BAN2401 Removes Brain Amyloid, Possibly Slows Cognitive Decline
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The last full day of the Alzheimer's Association International Conference, which ended today in Chicago, saw scientists pack a room the size of an aircraft hangar in anticipation of a late addition to the scientific program. They came to see the data behind a tantalizing press release issued earlier this month, which had claimed that BAN2401, the anti-Aβ protofibril immunotherapy being developed by BioArctic, Eisai, and Biogen, reduced amyloid in early Alzheimer's disease and also slowed cognitive decline. The upshot? According to results presented in Chicago by Eisai's Lynn Kramer, the antibody appears to have done what it was designed to do. Over 18 months, fibrillar amyloid fell in all treatment groups compared with placebo; indeed, plaques melted by a whopping 93 percent in participants on the highest dose. This dose was reported to have reduced cognitive decline by 47 percent as measured by the ADAS-Cog, and by 30 percent on the ADCOMS, a new composite measure to detect early cognitive decline. At 856 participants with MCI due to AD or mild AD, this trial is the largest one yet to post both amyloid reduction and a downstream benefit on symptoms.
But wait. There's a catch. The data set is complicated. That's in part because this Phase 2B trial started out with adaptive randomization, which means that as participants accumulated, new enrollees were more apt to be put on doses that looked likelier to be effective. The trial featured a Bayesian statistical analysis at 12 months, and ended with a more conventional, aka “frequentist,” analysis at 18 months. That was complex, but the scientists had planned it that way.
Unplanned, however, was a curve ball regulators threw their way in July 2014, well over a year after the trial had started enrolling. Driven by safety worries about ARIA-E, the European Medicines Agency insisted that APOE4 carriers be excluded from the highest dose, 10 mg/kg infused biweekly. By that point in time, 74 carriers had been enrolled at that dose. What's more, the EMA demanded that all APOE4 carriers who had been on that dose for less than six months stop the trial, effectively kicking out 26 people who had no ARIA-E. This left 48 in the highest dose group. ARIA-E is a temporary inflammatory reaction typically seen within the first three months of Aβ immunotherapy; it is being studied intensely by most companies developing anti-Aβ antibodies. Most instances of ARIA-E occur within the first three months of dosing.
Kramer said that the trial sponsors argued against this restriction, to no avail. Paul Aisen from the University of Southern California, San Diego, said this regulatory request was odd, and difficult to understand. The EMA’s constraint likely compromised the adaptive randomization, said Andy Satlin, who initially led the BAN2401 program at Eisai and is now at Intra-Cellular Therapies in New York. This may have contributed to an outcome whereby the dose that proved to be the best received a lower number of participants than the second-best dose. In effect, the adaptive algorithm, which was increasingly leaning toward the highest dose as the trial went on, bumped up against the EMA’s APOE4 constraint, and a disproportionate number of participants ended up in the nearest dose. Suzanne Hendrix, a biostatistician and president of Pentara Corp., Salt Lake City, told Alzforum the restriction in effect biased comparisons with the placebo group. "The trial ended up with a different population in those two arms. That is not a true randomization anymore," Hendrix said.
Hendrix noted that among people with MCI and early AD, APOE4 carriers tend to decline faster on the ADCOMS, a cognitive composite she co-developed in hopes of picking up subtle changes at early disease stages (Wang et al., 2016). Outside this ADCOMS data, the idea of APOE4 speeding up progression is not established in the field, however. AD scientists do agree that APOE4 hastens amyloid deposition and brings on symptoms at a younger age, but they not agree on an effect on progression. “APOE4 carriers have an earlier onset, but their expected rate of decline is not different from patients with other APOE genotypes. However, there are conflicting reports in the literature on this topic,” wrote Lars Lannfelt of Uppsala University in Sweden, who made the mouse antibody that led to BAN2401 (see full comment below).
Despite the skewed randomization, statisticians and clinicians who gathered in the hallways after the presentation were cautiously upbeat. "Overall the results are positive and the amyloid effect is impressive," Hendrix said. "I believe this antibody works," Aisen agreed.
So do others. “In summary, there is dramatic amyloid lowering, with some apparent slowing in decline at the highest dose,” wrote Stephen Salloway of Butler Hospital, Providence, Rhode Island. David Holtzman of Washington University, St. Louis, considers the overall data “very promising” (full comment below), and Jeffrey Cummings of the Cleveland Clinic in Las Vegas thinks the results support target engagement and suggest a dosing strategy for phase 3. Randy Bateman of WashU wrote, “The field is clearly moving forward with the ability of a fourth drug to remove amyloid to a normal level, as measured by PET. Now with aducanumab, gantenerumab, and n3pg, BAN2401 has demonstrated reversal of amyloid plaques to normal levels, representing a milestone in the history of Alzheimer’s disease” (full comment below). Other commentators quibbled that the sponsors could have anticipated scrutiny over the APOE4 distribution and included that subgroup analysis in their AAIC presentation.
