Finally: Big Win on All Outcomes for Lecanemab in Phase 3 Topline Results
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Eisai and Biogen yesterday announced positive topline results from the Phase 3 Clarity trial of their anti-amyloid antibody lecanemab. The drug slowed decline on the primary endpoint, CDR-SB, by 27 percent over 18 months, and also nudged down decline on all secondary clinical endpoints. The incidence of the brain edema known as ARIA-E was 12.5 percent, about one-third of that seen with Biogen’s approved anti-amyloid antibody Aduhelm.
- In Phase 3, lecanemab met primary and secondary endpoints.
- Biomarker data and detailed analyses will be presented at CTAD.
- The drug’s sponsors will apply for regulatory approval in the U.S., Europe, and Japan.
More detailed data, including biomarker findings, will be presented at the Clinical Trials on Alzheimer’s Disease conference in San Francisco on November 29. The companies plan to apply for regulatory approval in the U.S., Europe, and Japan, according to a press release.
Alzheimer’s researchers hailed the news as a major advance. In particular, they welcomed the straightforward findings after the highly contested rollout of aducanumab last year. “What the field needed was a clearly positive result from a trial completed and conducted per protocol,” Gil Rabinovici at the University of California, San Francisco, wrote to Alzforum. David Knopman at the Mayo Clinic in Rochester, Minnesota, agreed. “This pattern of clear-cut clinical benefits and a manageable adverse event profile is what the field has hoped for,” he wrote (comments below).
Developed originally by Lars Lannfelt of Sweden's Uppsala University, lecanemab, aka BAN2401, had shown a cognitive benefit in Phase 2 as well. Alas, those data were clouded by an uneven distribution of APOE4 carriers between treatment groups, which resulted from EMA requesting midway through the trial that APOE4 carriers no longer be allocated to the highest dose (Jul 2018 conference news; Nov 2018 conference news).
So far, at least, the Phase 3 data seem free of any controversy. Eisai and Biogen reported that the primary outcome was highly statistically significant at p=0.00005, and that secondary outcomes, comprising the ADAS-Cog14, ADCOMS, and ADCS MCI Activities of Daily Living, were all below p=0.01.
“I am pleased by the robustness of the topline results,” said Dennis Selkoe at Brigham and Women’s Hospital, Boston. Lon Schneider at the University of Southern California agreed the outcome is strong enough that it is unlikely to be overturned in sensitivity analyses that look for confounding effects. “The strong statistical effect facilitates the potential for reliable subgroup analyses that could give meaningful information on who might benefit,” he added (comments below).
That said, researchers also noted the absolute difference in CDR-SB scores was small, at 0.45, with some questioning how clinically meaningful this is. Others said they are awaiting the full dataset to examine issues such as subgroup effects, especially for APOE4 carriers, potential unblinding due to ARIA, and safety data. Many are eager to see biomarker findings, especially for tau.
Others noted that the focus will now shift toward how scientists can build on this result to grow the therapeutic benefit for patients. "Promising strategies include earlier intervention and/or combination with other treatment candidates, such as anti-tau immunotherapy. And, of course, we must continue to vigorously pursue new therapeutic approaches," wrote Paul Aisen of the University of Southern California.
In the bigger picture, researchers said the data strengthen the amyloid cascade hypothesis. “This confirms the importance of Aβ in disease pathogenesis,” said David Holtzman at Washington University in St. Louis (full comment below). "This is the first time a therapeutic antibody has clearly changed the course of Alzheimer's disease. It is a pivotal moment in the history of Alzheimer's therapy," said Randall Bateman, also at WashU.
Earlier trial results from lecanemab, donanemab, and aducanumab had linked plaque removal to slowing of cognitive decline, but the findings were often muddied by conflicting results or small sample size. “We are seeing converging data showing that significant plaque lowering can slow clinical decline in early stage AD, with Clarity AD providing the strongest evidence to date,” Rabinovici noted.
Researchers widely expect the data will lead the Food and Drug Administration to grant regular marketing approval. Some wondered whether the clear evidence of clinical benefit might also cause the Centers for Medicare and Medicaid Services to update its coverage determination for anti-amyloid antibodies as a class.
Many see this as the beginning of a new era of Alzheimer’s treatment. “The controversial accelerated approval of aducanumab may have served as a ‘soft opening’ for the amyloid therapy era, but if full FDA approval of lecanemab awaits, it could be for real this time,” Erik Musiek at WashU wrote to Alzforum (comment below).—Madolyn Bowman Rogers
References
Therapeutics Citations
News Citations
- BAN2401 Removes Brain Amyloid, Possibly Slows Cognitive Decline
- Second Look at BAN2401 Data Still Positive, Despite Snafu
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Comments
UCSF
After all the controversy around aducanumab, what the field needed was a clearly positive result from a trial completed and conducted per protocol, and it looks like Clarity AD delivered just that!
