The Importance of being Picky

This week the UCL Institute of Neurology who ran the randomised trial of the diabetes drug, Exenatide as a disease modifying treatment for Parkinson’s, have published a paper looking at particular groups who may benefit more from the treatment. 

The tenet of clinical trials is that you specify who can enter the trial, and you give one group the intervention (in this case drug) of interest, and you give another group something else (in this case placebo), and see which does better against a pre-specified list of measures. This implies a ‘winner-takes-all’ outcome that is beyond reproach. Either the new drug did better than no drug, or it didn’t – end of discussion. 

This approach is important. New drugs are met with excitement, clinicians want it to work, scientists have often spent years suggesting that it will, and patients are desperate for it to work. Therefore rigid and robust tests with a categorical ‘winner’ help to provide an unbiased outcome.

However, the disadvantage is that the baby can get thrown out with the bathwater. The randomised clinical trial, when done well is a robust and unbiased tool for making a judgement. However, it is not ‘perfect’. No matter how good the design of the study, there will be flaws and biases that are both explicit and hidden, and there is always the issue of ‘generalisability’ – how well the recruited volunteers represent the patient in clinic.

The UCL team have continued to look at the data. For a future trial, are there some people that are likely to do better from this treatment, and are the some people that will never respond. This is key and at the heart of this endeavour is the understanding that a ‘One-size-fits-all’ approach in Parkinson’s will never work.

As Exenatide, and other compounds, are proven to be safe for people with Parkinson’s, great care will need to be taken to ensure that the right people are chosen for trials of effectiveness. This will entail careful analysis and subgroup analyses of early studies.

In this analysis, it seems that people with a shorter duration of disease and less impact of disease (in other words, milder disease) may get more benefit from Exenatide. This fits closely with the hypothesis that lies at the heart of PREDICT-PD: very early identification of Parkinson’s will allow effective disease modification that may be enough to proactively prevent the onset of motor symptoms.

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onlinelibrary.wiley.com/doi/pdf/10.1111/ejn.14096

Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Aviles-Olmos I, et al. Post hoc analysis of the Exenatide-PD trial - factors that predict response. Eur J Neurosci. 2018 Aug 2.

Exenatide, a glucagon-like peptide-1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinson's disease in a randomised, placebo-controlled trial. Additionally, there were trends favouring the exenatide group in assessments of non-motor symptoms, cognition and quality of life. The aim of this exploratory post-hoc analysis was to generate new hypotheses regarding (1) whether candidate baseline factors might predict the magnitude of response to exenatide and (2) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multivariate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, non-motor symptoms, cognition and quality of life after 48-weeks treatment with exenatide were evaluated among post-hoc subgroups defined by age, motor phenotype, disease duration, disease severity, BMI and insulin resistance. In the subgroup analyses, exenatide once-weekly was associated with broadly improved outcome measures assessing motor severity, non-motor symptoms, cognition and quality of life across all subgroups, however tremor-dominant phenotype and lower MDS-UPDRS Part-2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once-weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of GLP-1 receptor agonists in PD. This article is protected by copyright. All rights reserved.

Remedies from the natural world

An article caught my eye this week as several comments received on this blog and in clinic relate to ‘natural’ remedies for Parkinson’s. To provide some background, my therapeutic philosophy is a common one: I will only prescribe or endorse treatments that have gone through robust, unbiased, reproducible testing, and where the benefits outweight the risks. I also believe that there are undoubtedly treatments that have the power to radically alter diseases that are under our noses in the natural world, and once they are identified, purified and tested, will revolutionise medicine. Exenatide is a perfect example: originally derived from the saliva of the Gila monster, this is now a powerful drug against diabetes and may even have the ability to halt or slow Parkinson’s. 

This article looks at whether blackberry juice can reduce levodopa-induced dyskinesia. The first thing to point out was that they didn’t test it in humans with Parkinson’s disease, this experiment involved the MPTP mouse model of Parkinson’s. Mice were given the same amount of levodopa and then different groups were given increasing doses of blackberry juice. The good news is that there was some benefit on the extra movements associated with ‘dopamine overdose’. However, this was mainly seen in the 15mL/kg group. To put this into a human context (assuming that it works as well in humans with Parkinson’s as mice with MPTP induced parkinsonism, which is a very  big assumption, a human would have to drink over a litre of pure blackberry juice per day to have less dyskinesia. 

Science is a journey of increments. These positive results may yield a useful weapon for people with Parkinson’s, but plenty of work needs to be done. I highly recommend blackberries, especially ones forraged on a nice walk in the woods, but I wouldn’t suggest they’re going to make your Parkinson’s better just yet.

