approval of aducanumab has been the most mixed-consequence and historical decision that has taken place in the public health arena during my professional career,” Rachelle Doody at Roche in Basel, Switzerland, wrote in a July 20 editorial in the Journal of Prevention of Alzheimer’s Disease. For a detailed update on aducanumab, see Part 2 of this story.

Is Accelerated Approval Opening the Flood Gates?
The June 7 approval of aducanumab set off furious controversy (Jun 2021 news; Jun 2021 news series). In part, this was because Biogen had applied for full approval, which the FDA’s advisory committee rejected. In what was widely seen as a bait-and-switch, the agency then approved aducanumab under its accelerated pathway without consulting the AdComs on that change (Nov 2020 news; Nov 2020 news; Apr 2021 news). A confirmatory trial is required for full approval, and Biogen this month submitted a draft protocol for this trial to the FDA (see Slide 6, quarterly update). Many researchers believe it will be difficult to enroll such a trial (Aug 2021 conference news). 

Lecanemab’s filing is different. For one thing, the antibody will be explicitly considered for accelerated approval from the beginning. For another, the application rests on published data, in which robust plaque removal correlated with a modest slowing of cognitive decline (Jul 2018 conference news; Nov 2018 conference newsSwanson et al., 2021). Indeed, this paper may have helped aducanumab. “The FDA highlighted this study to support [using] amyloid as a surrogate outcome measure reasonably likely to predict clinical benefit,” noted Michael Irizarry at Eisai, in an email to Alzforum (see Dunn et al., 2021). 

Another difference from aducanumab is that lecanemab trial data thus far suggest this antibody causes less ARIA, with an incidence of about 10 percent versus 35 percent. This may result in a more favorable risk-benefit analysis for treatment.

Eisai/Biogen will use a “rolling submission” process, whereby they deliver portions of the application to the agency as they complete them, according to a press release from Eisai’s partner BioArctic, the Swedish biotech company that originally developed this antibody (PR Newswire). The FDA has not yet set a date to review the full application. Nonetheless, BioArctic noted that the agency has agreed to using lecanemab’s ongoing Phase 3 trial, dubbed Clarity, as the confirmatory study to demonstrate clinical benefit. This confirmatory trial is fully enrolled, with 1,795 participants, and will read out in 2022 (Nov 2020 conference news). 

What about the other antibodies? Donanemab is currently recruiting into two Phase 3 trials. One of these is designed as a confirmatory registration study, with an enrollment goal of 1,500, and the other as a prevention study of 3,300 people (Jul 2021 news). As with lecanemab, the Phase 2 data that will form the basis for donanemab’s accelerated approval application are published (Mintun et al., 2021). Donanemab removes plaque faster than do the other antibodies. It requires only a short course of treatment, which may help to limit both cost and the burden to patients (Mar 2021 conference news; Aug 2021 conference news). 

Gantenerumab’s Phase 3 program, called GRADUATE, is the most advanced of the three investigational antibodies in that its two trials are scheduled to read out in 2022 (May 2019 conference news). Each trial includes about 1,000 participants. However, gantenerumab’s Phase 2 trials, which used a much lower dose, showed no cognitive benefit. It is unclear if Roche will apply for accelerated approval based on these data, or await Phase 3 results.

Thus far, gantenerumab is the only one of the four antibodies that can be injected under the skin, suggesting the potential for at-home administration. The other companies are also developing such formulations, with Phase 1 studies of subcutaneous lecanemab, donanemab, and aducanumab underway.

What would be the effect of having up to four immunotherapies available to treat AD? The health-care system would have some serious catching up to do. David Knopman at the Mayo Clinic in Rochester, Minnesota, said Alzheimer’s clinics are not ready to handle a large influx of immunotherapy patients. They have far too few dementia specialists, neuropsychologists, and neuroradiologists with the requisite expertise, and insurance coverage remains up in the air. “The resources necessary to provide treatment with anti-Aβ antibodies to the right patients with the necessary safety precautions are woefully inadequate,” he wrote to Alzforum (full comment below).