The results should not be considered surprising because they are highly consistent with what has been observed in previous trials of highly potent, anti-amyloid monoclonal antibodies given at high doses, including the EMERGE aducanumab trial, the TRAILBLAZER Phase 2 for donanemab, and the Phase 2 lecanemab trial. In totality, we are seeing converging data showing that significant plaque lowering can slow clinical decline in early stage AD, with Clarity AD providing the strongest evidence to date. The low rates of ARIA reported here are also encouraging and will impact the risk/benefit decision-making among patients and clinicians.
Of course, I am looking forward to seeing the primary data at CTAD 2022. A few burning questions include: How did clinical benefit and safety profile differ between APOE4 carriers and noncarriers, and how did ATN biomarkers correlate with each other and with clinical outcomes?
If, and when, the drug is approved by the FDA, I believe that initially we should be conservative, administering the treatment to patients who, by and large, would have met the inclusion/exclusion criteria for the trial, and then carefully monitoring for ARIA on a similar MRI schedule to that in the clinical trial. I hope the label will reflect that, and I anticipate Appropriate Use Recommendations for lecanemab reflecting these considerations will also be forthcoming. It will also be critical for CMS and other payers to revisit the previous National Coverage Decision and provide full coverage for an approved drug that demonstrates clinical benefit.
No one will argue that we have a cure here, but it seems that lecanemab moves the needle, opening the door for future treatments, or combinations of molecular-specific treatments, that will be increasingly efficacious. Having an effective treatment will also greatly facilitate the use of biomarkers for early and accurate diagnosis.
This is truly a major milestone for the field, likely marking the beginning of a new era in AD diagnosis and care. It is a moment of celebration for AD research and a moment of hope for patients and families living with AD. Much work remains, but now we can start to see light at the end of a long tunnel.
Mayo Clinic College of Medicine
The positive results announced yesterday by Eisai are heartening. Based on the information in their press release, the Phase 3 trial of lecanemab achieved its primary outcome and showed benefits on secondary outcomes as well. Lecanemab had a low rate of ARIA-E and ARIA-H, which is also gratifying. This pattern of clear-cut clinical benefits, and a manageable adverse event profile, is what the field has hoped for.
There is an important cautionary note however: The magnitude of the delay—which was a slowing of decline—was small. We can only hope that the benefit is durable and could grow with time. Those long-term properties are unknowable at this time.
Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases
I think the top-line data look rigorous and make biological sense, based on my knowledge of lecanemab and the excellent trial execution by Eisai. Learning the correlations between degree of amyloid lowering and clinical outcomes is key, and may be shown at CTAD. The tau PET and tau CSF outcomes will also be important. I am pleased by the robustness of the top-line results and the likelihood of accelerated approval first, then regular approval. CMS approval should follow. The outcomes so far appear to prove the “amyloid hypothesis” and make other Aβ monoclonal antibodies promising and combination treatment with an anti-tau monoclonals more feasible. Great news for our patients, I think.
University of Southern California Keck School of Medicine
Given that this is a press release, not a scientific report, and taking it at face value—often a chancy thing to do—the primary outcome is statistically significant at P < 0.0001. On its face, other things being equal and assuming a low risk of bias, the P value strongly suggests that the CDR-SB primary outcome is robust and not going to be overturned in sensitivity analyses.
For inferring clinical meaning, the -0.45 CDR-SB difference from placebo is small and would not be considered by many as a minimal clinically important difference, which is closer to -0.9. Others, however, will disagree and say that this difference between the change of scores—1.67 worsening over 18 months for placebo versus 1.22 for lecanemab—is clinically meaningful. Or perhaps that any reliably observed difference on any clinical scale is clinically meaningful. The trial, however, was planned from the get-go to be able to detect a difference of less than -0.40 with 90 percent power and was made large enough to do just that.
At this level of significance and large sample size, it would have been worrisome if the secondary clinical outcomes had not been significant, because they all intercorrelate with the CDR-SB. It is important to learn what the mean difference and standardized effect size is on the ADAS-cog14, because this is the only neuropsychological composite measure in the trial.
