Held 29-31 October in the Principality of Monaco, the 5th Clinical Trials in Alzheimer’s Disease conference offered new data from ongoing analyses of the Phase 3 programs on solanezumab and bapineuzumab. Both programs missed their primary endpoints. The news added up to a curious situation where, at present, it looks as if the biomarkers that are showing predictable and strongly convergent trajectories across natural history studies are not, so far, behaving as expected in therapeutic trials. “We see a dissociation of biomarker and clinical outcome,” said Reisa Sperling of Brigham and Women’s Hospital in Boston. Solanezumab slowed cognitive decline without affecting CSF markers of neurodegeneration. Bapineuzumab did improve those downstream markers, but flopped clinically. On volumetric MRI, both antibodies delivered a head-scratcher that is clouding this marker’s prospects as a potential surrogate and focusing renewed interest on more sensitive cognitive outcome measures. It is unclear at this point whether any of the known biomarkers are theragnostic, i.e., track or predict a drug effect. “We need better markers of synaptic response to fill this gap,” Sperling added.

When considering the data’s nuances—and there was a lot of nuance at CTAD—this disconnect begins to blur a bit, and the data may make more sense. Solanezumab mobilized soluble Aβ in plasma and appeared to nudge CSF concentrations. The finding recalled earlier studies with this antibody and led some attendees to wonder whether a peripheral sink effect might have been at play. Bapineuzumab, on the other hand, appears with more analysis to perhaps have had a hint of functional benefit in the mild subgroup after all, but that came at the cost of more white matter changes than was initially thought. Whatever benefit there was appeared to be disease modifying, not symptomatic. At the same time, a growing number of researchers are downplaying this once-prominent issue as a distinction without a difference, joining an argument one presenter has been making for some time (Doody, 2008). Confused? You are not alone. At CTAD, the program featured five talks by Sperling, Paul Aisen, Rachelle Doody, Nick Fox, and Steve Salloway, as well as a panel discussion to grapple with the data. Small group conversations could be overheard outside the auditorium throughout the conference, and no doubt continued over dinners and nightcaps. Read on for summaries of the data presentations and discussions.

First, a word about how information on this story is coming out. CTAD continued a data trickle that will go on at least through next spring. After the companies disclosed topline news last summer that their programs had missed primary endpoints, the actual results have been presented in bits and pieces at conferences last September, October, and most recently at CTAD. Yet more is to come at the AAN meeting in San Diego in March 2013. Some researchers bemoaned this gradual dissemination. Others were further puzzled that Lilly released its solanezumab data to investors but not to scientists on 9 October on the day of a major neurology conference in Boston, where an independent academic analysis of Lilly’s data was first presented (see ARF related conference story).

When asked about this, scientists at Janssen AIP, Lilly, and at various academic institutions pointed to the multiple forces that drive when data are released. All insisted that the drip-drip-drip was not strategic but a function of huge datasets being continually analyzed for successive questions. “As soon as we have new results, we present them at the next opportunity,” said Salloway of Brown University, Providence, Rhode Island. Companies are required to release topline information as soon as they get it, hence, the summer press releases. The Securities and Exchange Commission requires disclosure to shareholders, hence, Lilly’s posting of slides during the October investor call. Separate from that, Lilly and the Alzheimer’s Disease Cooperative Study have negotiated a unique agreement whereby the Alzheimer's Disease Cooperative Study (ADCS) analyzes Lilly’s raw data independently. Initiated by Richard Mohs and Eric Siemers at Lilly, this serves the field’s collective desire to learn as much as possible from these enormous datasets and keep a version in the public domain. It also was a response to a demand by journal editors, said Paul Aisen of the University of California, San Diego, who leads the ADCS. The agreement stipulates that the ADCS presents its analysis at conferences and takes the lead on publication. This means, in effect, that the ADCS communicates Lilly's Phase 3 results through its lens with the scientific community, while Lilly uses its internal analysis for guidance from the Food and Drug Administration about what to do next.