As the trial was enrolling, scientists conducted frequent interim analyses to steer new enrollees toward the doses that appeared early on to be most likely to work. This was done in hopes of making the trial more efficient (Satlin et al., 2016). It soon turned out that the action would be at the higher doses, and by the end of enrollment, 161 people were on 10 mg/kg biweekly, 253 people on 10 mg/monthly, and 247 people were on placebo. Only 52 people were in the 2.5 mg/kg biweekly dosing group, 51 in the 5 mg/kg monthly, and 91 people in the 5 mg/kg biweekly groups. Following the EMA request, the second-highest dose group ended up chock-full of APOE4 carriers, at 89 percent, compared with 30 percent in the highest dose group, and 70 percent in the placebo group.
At 12 months, a Bayesian analysis of the ADCOMS results estimated that the highest dose was 98 percent likely to slow decline. Separately, the trial's designers had previously set the criteria by which they would declare success at that time point to be an 80 percent likelihood of a clinically significant difference of 25 percent slowing of decline from baseline; the 12-month analysis calculated this likelihood to be 64 percent. The 80 percent was an awfully high bar, Hendrix told Alzforum, and may have been influenced by a push in the field at the time to reach for large effect sizes.
Bayesian trials had been debated in the Alzheimer’s field, but rarely put into practice. At AAIC, several commentators wondered if a simpler design could have worked as well. Hendrix expressed similar thoughts. "It's possible that with fewer dose arms, they might have met the primary endpoint at 12 months,” she said. On the other hand, Satlin said, the strong p values of the 10 mg/kg dose results may only have been achieved because the adaptive algorithm placed disproportionately more patients into this group than a conventional trial of the same size would have done.
So what were the results? Across the board, the antibody reduced amyloid in the brain. A time- and dose-dependent reduction saw PET SUVRs fall by up to 0.3 units in those on the highest dose, a 93 percent drop. Kramer said that on manual reads of the scans, 81 percent of treated patients went from amyloid-positive to amyloid-negative.
For the cognitive analysis, Kramer focused on the two highest doses. The 10 mg/kg biweekly group had a 47 percent reduction in cognitive decline as judged by the ADAS-Cog, and a 30 percent reduction on the ADCOMS. A 26 percent slowing on the CDR-SB was not significant. The 10 mg/kg monthly dose group—the one containing mostly APOE4 carriers—performed about midway in between placebo and the highest dose, showing a trend toward slower cognitive decline on the ADAS-Cog, ADCOMS, and CDR-SB but no statistical significance. The placebo group declined at a similar rate to placebo groups in recent large AD studies.
In a subgroup of patients who underwent spinal taps, CSF Aβ42 rose dose-dependently in all treatment arms, to more than 300-fold the level of the placebo group. Kramer said this was expected as the antibody pulled the peptide from plaques into the soluble fraction. Scientists generally believe that in the run-up to Alzheimer's dementia, CSF Aβ42 decreases as amyloid plaques deposit in the brain, sequestering it there. Kramer said studies were ongoing to determine how much of this Aβ was free versus bound to antibody. For CSF total tau, there appeared to be a slight reduction in the top two doses combined, though there was considerable scatter in the data.
And how about ARIA-E? As with other antibodies, it occurred in a dose- and APOE-dependent way, 48 times total across all groups, including two in placebo. Just shy of 10 percent of participants in the highest dose had an episode of ARIA-E, as did seven of that group’s 48 APOE carriers. Most ARIA-E was detected only on MRI, though five instances caused headache, visual disturbances, or confusion; two of those were in the highest dose, Kramer reported. In toto, this amounts to less ARIA-E than seen with gantenerumab or aducanumab.
Where does BAN2401 go next? "We view this as robust enough to approach regulatory authorities to discuss next steps in terms of additional trials or even breakthrough status," Kramer said in a press briefing before the main presentation.
In the general media, on social media, and among analysts, the results received the full range of responses, from an enthusiastic thumbs-up to a merciless drubbing over the uneven APOE4 carrier allocation. Both Biogen and Eisai’s stock prices dropped about 10 percent, but are starting to recover.—Tom Fagan and Gabrielle Strobel
References
Therapeutics Citations
Paper Citations
- Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. Epub 2016 Mar 23 PubMed.