The relatively low rates of ARIA-E, i.e. edema, at 12.5 percent, which is one-third of aducanumab’s rate, and of ARIA-E and ARIA-H, i.e. edema and hemorrhage combined, at 21.3 percent, and half that of aducanumab, suggest that lecanemab is relatively safer and easier to monitor even with twice per month infusions. But still, life-threatening ARIA and death are associated with lecanemab as they are with aducanumab. Importantly, for interpreting the clinical outcomes, less edema, fewer abnormal MRIs, and fewer treatment pauses decrease the level of functional unblinding and risk of bias in this trial compared to the aducanumab trials. The number and pattern of dropouts are important, too.
Again, with the caveat that taking a press release at face value, without clinical trial reports and data, is a bit of a wager, it is highly likely that lecanemab will receive regular marketing approval based on this trial alone, showing the FDA-required “substantial evidence for effectiveness,” with biomarker support from the Phase 2 trial as well (FDA 2018 guidelines).
With regular approval, CMS would most likely reimburse based on its own statutory “reasonable and necessary” criteria, which are similar to regular FDA marketing-approval criteria and why most FDA-approved drugs get Medicare coverage. (Here, we might beware organizations operating as patient advocates soliciting money by generating fear, uncertainty, and doubt about CMS coverage.)
More needs to be learned for lecanemab to find its place. The strong statistical effect, and very low P value, facilitate the potential for reliable subgroup analyses that could give meaningful information on who might benefit. We may see larger, reasonable, and reliable CDR-SB effects approaching a clinically meaningful -0.9 difference or beyond in relevant subgroups. For example, the aducanumab EMERGE trial (but not ENGAGE) showed greater effects for the oldest, over 75 or 80, the more impaired dementia, and the APOE4 subgroups, with the CDR-SB differences approaching and exceeding a 1-point difference. Will we see similar with lecanemab but at a necessary statistically robust level?
One last thing: The Clarity trial demonstrates that clinical outcomes trump biomarkers. There is little need for FDA to offer an accelerated approval pathway relying on biomarkers for Alzheimer’s disease as we currently think of it.
Disclosure: I am a project arm leader for the DIAN-TU/ Washington University trial of an Eisai anti-tau antibody in which lecanemab is used as a co-treatment; and co-PI for an NIH-funded grant for early phase trials of a novel Aβ vaccine intended for primary prevention.
USC Alzheimer’s Therapeutic Research Institute
This is a definitively positive, pivotal trial, hitting the primary and each key secondary cognitive/clinical endpoint. The results support full approval of lecanemab in early AD, and provide support for the amyloid therapeutic hypothesis (and for the FDA accelerated approval of aducanumab on the basis of amyloid reduction). It is encouraging for other amyloid-lowering therapies, such as gantenerumab and donanemab, that will read out in the coming months.
We will learn much from detailed analysis of the biomarker data, as well as genetic and safety data.
How can we build on this positive result? How can we increase the clinical benefit? Promising strategies include earlier intervention and/or combination with other treatment candidates (such as anti-tau immunotherapy). And, of course, we must continue to vigorously pursue new therapeutic approaches.
Washington University
The press release indicating that lecanemab hit its primary and secondary endpoints in slowing cognitive decline in very mild to mild AD is incredibly exciting. This is very encouraging for the field, and it will be very interesting to see the clinical data for the Phase 3 readouts for donanemab and gantenerumab soon.
At first glance from the release, it sounds like there is clinically meaningful lessening of cognitive decline, suggesting that the antibody will be helpful as a treatment. This confirms the importance of Aβ in disease pathogenesis and supports the idea that removing amyloid even before symptoms emerge has a chance to have an even greater effect, such as delaying the onset of clinical symptoms.
Washington University School of Medicine
These results are very exciting, though we all, of course, need to see the actual data before drawing any major conclusions. I think that the incomplete trials for aducanumab left the field at a tipping point: On one hand, the Phase 1b/2 trials for aducanumab, lecanemab, and donanemab, as well as the Phase 3 EMERGE trial for aducanumab, suggested that, as a class, plaque-clearing antibodies might slow cognitive decline in patients with very early stage AD (by 25-30 percent). On the other hand, the ENGAGE trial for aducanumab showed no effect, creating skepticism about the efficacy of this approach in general. If the Clarity AD data is as advertised, not only will it pave the way for full FDA approval of lecanemab, it may tip the scales in favor of plaque-clearing antibodies, suggesting that this class of drugs does in fact work as it did in the Phase 2 studies and EMERGE. This result makes me much more optimistic that donanemab will show similar results, and that a third trial with aducanumab might also be successful.
