Topline Result for First DIAN-TU Clinical Trial: Negative on Primary
DIAN participants and investigators today are grappling with difficult news. A topline analysis of the first Phase 2/3 clinical trial that the DIAN-TU trials platform mounted for carriers of dominantly inherited Alzheimer’s disease mutations showed that both of the trial’s investigational drugs missed the primary endpoint. That endpoint would have been a statistically significant difference between drug and placebo on the DIAN Multivariate Cognitive Endpoint (DIAN-MCE), a composite of four cognitive tests developed by DIAN for this stage and type of Alzheimer’s disease. The trial evaluated two investigational anti-amyloid drugs, Roche’s gantenerumab and Lilly’s solanezumab, against placebo and additional progression data drawn from the DIAN observational study.
“The initial negative results from the DIAN-TU trial regarding gantenerumab and solanezumab are terribly disappointing for the families and investigators who have committed so much time and effort to the trial over the past five years,” Catherine Mummery of University College London wrote to Alzforum (full comment below).
This negative result pertains to the entire study population taken together, i.e., recipients on all doses, and asymptomatic and symptomatic mutation carriers pulled into one. In other words, this topline analysis groups together asymptomatic participants who are some years away from the expected symptom onset for their respective family mutation with fellow participants who were already symptomatic at enrollment.
Additional analyses are ongoing. Given the small sample size and heterogeneity of disease stage in this trial, some of those analyses will focus on individual trajectories. Sometimes depicted as “spaghetti plots,” such analyses can relate a given participant’s drug exposure, or response to study drug, to where the person was in the 15-year pathogenesis of AD, for example.
“One big question is whether the high dose would have had an effect. My concern is we did not have the high dose up and running for long enough,” Randall Bateman of Washington University in St. Louis told Alzforum. Site investigators agreed that the trial may have been underdosed (see William Klunk and Lawrence Honig comments below).
The trial lasted for five to seven years. As planned in 2012, it started as a two-year biomarker target engagement trial, and later was upgraded into a registration trial that measured a cognitive endpoint after at least four years on treatment. But the investigators could not anticipate that between 2013 and 2017, the field at large would gain confidence about the safety of anti-amyloid antibodies. It did, hence sponsors started titrating participants to higher doses in several different trials of solanezumab, gantenerumab, and also Genentech/Roche’s antibody crenezumab.
The DIAN-TU trial increased the dose of solanezumab fourfold, and of gantenerumab fivefold, in summer 2017, midway through the trial. Alas, it may have been too little too late to meet the primary outcome.
The DIAN-TU trial results on the secondary outcomes are still being analyzed. Researchers do not know yet what the 19 other cognitive and clinical scales used in this trial showed. These include established instruments such as the CDR-SB and neuropsychiatric inventory, as well as many individual cognition tests such as maze learning, category fluency, pattern separation, and other tests. The DIAN-MCE comprises the Wechsler Memory Scale-Revised Logical Memory Delayed Recall, the Cogstate International Shopping List Test, the Wechsler Adult Intelligence Scale-Revised Digit Symbol Substitution Test, and the Mini-Mental State Examination
DIAN scientists have not yet seen any imaging or fluid-based biomarker data from the trial. “We still do not know what is really going on. In the next few weeks, we will get into that data, figure it out, and make headway,” Bateman told Alzforum.
Once the trial’s data is better understood, the sponsors will decide whether either antibody generated enough of a positive signal to warrant adding an open-label extension phase. “We do not know yet, based on how much target engagement and other findings we may have, whether we can offer an open-label extension,” Bateman said.
The current topline analysis compares data from 194 participants; 52 APP or presenilin carriers on gantenerumab, 50 mutation carriers on solanezumab, and 40 on placebo. To enlarge the placebo data set, the trial has FDA permission to also include natural history data from mutation carriers enrolled in the DIAN observational study, which is collecting the same type of progression data as does the DIAN-TU drug trial.
The data in this trial are being analyzed by three independent statistical teams, one at WashU, the sponsor DIAN-TU, and one at Roche and Lilly, the companies that develop the two respective antibodies and are partners in the DIAN-TU Pharma Consortium. The three teams met last week in St. Louis, cooped up together in a data analysis “cave” with security posted outside, and worked through the data. While most analyses are actively ongoing, the three teams quickly agreed on the topline result, Bateman said.
The investigators are legally bound to disclose topline data within two days of obtaining it, and Washington University, Roche, and Lilly each issued press releases. Letters to the participating sites have gone out, and the WashU team will hold a webinar with participating families as soon as they understand the data better, Bateman said.
Despite this setback, DIAN investigators are driving hard to start the next series of trials. An ongoing cognitive run-in to enroll people for the next drug arms will continue. DIAN-TU is on track to start testing a tau drug this year, as well as a primary prevention trial for young adult mutation carriers who do not yet have significant brain amyloid deposition. Roche’s two gantenerumab Phase 3 trials in late-onset AD are continuing, as is Lilly’s A4 solanezumab trial in presymptomatic LOAD.
