At the 8th Clinical Trials on Alzheimer’s conference held November 5-7 in Barcelona, 900 attendees traded results on trials from the closely watched Aβ antibodies aducanumab and gantenerumab to a long list of lesser-known therapeutic candidates. The most pressing issue discussed at this meeting was how to design trials to be able to see a drug effect in early AD, while the tools are still evolving. The field has learned much about the importance of rigorous dose-finding, exposure, and target engagement, but new frontiers have cropped up. How best to identify the right patient population, knowing how fast a given early-stage person is likely to progress, and measuring subtle improvement in barely impaired people have become the challenges of the day. To meet them, tools development is actively ongoing even as a larger clinical trials infrastructure is forming across both sides of the Atlantic.
Gantenerumab, Aducanumab: Bobbing Up and Down While Navigating Currents of Trial Design
The 8th Clinical Trials Conference on Alzheimer’s Disease, held November 5-7 in Barcelona, Spain, displayed the potential pitfalls of each of the many decisions that go into designing trials in early, pre-dementia AD. Amid a broad sense of optimism that anti-amyloid antibodies might actually be working, there was also a sobering humility about just how hard it may be to prove it. Curiously, two opposing trends demonstrated the challenges of trial design jointly faced by two of the most closely watched investigational immunotherapies. Gantenerumab, an N-terminal Aβ42 antibody by Roche, re-emerged to look rather seaworthy after appearing to sink under the flat-out negative result of an interim analysis in December 2014. Aducanumab, a similar antibody being developed by Biogen, looked to observers to be taking on just a little water at CTAD following its breezy Phase 1b results presented at AD/PD this past March. Of course, both antibodies are still the same, both programs are moving forward, and most observers at CTAD believed that the efficacy signals in the overall datasets for both of them are probably real. The respective antibodies' ups and downs as they chart a path through the clinical trials process reflect the challenges of conducting innovative trials when multiple elements—the tools to select participants, the management of side effects, and the ways of measuring progression—are evolving along the way. Read on for an update on both antibodies’ journeys.
First, gantenerumab, which was presented at four talks with various kinds of subgroup analysis at CTAD. Roche’s Robert Lasser prefaced the analyses by saying, “Scarlet RoAD is still a negative trial. We wanted to know what happened, and now we believe there was a signal.” To recap, the trial’s independent data safety monitoring board ordered a halt to dosing last December, and in July 2015 at AAIC, Lasser subsequently showed that the futility analysis prompting this decision had shown no benefit for gantenerumab treatment. That day, Lasser also showed an initial subgroup analysis to suggest that the trial population had comprised about equal parts people who did not progress over the trial’s two-year time frame, people who progressed slowly, and people who progressed quickly (see Dec 2014 news; Aug 2015 conference news). Importantly, the scientists now say, the interim analysis, done on 312 people who had completed the two-year trial, excluded the 190 people who by then had dropped out. It therefore did not factor in, as Roche scientists claimed at CTAD, that the placebo group had lost a disproportionate number of fast progressors. Their departure, in essence, rendered it impossible to detect a treatment benefit in their fellow fast progressors on gantenerumab.
The subgroup analyses presented at CTAD painted a picture of a trial that was masking a response in fast progressors because these people were leaving the placebo group to start symptomatic drugs such as acetylcholinesterase inhibitors or memantine, which the Scarlet RoAD protocol had forbidden. The trial targeted prodromal AD, i.e., it enrolled still-functional people who worry intensely about their memory, but did not allow them to take approved AD medications while they were helping test this investigational drug. As the trial went on, the fast progressors in the placebo group noticed their memory worsening, concluded correctly they must be on placebo or the drug was not working, and left the trial to go on symptomatic medications instead, Roche scientists said. In the treatment group, it was different. The fast progressors responded to gantenerumab, so they perceived little decline and stayed in the trial. But because the treatment group also contained slow progressors and non-progressors, the treatment benefit of the fast progressors could not be discerned.
There was intense buzz in the hallways about how AD trials remain full of surprises as the field learns collectively. Roche apparently had not anticipated that participants who were barely progressing, combined with a selective de-riching of fast progressors from the placebo group, could obscure a treatment effect in the interim analysis. “By losing untreated fast progressors, and turning treated fast progressors into slow progressors, an analysis that looks only at completers would cancel out a treatment effect,” one scientist summed up. Alzheimer clinicians at Scarlet RoAD sites in both Europe and the United States spoke only on condition of anonymity, but they agreed with this assessment. In fact, some had expressed displeasure in private all along about having to withhold AD medications. Clinicians recommended that stable use of approved Alzheimer’s medications be allowed in the next gantenerumab trial to pre-empt this incentive to leave. Acetylcholinesterase inhibitors are not indicated as standard of care for prodromal AD, particularly in Europe; however, in practice patients who participate in clinical trials know these drugs exist and can help a little, and they expect the best possible care, including access to these drugs, clinicians say.
Some trialists, notably Rachelle Doody of Baylor College of Medicine in Houston, have urged sponsors to track different progression rates in their trials (see Dec 2014 CTAD story). In 2010, when Scarlet RoAD started, trials were only just beginning to target prodromal, biomarker-confirmed Alzheimer’s, and requiring biomarker evidence of amyloid positivity was the big new thing. Researchers had no handle on how to predict progression rates at baseline. Five years later, that is changing. At CTAD, numerous groups, armed with data correlating progression with baseline characteristics in various observational cohorts, discussed the performance of experimental prediction algorithms—combining elements from ApoE genotype, baseline amyloid load, or performance on episodic memory tests or online tests. The emphasis now has moved to getting better at finding pre-dementia patients who are likely to decline measurably during the lifetime of a treatment trial.
At CTAD, Roche’s Lasser noted that of Scarlet RoAD’s 797 enrolled patients, a fifth progressed to dementia in the two years of the trial. At baseline, they had in common greater functional impairment on the CDR-sb and the FAQ. Beyond that, however, nothing jumped out of this dataset to lend itself as an easy inclusion criterion to find fast progressors, Lasser said. Also at CTAD, Paul Maruff of Cogstate, Melbourne, Australia, reported that in the AIBL natural history dataset, ApoE4 strongly predicted future memory decline in cognitively normal people; however, Lasser said that in Scarlet RoAD’s population of already mildly symptomatic people, ApoE4 offered no further predictive value.
To explore progression in the Scarlet RoAD cohort, Sylvie Retout of Roche took a modeling approach with data from ADNI. Showing spaghetti plots of stark differences in individual people’s trajectories over time, Retout said that small hippocampal volume and high scores on the FAQ and CDR-sb at baseline marked people who then declined rapidly. Retout used these features from ADNI to classify the Scarlet RoAD population at baseline to predict slow, medium, and fast progressors. Indeed, two years later, the predicted slow progressors had worsened two points on ADAS-cog, the “medium” group by five points, and the predicted “fast” group by six points. Other outcome measures used in this trial, such as the CANTAB and even the MMSE, showed similar trends; however, the CDR-sb did not, Retout said. About 250 patients per arm were available for these post hoc clinical analyses.
Separately, Retout sliced the data not by baseline predictors but by plasma gantenerumab concentration, i.e., exposure to study drug. She split the high-dose arm into people with low, medium, and high blood gantenerumab levels, and found that efficacy correlated with exposure. The largest treatment benefit, six points on the ADAScog, accrued to people with the highest blood antibody concentration, Retout said. This finding, as well, showed up on CANTAB and MMSE, but not CDR-sb. “The efficacy signal increases with gantenerumab plasma concentration,” Retout said.
In an attempt to understand the effect of the drug in the overall study population, including dropouts, Juergen Dukart of Roche computed slopes of progression for all patients in the trial. He then compared the slopes between the treatment arms. At CTAD, Dukart reported that this analysis revealed dose-dependent slowing of disease progression on all clinical scales used in the trial. He said that in a subsequent sub-analysis looking separately at dropouts and patients who completed the trial, the dropouts in the placebo group turned out to have had the fastest rate of progression when compared to patients in both treatment arms in all clinical scales used. Among the placebo group, people who left the trial were progressing up to four times faster than the people who stayed, Dukart said. When comparing the dropouts' reasons for leaving, those who left the placebo group more often cited lack of efficacy, whereas treatment group dropouts were more often due to cited side effects or other reasons, Dukart said. From the patient’s point of view, this makes sense, clinicians later commented. If you progress slowly or not at all, you cannot tell if you are on placebo or drug and see no reason to change. If you decline rapidly, you conclude the trial is not helping and may consider alternatives.