Solanezumab: The New Data
Before presenting results, Aisen explained how the ADCS handled this industry dataset. Three ADCS statisticians—Ron Thomas, Rema Raman, and Mike Donahue—each conducted his or her own analyses of Lilly’s raw solanezumab Phase 3 data. Each coded, input missing data, and programmed the models to reveal the implication of each statistical decision made along the way. Having been collected by Lilly through contract research organizations, with different forms and procedures than the ADCS has developed over time for its own trials, the solanezumab data needed to be transferred, and in places restructured, to fit the ADCS system. The statisticians handled out-of-window visits, missing scores, and at times had to deviate from Lilly’s statistical analysis plan (SAP). Why is this important? Because when the effect of a drug is small, as is true here, each decision the statistician has to make along the way can affect the p value of statistical significance, Aisen told Alzforum. At CTAD, Donahue gave a whole talk just on how ADCS statisticians treat missing clinical trial data. “We have analyzed Phase 3 data going back to tacrine,” Aisen said, “We have our own approach to imputation and analysis. We opted to follow the spirit of Lilly’s, yet apply some of the specific approaches we have gleaned from our experience.”

Despite the statistical challenges, a coherent picture of a cognitive benefit emerged, Aisen said. The effect is very small but statistically robust in pooled analyses, holding up across variations of the data. The benefit amounts to a 30 to 35 percent slowing of cognitive decline in the mild subgroup. This number fits with the data Lilly released to investors on 8 October, which claimed a 34 percent slowing. The ADCS analysis showed 1.5 points less decline in ADAS-cog 11, and 1 point less in MMSE for solanezumab than placebo in patients with mild AD. The ADL functional score showed 1.5 points less decline in the mild group, though this result has less statistical confidence. Neither the neuropsychiatric inventory nor the CDR Sum of Boxes showed any difference.

On biomarkers, the main result came from plasma Aβ. Solanezumab caused a sharp and sustained increase that is consistent with the antibody’s tight binding to monomeric Aβ. The CSF showed a more complex picture. The concentration of both Aβ40 and 42 rose in the mild to moderate AD group. The much smaller pool of free Aβ40 showed a decrease in treated patients, while free Aβ42 did not. The CSF numbers are based on smaller group sizes (13 to 66) than those for plasma (700s) or MRI (600s to 900s). To Aisen, the rise in plasma and CSF levels of total Aβ constitutes target engagement; many others agreed.

Florbetapir scans in the solanezumab PET imaging substudy showed no significant change between the groups. The mild subgroup had a trend toward less amyloid in the treated group, but it missed statistical significance. There was no effect at all on CSF tau or phospho-tau overall or in any of the subgroups. Whole brain volume was the same between groups. On hippocampal volume, too, the analysis showed no overall treatment effect. Of the subgroups the ADCS analyzed separately, one looking at people with confirmed amyloid positivity showed a trend. This is merely a hint in a subgroup of a subgroup. Still, its direction was toward more shrinkage in the treated group (for more on MRI atrophy, see below).

Solanezumab’s clinical effect may be related to Aβ reduction at synapses as opposed to protection of cells, said Rachelle Doody of Baylor College of Medicine in Houston, Texas. Other scientists at CTAD agreed with this assessment. For example, David Morgan of the USF Health Byrd Alzheimer's Institute in Tampa, Florida, noted that the solanezumab data jibe with what is known from mice. APP mouse models of amyloid deposition have cognitive deficits independent of neurodegeneration, tau pathology, or atrophy (e.g., Kotilinek et al., 2002). The antibody used to engineer solanezumab, m266, was reported to restore memory in mice without a measurable effect on amyloid (Dodart et al., 2002). A large and rapid increase in plasma Aβ soon after m266 injection is known from mice (Demattos et al., 2002). Lars Lannfelt of Uppsala University, Sweden, said that solanezumab prolongs the half-life of Aβ in plasma and delays its degradation in the liver and kidneys. This might explain the sustained elevation in plasma, though how much of this plasma Aβ might come from brain as opposed to from peripheral cells was not shown.