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Effects of blackberry (Morus nigra) fruit juice on levodopa-induced dyskinesia in a mice model of Parkinson's disease.

Fahimi Z¹, Jahromy MH¹.

J Exp Pharmacol. 2018 Jul 4;10:29-35. doi: 10.2147/JEP.S161782. eCollection 2018.

Abstract

BACKGROUND AND OBJECTIVE: 

Levodopa-induced dyskinesia (LID) is a movement disorder that occurs due to levodopa consumption for a long period to attenuate Parkinsonism. Plants have been the basis for medical treatments in human history and still widely practiced. Blackberry (Morus nigra) is one of the fruits rich in anthocyanin. The present study examined the effect of blackberry fruit juice on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice.

MATERIALS AND METHODS: 

In this study, 42 male mice were used, which were divided into six groups equally: one control group and five groups receiving MPTP injection. After confirmation of Parkinsonism in MPTP groups, one group was preserved without treatment and four other groups were treated with levodopa (50 mg/kg ip). After the onset of LID (2 weeks), one group was kept without additional treatment and three other groups were treated with three different doses of blackberry fruit juice (5, 10, and 15 mL/kg) with levodopa orally for 7 days. Abnormal involuntary movement scale (AIMS) and cylinder behavioral test were carried out according to the schedule. The collected data were analyzed using the SPSS software with the significant level of P<0.05.

RESULTS: 

Parkinson's disease was confirmed with AIMS test on the fourth day after MPTP injection. The onset of LID was observed after 2 weeks of levodopa treatment using both behavioral tests. The result of administration of M. nigra fruit juice for 1 week showed that this addition is useful in hindering LID. These effects were more pronounced at doses 10 and 15 mL/kg with nearly the same results on attenuating AIMS. Low dose of the fruit juice does not seem to affect LID significantly.

CONCLUSION: 

M. nigra fruit juice is effective to attenuate LID in an MPTP-induced Parkinson mice model.

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.

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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.)

Comparing apples and apples

Drug trials (or trials of any new treatment for that matter) are designed by comparing a group on the new treatment against a group on something else. That may be no treatment, the best available treatment, or placebo (or dummy treatment). In order to make a fair comparison, it is essential to compare like with like.

An extreme example of this would be to say that “men are faster than women”, having compared the Jamaican mens olympic sprint team, against a selection of girls from the local secondary school. This is obviously ridiculous in so many ways: adult men vs teenage girls, trained atheletes vs untrained and so on…

In studies of Parkinson’s, it is also important that we compare like with like. For the past 50 years, researchers have used the “Hoehn and Yahr Scale” to create standardised definitions. (The scale is named after Margaret Hoehn and Melvin Yahr who pioneered research into progression and epidemiology of Parkinson’s in the 1960s.) Designed to give researchers a simple and global assessment of disease severity, this is probably the most widely used Parkinson’s staging system in use. According to the latest version of this scale there are 6 stages from 0= Asymptomatic to 5 = wheelchair bound or bedridden unless unaided.

Despite its widespread use, until now there have been no systematic attempts to prove how useful and reproducible it is. The researchers in this study assessed the acceptability, reproducibility, content and validity of the scale. They compared how different raters scored people (known as inter-rater reliability), and how that compared with other scoring systems of stiffness, tremor and other features of Parkinson’s. They also looked at whether the same assessor gave the same patient the same score at different times (known as test-retest reliability).

The good news is that inter-rater reliability and test-retest reliability are incredibly high. In other words, if one clinician judges a person to have stage II, so will almost every other (trained) clinician. It also correlated quite well with other physical assessment scores.

As ever, it is not a perfect test. The difference between stages is not the same (in other words, going from I to II is not the same as going from III-IV). Nor does it correlate at all well with quality of life. It also does not take into account non-motor features of Parkinson’s. Furthermore, only 2.9% of more than 3000 participants were at the most advanced stage V, so may not be quite as reliable for these people.

In summary, we have a pretty good measure of giving a number to the amount that an individual is affected by Parkinson’s. Until we have a blood test/scan/marker of progression, this is the best we have, and we need to make sure we have ways of addressing its weaknesses. Using it we can compare like with like, and, hopefully, get ever closer to preventing people advancing through the scale.

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http://onlinelibrary.wiley.com/doi/10.1002/mds.27242/abstract;jsessionid=A596451DCF79B33BF34C1802EFD6E2CF.f04t03

Martinez-Martin P, Skorvanek M, Rojo-Abuin JM, Gregova Z, Stebbins GT, Goetz CG, et al. Validation study of the hoehn and yahr scale included in the MDS-UPDRS. Mov Disord. 2018 Jan 11;17:427.