Biomarker findings appear to line up with the company’s claim that the higher dose of gantenerumab may have done a little bit of good in some patients. Roche’s Tania Nikolcheva presented the trial’s florbetapir PET substudy. One hundred and fourteen people initially enrolled, but the stop to dosing left only 27 placebo, 21 low-dose, and 19 high-dose patients available for analysis of repeat scans at one year. Beyond the overall finding, previously reported at AAIC, of a modest 5 percent dent in global brain amyloid load on the higher dose, at CTAD Nikolcheva showed new data relating amyloid removal to gantenerumab exposure. Splitting participants into three bins of low, medium, or high blood gantenerumab levels, she saw that the high-exposure group had the biggest difference, up to 10 percent less brain amyloid than placebo. Dukart presented a separate post-hoc, voxel-wise analysis of the PET data, claiming that when analyzed by brain region, amyloid reduction on the higher dose reached up to 18 percent relative to placebo in areas where amyloid is known to build up strongly in AD, such as the precuneus. These differences were dose-dependent and statistically significant, Dukart said. He also correlated gantenerumab exposure in the CSF to amyloid PET SUVR and, like Nikolcheva’s plasma-based exposure analysis, connected higher exposure to more amyloid removal. “We are confident that the drug is doing something in a dose-dependent manner,” Dukart said.
On CSF biomarkers, a 10 percent reduction of phospho-tau on the higher gantenerumab dose had been reported at AAIC. At CTAD, Nikolcheva added that more reduction in CSF p-tau tracked with more reduction in amyloid PET. This correlation was dose- and time-dependent, Nikolcheva said. She reported a p value of 0.039 and a correlation coefficient of 0.43 for this association; 23 patients were available for this exploratory post-hoc analysis. “This indicates that targeting amyloid can influence downstream processes reflected by CSF tau,” Nikolcheva said, adding “Clearly we need to reproduce this data in a larger set and with higher doses.”
Even when taken with heaping grains of salt, as befits interpretation of post hoc analyses, the data suggest, if nothing else, that the gantenerumab doses in this trial were too low, researchers at CTAD widely agreed. The current open-label extension of Scarlet RoAD aims to offer participants higher doses of gantenerumab. The next Phase 3 trial will attempt to dose up to four times higher. In conversation, Roche scientists make a comparison to Biogen’s aducanumab. This antibody started showing treatment effects at 3 mg/kg, which roughly corresponds to the 225 mg at which Roche now believes to have seen a signal in fast progressors. The challenge for both programs then becomes one of managing the ARIA side effects, enabling amyloid clearance without hurting the patients.
Aducanumab has entered Phase 3 trials following the Phase 1b PRIME trial of 165 enrolled patients. This antibody has similarities (though also differences, see May 2015 news) in its Aβ42 binding characteristics and ARIA liability to gantenerumab. At CTAD, Biogen researchers presented bits of new data in three presentations. Jeff Sevigny reported an analysis on regional reduction in brain amyloid as measured by florbetapir PET. He noted that amyloid deposition was not driven by a single region but occurred in a set of regions known from natural history studies to accumulate amyloid deposition early on in AD. They include the anterior cingulate cortex, the frontal cortex, the posterior cingulate and parietal cortex, and the striatum, among others. In addition, Sevigny showed a correlation at one year between change in PET SUVR and two clinical measures, the CDR-sb and the MMSE. Aducanumab-treated participants who had one standard deviation or less of reduction on amyloid PET, as defined by the placebo group at week 54, continued to decline on these clinical measures, whereas clinical progression was slower in treated people who had more than a one standard deviation amyloid reduction. Sevigny cautioned that this correlation was drawn with exploratory clinical endpoints in this trial, which was primarily a safety and target engagement study.
More puzzling for observers was Sevigny’s report that aducanumab showed no benefit on two other exploratory outcome measures at one year. They are the free and cued selective reminding test (FCSRT) and a neuropsychological test battery (NTB). “We saw no treatment effect, but we did see floor effects, suggesting these tests are unsuitable for this amyloid-positive population with an MMSE of 20 or higher,” Sevigny said. In the minds of clinicians, this finding somewhat weakened the trial’s efficacy conclusion, which is generally considered strongest when a treatment benefit occurs consistently across all assessments. It also revived speculation heard earlier that the PRIME study’s exploratory clinical benefit on the CDR-sb may have been subtly influenced by a potential rater bias that can be inherent in an escalating-dose trial.
Vissia Viglietta of Biogen presented a post hoc analysis of those people among randomized PRIME population who most closely matched the type of patient Biogen is currently enrolling into its Phase 3 trials of aducanumab. The Phase 3 patients are similar to the PRIME population spanning the prodromal and mild parts of the AD continuum. One difference is that prospective patients will get picked for a screening PET scan based on a score at or below 85 on the RBANS cognitive scale, as opposed to the FCSRT test that was used in PRIME for prodromal subjects. Viglietta said that the RBANS better predicts amyloid positivity and might reduce screen failures due to amyloid negativity, which have bedeviled both PRIME and Scarlet RoAD, as well as the ongoing A4 trial. Of the 165 patients in PRIME, 92 met the Phase 3 criteria, Viglietta said, and their baseline characteristic made them seem a little less clinically affected, with two-thirds being prodromal and one-third mild AD, whereas two-third of the patients in PRIME overall had mild AD and one-third were prodromal. “This is overall a slightly milder population,” Viglietta said. The results in this subgroup were similar to PRIME overall in that the antibody dose-dependently removed brain amyloid while being associated with ARIA-E in a dose- and ApoE-dependent pattern. On the CDR-sb and MMSE, results still favored aducanumab.
Viglietta presented details about the aducanumab Phase 3 program. Two identical Phase 3 trials, called ENGAGE and EMERGE, will each combine ApoE 4 carriers and non-carriers, but dose them differently in an attempt to mitigate the risk of ARIA. In ApoE 4 carriers, the dose will be slowly titrated up to 3 or 6 mg/kg. Likewise, ApoE 4 non-carriers will slowly ramp up the dose and stop at 10 mg/kg. “We are trying to treat every patient at their optimal dose,” Viglietta said.
Biogen estimates that it will enroll about 3,000 patients across both studies, and randomize people 2:1 into treatment versus placebo. These trials allow symptomatic AD medications but require that participants have been on a stable regimen for eight weeks prior to starting aducanumab or placebo.
The studies will run for 18 months; people who complete it and have at that time an MMSE above 15 can then join a 24-month long-term extension study. In the extension study, they will know they are getting the antibody, Viglietta said, but will be assigned to a dose and participants will remain blinded to which arm they were in during the first 18 months. This will enable Biogen to conduct a delayed-start analysis to assess both lasting efficacy and safety similar to what Lilly attempted with solanezumab (Jul 2015 conference news). Enrollment is underway in the United States and soon to begin in other countries, for a total of 300 sites around the world, Viglietta said.
The aducanumab and gantenerumab results fueled discussion throughout CTAD about the CDR-sb as a primary outcome for pivotal Phase 3 trials in very mildly affected patients. This informant- and patient-based rating began as a tool to stage dementia, and is widely used for that purpose in the NIA-funded system of Alzheimer Disease Research Centers and in many clinics beyond. Clinicians broadly agree on its face value and ability to pick up inter-individual change, and sites throughout the world are able to administer it. When the ADAS-cog fell out of favor as being insufficiently sensitive in the increasingly early AD populations that treatment trials were targeting, the CDR-sb drew notice for its performance across the disease continuum in ADNI and for its mention in an FDA guidance on conducting trials in early AD (Kozauer and Katz, 2013). At CTAD 2015, however, debate intensified about the CDR-sb as a single primary outcome measure. Aducanumab, as well as the Merck BACE inhibitor verubecestat, have essentially hinged their success on it. The design of the next Phase 3 gantenerumab trial in prodromal AD is not yet known (for one perspective on this question, see also Q&A with Steve Ferris of New York University).—Gabrielle Strobel
- End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s Trial Futile
- Aducanumab, Solanezumab, Gantenerumab Data Lift Crenezumab, As Well
- CTAD Shows Alzheimer’s Field Trying to Reinvent Itself
- Shape of a Hug: How the Embrace of a Therapeutic Aβ Antibody Really Matters
- Outcomes, Outcomes: Cognition is Crux of New Alzheimer’s Trials
- Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013 Mar 28;368(13):1169-71. Epub 2013 Mar 13 PubMed.
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Outcomes, Outcomes: Cognition is Crux of New Alzheimer’s Trials
As more drugs are entering the trials pipeline in ever-earlier-stage patients, the question of how to measure success is coming to the fore. The conventional model of measuring efficacy with dual cognitive and clinical scales such as ADAS-cog and ADCS-ADL in mild to moderate Alzheimer’s is widely considered too insensitive for the prodromal or particularly the preclinical phases of the Alzheimer’s disease continuum. The field is in the middle of a transition, where a handful of trial sponsors have already used the revised diagnostic criteria and tried different outcome measures, and others are watching them closely to see what works and what doesn’t. Meanwhile, the doors of research have swung wide open for biostatisticians and neuropsychologists to come up with altogether new tools. Weighting the strengths and weaknesses of outcome markers creates an alphabet soup of a conversation. CDR-sb, MMSE, NTB, FCSRT, RBANS—confused yet? For context, and to capture some of the buzz at CTAD, read our Q&A with Steven Ferris, who directs the Clinical Trials Program and co-directs the Alzheimer’s Disease Center at New York University. Ferris has been involved in clinical trials for all approved and many investigational Alzheimer’s medications, as well as development of tools to track cognitive function. Questions by Gabrielle Strobel.
