Parkyvist in the picture: Building upon Kevin McFarthing’s Hope list

Parkyvist in the picture*

Building upon Kevin McFarthing’s Hope list

10th of August 2020

When I was born into Parkinson’s it wasn’t long until I ran into an impressive ‘list of hope’ – bit.ly/ParkinsonsHopeList – gathered by Kevin McFarthing. Kevin’s Hope List has two main sections: research projects that are in the discovery and preclinical stages, and projects in the various phases of clinical trials. All with a focus on Parkinson’s disease.

The clinical trial section includes entries from Clinicaltrials.gov, manually gathered company planned trials, those already completed but waiting for the next steps to be announced, early trials yet to be registered, trials registered on other clinical trial registries, and some in the regulatory phase. And – importantly – the list of hope is free to be built upon!

Why did Kevin create the Hope List and what is he hoping for himself, 8 years after his diagnosis with Parkinson’s Disease? You can read all about it in the Q&A below. Below the interview, I try to make some of the hope speak to even more of my readers with some drawings and vizzes. This lengthy blog post will conclude with a plea on the importance of opening up data FAIRly (Three blogs for the price of one ;)).

Part 1. Where hope is born. A Q&A with Kevin

“If there isn’t a cure then where can I find one?” | Kevin McFarthing on why he started compiling his ‘Hope list’

Kevin McFarthing

Diagnosis: 2012
Nationality: British
Hoehn en Yahr-scale: 2
Short bio: Originally a biochemist, Dr. Kevin McFarthing spent most of his career leading R&D groups in life sciences (Amersham), diagnostics (Serono), and consumer health (Reckitt Benckiser). He now runs the Innovation Fixer consultancy. He was diagnosed with Parkinson’s in 2012 at the age of 55.
Activism: Kevin maintains the so-called ‘Parkinson’s Hope List’, is author/editor of clinical trial highlights in the Journal of Parkinson’s Disease, regularly presents his insights, and recently co-authored the paper ‘Parkinson’s disease drug therapies in the clinical trial pipeline: 2020’ (McFarthing et al, 2020).
Mostly troubled by: Slowness, increasing lack of facial expression, manual dexterity, and early signs of voice problems.

Who are you?

I was born and raised in the North East of England. I’m married with two children and two grandchildren. I have a PhD in Biochemistry from the University of Liverpool. After University I worked for a company making products for use in life sciences research. These products could best be described as molecular tools. I then became Head of R&D for the diagnostics division of a large pharma company, developing tests for a variety of biomarkers.

The next step in my career was at Reckitt Benckiser as Head of R&D for Health & Personal Care. RB is a Financial Times Stock Exchange 100 (FTSE) top 20, multi-national consumer goods company with a large business in consumer medicines. At the time RB also had a sizeable prescription-only product for the treatment of opioid use dependence.

I then became Global Head of Strategic Alliances for the whole business, working with existing partners and bringing new ones on board, especially at the “front end” of innovation. When I left RB, I set up a consultancy business, Innovation Fixer Ltd, helping clients improve the effectiveness and efficiency of innovation management.

So – a career in industrial science with a healthcare focus.

When and how were you diagnosed?

I was diagnosed at 4pm on Monday 10^th December 2012, a date I understandably remember well. I was 55 with no future view other than a long and healthy old age. The diagnosis was blunt, as was the accompanying advice – there’s no cure and come back in six months.

How have you changed since?

I’d like to think that I haven’t changed much since the diagnosis, but my family thinks I’m quieter than I used to be; I’m probably more reflective.

Why did you create the Hope List?

As soon as I was diagnosed I started to find out as much as I could about Parkinson’s. This included looking for therapies in the pipeline. It’s probably the same with a lot of newly-diagnosed PwP, “If there isn’t a cure then where can I find one?”

My research moved from a disorganised list in Evernote to an Excel spreadsheet which, to cut the story short, became the Parkinson’s Hope List. I shared the list with a few people who gave me positive feedback. I then started to circulate it more widely and now it’s freely accessible at bit.ly/ParkinsonsHopeList. There are now over 300 projects on the list all the way from discovery to regulatory submission.

How do you keep up to date and how much time does it cost you?

Once the Hope List had been built, it has been relatively straightforward to keep it maintained. I see a lot of information from a lot of sources, particularly Simon Stott’s excellent www.scienceofparkinsons.com, (on Twitter at @ScienceofPD), but also Parkinson’s News Today. Twitter, of course, is a great source of Parkinson’s news, with one account to highlight, @Ingentium_PD.

