Is the horizon getting closer ?

Week after week we talk about the need for a disease modifying drug in Parkinson’s, and week after week we hope to reassure you, dear reader, (as well as ourselves) that this Holy Grail is getting ever closer. 

This week marks the publication of a study that may mark a turning point in this journey. Prothena Pharmeceuticals have run a study looking at the safety and tolerability of a new compound (excitingly called PRX002/RG7935). This is a compound that sticks to the toxic protein that is understood to cause the brain cell loss in Parkinson’s – α-synuclein. Once it sticks to this substance, it ‘flags’ the body’s immune system to come and clear up the mess. This, we think, reduces the amount of the α-synuclein that is floating around and causing damage. 

In this study 80 participants with mild-moderate Parkinson’s were given one of six different doses of this medicine or salt-water (placebo) through a ‘drip’. They attended once a month and the infusion lasted 1-2 hours. Neither the participants nor the investigators knew how much (if any) of the drug they were getting. They received three infusions in total.

I must stress that this study wasn’t designed to see if this did anything at all for their Parkinson’s. The study was too small, and too short for any changes to be detected. The primary purpose of this study was to evalute whether the medicine was safe and tolderable, with secondary objectives of studying what happens to the drug when it is in the body.

Overall, of the 55 participants that had any strength of the medicine, 50 completed the study, and 5 did not manage all 24 weeks of the study. 1 stopped because their Parkinson’s worsened, 1 decided to withdraw (reason not stated), 2 (both in the highest dose group) stopped because of side effects, and 1 also in the highest group withdrew. I also note that 3 out of 25 getting placebo also withdrew.

This study is a vital step. After extensive laboratory testing, a compound like this will be given to a very small number of totally healthy volunteers to ensure it is safe in humans. Then it will be given to a small number of volunteers with the condition to make sure it is safe in the ‘target’ population and to determine a range of safe doses, which is this study. Then it will be given to a moderately large sample to see if there are any suggestions of positive effects and to refine the ideal dose, and finally it will undergo a large study of affected individuals where the investigators (and cruicially the funders) hope to find that it has a true benefit.

All the participants in this study had had Parkinson’s for around 3 years (although this was as much as 15 years) and was moderately advanced. We hope that in future studies, the investigators take people with the earliest possible disease duration and learn lessions from the Alzheimer’s journey. 

This compound has been being studied in the earliest stages of the research process for around 10 years. The next stage of the path for this compound, the PASADENA trial, started almost exactly 1 year ago, and will be running until February 2021. I would expect results to come out towards the end of 2021, and then (hopefully) a phase 3 study will start which will take several more years to run and analyse. If all these steps are successful, we may be in a position to prescribe this medication in around 7-10 years from now.

RNR

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.

JAMA Neurol. Published online June 18, 2018. doi:10.1001/jamaneurol.2018.1487

Joseph Jankovic, MD; Ira Goodman, MD; Beth Safirstein, MD; Tonya K. Marmon, DrPH; Dale B. Schenk, PhD; Martin Koller, MD, MPH; Wagner Zago, PhD; Daniel K. Ness, DVM, PhD; Sue G. Griffith, MD, PhD, MRCP; Michael Grundman, MD, MPH; Jay Soto, BS; Susanne Ostrowitzki, MD, PhD;Frank G. Boess, PhD; Meret Martin-Facklam, PhD; Joseph F. Quinn, MD; Stuart H. Isaacson, MD; Omid Omidvar, MD; Aaron Ellenbogen, DO;Gene G. Kinney, PhD

Importance:Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression.

Objective:To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD.

Design, Setting, and Participants:Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3).

Interventions:Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period.

Main Outcomes and Measures:Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life.

Results:Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.

Conclusions and Relevance:Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149).

Trial Registration:ClinicalTrials.gov Identifier: NCT02157714.

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

Plain English - Type 2 diabetes linked to higher rate of Parkinson’s

Some of you may have already seen in the newspapers details of our recent study on the link between Type 2 Diabetes and Parkinson's disease... 

In our study, we used the Hospital Episode Statistics database and looked at a very large number of people (2,017,115) with a type 2 diabetes diagnosis during a hospital admission from 1999-2011, excluding people who already had a Parkinson’s diagnosis. We compared them to a group of over 6 million people from the same database without type 2 diabetes. Among the people with diabetes, 14,252 had a diagnosis of Parkinson’s during a later hospital admission, compared with 20,878 in the comparison group. After excluding people with some similar conditions, and controlling for age, sex and region of residence, we found that people with type 2 diabetes were 32 per cent more likely to have a subsequent diagnosis of Parkinson’s. The link was strongest among younger people (aged 25-44), and people with more complications from their diabetes.

Over the years, this link has proved less of a challenge to study and more of a challenge to interpret. For example, whilst most studies done on this subject suggest some sort of link between diabetes and risk of Parkinson's, the curious fact is that some suggest an increased risk of Parkinson's in those with diabetes, and some studies suggest a decreased risk. The difference may be accounted for by the design of the individual studies and requires further exploration. Our study adds to the literature and increases confidence that the association is such that type 2 diabetes increases risk, but whether this is due to common underlying mechanisms of disease or a true causal link between the two remains to be seen.

What is true, is that diabetes drugs may help treat Parkinson's, and we have already seen a great example of this in the last year. Exenetide appears to have a benefit on the symptoms of Parkinson's and furthermore may alter the underlying disease process. But before we can say that definitively, we need further studies.

- Alastair Noyce

Neurology
Eduardo De Pablo-Fernandez, Raph Goldacre, Julia Pakpoor, Alastair J. Noyce, Thomas T. Warner First published June 13, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005771

http://n.neurology.org/content/early/2018/06/13/WNL.0000000000005771

Objective
To investigate the association between type 2 diabetes mellitus (T2DM) and subsequent Parkinson disease (PD). 

Methods
Linked English national Hospital Episode Statistics and mortality data (1999–2011) were used to conduct a retrospective cohort study. A cohort of individuals admitted for hospital care with a coded diagnosis of T2DM was constructed, and compared to a reference cohort. Subsequent PD risk was estimated using Cox regression models. Individuals with a coded diagnosis of cerebrovascular disease, vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus were excluded from the analysis.

Results
A total of 2,017,115 individuals entered the T2DM cohort and 6,173,208 entered the reference cohort. There were significantly elevated rates of PD following T2DM (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.29–1.35; p < 0.001). The relative increase was greater in those with complicated T2DM (HR 1.49, 95% CI 1.42–1.56) and when comparing younger individuals (HR 3.81, 95% CI 2.84–5.11 in age group 25–44 years).

Conclusions
We report an increased rate of subsequent PD following T2DM in this large cohort study. These findings may reflect shared genetic predisposition and/or disrupted shared pathogenic pathways with potential clinical and therapeutic implications.