Q: There was a lot of discussion at CTAD about using the CDR-sb as an outcome measure. How did aducanumab fare with it in the PRIME trial?
A: To state this fairly, you have to give context. Two clinical outcomes were reported for this trial. It’s not common that companies collect clinical outcome information or report it in a Phase 1b trial. Remember, Phase 1b is for safety and learning how high you can go with dose and still have it be safe. The other aim, typically, is to confirm target engagement, so you do either CSF or amyloid PET to look for changes presumed to represent a direct biological effect of Aβ immunotherapy. It was a little unusual to measure clinical outcomes, and by using the CDR-sb, MMSE, FCSRT, and an NTB they did quite a bit.
They did see a clinical signal and achieved p values, even though the study was not powered to see an effect on these measures. The 30 people they had per dose was fairly large for Phase 1b but fairly small for assessing clinical outcome; researchers usually have at least 100 people per group for finding the best dose for clinical outcomes. Lo and behold, they see something. The effects were surprisingly big for a field used to seeing a couple of points of difference on the ADAS-cog. The CDR-sb is not a sensitive measure in small trials. It is usually used in larger, longer trials of 18 months or more. Seeing a clinical effect was what gave these results so much buzz.
Q: Then is there a problem?
A: The problem is when you have small group sizes, it can happen that you think you get an apparent effect that might be statistically significant but could be due to chance. That is why there is usually not much emphasis on clinical outcomes in such a small study. That said, this was a perfectly appropriate study design. Nobody did anything wrong, it’s just that you are limited in the extent it meets criteria for a robust double-blinded trial.
Q: How about the dose response?
A: That made it more believable, certainly with the dose-dependent amyloid effect, and also the dose-dependent clinical effect as originally reported.
Q: Why do you think it was not robustly double-blinded?
A: Because you escalate the dose as you go along. You recruit an initial 40 people for the first dose. You randomize to active or placebo. The groups are not evenly distributed between treatment and placebo because the trial’s primary goal is safety, so you want the majority of people to be exposed to the drug. They had 30 on drug and 10 on placebo. If you see no big safety problems, you enroll another 40 and increase the dose, again at 3:1. You do this sequentially. In a parallel three- or four-arm trial, i.e., Phase 2b and 3, you are randomizing at the same time to the planned distribution. It is a more robust blinding and minimizing of possible imbalances or other confounds. Here it was a Phase 1b dose titration safety study, that is why they did it this way. One possible implication of this design is that it reduces the certainty that what you see clinically is real.
For example, when you have a 3:1 ratio between active drug and placebo, it is not a totally blinded study in the sense that the patients and their caregivers know the design, and the people evaluating them know the design, and their expectation is that more people are on drug. So when you do a CDR rating, which is subjective, there could be some bias that happens when you are not completely blinded.
Q: What happens as the trial goes on?
A: A while later, sites do the next dose and the next dose. They know that the more recently recruited patients are likely to be on a higher dose. We saw at AAIC that the dose response conclusion got a bit weakened when they added a fourth dose later. It was an intermediate dose and did not follow the dose-response pattern. So there could have been something about the serial nature during the first three doses that made some people think they saw benefits. I emphasize again that I am not saying anybody was doing anything wrong, just that the nature of this design is a little bit prone to bias in the CDR rating. There could a subliminal expectation that the person in front of you is in a treatment arm.
Q: How about the amyloid PET?
A: That is not subject to that sort of bias.
Q: Are dose-titration designs the only concern with using CDR-sb as outcome?
A: No, my concern about the CDR-sb as an outcome measure is broader. If I asked 20 of my colleagues if they would pick the CDR-sb as the single primary outcome for a big pivotal trial in AD—particularly a trial with a mix of MCI stage and mild AD stage—most would say no. It strikes me that these next trials have been set up with some risk due to a less than optimal primary outcome.
A: The CDR-sb is not optimally sensitive to a treatment effect in this particular cohort that Biogen, and also Roche, have selected for their aducanumab and gantenerumab trials, respectively. The reason is that in this very mild group, there is not much scoring on the CDR-sb. It has six boxes that are rated, and a total score range of zero to 18. The lowest point is zero. People with a CDR 0.5—the population these trials are recruiting—usually have a total sum of boxes score below four at baseline. So they simply have not much room to get better. You want a scaling where the typical individual in your trial is in the middle of the range, so they have lots of room to change if they get worse or better. Also, it’s a rather coarse scale and will not pick up small changes. The CDR is a great dementia staging tool, but the CDR-sb is a relatively poor outcome measure for prodromal or MCI-stage therapeutic trials.
Q: What led to its use, then?
A: Historically, the regulatory authorities have valued performance-based cognitive outcomes such as the ADAS-cog. The ADAS-cog led to registration for drugs in mild to moderate AD but is relatively insensitive at earlier stages. Moreover, with their guidelines from the early 1990s, the FDA started requiring a dual outcome. In her talk at CTAD, Suzanne Hendrix explained to us that we pay a statistical price with a dual outcome. You have to win on both, and to have a required p level of 0.5 for one and for the other, that raises the bar. Since in the past decade no drugs succeeded, the FDA recently put out a signal in their guidance that at the early AD stage, they might consider a single primary outcome instead (Kozauer and Katz, 2003; Mar 2013 news). In the guidance, they almost off-handedly said, “... such as possibly the CDR-sb.” The CDR-sb had performed well in ADNI, tracking decline across the very early disease continuum. Still, I do not think the regulators adequately thought through the use of CDR-sb as a single trial outcome. Not only does it lack sufficient dynamic range at the early AD stage, it also negates the well-established FDA standard requiring inclusion of a performance-based cognitive measure. The CDR-sb is a rating scale, where the rater interviews an informant and the patient. It does not meet the old requirement that you show a benefit on an objective psychometric test.
Q: So the companies went with that?
A: They are understandably jumping at the opportunity of having a single rather than a dual primary outcome, which is certainly advantageous statistically. The problem is they put all their eggs in a less-than-optimal outcome basket.
Q: What would make a better outcome?
A: At CTAD, Suzanne Hendrix made a very strong case for the advantages and improved sensitivity of a composite that can include both clinical and cognitive performance components. That is what Biogen would be well-advised do, in my opinion. They could include the CDR-sb, and also some cognitive tests, maybe some ADLs that change early, and build a composite from that.
Q: These trials have started. Can they still change course?
A: They cannot add assessments once they are enrolling. Whatever is in the protocol as primary, secondary, and tertiary outcomes is what they have. The total array of assessments they collect is very good. However, they can still change their minds about what they are using as the primary outcome, provided they only include in their composite data that is already being collected. They have to justify it to the FDA and register their revised analysis plan before they lock the data at the end of the trial. Ideally, given what we are learning now, they could set some statisticians to work and figure out the best composite using the measures the trials are collecting. They probably have at least a year to get that done. I hope they will. We all want new treatments to succeed.
Q: Has it been done before?
A: Yes. I believe Lilly changed their primary outcomes with solanezumab, for example.
Q: How are other drugs performing on the CDR-sb?
A: That is only beginning to come out. The gantenerumab ScarletRoAD trial fared poorly with it. Some of their subgroup analyses reported at CTAD showed differences on other outcomes but not for CDR-sb. The Merck verubecestat trials have not reported any clinical results as yet.
Q: What do you suggest instead?
A: It’s worth considering that several other trials in early AD have opted for a composite. Eisai is using the ADCOMS composite they developed for both their antibody and BACE inhibitor (see BAN2401, E2609). Some preclinical AD trials are also using composites. The A4 trial, the planned API ApoE4/4 trial, and the DIAN trial each have developed a composite that they think is sensitive in their respective populations.
Q: Other outcomes are being used, as well. In the PRIME study, there was no change on a modified NTB and the FCSRT. Apparently there were floor effects, indicating these measures are unsuitable for this population.
A: I am not sure why there would have been floor effects. I have long pointed out that there is not a single NTB. It started with bapineuzumab, where John Harrison made a battery and called it NTB (Harrison et al., 2007). Now many different variations are called NTB; it has almost become a generic name for batteries that can be quite different, so you have to look at what tests are included. Still, you usually should not have floor effects on these batteries in MCI-stage and for mild AD. Floor means everybody is hovering around zero scores and can barely do the test. An NTB was used in the bapineuzumab trial in mild to moderate AD. People with MCI generally show significant impairment on an NTB, so I would not expect ceiling effects either.
Q: What about the FCSRT? It has been used in some prodromal/MCI-stage trials.