I release updates of the Hope List around every three months, and I give it a thorough “clean” about twice a year. This part takes quite a bit of time, trying to find out whether companies still exist and whether Parkinson’s is still a priority for them. Since I started releasing the list in 2017, over 130 projects have dropped off the list, of which only seven came off because they were launched or submitted for regulatory review.

If you look at the list, what makes you happy? And what is missing?

When I look at the list, I’m really impressed by the sheer numbers of projects – well over 300 – and the associated investment. The big gap is the lack of disease-modifying trials in the late stage, phase 3.

What is your take on disease-modifying trials? Why have so many failed in phase 3?

Disease-modifying trials (DMT) fail for several reasons: There is a lack of definable, biomarker-supported sub-types, which of course are an important reason why trials fail. But I think there are some more reasons. The UPDRS is unable to discriminate sufficiently well in longitudinal studies where there is an element of training and learning by patients. The placebo response can be very high. The placebo arm often doesn’t deteriorate very much, leaving too small a gap between placebo and active. The patient cohorts are either too wide (age 18-80, have PD) or too narrow (<60, drug-naive, need to stay off drugs). There are no validated biomarkers. It’s also not clear why all the spectacular phase 3 failures usually have a successful phase 2 trials behind them.

If you could change one thing, what would we be doing differently when it comes to clinical trials

I’d like to see less dependence on the UPDRS as the primary outcome measure.

What do you hope for yourself?

My symptoms have progressed relatively slowly, so I’d be very happy if something is found that stops that progression and, of course, the sooner the better. That would let me get on with the rest of my life focusing on life itself, not what gets in the way or might do so in the future.

What is your vision on patient-researcher collaboration?

I’ve engaged in a lot of patient-researcher collaboration and there are some superb scientists and clinicians engaging with informed, engaged and enthusiastic patients. Everybody benefits, from improved clinical trial protocols to the basic researcher who can say, when meeting a patient – “so that’s why my work is important”.

My vision for such collaboration is that both patients and researchers learn enough of the other’s language and experience to understand and empathise; to influence where it makes sense and to keep away when it doesn’t.

What would you main advice for the newly diagnosed be?

My advice for the newly-diagnosed has three Es:

Educate yourself about the condition and what you can do about it yourself.
Engage with Parkinson’s – it’s not going away any time soon so denial wastes valuable time.
Exercise – this is the only therapy so far proven to slow the progression. Have a mix of aerobic exercise that gets you hot and sweaty together with movement exercise that keeps you supple (always consult your doctor first).

I’d also advise the newly-diagnosed to be very careful about a lot of self-claimed “miracle workers” who claim to be able to reverse or cure Parkinson’s; or who propose magic supplements with no proof of safety or efficacy. They’ll not only take a lot of your money, but potentially damage your health. Again, always consult your doctor first.

Part 2. Hope, filtered, drawn and visualised

Kevin and co-authors have just published an article about a selection of hope: The ‘drug pipeline’ ((McFarthing et al, 2020). They analyse the 145 drug trials from Clinicaltrials.gov which are testing ‘drugs’ (or ‘pharmacological treatments’ in jargon) in order to “raise awareness of the clinical trial landscape in PD, both with researchers and the wider PD community”. Kevin has written a reflection on his Medium space.

My vision for patient-researcher collaboration is that both patients and researchers learn enough of the other’s language and experience to understand and empathise | Kevin McFarthing in this blogpost.

For patients and researchers to truly learn each other’s language – as Kevin envisions – lots of bridges still have to be built. Bridges that not only raise awareness of the drug pipeline out there but also truly enable both patients and researchers to feel confident enough to meet and interact halfway.

To begin crossing the bridge towards the expertise Kevin and his co-authors have myself, I have drawn the 14 ‘drug pipeline categories’ which Kevin and his co-authors discern. What are the agents under investigation? What is their intended mode of action? I hope that my drawings, short explanations, and visualisations that follow will also help some of you find the common language needed to confidently walk up to the authors and interact from your unique perspective.

Hope drawn in 14 drug categories

I. MECHANISM OF ACTION: Antioxidant (n=2)

In healthy cells, there is a balance between the production of highly reactive free radicals including reactive oxygens species (ROS) which may damage cells and the level of antioxidant which break ROS down. In the case of oxidative stress, ROS takes control and overpowers the antioxidant army. Oxidative stress is implicated in the pathogenesis of many diseases. Parkinson’s disease is one of them. Antioxidants which are being tested in PD clinical trials are Hydrogen and Deferiprone (an iron-chelator).