If this is the case, there are still many questions. I will be very interested to see how APOE4 genotype influences the response to lecanemab, both in terms of efficacy and ARIA. Debate will continue as to whether a 25-30 percent slowing over 18 months is clinically meaningful, and if it merits the cost and the ARIA risk. The biweekly dosing of lecanemab will also create some challenges in terms of infusion capacity, should it ultimately be approved.
One might assume that if lecanemab is granted a full, traditional approval by the FDA, this would circumvent the restrictions on anti-amyloid antibodies put in place by CMS, but it remains to be seen how that plays out.
At this point, we wait for the data release at CTAD and hope that there are no unexpected surprises that will muddy the waters. The controversial accelerated approval of aducanumab may have served as a “soft opening” for the amyloid therapy era, but if full FDA approval of lecanemab awaits, it could be for real this time.
Chiesi Farmaceutici S.p.A.
My immediate reaction is that this is an important result for the field. The data released on p values for the primary endpoint (CDR-SB) at six and 18 months seem to indicate a treatment effect that increases over time and thus is compatible with a disease-modifying effect.
The Eisai/Biogen press release did not mention the proportion of APOE4 carriers in the study, or if the positive effects of the drug are maintained in non-APOE4 carriers. We do not know the number of dropouts, or if they were fairly balanced between the two treatment groups. To exclude potential unblinding effects due to ARIA incidence, it is important to perform sensitivity analyses in subjects without ARIA. In terms of unblinding, it would be also interesting to see if the effect size is maintained on efficacy variables, such as the MMSE, that are completely objective and are not influenced by rater or informant subjective input.
Data on PET and CSF biomarkers (including total and free Aβ42 levels) will inform us of the potential mechanisms associated with the observed cognitive and clinical effects, and will guide researchers in optimizing monoclonal antibodies therapies and further pharmacological approaches.
Brigham and Women's Hospital, Harvard Medical School
As others indicated, this is great news for patients. No one expected a cure, so many patients and families will welcome any improvement upon placebo.
In my view, the concept of clinical meaningfulness or minimal clinically important difference is a moral one. Meaningfulness is set by patients' and their families' values. What is meaningful or important for one person will be different for another. I am therefore skeptical of any "cutoff" set in the literature, and would discourage regulatory bodies from basing decisions on such cutoffs.
University of British Columbia
Very encouraging topline results, and the prospect of the first, unequivocal disease-modifying therapy for Alzheimer’s disease is very exciting. The effect size is very small, which will undoubtedly create rigorous debate moving forward. But nevertheless, this is potentially a milestone result to build on.
Also of significant interest is the fact that while many amyloid-lowering therapies have efficacy signals pointing toward clinical benefit (and with lecanemab seemingly showing this with robust statistical significance), the disease clearly continues to progress despite brain amyloid being normalized. This could be due to many factors, including timing and duration of treatment, target specificity, optimal dosing, and genetic background. It is also possible that removing amyloid is only a piece of the puzzle, and that alternative mechanisms may be of at least equal, if not greater importance.
The lecanemab press release serves as great motivation to continue our search for additional mechanisms leading to AD, supplementing the critical progress being made.
University of Tokyo
The topline results of lecanemab Phase 3 Clarity AD unequivocally showed that the study achieved the primary endpoint, i.e., statistically significant difference in the 18-months change from baseline of CDR-SB by 27 percent, by the administration of an anti-Aβ humanized monoclonal IgG1 antibody that has a high affinity to Aβ protofibrils in vitro and has been shown to robustly remove brain amyloid deposits in early phase human trials. The incidence of ARIA-E, a major adverse effect of amyloid-removing antibody drugs, was 12.5 percent, which was relatively modest compared to those reported with similar antibody drugs. The results are very consistent with the previously published data of the Phase 2 trial, and will give a green light toward the regulatory approval and, hopefully, insurance coverage.
On the afternoon of September 28, members of Eisai's leadership gave a press conference at Eisai's main office located on the hillside of Tokyo's downtown. CEO Haruo Naito recollected their ~25 years’ journey that led to the first success of disease-modifying therapy in a confirmatory trial, now proving the amyloid target hypothesis in human AD. The attendees unanimously celebrated the achievement, while some asked questions as to the clinical meaningfulness of the effect size of 27 percent decline in progression speed and -0.45 change in the mean score of CDR-SB. Simulation analyses, e.g., regarding the estimation of effects to delay the progression of decline to a certain point, may be needed to give a sense of efficacy to a lay audience.