A: The FCSRT is a newer, fairly complicated verbal list learning task (Grober et al., 2010). It taxes the hippocampal-limbic network, which is impaired early on. Here, too, there should not be floor effects in an MCI population. The FCSRT has 16 words and usually three learning trials, so the maximum recall score is 48. MCI participants tend to recall at least a few words on each trial, for a score of 10 to 20. It surprises me that those two measures show no treatment effects but the MMSE would. The FCSRT is a single test, the NTB is a cluster of four or five tests, and both should be more sensitive than the MMSE to gradations of impairment in MCI.
Q: At CTAD, I heard some agreement when Paul Maruff of Cogstate reported that the MMSE adds mostly noise to composites, at least when tracking progression in the longitudinal AIBL data. Others said only the orientation items from the MMSE are useful, and have pulled those, for example into the Banner/API composite. What do you think about including the MMSE in composites?
A: I think it’s a bad idea except for orientation, because that taps a different domain from everything else. Other components of the MMSE are close to ceiling in this very mild population, so you just get noise. The likely reason people with preclinical or prodromal AD fail MMSE questions is they are not paying attention to their environment.
Q: But it’s used everywhere.
A: The MMSE has been widely used for decades simply as a screening tool for dementia. We use it at baseline and refer to a score range to broadly characterize severity. It’s almost like a language: a “minimental 24” is a person who is doing pretty well with mild impairment; a “10” is a profoundly impaired individual. But it is not a good outcome measure in a trial. That is why back in the 1980s everyone thought we needed something better and the ADAS-cog was created.
But now, a lot of people further dislike using the MMSE because it got commercialized very post hoc. It was created by the academic investigators Susan and Marshal Folstein, who published it 40 years ago (Folstein et al., 1975). It became the main first-pass instrument a neurologist or psychiatrist would use in an office visit to evaluate a possible AD patient. Then in 2001 copyright was passed on to a test company, which now demands payment every time you administer it. That is a major annoyance in the academic clinical community, and indeed its use by the 30 ADRCs has been phased out mainly because NIH does not expend limited resources on the licensing fee.
Q: I have been hearing a lot about RBANS at CTAD. What’s going on?
A: The RBANS is a psychometric battery developed by the neuropsychologist Chris Randolph (Randolph et al., 1998). It has been available for a while, but has been rediscovered because people want an alternative to the ADAS-cog for trials in milder populations. Some international trials are planning to use the RBANS, for example the European EPAD initiative.
Q: Another buzzword at CTAD was MedAvante?
A: Full disclosure: I am a paid member of their AD advisory board. They started by providing data quality services for trials in psychiatric disorders and then branched out into Alzheimer’s. They offer services related to the RBANS among other cognitive batteries and trial measures, including the ADAS-cog and CDR-sb. But rather than selling use of tests, their main business is contracting with pharma to improve data quality and minimize data errors in clinical trials. They offer rater training, and review and scrutiny of data either in real time or shortly after collection. They have an electronic system for querying possible data problems and ensuring corrections. If a rater is not properly administering a scale, the system picks that up and tries to fix it during the period the data is being collected.
It is all about minimizing noise in a trial. In the past, CROs have done this and, frankly, in many cases they have done it badly. MedAvante specializes in this and has sophisticated systems to optimize the accuracy of outcome measures. For example, with their centralized rater system for psychiatric trials, a small group of highly trained, specialized raters rate everyone in a multicenter trial by video conferencing. A problem with raters is that every site uses different ones, often with different training and uneven quality. One rater may score low, another high, or a rater scores lower one day and higher the next. All this increases “noise.” With a whopping drug effect, this does not matter, but if you have a modest drug effect, the large standard deviation can overwhelm your group difference, and the only way to achieve a required p value is to minimize error.
Q: What’s the difference between MedAvante and a CRO?
A: The CROs will continue to run the nuts and bolts of trials. But optimizing data quality is increasingly being transferred to companies like MedAvante from the old system of relying on CRO monitors, who used to visit sites and look at paper data records and have sites make corrections manually, after the fact. Now that most trials have adopted electronic data capture, companies like MedAvante play an increasingly important role.
Q: In your view, what are the main challenges in AD psychometrics these days?
A: We need more sensitive but robust clinical outcome measures for early stage trials. We need cognitive tasks that specifically tap early impairment in those brain areas and networks that have pathology early on, and that are validated against relevant AD biomarkers in the same types of subjects. Such tests could tell which individuals among cognitively normal people within a certain age range are most likely to have brain amyloid or tau pathology. The preclinical trials are here, and they are the new frontier. We need more sensitive tests that enable screening of large numbers of people cheaply, so that only people who score poorly get a PET scan or CSF assays to confirm likely “preclinical AD.” That would bring down the current 70-80 percent screen-failure rate of the A4 trial, screen-failure meaning a person is ineligible for the trial because a $4,000 PET scan indicates they are amyloid negative. And importantly, these same cognitive tests would probably also be optimally sensitive measures for tracking treatment response in a preclinical AD trial.
Q: Thank you for this conversation.
- Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013 Mar 28;368(13):1169-71. Epub 2013 Mar 13 PubMed.
- Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological test battery for use in Alzheimer disease clinical trials. Arch Neurol. 2007 Sep;64(9):1323-9. PubMed.
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No Available Further Reading
Truly New to Déjà Vu: Investigational Therapy News at CTAD
Besides news on the most closely watched anti-amyloid drugs, the 8th Clinical Trials on Alzheimer’s Disease (CTAD) conference, held in Barcelona, Spain, November 5-7, featured a parade of lesser-known investigational therapies. Spanning Phases 1 to 3, they are a motley mix of new approaches and repurposed wares. True to the history of Alzheimer’s drug development thus far, many fizzled out when it came to showing efficacy. Others are being advanced to the next phase, some with and some without having met primary endpoints in the previous trial. Parts 3 to 5 of this CTAD series summarize clinical trial results presented there, organized by Phase 3 on downward.
In the last session of CTAD, Michela Gallagher of Johns Hopkins University, Baltimore, fired up a tired audience with news that a proprietary low-dose formulation of the atypical antiepileptic drug levetiracetam, called AGB101, was set to start a Phase 3 efficacy study in amnestic MCI in early 2016. Using an atypical anticonvulsant drug, this approach grew out of basic cognitive neuroscience advances, developed in Gallagher’s and other labs over the past decade, about how information is encoded in the medial temporal lobe memory system of the brain. This treatment strategy targets an age-related hyperactivity of the hippocampus, which in people at the MCI stage of AD occurs opposite hypoactivity of the entorhinal cortex. Both functional MRI and high-resolution MRI have localized the hyperactivity to the CA3/dentate gyrus part of the hippocampus, tied it to decline toward dementia, and shown that amyloid-positive MCI patients are most prone to further hippocampal hyperactivity and faster decline (e.g., Celone et al., 2006; Hämäläininen et al., 2007; Yassa et al., 2010; Huijbers et al., 2015).
After a pilot study showed promise for levetiracetam, Gallagher and colleagues evaluated three doses of the drug in a Phase 2 study (May 2012 news; Mar 2015 news). In that trial, a low-dose range brought down hippocampal hyperactivity, restored entorhinal activity, and boosted performance on a memory task, though Gallagher cautioned that these comparisons were within-subject and the group showed large variability. Levetiracetam is FDA-approved at up to 3,000 mg daily for the treatment of epilepsy. This aMCI program will use 220 mg daily, which has been safe thus far, Gallagher said at CTAD.
Sites in the United States, Canada, and Europe will evaluate a low-dose, extended-release formulation of levetiracetam in a Phase 3 registration trial, Gallagher told the audience. People with MCI due to AD and a positive florbetapir scan will be randomized to take drug or placebo for 18 months. As currently designed, the trial’s success will hinge on the CDR-sb as a single primary outcome, following FDA guidance for trials at that stage of the AD continuum (Kozauer and Katz, 2013). The CDR-sb’s ability to capture small treatment effects in early AD was questioned at CTAD (see Q&A with Steven Ferris).
As a secondary outcome, Gallagher chose atrophy of the entorhinal cortex. Whole-brain and hippocampal atrophy have more commonly been used as outcome measures in trials; however, analysis of longitudinal cohorts such as ADNI and BIOCARD suggested to Gallagher that shrinkage in the entorhinal cortex precedes, and indeed predicts, shrinkage of the hippocampus in Alzheimer’s disease (Desikan et al., 2010; Eskildsen et al., 2013; Miller et al., 2013).
In the past, other members of the racetam class of drugs have been tried unsuccessfully in Alzheimer’s disease, though they are different molecules and were used at higher doses (e.g., Growdon et al., 1986; Croisile et al., 1993; Flicker and Grimley Evans, 2001).
Another entrant into Phase 3 is the serotonin receptor 6 antagonist RVT-101. This drug was developed and taken through Phase 2 by GSK under the name SB-742457, and sold in 2014 to the startup company Axovant. At CTAD, Axovant’s Lawrence Friedhoff presented no new data, but announced plans to evaluate this drug in dementia with Lewy bodies, as well. A Phase 3 study for AD has started enrolling.
