Another one bites the dust

This week’s medical journal, The Lancet, carries an editorial about the latest spate of anti-Alzheimer’s trials that have been stopped early. Two of the biggest pharmaceutical companies in the world, AstraZeneca and Eli Lilly, have announced that they have stopped phase 3 trials of a new kind of treatment called BACE inhibitors (β-amyloid precursor protein cleaving enzyme inhibitors). These studies were designed on the back of good evicence that they might work, and indeed the compounds have made it all the way to phase 3 trials – a large number of individuals with Alzheimer’s being given either the compound or placebo. These trials are hugely costly to run, and so typically, the drug companies and financial investors, tend to only back what they think will be a winning horse.

This year brings more disappointment for the Alzheimer’s community, Janssen stopped a BACE inhibitor trial in May, and Merck pulled their BACE inhibitor trial in February. 

The editorial comments that although these studies have been stopped frequently because an early look at the data suggest no meaningful effect, so no point in continuing the study, it is not necessarily the end of the road for these treatments, but that the prodromal phase of Alzheimer’s may be where the treatments will work.

I fear that the Parkinson’s world should ready ourselves for a similar journey. The road may be long, and fraught with disappointments, but the goal remains to develop a safe and effective treatment to stop or slow down Parkinson’s. Each failure does not sound the death knell, and each time we, as a global Parkinson’s community, must learn as much as we can from the failures to increase our chances of success. A vital lesson to learn from the Alzheimer’s world, is that established disease is likely to be a case of “too little, too late”. 

RNR

Alzheimer's disease research: the future of BACE inhibitors

Talha Burki

https://doi.org/10.1016/S0140-6736(18)31425-9

Treat the person not the scan

When learning clinical medicine, (junior) doctors can often show an over-reliance on blood tests and scans, rather than focussing on the patient and their holistic care. This can lead in turn to more intensive investigation, which is both costly and incurs extra risk, as well as in turn creating more ‘abnormal results’.

An important report has been published in pre-symptomatic Alzheimer’s this week, in the journal Lancet Neurology. The research team at the Salpêtrière Hospital in Paris studied over 300 older adults with subjective, but no objective, memory complaints. The participants completed detailed neuropsychological and cognitive assessment, structural and functional brain scans (MRI and PET), brain-wave tests (EEG), genetic testing and lumbar punctures. These tests were repeated every 6-12 months for over 2 years. They set out to see if they could identify particular markers that would identify who would develop prodromal Alzheimer’s. They separated their cohort into two groups: one with normal amyloid scans and one with evidence of amyloid build up in the brain. (Amyloid is one of two major abnormal proteins that are thought to cause this form of dementia)

With two years of follow up, only four individuals converted to prodromal Alzheimer’s. All four had some evidence of amyloid build up at the beginning of the study, although with such small numbers it is difficult to say this wasn’t due to chance. All four were also older than most (average age 80.2 years compared to 76.8 years), and ¾ had the genetic variant that confers the highest risk of Alzheimers, APOE-ε4, compared to 33/83 who were tested and didn’t progress. Importantly, evidence of amyloid in the brain did not seem to be a good discriminator for likelihood of progression from ‘the worried well’ to prodromal Alzheimers. In fact, the strongest findings from this study were that CSF and imaging markers of increased amyloid were associated with each other!

What does this mean for Parkinson’s? Firstly, we don’t have an equivalent brain scan, i.e. one that shows build up of α-synuclein with which to predict risk. Secondly, with these complex conditions one marker that doesn’t test the function of the individual will be hard pressed to be hugely predictive. Thirdly, one of the biggest limitations of this study is that the follow up was only 2 years. Given all these individuals had normal memory at the beginning, and most were highly educated, it is perhaps not suprising that so few converted to the prodromal stage.

This figure is worth considering as an alternative model of thinking about the earliest stages of Alzheimer’s and perhaps Parkinson’s

Two hypothetical models of the natural history of Alzheimer's disease

(A) Model 1 illustrates the dominant view of progressive deterioration: in Alzheimer's disease, cognition is progressively impaired from the preclinical phase (characterised by amyloid β deposition followed by tau pathology), to the prodromal clinical stage (with subtle cognitive changes), then the clinical stages of MCI and dementia. (B) Model 2 represents an alternative view of preclinical compensation that we have based on our data for brain β-amyloidosis. Cognition remains stable in the preclinical phase of the disease despite underlying brain lesions, until brain compensatory mechanisms are overwhelmed, leading to clinical disease. MCI=mild cognitive impairment. AD=Alzheimer's disease.

RNR

Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study.

Bruno Dubois et al

Lancet Neurology 2018, 17 (4), 335-346

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30029-2/fulltext?%7B$trackingTag%7D

BACKGROUND:Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease.

METHODS:The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid β deposition on18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and18F-FDG and18F-florbetapir PET every 24 months. We assessed associations of amyloid β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type.

FINDINGS:From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid β deposition and the remainder did not. The amyloid β subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β1-42concentration in CSF significantly correlated with mean18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β1-42to amyloid β1-40(r=-0·61, p<0·0001), and identified amyloid β deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid β deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]).