In toto, the Phase 3 solanezumab data support a small cognitive benefit and may call for a confirmatory study in mild AD, Aisen said. Researchers hope that studies in prodromal or preclinical AD (see ARF related news story on DIAN) will yield a larger effect. At CTAD, speculation was rampant about whether these data alone might sway regulators to approve the therapy.

Bapineuzumab: The New Data
Steve Salloway presented a prespecified subgroup analysis of the bapineuzumab patients with mild AD. It differed from a previous analysis in that it used a cutoff of 20, not 21, on the MMSE, because 20 is what the solanezumab analysis used. “We thought it would be informative to see how the data compare,” Salloway told Alzforum. On most measures, this analysis, like the first one, found no difference between antibody and placebo for either the ApoE-carrying or non-carrying patients. On one, however, it sighted a bit of a signal, that is, a statistically significant treatment effect on the DAD functional measure. Non-carriers showed a benefit of about four points on both doses, while the pooled analysis of carriers and non-carriers showed a similar benefit only for the higher dose. “We are not making very much of this effect,” Salloway said, and Janssen scientists reiterated that clinical development of intravenous bapineuzumab has ended. Also new in Salloway’s presentation was the analysis of the secondary clinical endpoint consisting of the CDR-SB, the NTB and the MMSE: no differences in the total study population in either study; subgroup analysis is ongoing.

Most of the new bapineuzumab data at CTAD came on biomarkers. Nick Fox of University College London toggled between MRI scans taken of the same subject at baseline and weeks 19, 45, and 71 to show how the brain’s ventricles subtly expanded, and the cortex and left hippocampus ever so slightly contracted.

 

image

image

Can you see it? Slight ventricular expansion in bapi-treated subject.

Image courtesy of Nick Fox/Janssen AIP, from CTAD website

Pooled analysis of both Phase 3 studies confirmed a mildly increased rate of brain volume loss in the bapineuzumab group at the higher dose, and in the mild subgroup at both doses. The difference came to about 2 milliliters per year for whole-brain volume, Fox said. In the left hippocampus, the difference was significant in non-carriers at the higher dose only. The ventricular effect was most pronounced, showing up as significant in the carriers, non-carriers, and pooled analyses.

Taken together, then, biomarker data on intravenous bapineuzumab suggest that the treatment nudged amyloid deposition but not soluble Aβ, clearly decreased CSF tau and phospho-tau (this was presented at a previous conference), and led the brain to shrink a bit faster. This means the antibody engaged its target, but it hardly helped at all clinically, Fox said.

If one includes the faint hint on solanezumab, this bapineuzumab MRI finding would be the third demonstration that anti-amyloid immunotherapy can subtly shrink the brain. (The first came in 2004 with AN1792, a discontinued Aβ42 vaccine; see ARF related news story). Why? The first instinct—that the shrinkage equals more neuronal death—is probably wrong because CSF tau went down with bapineuzumab. Is it amyloid removal? Maybe not alone, because the extent of amyloid removal was small. Does immunotherapy reduce the inflammation and debris associated with amyloid deposition? Does it change CSF absorption, or cause other fluid shifts in the brain? These notions warrant active study, Fox said. “We have to understand this.”

A propos fluid shifts, bapineuzumab has gained some notoriety for causing white matter changes, perhaps indicating leakage of fluid, proteins, or cells from vessel walls after amyloid drainage. Called amyloid-related imaging abnormality (ARIA), this finding has since been reported for other anti-amyloid therapies such as Bristol-Myers Squibb’s γ-secretase inhibitor BMS-708163/avagacestat and Roche’s antibody gantenerumab as well. The FDA requires close monitoring of this poorly understood finding, and the massive amounts of MRI data subsequently generated from this surveillance were the subject of a CTAD talk by Sperling.