Deep Brain Stimulation
Meanwhile, Constantine Lyketsos, also at Johns Hopkins, told the audience that deep brain stimulation of the fornix is poised to move into Phase 3 based on partial success in Phase 2. The fornix is a bundle of fiber tracts that carry signals from the hippocampus to other brain areas. This approach views Alzheimer’s disease as a circuit problem, and tries a circuit-based solution, Lyketsos said. Thought to strengthen connectivity, or perhaps even neurogenesis (Mirzadeh et al., 2015), deep brain stimulation requires surgery to embed a lead electrode into the brain and a stimulator pack under the skin. DBS has accrued ample safety and procedural experience, as some 100,000 people worldwide, most of them Parkinson’s patients, have been exposed to it. DBS of the fornix is the most advanced among several attempts to try stimulation in Alzheimer’s; another stimulates the nucleus basalis of Meynert (Sep 2013 news; May 2014 news). Following a promising pilot study in six patients (Laxton et al., 2010; Smith et al., 2012), in 2012 a seven-center Phase 2 trial began in the United States and Canada. At CTAD, Lyketsos presented its one-year results.
This trial enrolled 42 people with mild AD between the ages of 45 to 85, who had to have evidence of functional decline in the previous year to ensure they were progressing. Everyone had electrodes implanted in the area immediately anterior to the fornix, but subsequently participants were randomized to either have them activated (the “on” group) or not (the “off” group) for the following year. After that everyone had their stimulator turned on for an open-label, second year of study. Study staff was blinded such that the technicians who adjusted the stimulators were separate from the people who assessed the study participants, Lyketsos said. The whole two-year trial requires participants to come for 13 visits after the surgery and follow-up is nearly complete, Lyketsos said. “We do not have the problem of how to deal with missing data.”
On the primary objective—to learn whether AD patients tolerate neurosurgery and subsequent stimulation—the study succeeded. “This appears to be safer than we had been concerned about. The cognitive testing before and four weeks after surgery was practically identical. The surgery itself was not harmful, and adverse effects during the first year were very comparable between the groups,” Lyketsos told the audience.
The secondary objective—to learn whether DBS of the fornix worked—was more elusive. Both the “on” and the “off” groups declined significantly at one year after surgery, and neither the CDR-sb or the ADAScog13 showed a clear difference between the groups. Curiously, however, a biomarker outcome, brain glucose metabolism measured by FDG-PET, did show a “robust, widely distributed increase” in the “on” group, Lyketsos said.
Next, the researchers analyzed subgroups to see if some of the patients might have responded. They uncovered an age effect, whereby people with early onset AD appeared to have fared poorly on treatment, but people with late-onset AD LOAD looked as if they possibly had benefitted on the ADAS-cog and CDR-sb. Participants under 65 turned out to have had worse brain metabolic deficits than older participants already at baseline, and from there the younger patients declined faster on treatment than did the “off” group. Blood-flow imaging and FDG PET indicated that the younger patients had come into the study with more advanced brain disease than the older ones, even though they appeared equally impaired on the clinical measures on which they were being recruited. “The younger people were beyond the very mild disease we are targeting,” Lyketsos said. In the older patients, “there is a hint of a possibility that fornix DBS might work,” he added.
This was enough for the sponsor, the company Functional Neuromodulation Ltd., to go on, and the researchers are now designing a Phase 3 pivotal study. It will recruit people older than 65 who have early AD confirmed by amyloid PET. Lyketsos said the trial might include a composite outcome and follow people longer. Gil Rabinovici of UCSF noted that the sequence by which specific circuits come under attack can differ between early and late-onset AD. For example, some early onset AD cases are marked by more pronounced degradation of posterior cortical areas than the hippocampus. That, too, could explain why stimulation of the fornix works only in particular subsets of AD.
ELND005 in Limbo
This compound—aka scyllo-inositol or AZD-103—has a circuitous history, with clinical trials going on in Alzheimer’s disease since 2005. It started as a proposed anti-Aβ oligomer agent but, after it failed to improve cognition in Phase 2, it was recast as a signal transduction modulator that might be able to soothe agitation and aggression in advanced AD (see Apr 2008 conference news). It received fast-track designation from the FDA and was undergoing a Phase 2/3 trial when its company, Transition Therapeutics, announced last summer that that trial, too, had missed its primary endpoint. The company then terminated the trial’s 36-week safety extension.
At CTAD, Anton Porsteinsson of the University of Rochester School of Medicine and Dentistry, New York, talked the audience through the data. “This was a negative study,” Porsteinsson said. From a randomized population of 175 patients with probable AD in both the treatment and placebo groups, the researchers analyzed a modified intent-to-treat population of 167 patients in each group. Eighteen patients in each arm dropped out of this 12-week trial. Diarrhea, cough, lethargy, and falls were more common in the drug than the placebo group, but clinicians generally feel that the suffering of agitated patients at this stage of AD, and the burden on their caregivers, is so great that this safety profile would be acceptable. The problem was that the groups were no different on the primary outcome, a modified version of the neuropsychiatric inventory (NPI), or on either secondary endpoint, an agitation/aggression excerpt of the NPI and a modified clinical global impression of change.
“What else can we learn from this? Is there a signal buried under main findings?” Porsteinsson asked in his CTAD talk. He then presented a post hoc subgroup analysis. It suggested a trend shy of statistical significance that the most severely affected patients might have benefitted. They are people whose NPI scores were not only high but also marked by acting out aggressive behaviors such as shoving, slamming, or intruding. The patients who did not respond had more of the milder behaviors this version of the NPI records, such as fidgeting and stubbornness. “The most severe patients seem to have responded,” Porsteinsson said. The company hopes to continue developing this compound, but has to secure funding, Porsteinsson wrote to Alzforum. Transition Therapeutics posted slides from Porsteinsson’s presentation on its website. For Phase 2 results, see Part 4 of this series.—Gabrielle Strobel
- Epilepsy Drug Calms the Hippocampus, Aids Memory
- More Evidence That Epilepsy Drug Calms Neurons and Boosts Memory
- Outcomes, Outcomes: Cognition is Crux of New Alzheimer’s Trials
- Fornix First—Atrophy Foreshadows Decline in Normal Aging?
- X Marks the Spot? Nucleus Basalis for DBS in Alzheimer’s
- Keystone Drug News: Phase 2 Anti-oligomer Sugar Alcohol—How Might It Work?
- Truly New to Déjà Vu: For Five Hopefuls, Lights Go Out After Phase 2
- Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, DePeau K, Rentz DM, Selkoe DJ, Blacker D, Albert MS, Sperling RA. Alterations in memory networks in mild cognitive impairment and Alzheimer's disease: an independent component analysis. J Neurosci. 2006 Oct 4;26(40):10222-31. PubMed.
- Hämäläinen A, Pihlajamäki M, Tanila H, Hänninen T, Niskanen E, Tervo S, Karjalainen PA, Vanninen RL, Soininen H. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging. 2007 Dec;28(12):1889-903. Epub 2006 Sep 25 PubMed.
- Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage. 2010 Jul 1;51(3):1242-52. PubMed.
- Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, Amariglio RE, Marshall GA, Rentz DM, Johnson KA, Sperling RA. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain. 2015 Apr;138(Pt 4):1023-35. Epub 2015 Feb 11 PubMed.
- Kozauer N, Katz R. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013 Mar 28;368(13):1169-71. Epub 2013 Mar 13 PubMed.
- Desikan RS, Cabral HJ, Settecase F, Hess CP, Dillon WP, Glastonbury CM, Weiner MW, Schmansky NJ, Salat DH, Fischl B, . Automated MRI measures predict progression to Alzheimer's disease. Neurobiol Aging. 2010 Aug;31(8):1364-74. PubMed.
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- Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.
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No Available Further Reading
Truly New to Déjà Vu: For Five Hopefuls, Lights Go Out After Phase 2
More candidate therapies have landed on the scrap heap of Alzheimer’s clinical trials, freeing up sites, investigators, and participants to try something else. At the 8th Clinical Trials on Alzheimer’s Disease conference, held November 5-7 in Barcelona, Spain, Rachelle Doody of Baylor College of Medicine in Houston closed the book on Roche’s monoamine oxidase B MAOB inhibitor sembragiline. Doody presented a straight-up intent-to-treat analysis of all 542 patients with probable Alzheimer’s who had entered a Phase 2 study called MAyflOwer RoAD. MAO B inhibition was being tried as a neuroprotective approach targeted to reactive astrocytes. Sembragiline is a safer, more selective follow-on compound to a previous MAO inhibitor, lazabemide, which inhibited both MAO A and B and was toxic to the liver, Doody said.
