Hope fatigue: will there ever be a cure?

Saturday 1 February 2020

At the start of 2020 there was a flurry of posts on various Parkinson’s forums about all the promising research and clinical trials in progress, not to mention a few puns around “20/20 vision”.

Rather than repeat it all here (and probably get some of it wrong), I would refer you instead to The Science of Parkinson’s take on the topic, The Road Ahead: 2020. It’s a long article so I’ve attempted to summarise the drug trials referenced at the bottom of this post.

Wow. There are a lot of candidate treatments currently being tested, and many threads of more fundamental research also in progress. But we’ve been down this road before.

One thing that Dr Simon Stott alludes to in his post is the idea of “hope fatigue”. Despite the long list of therapies currently in clinical trials, the sobering reality is that the underlying cause of Parkinson’s is not understood, the different types of Parkinson’s are not fully identified or understood and there have been no significant new drugs since the discovery of levodopa and the dopamine agonists in the 1960s. In the last 50 years or so, there have been numerous headlines about promising new medicines that have all come, essentially, to nothing. For long sufferers of the disease, hope fatigue is a very real phenomenon.

Of course, eventually there will be a cure, or at least treatments to improve life with the disease. The human race is too smart, and the collective effort being put into neurodegenerative diseases too great, for us not to figure something out.

The real question is when? Will there be a cure, for example, in my lifetime?

Crystal ball gazing is a hazardous pursuit, but let’s see what the data tells us.

Firstly, let’s look at the amount of Parkinson’s research. A count of research papers on PubMed with the tag “Parkinson’s” reveals that the number of papers published has quadrupled over the last twenty years.




Compared to other neurological conditions, Parkinson’s doesn’t do too badly in terms of the amount of research published. But it is dwarfed by research into conditions like diabetes and the work across different types of cancer or even HIV.

What about funding for research? We would expect this to be correlated with the number of papers published.

After gradual reductions in real terms over recent years of the amount that governments in, for example the UK and the US, have been setting aside for research across all the medical sciences, is on the increase. For example, the United States Congress recently passed its budget for Fiscal Year 2020 which included a $2.6 billion increase for the National Institutes of Health (NIH), bringing the agency’s budget up to $41.46 billion.

However, Parkinson’s only gets a tiny slice of the government research funding pie. More significant is private funding for research. The biggest source for this is the Michael J Fox Foundation. Their annual contribution to Parkinson’s research has increased by 42% over the five years since 2014 (watch out for the slightly misleading scale on the graph). This increase in funding is consistent with the increase in the amount of research output that we saw earlier.

In summary, the amount of research into Parkinson’s is high compared to other neurological conditions and has been consistently growing over recent years, but it is still small compared to many other medical conditions.

Does it deserve more funding? Given the number of people affected, maybe. But in the majority of cases, people can still have a reasonable life for quite a few years with Parkinson’s and it’s a very different story for most types of cancer for example. Or Alzheimer’s for that matter.

What can we learn from other conditions?

AIDS/HIV is essentially resolved from a medical perspective though the antiretroviral drugs used to treat it remain too expensive for many. The total global spend between 2000 and 2015 on the disease was an astonishing $562 billion according to the Institute for Health Metrics and Evaluation (IHME) at the University of Washington. Yes, that’s half a trillion dollars. More than the annual GDP of Thailand with its population of 70 million.

Similarly, research spending on cancer, which has made great progress in the last couple of decades, runs into tens of billions of dollars per year.

The lesson is clear: finding cures for tricky medical conditions requires a lot of funding, way more than Parkinson’s or Alzheimer’s currently receive. We’ll get there in the end but at current levels of investment it will take time.