There are two kinds of ARIA: E for vasogenic edema, indicating fluid seeping out of blood vessel walls or collecting in sulci, and H for hemosiderin deposit, indicating a microhemorrhage. At CTAD, Sperling presented preliminary results of a large study that determined the incidence of ARIA-E by giving a final read to every one of the 15,000 MRI scans taken during the bapineuzumab Phase 3 program. Two radiologists independently viewed the scans. Every time they found an ARIA-E, they pulled up that person’s prior scan to see if the abnormality had been there before. In this way, they called some 30 percent more cases than had been noted during the conducting of the trial.

The incidence of ARIA-E rises with ApoE status and with dose. About 1 percent of patients on placebo had ARIA-E, but so did one in five ApoE4 carriers on 0.5 mg/kg bapineuzumab. Among ApoE homozygote patients, it was one in three. Among ApoE4 non-carriers, the ARIA-E incidence at that dose was 5.6 percent, but the highest (and discontinued) dose of 2.0 mg/kg brought it to 19.9 percent. Most ARIA-E developed after the first three infusions.

Why were some ARIA-E incidences overlooked? Awareness of this side effect is new; indeed, it emerged during bapineuzumab’s development. Local radiologists missed some edemas on the first read. In many cases, the first ARIA-E was small, Salloway told Alzforum, and grew by the time of the subsequent scan. Midway through the study, a central read was instituted, but there, too, not all radiologists picked up every finding right away. Some site PIs did not acknowledge all findings, Sperling told the audience.

Sperling told Alzforum that the people with ARIA-E tend to be prone to ARIA-H as well, but this analysis is still underway.

How bad is ARIA? It is too early to say, Sperling said. A majority were asymptomatic, but about one in six were linked to symptoms such as headache, confusion, and cognitive changes. When patients were taken off the drug, the abnormality resolved over a period of months. A preliminary analysis of the Phase 3 final-read data shows that, clinically, ARIA-E appeared to make no difference on the course of a person’s Alzheimer’s disease. People with ARIA-E did not decline any faster or slower on the ADAS-cog or DAD than those without, though the scientists need to dig deeper into the data to check if differential dropout might have biased this finding. Some scientists believe that ARIA-E is a sign of amyloid clearance. Others noted that it will be important to watch what becomes of these patients in the longer term. In ApoE4 carriers but not non-carriers, the treatment group had more seizures than the placebo group.

Finally, on imaging, Sperling emphasized that 36 percent of ApoE4 non-carriers who joined the bapineuzumab amyloid PET substudy fell below the preset threshold for amyloid positivity. At CTAD, Sperling told the audience that a look at amyloid PET data of the solanezumab Phase 3 trials, which Lilly had shared with her, showed the same thing for the ApoE-negative participants in those trials. Both large Phase 3 programs appear to have enrolled a third of patients who arguably may not have Alzheimer’s disease but something else. Florbetapir is clinically approved to rule out Alzheimer’s. “This is a large number, and it is a problem,” Sperling said.

In discussion, researchers expressed a consensus that bapineuzumab failed over dose. It could not be safely given at high enough doses to make a difference. Others noted that the picture was still incomplete. For example, critical data on drug exposure antibody levels in plasma and CSF are still missing for both programs, as is a full analysis of the amyloid-positive versus negative participants. Several researchers cautioned that when a drug effect is as small as solanezumab’s, type 1 error, aka false positive, is always a concern, even when the statistics look internally consistent.

“These are valuable data, but I can’t overstate how disappointing that was to our patients and families,” said Fox. Other site leaders agreed, but noted that their patients felt they did contribute to science and want to participate again.

Some slide sets on Bapineuzumab, plus a one-hour audio recording on solanezumab, have been uploaded to the CTAD website. The recording features an attempt by Sperling to synthesize the data available thus far on both antibodies, as well as a subsequent panel discussion. Play it to get a sense of where the field stands at this point.—Gabrielle Strobel.

This is Part 2 of a seven-part series. See also Part 1, Part 3, Part 4, Part 5, Part 6, and Part 7. Read a PDF of the entire series.