Meanwhile, Bateman emphasized that today’s topline result reflects only the beginning, not the final conclusion of the trial result. He hopes participating families, and the field at large, will hold judgment until all data are in. “We were required to get this out on short notice, but I ask people to get the full story before you draw conclusions. We are still focused on this trial, on these drugs, and what can we do with them. There may be some next steps with these drugs. Please stay tuned,” Bateman said.—Gabrielle Strobel
No Available Further Reading
University of Pittsburgh
I guess we have become so accustomed to hearing this sort of news that I can’t say I was surprised. However, I am disappointed in that I hoped for a better outcome in this highly amyloid-driven form of ADAD.
We must keep in mind that we can’t really interpret this result until we see the biomarker findings and know whether the drugs had the intended impact on their target (amyloid). If they did have a significant impact on amyloid load, then the lack of a clinical signal is a big disappointment, indeed. If not, then we need to question whether the drugs (or their doses) were adequate anti-amyloid therapies. We know that DIAN-TU started with drugs and doses typical of the other now-failed immunotherapy trials and only recently increased dosage after we all learned from the aducanumab Phase 1b trial.
We know that in research, the only guarantee is that if you stop trying, then nothing will change. The field in general is committed to this group of brave folks who carry ADAD mutations and ask for little more than a better life for their children. As a field, we won’t stop trying.
Columbia University College of Physicians & Surgeons
I’d like to disclose that I am a DIAN-TU site investigator. I know no more than the rest of the public regarding the topline results. I heard the news early this morning, having been sent the press releases.
The topline results are that for this particular population of carriers of autosomal-dominant Alzheimer’s disease (ADAD) mutations, neither drug studied, gantenerumab or solanezumab, at the doses and duration of treatment in this study, showed efficacy on the primary outcome clinical measures. To be precise, there was no statistically significant slowing of disease progression, as measured on composite testing of cognition/memory.
It is not overly surprising that this clinical endpoint was not met, for the following reasons:
(a) The number of subjects was very small (total N = 194, with three arms). For example, for solanezumab, at the end of four years (not all at the final dose level), there were only 36 drug and 32 placebo participants to be compared.
(b) The subjects were heterogeneous. This was of necessity, coming from a small genetic group. They differed in that they had mutations in different genes (APP, PSEN1, PSEN2), and had different mutations within each gene. Importantly, subjects were in different portions of the clinical trajectory; Clinical Disease Rating scores ranged from normal (0), to mild cognitive impairment (0.5), to mild dementia (1.0). Clinical measures move very differently in these different phases of the disease process.
(c) The drugs were likely markedly underdosed, both in dosage, and duration. For both solanezumab and gantenerumab, the likelihood of underdosing was recognized mid-study, and drug doses were escalated. But because of the timing of this decision, many participants received relatively short durations of the higher dose. For example, for solanezumab, the dose was increased from 400 mg every four weeks (about 6 mg/kg/four weeks) to 1,600 mg every six weeks (about 22 mg/kg/four weeks). But only about 25 percent of the total doses of solanezumab in this study were delivered at the 1,600 mg level, per the Lilly release. Furthermore, even the higher dose may be an “underdose.” A similar antibody—crenezumab, for which Phase 3 trials were terminated early due to apparent inefficacy in the sporadic AD population—was being dosed safely at doses of 60 mg/kg in Phase 3 trials. Additionally, the duration of dosing in a disease that develops over decades may also be insufficient.
Hopefully, analysis of secondary outcome measures, including the extensive cerebrospinal fluid testing, magnetic resonance imaging sequences, and amyloid PET and tau PET scans may shed light on whether there was any movement of biomarkers of the Alzheimer’s disease process.
Regardless, this trial is extremely important and valuable, because it showed that it is feasible to perform a randomized clinical trial on this population of presymptomatic and early symptomatic carriers of ADAD mutations. Through the extraordinary cooperation of the subjects, and the exceptional dedication and cooperation of the site coordinators and their teams, this study was able to provide for a period of up to 5 to 7 years of randomized drug treatment (or placebo treatment in non-carriers who did not wish to know their status) with very few subjects dropping out. This will provide an important dataset for future research.
The initial negative results from the DIAN-TU trial regarding gantenerumab and solanezumab are terribly disappointing for the families and investigators who have committed so much time and effort to the trial over the past five years.
We now need to go through the results in detail to understand what underlies the results, and learn from them to enhance design of future studies. We do not know yet whether an extension study will be planned, and await further information at ADPD.
On a personal level, I want to express my heartfelt gratitude toward our participants and their families. We will gain a huge amount from this study, as the information gathered from their involvement is crucial to the advancement of therapies in genetic and sporadic forms of Alzheimer’s disease.
DIAN-TU is a visionary study comprising valiant volunteers.
The negative primary outcome is disappointing. Additional analyses are underway to learn as much as we can about Alzheimer’s disease from this trial. A platform has been created and is moving forward to test future drugs for individuals with this uncommon genetic form of AD. I salute the courage and commitment of the study participants who made this study possible.