This trial was fairly standard, comparing two doses of drug to placebo for one year, plus 12-week follow-up. Twenty percent of the patients dropped out. The drug was safe but showed no difference between groups on its primary endpoint, the ADAS-cog, Doody showed. Because the observed drug concentrations in this study predict almost complete occupancy of the MAO-B enzyme in vivo at both doses, the hypothesis was tested. “Sembragiline at these doses does not slow cognitive decline in AD,” Doody said.
On one secondary endpoint, the Behavioral Pathologies in Alzheimer’s (BEHAVE-AD) scale, the drug did show a difference. The placebo group developed behavioral disturbances driven by a large minority of patients, Doody said. Another secondary, the ADCS-ADL scale of daily function, showed a trend but fell short of statistical significance. A post hoc analysis indicated that patients whose behavioral symptoms were more severe may have benefitted from sembragiline; however the study was not designed to assess behavioral symptoms and this signal would need to be reproduced, Doody said. Roche has discontinued development of sembragiline.
The axe also fell on a histamine H3 receptor antagonist by the French pharmaceutical company Laboratoires Servier. Called S 38093, this drug underwent two large Phase 2 trials, one as single treatment and one in addition to donepezil. They were conducted in 40 different countries, though not the United States. At CTAD, Servier’s Annette Merdes gave a postmortem on this program. Together, more than 1,300 patients with mild to moderate Alzheimer’s disease participated in these studies. The drug was reasonably safe, though treated patients did have more falls than people on placebo. However, neither of three doses—2, 5, or 20 mg/day—taken for a year, outdid the placebo on any measure of cognition, function, clinical global impression, or caregiver burden. This program, too, saw a trend for a benefit on neuropsychiatric symptoms in one trial, but that did not hold up in the companion study. “We saw no clinically relevant finding. The program has been stopped,” Merdes told the audience.
In a warning perhaps to the flurry of early stage trials that are ramping up, Merdes noted that further analysis of the placebo response in this trial indicated that the patients with the mildest disease, who had been diagnosed most recently, were most prone to demonstrating a strong placebo effect.
The end came for yet another treatment approach, the NGF gene therapy Cere-100. This attempt at neuroprotection had, in various incarnations, been undergoing clinical evaluation ever since Mark Tuszynski of the University of California, San Diego, started the line of research in 1999 (Dec 1999 news). Earlier this year, the company developing Cere-100 announced the end of the program, and at CTAD, UCSD’s Mike Rafii presented the data of the final study. This was a multicenter ADCS trial controlled by sham surgery, an invasive way of blinding a study that had generated controversy in the past (Kim et al., 2005).
Of 88 screened patients, 49 were enrolled and assigned 1:1 to Cere-110 or control surgery. Both the procedure and the AAV2 vector used to ferry in the NGF gene were safe, Rafii reported. Of the six deaths over the course of this two-year trial, four occurred in the placebo group and the other two were not related to study procedures. The problem, as so often, was efficacy: Two years after the surgery, the treated patients were no better off than placebo recipients on the ADAScog and ADCS-ADL; they were even trending worse than the placebo group on the MMSE and CDR-sb. FDG-PET and MRI volumetry were also not different between the groups, suggesting that the NGF expression, to the extent it occurred, was unable to boost the brain’s metabolism or slow neurodegeneration.
On a procedural note, the trial did show that it is feasible to conduct multicenter trials of controlled steretotactic surgery and that patients will enroll knowing they might end up with sham surgery. To maintain the blind, the study employed an unblinded surgery team and a separate, blinded neurology team, Rafii said. This implies that if the field revives gene therapy and new candidate therapies roll around, the necessary trials to evaluate them can be done. Applauding the bravery of patients in this study, Mary Sano of Mount Sinai School of Medicine, New York, agreed, saying “This seems safe and doable now.”
For CERE-110 itself, the epilogue in due time will come in the form of neuropathologic examination of how many cholinergic neurons remained in these patients, and whether NGF was expressed and adequately distributed in the brain.
Getting exhausted with all the flameouts? Almost there. Two more negative answers, then this Phase 2 story ends on a more positive note. Phase 2 is, after all, a better place for ineffective drugs to die than Phase 3. At CTAD, the “Alzheimer’s is Type 3 Diabetes” hypothesis posted two negative answers on therapeutic validation. For one, an investigator-initiated trial showed that the insulin analog detemir is ineffective in treating Alzheimer’s disease, at least in a four-month course tested in this trial. Suzanne Craft from Wake Forest University Medical School in Winston-Salem, North Carolina, told the audience that she compared the long-acting insulin analog to regular insulin and placebo, both delivered intranasally. In 11 AD patients per group, 20 international units of detemir twice daily had no effect on a memory Z score and MRI volumetry, but the same amount of regular insulin did show a signal on both measures. Meanwhile, the Alzheimer’s Therapeutic Research Institute at the University of Southern California is conducting the NIA-funded Phase 2/3 trial of intranasal regular insulin called SNIFF. This multicenter study had to stop temporarily over a problem with the insulin nebulizer, but is now back on track, Craft said.
Metformin, a potent and widely used insulin sensitizing drug, fell on its sword. Steven Arnold of the University of Pennsylvania, Philadelphia, reported that his study enrolled 20 people with mild to moderate AD, with about the same late-60s age distribution as Craft’s study. All completed an eight-week course of up to 4,000 mg/day of metformin. This was primarily a biomarker study, Arnold said. Metformin failed to budge readouts on resting cerebral perfusion as measured by ALS MRI, nor CSF Aβ, tau, or phospho-tau. Cognitive outcomes were similar, with neither the Montreal Cognitive Assessment (MOCA), the functional rating scale (FRS), or some other paper and pencil tests showing any change, Arnold said.
After five no-gos, here is a new contender. The serotonin receptor antagonist ITI-007 is slowly wending its way toward Phase 2. This drug is being developed primarily for schizophrenia, as a reportedly safer alternative to current antipsychotic drugs such as clozapine and benzodiazepines, both of which are prescribed off-label to treat disturbed behavior and sleeplessness in dementia, as well. ITI-007 is what used to be called a “dirty drug” in that it hits serotonergic, dopaminergic, and glutamatergic receptors, though its developers claim that its higher potency for 5-HT2A than the other receptors give it a wide dosing range that can be exploited to treat different conditions. In schizophrenia, doses of up to 60 mg per day have completed one Phase 3 study while another is ongoing, and two Phase 3 trials in bipolar disorder are about to start (see company press release; clinicaltrials.gov).
For an indication in Alzheimer’s, the company Intra-Cellular, which licensed ITI-007 from Bristol Myers Squibb, thus far has only conducted one small safety and pharmacokinetics study of up to 20 mg/day, which Robert Davis of Intra-Cellular previously reported at CTAD (see Dec 2014 conference news). In Barcelona, Davis merely added data from a small trial conducted in France in 19 people with insomnia, saying that doses as low as 1 to 10 mg/day helped people stay asleep, with longer slow-wave sleep in the first half of the night and longer stage 2 sleep in the second half. Poor sleep is increasingly being implicated both in increasing risk and worsening behavioral symptoms of Alzheimer’s disease. A Phase 2 trial of ITI-007 to soothe neuropsychiatric symptoms of Alzheimer’s is being planned to start in summer 2016, Davis said in Barcelona. “This drug is very safe. We think it will be useful to test behavioral disturbances in dementia, such as depression, anxiety, and aggression.” For Phase 1 results, see Part 5 of this series.—Gabrielle Strobel
- NGF Gene Therapy Trial Begins
- New Treatments for Alzheimer’s Behavioral Symptoms on Horizon
- Truly New to Déjà Vu: Phase 1 Means ‘Check!’ for Some, ‘Out!’ for Others
- Kim SY, Frank S, Holloway R, Zimmerman C, Wilson R, Kieburtz K. Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers. Arch Neurol. 2005 Sep;62(9):1357-60. PubMed.
No Available Further Reading
Truly New to Déjà Vu: Phase 1 Means ‘Check!’ for Some, ‘Out!’ for Others
The 8th Clinical Trials on Alzheimer’s Disease conference, held November 5-7 in Barcelona, Spain, featured results on at least four clinical trial debutants, i.e., Phase 1 entries. One evoked Queen Marie Antoinette’s acerbic observation, “There is nothing new except what has been forgotten.” For those who have forgotten tramiprosate, aka Alzhemed, aka Vivimind—well, it’s back, and the new version is better than ever if you believe its new sponsors. At CTAD, Anton Porsteinsson of the University of Rochester School of Medicine and Dentistry in New York told the story of how this failed medication is making its comeback.
Alzhemed’s active ingredient is homotaurine, aka 3-amino-1-propanesulfonic acid. Naturally found in seaweed, it is an analog of taurine, an amino acid ingredient of some brands of infant formula and energy drinks such as Red Bull. Alzhemed underwent a clinical development program in the early 2000s. When a North American Phase 3 trial missed both primary endpoints, a concurrent European Phase 3 study was stopped early. The compound was subsequently rebranded and sold as a nutraceutical, unregulated by the FDA (Jun 2007 conference news; Nov 2007 news; Oct 2008 news).