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  1. CTAD provided excitement, important insights, and new questions, as would be expected for a first-rate meeting focused on the latest word in Alzheimer's trials. In my view, the key take-away was that giving a therapeutic agent which solely targets Aβ was found to significantly slow cognitive decline in AD patients. This result for Lilly’s solanezumab in an 80-week trial was statistically significant at p As regards biomarker results, why was there no significant decrease in CSF phospho-tau levels with solanezumab, whereas this biomarker showed a small but significant decrease in the bapineuzumab trial despite a lack of cognitive benefit in the analyses reported so far? This apparent paradox might be explained by considering the mechanisms of action of the two antibodies. Solanezumab (and its mouse precursor 266) principally binds and sequesters soluble Aβ monomers, although it remains possible that it also binds some portion of soluble oligomers in the AD brain. By chronically sequestering monomers, solanezumab may cause a gradual shift in Aβ equilibrium in the brain so that soluble oligomers and plaque-associated fibrils slowly decrease in concentration in the cortex, presumably contributing to solanezumab’s clinical benefit over 18 months.

    <p>Nevertheless, the levels of some or many neurotoxic oligomers may not go down much with solanezumab. Because soluble oligomers isolated from AD cortex have been shown to induce selective tau phosphorylation and neuritic degeneration (Jin et al., 2012), these changes may not have been sufficiently blunted by the principally monomer-directed solanezumab. On the other hand, bapineuzumab (and its mouse precursor 3D6) binds and neutralizes soluble Aβ oligomers from AD brain quite effectively (Shankar et al., 2008), and it can also affect amyloid plaque burden modestly in AD patients (Rinne et al., 2010). Therefore, bapineuzumab may have bound and neutralized phospho-tau-elevating Aβ oligomers better than solanezumab, but still not enough to slow clinical decline within 18 months. Other reasons for the apparent clinical-biomarker disconnect of the two antibodies could be trial related, for example, that not enough CSF samples from mild subjects were available to detect any small phospho-tau lowering effect that solanezumab might confer.

    </p><p>Many of us who attended CTAD came away with the impression that one reason for the different clinical outcomes of the solanezumab and bapineuzumab trials was the large difference in doses. Although the two antibodies have quite distinct properties that limit the meaningfulness of comparing doses, solanezumab was dosed at 400 mg per month, whereas bapineuzumab was dosed at 0.5 or 1.0 mg/kg (~35-70 mg) every three months due to its considerable risk of inducing ARIA-E. Thus, the cumulative three-month solanezumab dose was ~15-30-fold higher than that of bapineuzumab. Even higher solanezumab doses than this could potentially prove beneficial, whereas bapineuzumab cannot be dosed at such high levels, at least by the iv route. Other reasons for the different clinical outcomes of the solanezumab and bapineuzumab trials may well be revealed by deeper analyses of the data, particularly the correlations of patients’ total antibody exposures to their cognitive and biomarker outcomes.

    </p><p>Regarding other biomarkers used in these trials, vMRI has once again shown the “paradoxical” effect of slightly more hippocampal or whole brain volume loss in these trials. The explanation is unknown, but my speculation is that it may relate to changes in fluid balance in the AD cortex with the partial clearance of Aβ and consequent improvements in the robust inflammatory cell changes that occur in AD. PET imaging of fibrillar amyloid burden showed a trend towards reduction with solanezumab and with bapineuzumab. Thus, each antibody engaged its intended target, and this was further supported by how solanezumab shifted CSF Aβ40 levels: more bound and fewer free monomers.

    </p><p>The central point is that solanezumab’s clinical benefit—while modest at 18 months—confirms that an agent which could only be targeting Aβ can slow cognitive decline and move certain biomarkers in mild AD. This appears to represent the first proof from human trials of the Aβ hypothesis, and strongly encourages new, carefully designed trials of anti-Aβ monoclonals in mild, very mild, and/or presymptomatic AD. The results also recommend other Aβ-lowering approaches such as Aβ vaccination and β- or γ-secretase modulation. The next trials should rely on composite cognitive endpoints that are especially sensitive for the episodic memory deficits of early AD. And biomarkers of neuronal health should continue to be included, both CSF phospho-tau and new CSF indicators of synaptic structure that must be found. Finally, the results presented at CTAD, while suggesting that better Aβ-directed trials are ahead, take nothing away from the importance of accelerating strategies for tau and for cellular inflammation, as multimodal treatments for AD would be highly desirable.