Improving Accelerated Approval
Will future accelerated approvals prove as divisive? Aducanumab’s case has renewed attention to longstanding complaints about this regulatory pathway. Critics bemoan that few drugs put on the market via this process end up being withdrawn, even if they subsequently fail to produce evidence of meaningful efficacy. For cancer, a recent paper tallied the annual cost to Medicare of such drugs as exceeding $200 million (Shahzad et al., 2021). In the September 23 JAMA, Ezekiel Emanuel at the University of Pennsylvania, Philadelphia, proposed four reforms to the accelerated approval process. A medical professor, Emanuel chairs UPenn's department of medical ethics and health policy.

First, he writes, the biomarker used for approval should be established as a predictor of long-term clinical benefit. Second, the confirmatory trial should already be enrolling at the time of accelerated approval. Third, it should have a timely completion date. Fourth, the drug should be approved only for people who would have met the clinical trial inclusion and exclusion criteria.

The aducanumab approval met none of these criteria. Lecanemab so far meets the second and third, as do donanemab and gantenerumab. Eric Siemers, formerly at Lilly and now of Siemers Integration LLC, believes donanemab’s positive Phase 2 data strengthen the case for Emanuel's first criterion, i.e., that plaque removal predicts cognitive benefit. However, Siemers thinks other biomarkers, such as plasma p-tau231, might become better AD surrogate endpoints in the future. “With further advances in the field, other biomarkers might reach the threshold of ‘reasonably likely’ to predict clinical efficacy, but without also predicting the occurrence of ARIA,” he suggested (full comment below).

In an October 1 JAMA Internal Medicine editorial, Bishal Gyawali at Queen’s University in Kingston, Ontario, Canada; Joseph Ross at Yale School of Medicine in New Haven, Connecticut; and Aaron Kesselheim at Brigham and Women’s Hospital, Boston, suggest similar reforms to the accelerated approval pathway as did Emanuel. They go further, adding a call for accelerated approvals to be automatically withdrawn when the confirmatory trial is negative. They also suggested a price cap for drugs approved through this pathway.

“For the public and physicians to trust the pathway and the clinical value of drugs with accelerated approval, reforms as well as the timely completion of postapproval trials are needed,” they wrote. Kesselheim was a member of the AdComs panel that evaluated aducanumab, and resigned in protest of the decision.—Madolyn Bowman Rogers

Comments

  1. At the level of dementia care, the accelerated approval of aducanumab, and its enabling of the approval of perhaps three other anti-Aβ antibodies (donanemab, lecanemab, gantenerumab) under the same pathway, promises to have a large impact in countries where the drugs gain approval. Even if only a modest number of prescriptions for aducanumab, and others with the similar mechanism of action, are written, it’s clear that the resources necessary to provide treatment with anti-Aβ antibodies to the right patients with the necessary safety precautions are woefully inadequate.

    There are too few dementia specialists, too few neuropsychologists, to collaborate with physicians on the diagnosis of mild cognitive impairment and mild dementia, too few persons with expertise in interpreting CSF Aβ and tau assays. There is complete absence of infrastructure or reimbursement for Aβ PET imaging, and there are too few neuroradiologists with expertise in recognizing ARIA. 

    Of course, all of those deficiencies are additive (or multiplicative) with the deficiencies in our knowledge of aducanumab’s long-term prospects for benefit. One can only hope that sponsors of the agents in the wings will be responsible citizens and publish, in peer-reviewed journals, their detailed controlled and open-label results. Adding cost considerations into this mix is even more daunting.

    It’s too early to tell how soon clinical trial design will change, or be forced to change. Grill and Karlawish, 2021, have written a nice article about this, citing the experience of multiple sclerosis in the post-β-interferon days. β-Interferon and aducanumab make for an imperfect comparison, in that with β-interferon there was a robust clinical signal, i.e., reduced rate of exacerbations, while with aducanumab, there was no consistent clinical outcome signal.

    Perhaps one or more of the other anti-Aβ antibodies will find some genuine clinical benefits. A consistent clinical signal with an anti-Aβ antibody will be what drives changes in future trial designs. Trial designs that involve active comparators or background treatment of all participants with an anti-amyloid agent will then become necessary. Such designs are necessarily more complex logistically and more expensive than currently, but such designs are feasible.

    References:

    . Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials. Neurology. 2021 Sep 7;97(10):496-500. Epub 2021 Jun 4 PubMed.