In 2013, the Lexington, Massachusetts-based startup company Alzheon picked up this thread. It licensed a prodrug version, ALZ-801, whose pharmacokinetic and -dynamic properties it claims will cause fewer gastrointestinal complaints, achieve more consistent drug levels in the blood, and last longer so that patients need take a pill only once, not twice, a day. Company scientists further claim that the rubble of the Alzhemed program contains promising signals of efficacy in certain subgroups. Those signals, combined with some of Alzhemed’s safety data the FDA may accept, could speed up development of this approach the second time around, Porsteinsson said. Porsteinsson serves on Alzheon’s scientific advisory board.
Porsteinsson presented a post hoc analysis of the ApoE4 homozygous participants of the two Alzhemed Phase 3 studies. Together, the two trials contained 252 ApoE4/4 patients with mild to moderate AD. Unlike the whole study population, those among this subgroup who received the high dose had a statistically significant treatment benefit on the ADAScog of 2.85 and 4.56 points at 52 and 78 weeks, as well as a trend on the CDR-sb, Porsteinsson said.
In the meantime, Alzheon on November 6 issued a press release about starting two Phase 1b trials. One is a dose-ranging study assessing ALZ-801 tolerability and pharmacokinetics in healthy elderly volunteers, the other a bioequivalence study to assess pharmacokinetics and food effects of a tablet formulation. Details were not disclosed, and these trials are not listed in clinicaltrials.gov. At CTAD, Porsteinsson said the next step would be a Phase 2/3 study comparing one dose of Alz-801 to placebo in 200 patients each with mild to moderate Alzheimer’s disease who are positive for ApoE4. The trial will likely last for up to 78 weeks, Porsteinsson said, and the ADAScog and CDR-sb will serve as co-primary outcomes.
Other scientists at CTAD noted that homotaurine is a GABA A receptor agonist (Caltagirone et al., 2012), and that tramiprosate’s amyloid-reducing mechanism was not rigorously validated in a clinical trial, nor target engagement conclusively shown in humans.
With the ALZ-801 program intending to skip Phase 2, it’s arguably farther along than two other Phase 1 candidates presenting at CTAD, both of which are transitioning to Phase 2. One is AAD-vac1, an active vaccine designed to prompt the formation of antibodies against a pathological conformation of tau protein. At CTAD, Matej Ondrus of AXON Neuroscience in Bratislava, Slovakia, presented results of the first Phase 1 trial. It enrolled 30 people with mild to moderate Alzheimer’s and randomized them to one of two doses of the vaccine or placebo, injected under the skin once a month, for a three-month blinded period followed by three months of open-label treatment for everyone. On safety, Reinhold Schmidt of the University of Graz, Austria, had previously reported at AAIC that the study had two withdrawals because of adverse events, one of which might have been due to the study medication. Besides that, the vaccine appeared safe and well-tolerated.
At CTAD, Ondrus added that 29 of the 30 participants responded to the antigen by making antibodies against what Axon calls peptide 108 with titers that rose with each dose after the second injection. Some commentators considered the presented titers high for an aging population. Vaccines against Aβ have struggled to elicit both high response rates and high titers. AAD-vac1 uses the adjuvant aluminum hydroxide, aka Alhydrogel.
Ondrus showed ADAS-cog scores, noting that their variability in this small sample precluded a statistical analysis but that the participants appeared to stay stable for the six-month course of the trial. Data correlating cognitive response to titers in individual patients were not shown. In response to a question about CSF biomarkers, Ondrus noted that lumbar puncture was optional in this trial. He said four patients completed it, and the data were still being assessed. The trial concluded in March 2015. A Phase 2 trial is set to enroll its first patient this December, Ondrus noted.
Another Phase 1 tau immunotherapy, Roche’s RG7345, appears to have bitten the dust. This monoclonal antibody directed against the tau phosphoepitope pS422 was in Phase 1, but in October 2015, Roche removed it from its active development pipeline.
A repurposed drug just advanced from Phase 1. AZD0530, aka saracatinib, is a tyrosine kinase inhibitor originally developed to treat cancer. It is now being used as a way to test fyn kinase as a therapeutic target in Alzheimer’s disease. At CTAD, Christopher van Dyck of Yale University School of Medicine in New Haven, Connecticut, told the audience that doing so is tricky. “This drug does not appear to have a wide therapeutic index. The effective brain levels that we are trying to achieve are close to those where toxicity starts,” van Dyck said. This means that drug levels need to be monitored to keep trial participants safe.
In a Phase 1b dose-finding trial, 50 mg/day of saracatinib fell short of achieving adequate CSF levels of the drug, 100 mg achieved them in half of the participants, and 125 caused tolerability or safety problems in some participants. Diarrhea, headache, nausea, and fatigue were common adverse events, and one person was hospitalized with congestive heart failure and pneumonia, which were considered possibly related to study drug, van Dyck said. To optimize dosing in individual participants, the scientists are monitoring blood levels, as the drug’s plasma concentration accurately signal its CSF concentration, van Dyck said.
The Phase 2 study is being coordinated by the Alzheimer’s Therapy Research Institute at the University of Southern California. For this 152-patient, 23-center trial of a one-year course of saracatinib, patients randomized to drug start on 100 mg/day and increase to 125 mg only if their plasma drug level is deemed to be insufficient, van Dyck said. Because this is a proof-of-concept study, not a registration trial, van Dyck opted for a biomarker that reflects the drug’s mechanism of action. Saracatinib’s effect on fyn kinase is thought to affect synaptic activity, hence FDG-PET appears to be a logical way to measure if it is biologically active in the brain of Alzheimer’s patients, van Dyck said.
a id="earliest" name="earliest">The earliest results in a new Phase 1 program came from MEDI1814. Amanda Dudley of AstraZeneca said that the first clinical trial for this antibody is beginning to show target engagement in the central nervous system. Dudley presented an interim analysis of this ongoing study. MEDI1814 is the latest in a long list of antibodies directed against Aβ42. Its unique wrinkle is that it arose from a different approach toward reducing ARIA than its competitor crenezumab. That antibody, now entering Phase 3, reduced microglial activation by engineering the Aβ recognition region onto a IgG4 antibody isotype instead of the more common IgG1. MEDI1814 is an IgG1; to reduce effector function, its FC tail carries mutations that interfere with binding to microglial receptors, Dudley said. This antibody came about when AstraZeneca bought MEDIMMUNE, a company better known for its influenza vaccines and focus on cancer, inflammatory and autoimmune diseases.
The first trial is an ascending study, in which a group of people with mild to moderate Alzheimer’s get a single or multiple injections. Once that proves safe, a second group gets a higher dose, etc. The sites monitor for adverse events, conduct MRIs at baseline and after five weeks to look for ARIA, and measure the antibody’s behavior in blood and CSF.
Within a dose range of 25 to 300 mgs, data are available thus far up for doses up to 40 mg in the first 21 of 121 planned patients, Dudley told the audience. No safety signals have cropped up yet. The antibody’s rise and fall in blood follows what was modeled previously, Dudley said. As expected, total plasma Aβ42 goes up as it binds the antibody and assumes the antibody’s half-life, which is longer than that of unbound Aβ42. Most importantly, in the CSF, the concentration of free Aβ42 drops, along with a rise of total Aβ42. This happens in a dose-dependent manner, Dudley said, noting that thus far in the trial, she has seen free CSF Aβ42 go down by 60 percent. Aβ40 does not change. Conducted at eight centers, this trial will continue for the better part of next year, Dudley said.—Gabrielle Strobel
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Health Interventions Boost Cognition—But Do They Delay Dementia?
It has become a mantra in the Alzheimer’s field that staying active—physically, cognitively, and socially—can protect the brain against decline. But can this be turned into a viable intervention? At the 8th Clinical Trials in Alzheimer’s Disease conference in Barcelona, Spain, November 5-7, leaders of three European trials reported success in delivering multi-domain interventions to large groups of people in primary care settings. Participants in the multiyear trials by and large followed the programs and improved their overall health, with few people dropping out, the researchers said. In both the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and the French Multidomain Alzheimer’s Prevention Trial (MAPT), old people scored cognitive gains over control groups, though the benefit was modest. It is still unclear if these gains will last long-term, or if they will translate to lower rates of cognitive decline and dementia. A third study, Prevention of Dementia by Intensive Vascular Care (PreDIVA), addressed this question, and will report topline results shortly.
“We may be on the right track with our multi-domain interventions, but we have not yet managed to define what are the optimal interventions or target populations,” said Edo Richard at the University of Amsterdam, who co-leads PreDIVA. Future studies might see more dramatic results by targeting populations at higher risk of cognitive decline, he suggested.
The three trials collaborate under the umbrella of the European Dementia Prevention Initiative (EDPI), and will pool data to help design later studies (see Sep 2012 news). Together, the trials include 6,412 participants and a variety of methodologies, interventions, and outcomes, providing a database for determining what works best, Richard said.