    References:

    . Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5819-24. PubMed.

    . Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):837-42. PubMed.

    . 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010 Apr;9(4):363-72. PubMed.

  2. Soluble β amyloid has a beneficial physiological role for the normal functioning of neurons. In the AD brain, the increase in soluble β amyloid concentrations, mainly via a decrease in its clearance, could simply represent the brain's attempt to medicate the neuronal suffering and death that occur for still-unknown reasons. The decrease in β amyloid clearance would lead to β amyloid accumulation with formation of neurotoxic oligomers and plaque deposition.

    <p>I would expect that any drug that lowers soluble β amyloid concentrations in the AD brain will worsen the situation. In many cases of familial AD, point mutations of presenilins lead to a loss of function of the γ-secretase complex, with less ability to produce β amyloid from APP (Chavez-Gutierrez et al., 2012). Consequently, this would lead to a compensatory decrease in β amyloid clearance and then β amyloid accumulation with formation of neurotoxic oligomers and plaque deposition. Again, in familial AD any drug that decreases the brain concentration of β amyloid would worsen cognition. This hypothesis could explain the detrimental cognitive effects observed with semagacestat and avagacestat (both decrease β amyloid levels in CSF), the neutral effects of bapineuzumab (no effects on β amyloid levels in CSF), and the relatively beneficial effects of solanezumab (small increases in β amyloid levels in CSF).

    </p><p>In conclusion, I propose that the accumulation of β amyloid in the brain of sporadic AD patients is a compensatory reaction to neuronal death. In the brain of familial AD patients, it would be an accumulation of β amyloid as a compensatory reaction to loss of presenilin function. API and DIAN prevention trials in presymptomatic subjects could test this unorthodox view.

    References:

    . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. PubMed.

  3. Dr. Imbimbo’s perspective has been voiced before by a minority of AD investigators who believe that lowering brain Aβ levels in various ways would perforce be detrimental to the patient’s cognitive status. There is certainly nothing wrong with revisiting this line of reasoning, as it remains important to openly debate all possible explanations for the complex pathogenic process of AD. Even so, several statements in Dr. Imbimbo’s commentary do not fit with published data.

    <p>First, the straightforward declaration that “soluble β amyloid has a beneficial physiological role for the normal functioning of neurons” is more unsettled than he implies. Only a few published studies have addressed the normal function of soluble Aβ at physiological levels, and more than one molecular function has been suggested without widespread confirmation in multiple labs. Importantly, some such papers have examined Aβ42 peptides, and yet studies of normal Aβ should be focusing on Aβ40, since this is ~10-fold more abundant physiologically and since Aβ42 has a confounding tendency to aggregate into oligomers (even at nanomolar concentrations) that have quite different biological properties than do Aβ40 monomers. So we need more detailed studies of the normal activities in neurons (and other cells) of <em>endogenous</em> Aβ40 (not synthetic Aβ42) at entirely physiological levels. Pending these, it remains possible that Aβ peptides are simply byproducts of the physiological processing of APP by β- and γ-secretase that, respectively, release the bioactive APPs-β and AICD derivatives, and that the Aβ fragment per se did not acquire an important salutary function during evolution, particularly as regards cognition. More evidence for such a normal function is needed.

    </p><p>Second, there is abundant evidence from numerous labs that soluble Aβ concentrations in the brain are substantially elevated in preclinical and clinical AD subjects versus age-matched normal subjects, and are far above the physiological levels found in young brains (e.g., Naslund et al., 2000). Therefore, the lowering of soluble Aβ by current experimental therapeutics would be very unlikely to bring these high levels fully down to or below those found in the normal cognitive state. Indeed, in the interrupted semagacestat study that Dr. Imbimbo references, no evidence has been published that brain Aβ levels fell precipitously into the normal range, and any adverse cognitive side effects are more likely to be attributable to interference with the normal functions of one or more of the many other substrates (including Notch) that semagacestat could affect.