  2. There has been some confusion and controversy in the field regarding the accelerated (not full) approval of aducanumab. The FDA has used the accelerated approval regulatory pathway since 1992, though primarily for HIV and cancer treatments. It allows a drug to be prescribed based on studies showing a change in a biomarker that is “reasonably likely” to predict efficacy based on clinical outcomes. A requirement is that a subsequent study demonstrate clinical efficacy, and if such a study is negative, the drug can be removed from the market. This situation is quite different from a full approval of a new drug.

    In the case of aducanumab, an Advisory Committee meeting was held to discuss full approval and, as has been widely reported, the committee was not supportive. The accelerated approval pathway was not discussed at the meeting. 

    At the time of this meeting, it was clear that treatment with aducanumab and lecanemab both resulted in substantial reduction in neuritic amyloid plaque load based on PET imaging. The clinical data on aducanumab are much less clear-cut from the Phase 3 ENGAGE and EMERGE trials. The clinical data from the lecanemab Phase 2 trials, while promising, must be interpreted with caution given the complex adaptive study design. Given the mixed clinical data from the Phase 3 aducanumab studies and the Phase 2 lecanemab studies, the argument that lowering of plaque load was “reasonably likely” to predict clinical effects could not be made; hence, the Advisory Committee only discussed full approval. 

    On March 13, 2021, Eli Lilly and Company announced in a press release, and with a paper published simultaneously in NEJM, that a Phase 2 study of the drug donanemab caused marked reduction in amyloid plaque based on amyloid PET, and also showed statistically significant improvement in the clinical measure that was the primary outcome for the study, the iADRS. With the new data from donanemab, in addition to the data from aducanumab and lecanemab, at that point the FDA apparently felt that plaque reduction did meet the hurdle of “reasonably likely” to predict clinical efficacy. This conclusion by FDA would be consistent with the accelerated approval given for aducanumab on June 7. The FDA is requiring a subsequent study for aducanumab as required by the accelerated approval pathway, but for unclear reasons FDA allowed nine years to complete the study. 

    Given the precedent for accelerated approval based on plaque reduction established by aducanumab, not surprisingly this pathway is being utilized for lecanemab and donanemab. Discussions with FDA regarding gantenerumab are reported to be underway. 

    While plaque reduction based on amyloid PET has apparently reached the threshold of “reasonably likely” for the FDA, the fact that other biomarkers might prove even more useful (e.g., NfL, p-tau231) should be noted. Based on available data to date, plaque reduction would also be expected to be accompanied by ARIA, which immediately complicates the assessment of the risk/benefit ratio.  With further advances in the field, other biomarkers might reach the threshold of “reasonably likely” to predict clinical efficacy, but without also predicting the occurrence of ARIA.

  3. Like many fields before us, we wrestle with the central question of the validity of a biomarker to be used as a surrogate endpoint in clinical trials. Beyond the vague legal term "reasonably likely" used by the FDA in its texts, numerous methodologists have already tried to answer this difficult question, proposing several scales (Prentice, 1989; Kim et al., 2016; Fleming and Powers, 2012; Ciani et al., 2017). Among them, Ross Prentice's criteria are widely used and cited in the oncology field.

    In a recent viewpoint with Vincent Planche (Planche and Villain, 2021), we have detailed how these four “Prentice criteria” would apply to anti-amyloid therapies:

    First, before validating amyloid load (measured by amyloid PET) as a surrogate endpoint in clinical trials, a clinical trial of the same drug should have proven to be positive on clinical outcomes. This is arguably the case for anti-amyloid therapies so far.

    Second, there should be a statistical demonstration (mediation analysis) that the amyloid load mediates the treatment effect on the clinical outcome. This, to our best knowledge, has never been done so far, beyond the non-significant correlations between amyloid load loss and CDR-SB progression of aducanumab Phase 3 trials and donanemab phase II trial (Liu and Howard, 2021). 

    Third, there should be a demonstration that the drug has an effect on the potential surrogate marker. This third point is the only one that is not debated regarding aducanumab and the other three other anti-amyloid drugs cited in this article, lecanemab, donanemab, and high-dose gantenerumab.

    Finally, amyloid load should be associated with the clinical outcome. In the AD field, the relationship between amyloid and clinical symptoms is highly debated: from the theoretical questioning of the “amyloid cascade” (Karran and De Strooper, 2016), to its implication in the definition of AD (Dubois and Villain et al., 2021). 