In Japan, Eisai will complete the submission of application data by next spring, which hopefully will be reviewed and approved by the end of 2023. There remain a number of important tasks to prepare for the implementation of the initial DMT in dementia clinical practice in Japan. Nonetheless, we appreciate the top-line results of lecanemab as the beginning of a new era in the history of AD therapeutics and research.
University of California, San Francisco
The press release is promising. The nature of press releases is to simplify and put a rosy spin on things, and we have seen puff-piece press releases in the past. I am therefore eager to see more details.
Specific concerns relate to how analyses were done and if they preserved the randomization (e.g., if randomization was stratified, analyses must reflect that stratification) and evidence that unblinding of participants (i.e., knowledge of treatment status) did not contribute to findings. Examples of such evidence would be results for outcomes with no self- or proxy-reported components.
University of Kansas
This is an encouraging press release, but of course we need to see the details to get more perspective and a better sense for the strengths and weaknesses of the data. I imagine there will be some speculation regarding to what extent side effects contributed to unblinding and in general affected the final analyzed datasets and trial endpoints.
It will certainly be interesting to compare Phase 3 lecanamab data to Phase 3 aducanumab data, and to the soon-to-be-reported Phase 3 data for donanemab and gantenerumab. All these data will give us some insight into the extent amyloid removal can mitigate cognitive decline in AD, and start to give us a feel for the potential ceiling of the amyloid removal approach. I hope we can soon begin to form an impression on how this intervention may compare in efficacy to that of the cholinesterase inhibitors.
This being said, there is not much to argue about in the press release aside from the statement that these clinical trial results “prove the amyloid hypothesis.” As someone who studies disease mechanisms, I’m not sure this study informs questions of AD etiology. To my mind this study, along with other amyloid antibody trials, is better positioned to inform the question of how toxic Aβ is in people’s brains. One would think if this approach was to have a transformative effect, the answer would be very toxic, if no effect then not toxic, and if a small effect then a little toxic. Data from Clarity would seem to argue Aβ is more on the minor than major end of the toxicity spectrum.
UK Dementia Research Institute@UCL and VIB@KuLeuven
It is only a press release, so difficult to say something definitive, BUT this has been the most exciting news of my career. I have always believed that amyloid is a trigger of the disease (Karran et al., 2011) based on all the hard basic research, which is unequivocal.
That said, the trigger of the disease means that amyloid triggers a long preclinical cellular phase (De Strooper and Karran, 2016) that stands between the first appearance of the plaques and the clinical outcome of dementia. This cellular phase might encompass processes that become independent of the trigger or irreversible (for instance neuronal loss). The clinical trials measure, however, the outcome of this process at the final stage, i.e., cognition and behavior will be altered only after quite some serious damage to the brain has already occurred.
Until the 28th we did not know whether amyloid pathology was still involved at that stage or not and whether reversing amyloid pathology at such late stage (I consider MCI a late stage of the disease) would make sense.
We need to see the data to fully understand how clinically relevant the stabilization is, but theoretically the difference with placebo should grow over time. Furthermore, treating earlier (e.g. biomarker-positive, clinically normal) might give even an better benefit (Karran and De Strooper, 2022).
Another question is whether patients need to be continuously treated or not. In the latter case, these antibody treatments might be great, but dosing chronically will make this drug much too expensive. I hope that the price setting remains reasonable and not $50,000, as Aducanumab initially.
These results strongly suggest that we revisit previous drug targets such as γ-secretase and BACE, as small compounds modulating these activities might be, in the long run, the only cheap and feasible prevention for AD. The alternative might be to reconsider active immunization.
Last but not least, this success should also stimulate much broader investment in other relevant targets in various neurodegenerative diseases, as it is clear that knowledge and perseverance will prevail ultimately. A big kudo to Lars Lannfelt, the inventor of this antibody, and to Eisai/Biogen for their perseverance and continued investment in this area. They followed the science!
I am cautiously optimistic that this may be a breakthrough. Based on the top-line results, it appears that there was a statistically significant benefit from lecanemab, a monoclonal antibody targeting protofibril Aβ, in slowing progression of cognitive impairment in early Alzheimer's disease. It is not a cure for Alzheimer’s disease, and it is not yet clear to me whether the slowing of cognitive decline was clinically significant.
Lecanemab is safer than aducanumab and appears to be more effective.
As an Alzheimer’s patient, would I take it? No, because I have already had life-threatening ARIA from aducanumab (VandeVrede et al., 2020). As a neurologist, would I prescribe it? I would first want more information on efficacy.