INTERPRETATION:Brain β-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent.

FUNDING:Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

On the road to nowhere

This week brings the publication of the (much-anticipated) EXPEDITION 3 study. This reports the results of a very large drug trial of a drug that is hoped to reduce the progression of Alzheimer’s disease. As you might be able to tell by the name, it has been preceded by two previous similar studies.

What is unique about this study? Firstly, the people involved all had ‘early’ Alzheimer’s disease. Secondly, participants had to have ‘evidence’ of Alzheimers pathology – this is key because in the previous studies although all the participants had dementia, a significant number ended up having dementia of another cause.

What are the other notable aspects of the design? The scales they used assessed ‘everyday’ performance (as best as a validated scale can), rather than an abstract cognitive assessment; the study compared cognitive performace after 18 months of treatment, which is a reasonable time given the tradeoff of the cost of a trial such as this, and the rate of progression of the disease.

What are the results? Unfortunately, there was no significant difference when comparing the two groups after 18 months.

There are many lessons for researchers in the Parkinson’s world to learn from this study. A potential reason for failure is that even at the stage of ‘mild’ dementia, there may be too much ‘toxic protein’ in the brain for the process to be reversed, or slowed. To overcome this would require recruiting people with evidence of the disease, but without symptoms. Fortunately, this is exactly whom we hope to identify in PREDICT-PD. Another potential reason for the failure of this drug in three trials is that with solenizumab, they’re barking up the wrong tree. The drug has been specifically designed to reduce the amount of abnormal amyloid protein in the brain. However, although there is strong evidence for the Amyloid Hypothesis, the lack of efficacy of anti-amyloid treatments has brought many in the field to challenge the concept. In Parkinson’s there is less doubt over the Synuclein Hypothesis, and the challenge remains to find a compound that can reduce it, or stop it accumulating and causing brain destruction.

RNR

http://www.nejm.org/doi/full/10.1056/NEJMoa1705971?query=BUL

Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

Abstract

BACKGROUND

Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.

METHODS

We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).

RESULTS

A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.

CONCLUSIONS

Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer’s disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)

Food for thought

The race is on, and waiting for the start gun is a loser’s strategy!

At least this is true in the race to beat neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s. Many studies to stop or slow these conditions have failed when they recruit people with established disease. By this point the disease-causing proteins (β-amyloid and tau in the case of Alzheimer’s and α-synuclein in the case of Parkinson’s) are too widespread for benefit to be noticeable. The best metaphor I’ve heard is that it is easier to blow out a match than put out a forest fire.

This week sees the open access publication of a nutritional supplement for prodromal Alzheimer’s disease. Participants were recruited if they fulfilled one of the internationally agreed definitions of Prodromal Alzheimers. To do this they needed some memory impairment that wasn’t severe enough to impact on their daily life, and some other evidence of underlying Alzheimer’s. This could be MRI, amyloid-specific PET scans or spinal fluid findings supportive of Alzheimer’s. Participants either drank a nutritional supplement, that has been designed to give large doses of micronutrients that theoretically counteract some of the damage caused by Alzheimers, or a similar tasting placebo drink. They had neuropsychological assessments at 6 months, 1 year and 2 years from the start.

Unfortunately, this study didn’t reach its primary endpoint of improved composite scores of the neuropsychological testing. However, it also had several secondary outcomes, and they did find that the people taking the supplement had a relative preservation of the hippocampal volume on MRI scans after 2 years compared to those taking placebo. The hippocampus is a brain structure that is central to memory, and is usually found to be shrunken in brain scans of people with Alzheimer’s.

So is this study the death knell for the supplement, especially after studies of its effects in people with established disease also failed to meet their primary target? Well, not necessarily. This study used ‘surrogate outcome measures’. The real question in disease preventing trials is: did the intervention prevent the disease? When dealing with a ‘prodromal’ or ‘prediagnostic’ condition, this might take many years. Clinical trials are incredibily expensive and labour intensive to run and so often use surrogate measures to shorten the duration of the study. This is akin to saying “I can run a mile in 5 minutes, therefore I can run a marathon in 2 hours 10 minutes.” This is misleading, as the two are not necessarily compatible enough to know that performance in one test is indicative of the other. Secondly, the fact that there was less shrinking of a key, and relevant, brain structure suggests that there might be some benefit. There are extension studies that are ongoing and data will be published when those are complete. We eagerly await their results.

As a final thought, this study lends strong support to our endeavours at PREDICT-PD, and those of others around the world. There is a strong desire to get a robust method of diagnosing Parkinson’s. This is not just an abstract academic exercise, but is of key concern to the public and pre-diagnostic states are being carefully examined by industry too. It is essential to bring together all three groups of stakeholders if we are to succeed in our fight against these neurodegenerative diseases.

RNR

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30332-0/fulltext

Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. The Lancet Neurology. 2017 Dec;16(12):965–75. 

BACKGROUND:Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial.

METHODS:LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705.

FINDINGS:Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was -0·028 (SD 0·453) in the active group and -0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI -0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of -0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention.

INTERPRETATION:The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.

FUNDING:European Commission 7th Framework Programme.