II. AGENTS: Botanical (n=4)

In this category, the authors categorised agents derived from herbal extracts where the mechanism of action is unknown or unclear. E.g. think of a trial investigating the effect of lingzhi (a mushroom extract) on untreated early Parkinson’s Disease. Also, trials investigating botanical mixtures of unknown origin (such as DA-9805) are on its way.

This category includes trials that focus on either intracerebral cell transplantation or peripheral delivery of cells. The first category concerns the direct replacement of lost neurons in the cerebrum, which is the upper part of the brain. Furthermore, methods differ in the types of stem cells which are the source of the to-be-replaced-neurons. Sources include adult stem cells (undifferentiated cells found living within specific differentiated tissues in our bodies that can renew themselves), embryonic stem cells and induced pluripotent stem cells that are created in the laboratory.

dopaminergic_ccby_sparks4pdvclinicaltrials

IV. MECHANISM OF ACTION: Dopaminergic symptom relief (n=34)

Trials in this category focus on either restoring, replacing, or mimicking the neurotransmitter dopamine. Examples of the focus of trials in this category are e.g. variation in the delivery dose and testing substances that prolong the effect of medication (e.g. subcutaneous administration of levodopa and carbidopa).
The authors also categorise a trial investigating AADC gene therapy under this category. The AADC enzyme – which is coded for by the AADC gene – is responsible for the final step in the synthesis of some key neurotransmitters such as dopamine. Gene therapy in this context aims to restore the ability to make dopamine in the striatum of the brain, rather than receive it from the substance nigra.

Impairment of energy management in mitochondria is thought to play a role in the development of Parkinson’s disease. Trials in this category aim to investigate and ultimately restore mitochondrial function. Examples include the administration of gold nanocrystals to influence the NAD metabolism in mitochondria and the administration of ursodeoxycholic acid (UDCA) to increase the ATP levels in the brain. The ratio of NAD+ to NADH – two forms of nicotinamide adenine dinucleotide – dictates how effectively the cell can produce ATP. ATP – adenosine triphosphate – is the transporter of chemical energy within cells.

VI. MECHANISM OF ACTION: GBA (n=4)

This category is applied to agents that enhance the activity of glucocerebrosidase (GCase). GCase is an enzyme that helps digest the waste in the lysosomes of our cells. Mutations in GBA1, which codes for GCase, are a risk factor for the development of Parkinson’s. Genetic variations outside of the GBA gene can also influence GCase protein levels (Schierding, 2020).
In clinical trials, compounds with exotic names such as GZ/SAR402671 are tested in people with Parkinson’s with a known GBA mutation. Ambroxol is being trialed in two places pursuing two different purposes: disease modification and as a treatment for Parkinson’s disease dementia.

VII. MECHANISM OF ACTION: GLP-1 agonist (n=6)

Glucagon-like peptide 1 (GLP-1) agonists are drugs that stimulate the GLP-1 receptor. Such drugs are currently used in the treatment of type 2 diabetes. Parkinson’s disease and type 2 diabetes share common pathophysiological mechanisms. GLP-1 receptors are not only present in the pancreas but also in several parts of the brain. GLP-1 agonists can cross the blood-brain barrier and stimulate such GLP-1 brain receptors, supposedly providing neuroprotection in several different ways (Foltynie, 2016). Trials are underway investigating e.g. the safety and efficacy of liraglutide and the effect of lixisenatide and two trials with exenatide: one at the University of Florida (phase 2) and one at the University College in London (phase 3).

Immunotherapy trials could have been allocated to “targeting alpha-synuclein” but the authors felt this mechanism of action deserved its own category. The primary goal of immunotherapy drugs in this category is to artificially alter our immune system to let it ‘attack’ alpha-synuclein in order to disrupt the formation of alpha-synuclein aggregates. (Chatterjee, 2019). Alpha-synuclein is a protein of 140-amino acids expressed abundantly in the brain.
This category includes trials with codes attached that show the origin of the company behind the trial (e.g. ABBV-0805, BIIB054). Another example is prasinezumab.