So, as I gaze very speculatively into my crystal ball, what I see is:

  1. An ageing population and more people being diagnosed with Parkinson’s every year
  2. Steadily increasing research funding from governments and private organisations, and a corresponding increase in research output, but at an absolute level lower than many other conditions
  3. Over the next 10 years, the approval of some drugs that slow progression of the disease for some people
  4. Over 10-20 years, an understanding of the underlying cause(s) of some variants, and perhaps treatments that can restore missing neurons, thereby reversing the disease
  5. Over 20-40 years, science starts winning the war, systematically understanding the different variations of Parkinson’s, developing reliable screening for risk factors, and finally finding a cure (or set of cures)

Where does that leave hope?

Given these assumptions, I don’t follow every research thread or get excited at every news headline. But it’s not really a case of hope fatigue. For myself I don’t expect to be cured (and would be pleasantly surprised if this did happen). But I have every hope – indeed expectation – that the next generation won’t have to suffer from the disease that James Parkinson first described 203 years ago.



Table of current trials

Target
Drug under development or in clinical trials
Companies/ parties involved
Alpha synuclein immunotherapy
(attacking the build up of alpha synuclein using either the brain’s own antibodies or artificial ones)
Prasinezumab Roche, Prothena Biosciences
BIIB054 Biogen, SPARC
MEDI131 AstraZeneca
Lu AF82422 Lundbeck, Genmab
BAN0805/ABBV-0805 AbbVie, BioArctic Neuroscience
AFFITOPE PD01A AFFiRiS
UB-312 United Neuroscience
NPT088 Proclara Biosciences
NPT520-34 NeuroPore Therapies
NPT200-11 UCB
ENT-01 Enterin
YTX-7739 Yumanity
Mannitol Clinicrowd
Anle138b MODAG
LRRK2 inhibitors (for people with a PD-inducing mutation in the LRRK2 gene) DNL-201 Denali Therapeutics
BIIB094 Biogen, Ionis Pharmaceuticals
PINK1 and PARKIN inhibitors TBA Mitokinin
TBA Vincere
iCP-Parkin Cellivery
GBA therapies Ambroxol Cure Parkinson’s Trust, Van Andel Institute
Venglustat Sanofi Genzyme
LTI-291 Lysosomal Therapeutics
TBA Prevail Therapeutics
AVR-RD-02 AVROBIO
ESB1609 E-scape Bio
S-181 Surmount Bio
c-Abi and TORC1 inhibitors (boosting the body’s natural autophagy mechanism) Nilotinib Georgetown University
K0706 SPARC
FB-101 1ST Biotherapeutics, Neuraly
Radotinib Il-Yang Pharmaceutical
IkT-148009 Inhibikase Therapeutic
RTB101 resTORbio
NLRP3 inhibitors and other anti-inflammatories Inzomelid Inflazome
NT-0167 NodThera
Azathioprine Cambridge University
XPro1595 INmune Bio
Sargramostim Parkinson’s Nebraska
GLP-1R agonists (protecting further neurons from dying) Exenatide
Lixisenatide
Liraglutide
Semaglutide Novo Nordisk
NLY01 Neuraly
PT320 Peptron
Neurotrophic factors (growth hormones for neurons) GDNF Cure Parkinson’s Trust, Brain Neurotherapy Bio, Genecode
CDNF Herantis
Mitochondria boosters UDCA University of Minnesota
CNM-Au8 Clene Nonomedicine
Terazosin
EPI-589 BioElectron
CuATSM Collaborative Medicinal Development
Nicotinamide Riboside
AMX0035 Amylyx
Statins (for neuroprotection) Lovastatin
Simvastatin PD-STAT
Iron reduction Defeiprone Apopharm
PBT434 Alterity Therapeutics
Plasma infusion GRF6021 Alkahest
Other neuroprotection Lingzhi
Ceftriaxone
KM-819 Kainos Medicine
DA-9085 Dong-A ST
ANAVEX2-73 Anavex
Cell transplantation N/A Transeuro
N/A International Stem Cell Corporation
N/A Center for iPS Cell Research and Application
N/A BlueRock Therapeutics
N/A Aspen Neuroscience

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