References:
VandeVrede L, Gibbs DM, Koestler M, La Joie R, Ljubenkov PA, Provost K, Soleimani-Meigooni D, Strom A, Tsoy E, Rabinovici GD, Boxer AL. Symptomatic amyloid-related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimers Dement (Amst). 2020;12(1):e12101. Epub 2020 Oct 9 PubMed. Correction.
Goizueta Institute @ Emory Brain Health
The data on lecanemab is certainly good news for the field, and finally some hope for those suffering from this terrible disease. However, if we use the analogy to the war on cancer, a battle has finally been won, but the war is far from over. Twenty-seven percent slowing of rate of decline is simply a start. We must strive to do better. I hope what appears to be a clear-cut clinical disease-modifying effect in terms of multiple cognitive and functional measures and associated biomarkers, along with a lower incidence of ARIA and severe ARIA than I might have expected, enables a push to test this antibody in the presymptomatic stages of disease. I would predict lecanemab and other drugs with similar actions will have a much bigger impact, delaying time to symptom onset quite significantly.
Those positive notes aside, I think there is important follow-up that needs to be done. First and foremost, continued assessment of this drug, if approved (which I assume would be likely based on the public information), in a real-world population is essential. In most of these immunotherapy trials, it’s a pretty select population that is being studied, and additional data is likely needed to support effectiveness and safety in diverse populations. Longer term-studies looking for durability of effect are essential as well.
Second, I imagine that there are both “responders” and “nonresponders” in the treated group. Given the likely costs of an antibody-based therapeutic, future efforts to identify those who are likely to respond the best could be highly informative. Third, some clarity (pun intended) on why this particular antibody seemed to be a bit more effective and a bit safer than Aduhelm and other previous anti-Aβ antibodies is important. Is the intent-to-treat population or the dosing regimen different enough to explain the apparent success? Or are the antibodies different enough both in terms of effector function, aggregate binding profile and avidity, to explain the difference, especially with respect to side effects? I know lecanemab is advertised as targeting toxic oligomers better, but I remain agnostic about that claim as the underlying reason for its apparent efficacy.
On a more general note, I hope ALL in the field embrace this as step in the right direction. I have always been surprised how some in our field seem to almost rejoice when an amyloid or Aβ targeting agent fails. No one in the field should ever want any drug trial in AD to fail—the unmet medical need is too large.
I think these and numerous other studies tell us what genetics, pathology, and human biomarker studies have told us for many years: Amyloid is important, but by the symptomatic phase of AD, many other factors are contributing to cognitive dysfunction and neurodegeneration (Golde et al., 2011). By targeting amyloid in early symptomatic disease, we can see a benefit. But that benefit is still limited. This stage of disease is not early from a pathologic point of view. Let’s hope trials of such drugs in biomarker-positive individuals without impairment do happen and hopefully provide a larger impact, delaying onset of symptoms by many years. In the symptomatic phase, it is likely we are going to need additional interventions targeting different pathways and different aspects of pathology and brain cell-function to actually improve symptoms and dramatically slow or halt decline (Golde, 2022).
References:
Golde TE, Schneider LS, Koo EH. Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron. 2011 Jan 27;69(2):203-13. PubMed.
Golde TE. Disease-Modifying Therapies for Alzheimer's Disease: More Questions than Answers. Neurotherapeutics. 2022 Jan;19(1):209-227. Epub 2022 Feb 28 PubMed.
University of Nevada Las Vegas
This study is a big step forward, indeed a breakthrough, for Alzheimer’s therapeutics. It confirms the relationship of plaque lowering and slowing of cognitive decline. It supports the amyloid hypothesis and will encourage both monoclonal and amyloid research.
There is much more to learn. How did E4 carriers respond? What are their ARIA features? What species beyond the plaque may be involved in the response? What is the role of amyloid’s influence on tau?
UC Irvine Institute for Memory Impairments and Neurological Disorders
While there is need to withhold judgment until we can see the data, this is excellent news. At some level, just having what appear to be unambiguous findings is a good thing, but the preliminary report that the primary and key secondary outcomes are all supportive is heartening.
Clearly, there are important aspects that we’ll be eager to hear about, including how potential unblinding was handled, whether there are downstream biomarker effects, and whether subgroups differentially responded.
Another aspect that is quite exciting is the reported diversity of the sample. The field may be able to learn from the efforts in this trial to do better in others. This is a major focus for an ongoing preclinical AD trial of lecanemab, the AHEAD Study. Hopefully these positive results in early AD will spur even greater interest in AHEAD, including among diverse participants.