- Satlin A, Wang J, Logovinsky V, Berry S, Swanson C, Dhadda S, Berry DA. Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease. Alzheimers Dement (N Y). 2016 Jan;2(1):1-12. Epub 2016 Feb 4 PubMed.
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Comments
Austin Hospital
I agree that the result is encouraging, and my quibbles should not detract from the positive message.
A criticism not mentioned in this story is the visual reading of the amyloid scans. Twenty-three percent of the placebo group also "became negative at follow-up." This does not happen and is most likely due to poor consistency in the reading. Florbetapir scans are hard to read if the amyloid level is up but not greatly elevated. I suspect the entry reads and the final reads were not done by the same readers or randomized. All the entry and final scans need to be de-identified and read in random order by the same readers.
It also would be good to see the entry amyloid level and the final level in centiloids. The average entry level SUVR was 1.41, but as we do not know the details of the quantitative method, we cannot get a feel for how high this was compared to the expected level in early AD (i.e., 100 CL) or how it compared to other studies.
Uppsala University
EU regulatory authorities requested in 2014 that BAN2401 be restricted from the top dose due to a few ARIA-E cases. At this time the EMA had not been exposed to many ARIA-E cases, and took a very cautious position. Patients who had been in the BAN2401 trial for less than six months and were APOE4-positive were taken out of the study. Patients with this genotype who had been in the study more than six months could continue. This led to an imbalance in the two top doses, with more patients in the 10 mg/kg monthly group than the twice-monthly group, and also more patients with APOE4 in 10 mg/kg monthly than twice a month.
Does it has an effect on study outcome? I do not think so! APOE4 carriers have an earlier onset, but their expected rate of decline is not different from patients with other APOE genotypes. However, there are conflicting reports in the literature on this topic. Our epidemiological, population-based data tells us that rate of decline does not differ between APOE4 carriers and noncarriers.
BAN2401 is the first study so far with an effect of treatment and a size large enough to make subgroup analysis meaningful. When these analyses have been completed we will be able to evaluate possible differences between APOE4+ and APOE4-. As approximately 70 percent of patients in this clinical study, and other clinical studies, are APOE4+, effect of the treatment should not deviate from the total result in a great manner.
Once complete, subgroup analyses and other ongoing analyses will give more information on the topic.
University of Nevada Las Vegas
These are exciting results. They strongly support target engagement, suggest a dosing strategy, and suggest efficacy on clinical measures. The challenges with randomization raise questions that must be solved with future trials. This is a strong Phase 2 result that informs plans for Phase 3; this is what we hope for from Phase 2.
Washington University School of Medicine
The field is clearly moving forward with the ability of a fourth drug to remove amyloid to a normal level, as measured by PET. Now with aducanumab, gantenerumab, and n3pg, BAN2401 has demonstrated reversal of amyloid plaques to normal levels, representing a milestone in the history of Alzheimer’s disease. This has the potential to slow clinical decline in the symptomatic stage of Alzheimer’s and even more promise to slow, delay, or stop dementia if used before symptom onset.
Brown University
I am cautiously optimistic. The reported level of amyloid lowering was surprisingly high, more than 80 percent amyloid negative by visual read. This is interesting in that the antibody has higher affinity for protofibrils than plaques.
The cognitive results at the biweekly dosing are encouraging, but the CDR is non-significant. This is interesting, too, given that 70 percent of the ADCOMs comes from the CDR. The authors did not report the actual change in the cognitive measures, which makes the outcomes hard to evaluate. It is hard to know the significance of the percentage change reported. For example, they reported a CDR-SB change of 26 percent compared to placebo for the highest dose, but the p value was not significant. It is also not clear if they controlled for multiplicity. The monthly 10 mg dose had less clear of an effect. I did not see the number of participants on background AD therapy. The authors also did not report outcomes by disease stage or carrier status.
In summary, there is dramatic amyloid lowering with some apparent slowing in decline at the highest dose. Further study is needed to evaluate efficacy.
Washington University
The new data clearly showed that the anti-Aβ antibody BAN2401 was able to significantly remove amyloid from brain, as quantified by amyloid-PET imaging, in very mildly to mildly impaired individuals with amyloid deposition.
The highest dose administered, 10 mg/kg every other week, also resulted in significant slowing of cognitive decline compared to placebo by about 30 percent, as measured by the ADCOMS composite. This is very promising.