    </p><p>Third, it is not correct to simply say that “point mutations of presenilins lead to a loss of function of the γ-secretase complex, with less ability to produce β amyloid from APP.” Many presenilin mutations have been shown to increase Aβ42 production with relatively little or no change in total Aβ or Aβ40 levels. The elevated Aβ42/40 ratio can then allow the formation of Aβ42 oligomers, which can induce synaptotoxicity. This sequence is supported by numerous studies of mouse models bearing AD-causing presenilin mutations, as well as by studies of human brain tissue and CSF. Indeed, recent biomarker analyses of young presenilin mutation carriers showed that an early elevation of CSF Aβ42 levels began to decline to subnormal levels some 20-25 years prior to symptom onset, as fibrillar Aβ42 began accumulating in brain parenchyma (Bateman et al., 2012).

    </p><p>Fourth, compelling evidence appeared recently that a lifelong decrease in total Aβ production from inheritance of a novel mutation in APP (A673T) confers strong protection against the development of AD, and it was even associated with significantly less cognitive decline in non-AD elders (Jonsson et al., 2012). The mutation was shown in cell culture to lower Aβ some 40 percent by decreasing the β-secretase cleavage of APP. This “natural human experiment” is perhaps as clear-cut an indication as we can get that chronically subnormal Aβ levels in the brain are not associated with a cognitive detriment, either during brain development or with age.

    </p><p>Fifth, Dr. Imbimbo’s interpretation seems the opposite of what the new solanezumab data actually suggest. An antibody that lowers essentially all forms of soluble Aβ very avidly by targeting its mid-region has been found to significantly slow the rate of cognitive decline on well-validated tests by ~34 percent over 80 weeks, without significant side effects. If Dr. Imbimbo’s concepts were correct that “in the AD brain, an increase in soluble β amyloid concentrations … could simply represent the brain's attempt to medicate the neuronal suffering and death that occur for still-unknown reasons” and that “any drug that lowers soluble β amyloid concentrations in the AD brain will worsen the situation,” then solanezumab’s presumed lowering of soluble Aβ levels in brain (and <em>free</em> Aβ40 levels in CSF) should have had a negative effect on cognition.

    </p><p>Finally, Dr. Imbimbo’s reprise of the longstanding speculation of a “still-unknown reason” for neuronal death in sporadic AD has not yet led to identifying an antecedent precipitant of neuronal death unrelated to Aβ, despite decades of research by hundreds of laboratories. And the notion that “the accumulation of β amyloid in the brain of sporadic AD patients is a compensatory reaction to neuronal death” seems counterintuitive (neurons are the principal source of Aβ) and is not supported by human or animal model data of which I am aware. Indeed, the general hypothesis that Aβ undergoes “compensatory” rises or falls whenever levels of the peptide change in one direction or another requires experimental evidence.

    References:

    . Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000 Mar 22-29;283(12):1571-7. PubMed.

    . Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. PubMed.

    . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.

  4. Regarding the question of how presenilin FAD mutations affect Aβ production that is being debated here, current research suggests a complex answer. In brief, mutations causing FAD affect γ-secretase processing at three levels to different extents. The most consistent effect is, however, that the mutations interfere with the fourth cycle in the progressive cutting of the Aβ processing, which causes the cleavage of Aβ43 and Aβ42 to Aβ40 and Aβ38, respectively. This probably happens by destabilizing the retention of the peptide in the protease. (For a full explanation, see Chávez-Gutiérrez et al., 2012.)

    References:

    . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. PubMed.

  5. Lilly is pleased that the solanezumab data have stimulated such interesting mechanistic discussions. Whether solanezumab has cognitive effects due to binding to Aβ monomers, equilibria shifts affecting Aβ oligomers, or other species of Aβ (including intracellular), cannot be answered definitively at this time. We will also continue to investigate these mechanistic possibilities, but would like to emphasize that, regardless of the mechanism, we are pleased that the rate of cognitive decline in the pooled Phase 3 studies was slowed by 34 percent.