University of Pennsylvania
By definition, Phase 3 trials test whether a drug treats a disease. Some trials also change how we define a disease. CLARITY-AD may well be one of those revolutionary trials. If in fact it validates the amyloid hypothesis (remember, we’re working from a press release), then it will inaugurate both a new treatment and also a new way of diagnosing and talking about Alzheimer’s using biomarkers. I expect the CDR will fast become one of the most talked-about measures of 2023.
Acumen Pharmaceuticals
This is a groundbreaking result with regard to AD research and treatment. Since donepezil was first approved by FDA in 1996, there has likely been no new information as impactful as the press release from Eisai on September 27, 2022, stating that the Phase 3 Clarity study, testing lecanemab 10 mg/kg Q2weeks versus placebo, showed a statistically significant difference between drug and placebo on the primary outcome measure, the CDR-SB. While other drugs have achieved promising results, and aducanumab was given accelerated approval by FDA in 2021, this clearly positive Phase 3 study represents a landmark for the field.
While we are all awaiting more a complete report at CTAD, the results included in the release are quite informative. Lecanemab treatment reportedly reduced clinical decline on the CDR-SB by 27 percent compared with placebo at 18 months. The difference in actual CDR-SB scores was 0.45 points at 18 months, which was highly statistically significant with a p value of 0.00005 in the intent-to-treat population. For context, CDR-SB scores generally worsen by about 1.0 to 1.5 points per year in placebo groups, so the 0.45 point difference in an 18-month study would appear to be clinically important. Clinical secondary outcomes were also apparently statistically significant, and those will be of great interest when they are presented at CTAD.
Safety, in particular ARIA-E, is also an important aspect of several monoclonal antibodies being tested for AD, and the results for lecanemab were of interest. In the Clarity study, incidence of ARIA-E was 12.5 percent in patients treated with lecanemab compared to 1.7 percent of patients treated with placebo. Symptomatic ARIA-E was 2.8 percent in the lecanemab group, with no cases of symptomatic ARIA-E in the placebo group. Additional information regarding the relationship to ApoEe4 carrier status will be of interest. The management of the clinical use of lecanemab will also be of interest, including whether ApoE genotyping should be obtained prior to initiating therapy and the necessity for surveillance MRIs looking for ARIA.
Broadly speaking, these Clarity results are a major breakthrough for the field. The “clinical meaningfulness” of the efficacy can be debated, but there is little doubt that the effect on CDR-SB is real. As with any drug, efficacy must be weighed against safety, and the Clarity results are no exception. There will be debates about the benefit/risk profile, primarily related to the clinical meaningfulness of the efficacy versus the risk of ARIA. But the clarity of the Clarity results with regard to efficacy, as evaluated by the CDR-SB, can not be debated, and that is a major advance for patients and the field.
TrueBinding
It is interesting that lecanemab shows indications of slowing cognitive decline in very mild to mild AD. It will be good to see the actual data. Lecanemab is an anti-Aβ protofibril antibody and highly selective for Aβ oligomers/protofibrils in the brain. This antibody is not solely for oligomers or protofibrils. It would be interesting to characterize which particular oligomers bind to this antibody and which particular types of amyloid plaques are dissolved by it.
Of early Alzheimer's patients taking aducanumab in Phase 3, 40 percent were hit with ARIA and, in the 10-mg/kg group who experienced ARIA-E, 26.0 percent reported symptoms. Keeping these factors in view, it is worth knowing about the ARIA-E score or autoimmune complications, particularly in patients carrying APOE4 allele.
We published that anti-oligomeric monoclonal antibodies significantly reduce amyloid load and improve cognition. Amyloid clearance was significantly correlated with reduced tau hyperphosphorylation and improvement in cognition. These results demonstrate that systemic immunotherapy using oligomer-specific monoclonal antibodies attenuates behavioral and pathological impairments in 3xTg-AD mice (Rasool et al., 2013). It would be interesting to evaluate the effect of lecanemab on normal tau or hyperphosphorylated tau.
References:
Rasool S, Martinez-Coria H, Wu JW, Laferla F, Glabe CG. Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice. J Neurochem. 2013 Aug;126(4):473-82. PubMed.
Abington Neurological
Lecanemab likely demonstrates a class effect for drugs that robustly remove amyloid. This is wonderful news for our patients in the long term.
In the short term, lecanemab's results indicate that aducanumab's FDA approval last year was a good move, and Medicare's NCA was a terrible mistake.