A potential problem with interpreting the cognitive data from the highest dose is that this group has a much lower percentage of APOE4-positive individuals. At least one study has shown that amyloid-positive individuals with very mild or mild dementia who are amyloid-positive progress faster if they are APOE4-positive (Shi et al., 2017). Short of knowing the differences in percentages of individuals who are APOE4-positive between the high dose versus the placebo group in this study, it’s hard to know how much this imbalance confounds the interpretation of the data.
References:
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28;549(7673):523-527. Epub 2017 Sep 20 PubMed.
Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School
Overall, the BAN2401 results are encouraging that decreasing amyloid burden with high doses of immunotherapy may be able to slow clinical decline, but given the complexity of the study design and cohort data, it is important not to over-hype the clinical results.
Regarding the concern that the 30 percent APOE4 carriers in the highest dose group (10mg q 2 weeks) versus 70 percent APOE4 carriers in the placebo group confounds the result, it’s worth noting that the second-highest dose has plenty of APOE4 carriers and shows a similar pattern of slowing of decline, albeit less significant. Given the increased risk of ARIA in APOE4 carriers—it will be important eventually to look at each of the dose cohorts to understand how many APOE4 carrier “completers” were included in the analyses—the overall ARIA rates were reassuring.
The dose relationship in degree of amyloid decrease on PET imaging was pretty convincing. I do have some concerns that the 5mg q 2 weeks group had a similar reduction in amyloid PET as the 10mg q month but did not show an apparent cognitive benefit (indeed was slightly worse than placebo on some time points). The 5mg q 2 weeks however, was a much smaller cohort, so again it is important not to over-interpret the clinical data.
This trial was designed as a Phase 2 trial to assist with dose finding for safety and proof-of-concept efficacy, and appears to have succeeded in that goal. This means, however, that interpretation of nominal p values for each of the outcomes in each group must be approached with caution.
Despite these caveats, overall I took the BAN2401 results as a much-needed replication, in a larger cohort, of the findings from the aducanumab PRIME data. Both studies suggest that being aggressive with high-dose immunotherapy can substantially decrease fibrillar, and potentially alter other forms of, Aβ in a very mildly impaired population who were selected on the basis of the target pathology. Both studies suggest that the highest dose with the greatest amyloid reduction was associated with some evidence of slowing of cognitive and functional decline.
The longer term follow-up aducanumab PRIME data presented at AAIC, however, also suggest that we may need to intervene even earlier in the course of AD with aggressive anti-amyloid treatment to be able to bend the curve of clinical decline for multiple years, and ultimately prevent progression to the devastating later stages of dementia.
Acumen Pharmaceuticals
The results of the Phase 2 BAN2401 trial are indeed promising, and the field will be anxiously awaiting more definitive Phase 3 results. The trial design of this Phase 2 study was quite complex, with several interim analyses, Bayesian statistics, and a “play the winner” approach to dose selection. Like virtually all Phase 2 studies in neuroscience, different results within the study were more or less clear. And like virtually all Phase 2 studies, the results should not be taken as a precise measure of the results likely to be achieved in Phase 3.
The reduction in plaque load taken broadly was impressive. While this antibody was thought to target protofibrils, the robust plaque reduction and appearance of ARIA-E would suggest that it is also targeting deposited β-pleated sheet plaques. The ability of in vitro protein binding studies to predict the exact in vivo binding of a monoclonal antibody may be limited.
The potential confound of less prevalent APOE4 carriers in the highest dose group is unlikely to completely account for the cognitive results. Early literature suggested that ApoE status determined age of onset but not rate of progression. More recent studies (as reviewed by Kennedy et al., 2014) show a possible effect on rate of progression, but the effect is small. Researchers at Eisai will no doubt use their placebo group to compare rate of decline in carriers versus noncarriers, and then use those data to model a “corrected” high-dose clinical response.
Perhaps most importantly, four monoclonal antibodies directed against Aβ monomers, oligomers, or deposited plaque now have shown clinical measures that are at least directionally showing benefit (solanezumab, crenezumab, aducanumab, and now BAN2401). Ongoing studies of solanezumab and crenezumab at substantially higher doses, the Phase 3 trials of aducanumab, and what we expect to be Phase 3 trials of BAN2401 will provide more definitive results.
References:
Kennedy RE, Cutter GR, Schneider LS. Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease. Alzheimers Dement. 2014 May;10(3):349-59. Epub 2013 May 25 PubMed.
UCSF
I agree with others that the data, as reported thus far, should be interpreted with caution.