    As a whole, beyond agencies’ definitions, the field should not lightly establish what makes a biomarker “reasonably likely” to be used as a valid surrogate endpoint for future clinical trials. Instead, rigorous methodology should be applied to this key element, as performed in the rest of our work.

    References:

    . Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989 Apr;8(4):431-40. PubMed.

    . The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses. JAMA Intern Med. 2015 Aug;175(8):1389-98. PubMed.

    . Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012 Nov 10;31(25):2973-84. Epub 2012 Jun 18 PubMed.

    . Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward. Value Health. 2017 Mar;20(3):487-495. Epub 2016 Dec 22 PubMed.

    . US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?. JAMA Neurol. 2021 Nov 1;78(11):1307-1308. PubMed.

    . Can we learn lessons from the FDA's approval of aducanumab?. Nat Rev Neurol. 2021 Nov;17(11):715-722. Epub 2021 Sep 17 PubMed.

    . The amyloid cascade hypothesis: are we poised for success or failure?. J Neurochem. 2016 Oct;139 Suppl 2:237-252. Epub 2016 Jun 3 PubMed.

    . Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484-496. Epub 2021 Apr 29 PubMed.

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References

Therapeutics Citations

  1. Lecanemab
  2. Donanemab
  3. Gantenerumab
  4. Aduhelm

News Citations

  1. Aduhelm Administration Remains a Trickle, ARIA a Concern
  2. Aducanumab Approved to Treat Alzheimer’s Disease
  3. FDA Advisory Committee Throws Cold Water on Aducanumab Filing
  4. Aducanumab Still Needs to Prove Itself, Researchers Say
  5. Advisory Committee Again Urges FDA to Vote No on Aducanumab
  6. Seeking Real-World Data on Whether Aducanumab Works
  7. BAN2401 Removes Brain Amyloid, Possibly Slows Cognitive Decline
  8. Second Look at BAN2401 Data Still Positive, Despite Snafu
  9. BAN2401 Forges AHEAD into Phase 3, Preclinical AD
  10. Can Donanemab Prevent AD? Phase 3 TRAILBLAZER-ALZ3 Aims to Find Out
  11. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
  12. On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away
  13. Keep Your Enthusiasm? Scientists Process Brutal Trial Data

Series Citations

  1. Fallout Continues After Aducanumab Approval

Paper Citations

  1. . Medicare and the Shocking US Food and Drug Administration Approval of Aducanumab: Crisis or Opportunity?. JAMA Intern Med. 2021 Oct 1;181(10):1278-1280. PubMed.
  2. . Commentary: The US Expert Panel on the Appropriate Use Recommendations of Aducanumab in Clinical Practice. J Prev Alzheimers Dis. 2021;8(4):411. PubMed.
  3. . Editorial: Impact of Aduhelm Approval on Care and Policy. J Prev Alzheimers Dis. 2021;8(4):396-397. PubMed.
  4. . Commentary: Aducanumab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2021;8(4):412-413. PubMed.
  5. . Immunotherapy for Alzheimer's Disease: Current Scenario and Future Perspectives. J Prev Alzheimers Dis. 2021;8(4):534-551. PubMed.
  6. . Editorial: How Will Aducanumab Approval Impact AD Research?. J Prev Alzheimers Dis. 2021;8(4):391-392. PubMed.
  7. . A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021 Apr 17;13(1):80. PubMed.
  8. . Approval of Aducanumab for Alzheimer Disease-The FDA's Perspective. JAMA Intern Med. 2021 Oct 1;181(10):1276-1278. PubMed.
  9. . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 May 6;384(18):1691-1704. Epub 2021 Mar 13 PubMed.

External Citations

  1. Oct 8 Businesswire
  2. Slide 6, quarterly update
  3. PR Newswire
  4. Shahzad et al., 2021

Further Reading

Primary Papers

  1. . Editorial: Consequences of the FDA Decision on Aducanumab for Patient Care and Research. J Prev Alzheimers Dis. 2021;8(4):393-395. PubMed.
  2. . A Middle Ground for Accelerated Drug Approval-Lessons From Aducanumab. JAMA. 2021 Oct 12;326(14):1367-1368. PubMed.
  3. . Fulfilling the Mandate of the US Food and Drug Administration's Accelerated Approval Pathway: The Need for Reforms. JAMA Intern Med. 2021 Oct 1;181(10):1275-1276. PubMed.