The FINGER study enrolled 1,260 Finnish people aged 60 to 77 who scored high on a calculation of dementia risk factors, including hypertension, high cholesterol, and obesity. For two years, both the control and experimental groups received advice on eating better, exercising, and staying mentally and socially active. The experimental group also underwent a more intensive regimen that included exercise classes, computerized cognitive training, and a customized diet plan. At the 2014 AAIC in Copenhagen, Denmark, Miia Kivipelto of the Karolinska Institute in Stockholm announced topline results, whereby the experimental group outperformed controls on the Neuropsychological Test Battery, which measures multiple aspects of cognitive function (see Jul 2014 conference news).
At CTAD, Kivipelto presented more data. Both groups improved their baseline cognitive scores, but the intervention group scored about 25 percent higher than controls on global cognition. On memory tests, the intervention group scored 40 percent higher, while performance on tests of executive function and processing speed was about twice as good as in controls. The overall effect on cognition was modest, however. The control group improved their scores 0.16 standard deviations over baseline measures, compared to 0.20 in the intervention group, for a difference of only 0.04 standard deviations with the intervention (see Ngandu et al., 2015). Even so, the difference may be meaningful, Kivipelto said, as cognitive decline over the course of the study was 30 percent more likely in the control group than in the treatment group. She noted that the size of the benefit equates to what would be expected with drugs. If sustained, these changes could have a large impact on public health, she wrote to Alzforum.
Importantly, Kivipelto said, the study showed that this multi-domain approach is feasible in real-world, primary care settings. Most people completed the trial, with a dropout rate of 12 percent. Participants came to 90 percent of their scheduled sessions with health coaches, and said they enjoyed them, Kivipelto added. The intervention group reported exercising more and eating more fish and vegetables than controls, demonstrating that they did change their behavior, at least in the short term. They scored higher in measures of mobility, ability to perform daily activities, and quality of life. The only adverse event they reported was sore muscles from exercise.
Ongoing analyses of subgroups suggest that carriers of the ApoE4 allele reaped greater benefits. They improved significantly more than non-carriers on tests of global cognition and executive function, with a trend toward better performance on tests of memory and processing speed. Moreover, in ApoE4 carriers, the intervention counteracted a shortening of telomeres seen in the control group, Kivipelto said. These structures cap the ends of DNA strands, and their shortening is believed to correlate with cellular aging.
“This intervention maintains cognition and improves quality of life and function. It is a pragmatic model that can be tested and adapted to various settings and countries. We should implement this,” Kivipelto said.
The MAPT study in France tested similar interventions, plus omega-3 supplements containing docosahexaenoic acid (DHA), a fatty acid found in fish oil and believed to support brain health. The three-year study enrolled 1,680 people over 69, a slightly older population than the FINGER study. Participants took a cognitive composite that included orientation questions from the Mini-Mental State Exam, the Free and Cued Selective Reminding Test, as well as tests of executive function and verbal fluency (see Nov 2012 conference news). Data collection finished in 2014.
At CTAD, Bruno Vellas of the University of Toulouse, France, presented the results from the trial. Like FINGER, the MAPT program sharpened cognition. People on the multi-domain intervention improved their scores over baseline, while the placebo group declined. For the multi-domain intervention alone, the effect missed significance, but the multi-domain intervention plus DHA resulted in a statistically significant improvement, Vellas said. “This confirms the FINGER data in an older population and with longer follow-up. Moreover, in MAPT we were able to prevent cognitive decline over a three-year period,” Vellas wrote to Alzforum. About one-fifth of the participants dropped out of the study.
The MAPT data hint that people who started off in worse shape benefitted more. They included subgroups of people who at the start of the study were cognitively impaired, carried the ApoE4 allele, or had brain amyloid deposits. As in the whole cohort, people in those subgroups who got the multi-domain intervention plus omega-3 maintained their cognition, while the other intervention groups typically declined, as did the placebo group. The effect sizes for the benefit appeared larger in the subgroups than in the cohort overall, although this needs confirmation in additional trials, Vellas said. It may be that these subgroups progress faster, making it easier to detect a treatment effect, he suggested.
Imaging substudies added to the picture, though they did not complete it. In 60 participants, the researchers performed FDG PET at baseline, six, and 12 months to measure brain metabolism. Dwindling metabolism marks cognitive decline. In those who received both the multi-domain intervention and omega-3, brain glucose metabolism increased in many clusters throughout the brain, Vellas said. The other intervention groups had smaller, transient improvements, and the control group stayed stable. Brain volume was another story, however. Carole Dufouil of INSERM in Bordeaux, France, presented data from a much larger substudy of 503 participants who underwent structural MRI at baseline and at the end of the trial. She saw no difference between any of the groups in total brain volume, hippocampal volume, or white-matter hyperintensities. Dufouil will follow up with another MRI scan two years after the end of the trial, she said. “Perhaps MRI is not as sensitive as other measures,” Vellas wrote to Alzforum.
It is unclear if these interventions benefited people by improving the health of their brain vasculature, or by moving AD biomarkers. Future trials should measure whether the intervention lowers brain amyloid, Vellas suggested. He also wants to target people with low DHA levels at baseline. In MAPT, those in the lowest quartile of DHA declined cognitively, but when they took omega-3 supplements they stayed stable, regardless of whether they also got the multi-domain intervention. “It seems it is necessary to restore brain health to people with poor DHA status to increase the long-term clinical benefit of the multi-domain intervention,” Vellas said. These results in a subgroup analysis must be confirmed by further trials, he added.
The PreDIVA study took a different tack. It provides intensive cardiovascular care and uses a diagnosis of dementia as the outcome. This study enrolled 3,532 people aged 70 to 78 at 26 primary health care centers in the Netherlands. Participants came in for a clinic visit every four months for six years. At baseline, their cognition was normal but the majority had one or more cardiovascular risk factors: 33.3 percent had cardiovascular disease, 25 percent were overweight, and 10 percent had had a stroke. Their average systolic blood pressure was 155 (see Richard et al., 2009; Richard et al., 2010; Ligthart et al., 2010).
Data collection wrapped up in spring 2015. At CTAD, Richard reported that hypertension improved significantly more in the intervention group than in controls, indicating the intensive cardiovascular care improved heart health over the six years of the trial. “Long-term vascular care seems to work to drop risk factors,” Richard noted.
Richard and colleagues are still analyzing data for the primary outcome measure, and expect to have results soon. Because researchers were able to collect data on the primary outcome from nearly all participants who dropped out, they could include 98 percent of the participants in the analysis. Overall, 16.5 percent of the cohort died, and 6.7 percent, or 233 people, were diagnosed with dementia from any cause. “I think that’s the largest number of incident cases that has ever been reported as a primary outcome in a trial,” Richard told Alzforum. He noted that the researchers collected data on subtypes of dementia, so they will be able to determine whether the intervention was more effective against vascular dementia or Alzheimer’s. He believes that having a simple, pragmatic outcome measure like dementia incidence will help researchers determine whether the intervention made a difference in people’s lives. Neuropsychological test batteries measure subtle changes more sensitively, but it not always clear how clinically meaningful those are, Richard added.
Others liked the approach as well. “I congratulate your methodology. Such a big study with such complete follow-up is hard to achieve,” Rachelle Doody of Baylor College of Medicine, Houston, said at CTAD.
In a larger sense, what do the findings from these three trials mean for dementia prevention? FINGER and MAPT demonstrate that multi-domain interventions support cognitive function, but not that this will then delay decline and dementia in the long term, Richard said. Not all people keep up lifestyle changes, hence the effect of such interventions tends to diminish over time, he noted. The FINGER researchers will conduct five-year and seven-year follow-ups to determine how well participants maintain their healthier lifestyles. “We hope people have learned the benefits of these changes, and decide to maintain them,” Kivipelto told the audience.
Many researchers in the field believe the findings support the importance of public health interventions, but more data will be needed to determine the best approach. “We still don’t know what target population will have the best results, and what types of intervention are the most cost-effective. At a time when resources are limited, that’s important,” Sandrine Andrieu at INSERM, Toulouse University, France, wrote to Alzforum. She worked on the MAPT trial. Kristine Yaffe at the University of California, San Francisco, noted, “We need a similar multi-domain intervention trial in the U.S.” Yaffe predicted that cognitive decline might eventually be treated with a combination of drugs and lifestyle changes.
In the meantime, EDPI researchers are collaborating on a new trial. They have pooled data from their studies to determine the most effective lifestyle interventions. Now they are using an interactive internet platform to support about 4,250 older adults with cardiovascular disease in making these changes. Called Healthy Ageing Through Internet Counselling in the Elderly, HATICE will measure if this approach improves the management of cardiovascular disease and prevents cognitive decline. The study has enrolled about 1,000 participants to date, Richard said.—Madolyn Bowman Rogers
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