The regulatory requirement to exclude ApoE4 carriers from the high-dose group is unfortunate. It compromised the randomization process, and makes it very difficult to interpret a signal for a clinical benefit in the high-dose group. Note that this was the only dose in which a significant benefit was found on clinical outcomes.
The evidence for target engagement is encouraging, but the conversion of a proportion of patients receiving placebo from amyloid-positive to amyloid-negative on visual reads raises questions and concerns about the reported PET outcomes.
Despite our best efforts as a scientific community to provide a critical appraisal of the data, I fear, based on most media coverage I've read and patient inquiries I've received, that the hype is not commensurate with the data presented. I hope to be proven wrong.
Yale University
I am curious what other people think about the PET scan results. In my experience doing in vivo optical imaging in mice, and from my read of the literature, I don't see strong evidence that pre-existing amyloid plaques can be made to completely evaporate, regardless of the manipulation or treatment. While it has been shown that antibody treatment can reduce the deposition of amyloid plaques when used over extended intervals in mice, I think it is much less certain whether pre-existing, compact plaques—composed of highly insoluble material—can truly be removed.
Although I am no expert in PET imaging, I am raising the concern that the reported decrease in PET signal is at least partly an imaging artifact. For example, one possibility is that after antibody treatment there is a change in the microenvironment around plaques, such as microglial and astrocyte activation leading to increased plaque encapsulation by glial cells, as shown in the Biogen Nature paper a few years ago (Sevigny et al., 2016) and initially by us in Condello et al., 2015. Could this lead to a change in the dynamics of binding and elimination of PET probes, such that it would lead to overall diminished binding, or a change in the temporal course of binding, resulting in reduced signal, which is interpreted as a decrease in amyloid plaque levels?
I would point out that even if plaques cannot be removed, it is still possible that these antibodies could exert a therapeutic effect by increasing plaque encapsulation by microglia. We have recently shown that this encapsulation function could be neuroprotective by insulating plaques from the adjacent axons and synapses, and by making plaques more compact and inert (Yuan et al., 2016).
References:
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.
Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun. 2015 Jan 29;6:6176. PubMed.
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron. 2016 May 18;90(4):724-39. PubMed.
The University of Exeter
Overall results are impressive. Whilst it will be important to see the results of a subanalysis examining the impact of APOE4 on outcome, it seems unlikely that this could account for 80 percent of individuals becoming amyloid-negative. The potential impact on cognitive/clinical impact will be critical, though. Despite this caveat, these are by far the most positive Phase 2 results we have seen in the last 15 years.
These results are exciting and promising not because they remove plaque, but because they neutralize the cytotoxicity of the Aβ profibrils, one of the soluble aggregates of this protein, that with the soluble oligomers are responsible for killing the brain cells.
That these protein forms are AD causative agents was reported in 1998 (Lambert et al.), and the same group showed later that antibodies against them neutralized their cytotoxicity (Lambert et al., 2001). We should stop linking plaque removal with beneficial effects on AD; i.e., it has been shown that many elderly people have normal cognitive function despite having plaque levels comparable to AD patients. That plaque removal may be damaging was reported in 2015, when it was shown that some monoclonal antibodies that failed clinically, although they removed plaque, also released the toxic forms of amyloid, which killed neurons (Liu et al., 2015). We should remember that all of the clinically failed AD immunotherapies, while successful in removing plaque, did not neutralize cytotoxicity of the released soluble forms, i.e., oligomers and protofibrils.
It is interesting that the antibody BAN2401 apparently does not act as an effector of inflammation. It would be important to have more information about its Fc region, especially its glycosylation pattern.
These promising results challenge the concept of plaque being that AD causative agent; a notion that has hampered progress in AD drug development. I am afraid the plaque speculation is a good case of “old customs die hard.” Hopefully, these new agents neutralizing soluble oligomers cytotoxicity will change strategies used in AD drug development.
References:
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.
Lambert MP, Viola KL, Chromy BA, Chang L, Morgan TE, Yu J, Venton DL, Krafft GA, Finch CE, Klein WL. Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J Neurochem. 2001 Nov;79(3):595-605. PubMed.
Liu YH, Bu XL, Liang CR, Wang YR, Zhang T, Jiao SS, Zeng F, Yao XQ, Zhou HD, Deng J, Wang YJ. An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect. J Neuroinflammation. 2015 Aug 28;12:153. PubMed.
RIKEN Center for Brain Science
Just a general comment: A number of candidate medications showed promising results in Phase 2 trials and then failed in Phase 3 trials. Scientifically speaking, this should happen only rarely, because the sample size is much larger for the latter. I hope the stock market is not causing any bias.
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