IX. MECHANISM OF ACTION: Kinase inhibitor (n=4)

Protein kinases catalyse protein phosphorylation, one of the major mechanisms that regulates cellular activities. (Mehdi, 2016). Kinase inhibitors represent a broad category encompassing agents blocking specific kinase activity. E.g. mutations in the LRRK2 gene – coding for Leucine-Rich Repeat Kinase – lead to overexpression which is implicated in the pathogenesis of Parkinson’s Disease. Some examples: An LRRK2 inhibitor is being tested in a clinical trial. Another kinase inhibitor is inhibiting c-Abl tyrosine kinase. c-Abl tyrosine kinase activation leads to oxidative stress and is associated with many neurodegenerative diseases.

X. TARGET: Microbiome/Gastrointestinal system (n=6)

Microbiome/GIT concerns a category of agents specifically targeting the gastrointestinal system. E.g. think of a trial in which rifaximin – a broad-spectrum oral antibiotic – is being tested (MICRO-PD), one in which fecal microbiota transplantation (a technique in which intestinal microbiota are transferred from a healthy donor to the patient) and a trial that aims to treat anxiety in Parkinson’s Disease with a multistrain probiotic.

XI. MECHANISM OF ACTION: Neurotrophic factors (n=3)

Neurotrophic literally means ‘growing neurons’. Biomolecules labeled as neurotrophic factors support the growth, survival, and differentiation of both developing and mature neurons. This category has attracted a lot of hope from the Parkinson’s community. A BBC documentary was made about the GNDF (Glial cell line-derived neurotrophic factor) trial. This trial was catalysed by a great Parkinson’s advocate, the late Tom Isaacs. Currently, two trials are looking into gene therapy for Glial cell line-derived neurotrophic factor (GDNF) and one into Cerebral Dopamine Neurotrophic Factor (CDNF).

XII. MECHANISM OF ACTION: Non-dopaminergic symptom relief (n=41)

Neurodegeneration in patients with Parkinson’s disease is not limited to the substantia nigra where dopamine is produced. Other areas of the brain are also affected to a greater or lesser extent. Non-dopaminergic symptom relief concerns trials investigating the impact on neurotransmitters, other than dopamine, including (nor)adrenergic, serotonergic, glutamatergic, and cholinergic systems. Which is an as broad category as it sounds 🙂 Apart from motor symptoms this category also addresses autonomic dysfunction, neuropsychiatric symptoms, and systemic symptoms such as pain and fatigue. Examples include a trial with clonidine, an adrenergic receptor agonist, to treat impulse control disorder, and a trial with droxidopa for fatigue. Droxidopa is a precursor to the neurotransmitter noradrenaline.

The ‘other’ category consists of trials that the authors didn’t give a category of their own. Trials range from using Xenon for the treatment of anxiety and pain in PD, the effect of blood plasma transfusions on neurological symptoms, the effect of carvedilol on cardiac symptoms in early PD to studying the effect of terazosin which supposedly can block cell death. And 12 more trials with different mechanisms of action and agents : )

XIV. TARGET: aSN (n =5)

aSN is short for alpha-synuclein, a protein of 140-amino acids expressed abundantly in the brain. Five trials are using small molecules to target a-synuclein, e.g. mannitol and memantine. Mannitol supposedly is an aggregation inhibitor of aSN, which is taken to be good news since the aggregation of aSN supposedly contributes to pathogenesis*. Memantine is a partial NMDA (N-methyl-d-aspartate receptor) receptor antagonist which means that it fits in the receptor and partly deactivates it supposedly preventing alpha-synuclein accumulation at the same time. Abnormal expressions of both alpha-synuclein and N-methyl-d-aspartate (NMDA) receptors are observed in Parkinson’s.

* Whether through a loss-of-function (LOF) of the native protein and/or a toxic gain-of-function (GOF) and/or something else altogether is a current topic of debate that even made it to the book Brain Fables.

Hope visualised

I have played around with the ‘drug pipeline’ data and made some vizzes. Below each of the 145 trials is assigned to one of the 14 drug categories just described. The colours in the circles give additional information about the purpose of the drug. You can interact with the visualisation, e.g. by making a selection of the data you want to see (just not so easy on a mobile phone though).

DMT stands for disease-modifying therapies. These are drugs that are being tested in the hope they will be able to alter the course of Parkinson’s. The others are symptomatic treatments divided by the type of symptom which is addressed. Symptomatic treatments don’t change the course of the disease but do (temporarily) mask the ongoing neurodegenerative process by reducing the symptom burden.

Below you can find a few more vizzes. They were made with Tableau Public which is free for all to download and explore if you’d like to give it a try yourself (Or better even: try an open source data visualisation programme while you are at it).