Given the recent data, Medicare should cover aducanumab now. I have people in front of me now who could benefit. Time is brain.
Michigan State University
GREAT NEWS!
1. This outcome validates the value of mouse APP models of amyloid deposition, as the first benefits of amyloid immunotherapy were observed in them, as well as the first hemorrhages/ARIA.
2. The 25-40 percent reduced rate of decline is similar to the contribution of amyloid to cognitive decline variation in the pathology studies from the ROSMAP cohorts.
3. Ironically, on the same day, CMS announced a reduction in the co-pay for Medicare due to the denial of Aduhelm coverage that they expected last year. The payor mismatch between drug costs and residential care costs needs to be addressed by Congress for full patient benefits to follow.
Cant wait to see the data :). Cheers to Lars Lannfelt.
Most all scientists commenting so far seem to embrace the manufacturer’s assertion that lecanemab “works” by its specific antibody grabbing amyloid from brain plaques, thus somehow slowing MCI, the prelude to AD.
Another possibility is that the infusion works by attaching to an antigen shared by microbes, especially spirochetes, thereby slowing or killing the organisms (Allen, 2016; MacDonald, 2021; Senjani, 2022). Pioneering work of Judith Miklossy must be recognized in this context (Miklossy, 2016).
These organisms have been implicated many times in the pathogenesis of AD. Brain amyloid has been seen as a primitive defense against brain infectious agents invading the brain (Moir et al., 2018). The use of antibodies to fight infections is now well-established, as underlined by a recent commentary from the Infectious Diseases Society of America (Cohen, 2022). If found true, this would have major import. AD could possibly be treated by an already-licensed antibiotic plus a biofilm buster. No such clinical trials have been held.
Also, AD research would now seem to have facets in common with Lyme investigations, so fruitful exchanges between investigators could occur.
References:
Allen HB. Alzheimer's Disease: Assessing the Role of Spirochetes, Biofilms, the Immune System, and Amyloid-β with Regard to Potential Treatment and Prevention. J Alzheimers Dis. 2016 Jun 27;53(4):1271-6. PubMed.
MacDonald AB. Borrelia invasion of brain pyramidal neurons and biofilm Borrelia plaques in neuroborreliosis dementia with Alzheimer’s phenotype. Microbiol Infect Dis. 2021; 5(1): 1-11. Microbiology & Infectious Diseases
Senejani AG, Maghsoudlou J, El-Zohiry D, Gaur G, Wawrzeniak K, Caravaglia C, Khatri VA, MacDonald A, Sapi E. Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer's Disease Brain Tissues. J Alzheimers Dis. 2022;85(2):889-903. PubMed.
Miklossy J. Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques. J Alzheimers Dis. 2016 Jun 13;53(4):1459-73. PubMed.
Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimers Dement. 2018 Dec;14(12):1602-1614. Epub 2018 Oct 9 PubMed.
Cohen MS. Antibodies for prevention and treatment of infectious disease. Infectious Diseases Society of America “Science Speaks” blog. (2022) July 7 Infectious Diseases Society of America “Science Speaks” blog
Duke University
I am very hopeful about the top-line results because they report a positive effect on clinical outcomes, which are what matter to our patients and families. That is the piece that was much less convincing in the previous studies. We knew from previous studies that antibodies against amyloid can effectively clear amyloid from the brain, but that only matters to a patient if removing amyloid allows memory and cognition to improve, or at least substantially slows any further loss of memory and thinking ability.
We hope the clinical benefit holds true over time and can be reproduced and validated, and we hope the benefit-to-risk ratio continues to look acceptable. Questions still remain about safety: Is the risk of brain bleeding and swelling associated with these drugs worth the clinical benefit, and what is the best way to minimize and monitor for those risks while patients are being treated?
University of Exeter
Although on the face of it these are encouraging results, I am concerned that the apparently positive results may be due to withdrawal bias. There will need to be an analysis of different withdrawal rates in the treatment and placebo groups, stratified by whether participants had MCI or mild AD at the outset. If more mild AD patients withdrew from the treatment group than the placebo group, because of treatment-related symptoms, this would leave a larger pool of MCI patients in the treatment group, with a lower risk of progression. Given the small effect size, and the difficulty of using CDR-SB for subtle change in MCI/mild AD patients, the apparent positive effects seen in this study may be undermined by small differences in withdrawal rates. I am concerned that these apparently encouraging results will not withstand rigorous analysis, as has been the case with other anti-amyloid approaches, as demonstrated by a recent negative meta-analysis (Ackley et al., 2021).
References:
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.
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