  6. The fact that there is a silver lining to the solanezumab trial is welcome news, even though it is tempered by the study’s failure to meet the primary endpoint and that the data were pooled from different trials to gain statistical significance. Whether such results represent a clinically meaningful therapy for patients and their families remains to be seen.

    If one accepts the optimistic interpretation and considers the solanezumab trial a success, then the study raises a non-trivial problem for the field; these results invalidate the theragnostic value of the biomarkers and raise questions about the dynamic biomarker trajectory proposed by Jack et al. (1). In one case, the biomarkers moved in the right direction without cognitive benefits (bapineuzumab), and in the other case, cognitive benefits appeared without the biomarker response (solanezumab). These findings pose a significant problem for the current thought process regarding AD pathogenesis, as well as for the planned presymptomatic clinical trials.

    The solanezumab study will indeed represent the first proof from human trials of the Aβ hypothesis, if these results are replicated. However, if there is one lesson learned from all the failed trials of the past decade, it is that an amyloid-focused strategy is not effective in patients who already show neurological deficits. Thus, the Aβ hypothesis may have become irrelevant in practical terms for yielding a therapeutic treatment for the patient population that needs it the most.

    Starting the therapy in presymptomatic patients is no panacea either. Only a fraction of patients will be willing to undergo the treatment in the absence of neurological symptoms (What, me? I feel fine!). Since there is no way to know with certainty who will develop AD, a substantial fraction of the population will receive unnecessary treatment or overtreatment (e.g., prostate cancer patients). The financial burden of such a potentially lifelong treatment will be unsustainable, especially if started at presymptomatic stages. Finally, there is no guarantee that results from a trial that was successful in a specialized, early onset, younger AD patient population will be applicable to the much older, heterogeneous, late-onset sporadic AD patients (see, e.g., 2, and comments by Daniel Davis on the paper.

    Therefore, practically speaking, we need a therapeutic strategy that will be effective in symptomatic late-onset AD patients, the 99 percent. This goal may be difficult, but not impossible if we allow ourselves to think innovatively and act boldly by exploring alternative therapeutic strategies.

    It is gratifying to hear amyloid proponents emphasize the importance of accelerating strategies for alternative pathological mechanisms (such as tau and cellular inflammation). However, in the environment of extremely limited resources, every dollar spent on the amyloid strategy is a dollar taken away from pursuing these alternative strategies. There is a reason why most major pharmaceuticals have moved away from the amyloid approach; will the academic world follow suit?

    References:

    . Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.

    . Drug policy for an aging population--the European Medicines Agency's geriatric medicines strategy. N Engl J Med. 2012 Nov 22;367(21):1972-4. PubMed.

References

News Citations

  1. The Solanezumab Benefit: Oh, So Small, But Probably Real
  2. Philadelphia: Can a Shrinking Brain Be Good for You?
  3. CTAD: Turning the Ship Around Toward Early Trials
  4. CTAD: Regulatory Science Gains Prominence in AD Research
  5. CTAD: Adaptive Antibody Trial to Try Bayesian Statistics
  6. CTAD: ApoE Carriers Sought for Trial of NSAID Derivative
  7. CTAD: EEG Gains Luster as More Trials Incorporate Biomarkers
  8. CTAD: AD Treatment Might Not Lower Healthcare Costs

Paper Citations

  1. . We should not distinguish between symptomatic and disease-modifying treatments in Alzheimer's disease drug development. Alzheimers Dement. 2008 Jan;4(1 Suppl 1):S21-5. Epub 2007 Dec 21 PubMed.
  2. . Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci. 2002 Aug 1;22(15):6331-5. PubMed.
  3. . Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002 May;5(5):452-7. PubMed.
  4. . Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science. 2002 Mar 22;295(5563):2264-7. PubMed.

Other Citations

  1. ARF related news story on DIAN

External Citations

  1. Alzheimer's Disease Cooperative Study
  2. CTAD website

Further Reading