University of Melbourne
I am disappointed, but not surprised. The trial sizes were very small, and cognitive readouts are notoriously relatively insensitive. The baseline intake was very heterogeneous in terms of cognitive status (CDR ranging from 0 to 1) and the escalation of dosage came late in the course of these trials. In retrospect, it would have been a miracle if there were a significant cognitive result. Solanezumab in sporadic disease required large numbers (>600) to see a 15-30 percent cognitive slowing effect.
I’m hopeful that we will see some interesting biomarker data from the secondary analyses, including blood, CSF, and PET/MRI, particularly for gantenerumab, which has shown a strong movement in the PET Aβ signal in sporadic AD.
Dementia Reserch Center
I share the disappointment. Although the headline result is sadly negative, what has been shown for the first time is that it is possible to run a trial like this in familial AD.
New ground has been broken in terms of showing that affected and at-risk family members will take part—and will stay the course even with repeated lumbar punctures and scans and regular infusions over several years. And they did stay the course with great dedication and commitment. More families are engaged in research than ever—and will, I am sure, be keen to take part in future studies. We need now to learn as much as we can from this study, while preparing for the next trials.
Neuroscience Research Australia
Naturally it is disappointing that neither drug was found to slow cognitive decline. The trial was long in comparison to others—at least four years and up to seven for some participants. It represents a huge commitment on the part of participants and families, most of whom are at a stage of life where they are heavily involved in careers, bringing up children, and generally in the prime of life.
The logistics of arranging infusions or injections in the home every four weeks, together with blood collection, ECGs, and regular cognitive testing, was something I found astounding. As a site PI, I can't speak highly enough of the trial leaders at WashU and in particular the nurses who administered the doses. It shows that a long and arduous trial is feasible with this highly motivated group of participants.
I can't say that I was overly surprised that the primary endpoints were not met, in view of previous disappointments in targeting amyloid. Nonetheless, the unknowns are being dealt with one by one. Dosage is one: We will need to wait for the biomarker analysis to see whether the increased doses have had an adequate effect on amyloid deposition. Could it be that if the higher doses had been used for a longer period, an effect on cognition might have emerged?
Another question concerns the make-up of participants: How many of the participants were actually at a stage where cognitive decline could be detected? The more detailed analysis may throw light on these issues. Finally, we know that Aβ deposition is the first step in the AD process; reducing or removing amyloid on its own may be only part of the answer.
We are still waiting for effective tau-based therapies, though as mentioned above we hope that trials will begin within a year. Targeting tau is the logical next step: Families with dominantly inherited AD remain ideally placed to help us answer these questions. We are indebted to them.
Alzheimer Center Amsterdam; Head EQT Life Sciences Dementia Fund
I was disappointed but also not completely surprised. Reasons include the small sample, the late increase in dose, and the unknown test characteristics of the four cognitive tests in this population, especially since some of the participants did not have any symptoms or signs when they enrolled in the trial.
I did have some hope, however, for the gantenerumab arm given the specifics of this antibody.
That said, I am very curious to see the biomarker data, because they will teach us a lot on how to proceed. It also shows me how important the next step will be, which was proposed by WashU, to start a cognitive run-in before we add treatment arms. This will allow us to know more about the natural course of the cognitive and biomarker data before randomization.
Another disappointing but not unexpected result. The hope is that we can learn a lot about the clinical trial design with regard to “confounding” parameters.
A major underestimated problem is the effect size of the pharmacodynamic interactions between β-amyloid physiology and co-medications, common genotypes, and tau load—not with regard to amyloid load reduction as a biomarker, but more importantly on the cognitive readout. There is increasing evidence that different co-medications and genotypes related to dopamine and serotonin can affect cognitive readout. In combination with the relative modest effect of amyloid on functional outcome through its glutamate and nicotinic interaction, this can lead to large variability in outcome, especially when dealing with relatively small numbers of subjects in the treatment arms and therefore possibly masking any beneficial effect.
Icahn School of Medicine
Reducing amyloid two decades before symptoms does not guarantee that the intervention begins before pathology. An unanswered question is whether there would be success if those people at risk had an anti-amyloid drug on board so early that amyloid accumulation never began. Samantha Burnham and Colin Masters’ new data suggest that the inflection point in LOAD is around age 45, so for primary prevention, the trial would have to begin in 40- to 45-year-olds.
That said, a better way to retool might be to focus more resources on understanding how lifelong APOE2 or APOE3 Christchurch prevents AD. That strategy now comes pre-validated in living humans and with proven safety.
Many other approaches are being investigated. The AMP-AD has used big-data approaches to mine the network changes in sporadic AD brains, and they have hundreds of new leads on their "wall of hits." The issue is whether to abandon amyloid reduction. I think the answer is no, because every study indicates that amyloidosis is a key driver way upstream. We might eventually have to clear the amyloidosis before we can see any benefit from anti-tau or anti-inflammatories.
And we might have to stimulate neurogenesis (with a drug like BCI-838), but again, that may only help if the amyloidosis is purged first. The exception is SNAP patients with symptoms before any radiologically detectable pathology. Maybe SNAP would be a population in whom to test whether there is any benefit of stimulation of neurogenesis.
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