2021: Wish list

# # # # Here at the Science of Parkinson’s, we don’t like making predictions – that’s a fool’s game. We would rather focus our attention on interesting ideas and trends, discussing what we hope to see happen in the future, and exploring different ways and means by which change could occur. It is done in the hope that someone will pick up the ball and run with it (ideally, they already have the ball!). In today’s post, we will outline the SoPD wish list for 2021.  # # # #

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My parents recently took my young neice and nephew to the Pūkorokoro Miranda Shorebird Centre, just south of Auckland city in New Zealand. There, the kids were introduced to Bar-tailed Godwits – a long-billed, long-legged wading bird.

Bar-tailed godwit. Source: Wikipedia

To look at them, there is nothing very remarkable about Godwits… that is, of course, until you look at how far they migrate each year.

You see, Godwits have a rather busy calendar, with a lot of their time being spent racking up air miles.

These little bird fly from Alaska to New Zealand and back (via either China) every year!

Source: Wingthreads

The round-trip is over 29,000 km (or 18,000 miles), and the journey across the Pacific Ocean from Alaska to New Zealand is the longest non-stop flight of any bird in the world (in fact, it is the longest trip made without pausing for food by any animal – Source).

My nephew is 8 and my neice is 10.

They were rather “meh” about the birds, and somewhat more impressed by the ice cream that they got for the ride home.

Source: Morellisices

I on the otherhand was fascinated with these little birds when my mum was telling me about their day out. So many questions were popping into my head (like the obvious “what possesses them to fly that far?!?” and “how on Earth do they know where they are going in the middle of the Pacific ocean?!?“). But I was equally impressed by how much they could accomplish in the span of a 12 month period (I mean: 30,000 km!!!).

And naturally that got me thinking about the annual “Wish list” post for the SoPD website, which discusses what I am hoping to see from Parkinson’s research over the next 12 months (beyond the obvious curative therapies).

In today’s post, we discuss our wish list for Parkinson’s research in 2021.

WISH #1:  A failure to communicate

When a virus infects a cell, it will busily start try to replicate itself. And as it does this, there is a pretty good chance that it will mutate as copies of the virus are made. Tiny little alterations will randomly be applied to its genetic make up (DNA or RNA), and if they don’t mess up the replication process, those changes will be carried forward in future versions of the virus.

Source: Elife

This is how all organisms evolve over time – a genetic process of iterative change. But given the rapid speed of viral replication, these particular variations can quickly add up. The genetic changes are extremely subtle and individually do not radically change the nature or appearance of the virus. But given the rapidity of viral turnover, these alterations can build up and in some cases have important consequences when a society is trying to develop carefully designed vaccines against that virus. Variants of a virus may be able to evade a vaccine that has taken enormous time and resources to produce, and go on to mutate further.

Source: Forbes

Given this circumstance (the risk of new variants), it makes good sense that Government organisations and a sensible society would do everything in their power to make sure that this type of message is communicated and hammered home to prevent unnecessary hardship..

Over the last 12 months, I have been in awe of the extreme efforts of some corners of our international community to confront and deal with the COVID-19 pandemic (the frontline workers and vaccine programmes deserve our eternal gratitude). But equally I have been utterly horrified by:

1. the complete lack of clear communication from parties in positions of authority, and
2. the misdirection that has resulted from our over-reliance on artificial intelligence algorithms in company search engines.

My point here is: Communication is important.

Mixed messaging from those who lead is a recipe for disaster. I appreciate that a pandemic is a rapidly evolving situation, with information changing on a regular basis. But all too often over the last 12 months, the communication of clear, prudent information has been trumped by political and economic agendas.

Source: Icon

And while I am all for free speech (as long as it doesn’t cause hardship), I worry deeply about the influence that artificial intelligence algorithms are having on our society. I appreciate the complications of determining what ‘truth’ is and limitless thirst for information on the internet, but the current batch of search engine algorithms care nothing about the information being communicated and only appear to want to send us tumbling down a “rabbit hole”, where they can sustain us with targeted advertising.

Source: Memearsenal

And this does not just apply to the COVID-19 situation.

We also need to be very careful in our messaging and communication within the Parkinson’s community. The research community has a responsibility to share and disseminate the scientific findings, in language that the lay person (whose taxes and generous charitable donations have paid for the research). In the absence of good communication, individuals will seek information from all kinds of dark corners of the internet, where the content may be advertised by a pretty looking website but completely lacking any kind of data or supporting evidence.

This idea of being careful in our communication particularly applies to how researchers and biotech companies alert the Parkinson’s community to the results of clinical trials. In 2020, we had the example of the pharmaceutical company Roche announcing the negative results of the highly anticipated PASADENA study as a single sentence in its sales results for the 1^st Quarter (Click here to read more about this).

To be fair to Roche, later in the year the announcement of post hoc analysis findings – indicating that their treatment may have have had some potential effects in the PASADENA trial (Click here to read more about that) – was handled in a better fashion (in that a full press release was involved).

While the timing of these clinical trial announcements is a tricky business and the news will have repercussions on the financial markets, there is a human side to communication and messaging. It seems kind of obvious, but all to often in these situations the hundreds of courageous volunteers and their families who have been involved in these large, multi-year trials are forgotten.

Thus, in 2021 I am hoping for better communication.

And yes, I fully appreciate that as a communicator of scientific research (whose website is full of typos) that I’m putting my neck out here. These words will definitely come back to haunt me, but some of the developments of the last 12 months have really concerned me. So I ask everyone to leave the mistakes of 2020 to the history books and let’s focus on improving our communication, our messages and the channels via which they are passed.

(Apologies for the rant)

 

WISH #2:  The new two lane road of clinical development

The author of this blog is an employee of The Cure Parkinson’s Trust. Our primary goal is to fund research that demonstrates the potential to change the trajectory of Parkinson’s – to slow, stop or reverse the condition.

One interesting trend that I have noticed over the last year or so has been the rise of biotech firms and researchers focusing not only the potential of their experimental therapy to correct an aspect of Parkinson’s, but also (in parallel) the development of tools to determine if that agent is actually working and hitting their target.

Source: Feweek

Rather than simply relying on clinical assessment-based measures of Parkinson’s to reveal if an experimental therapy is working, biotech firms and researchers are also developing novel methods of evaluating target engagement and biological efficacy of their experimental therapies.

Last year, a key theme that was discussed here on the SoPD was alternative experimental methods of restorative therapy for Parkinson’s, and numerous posts were written exploring some really futuristic/”blue sky” approaches (Click here, here, here and here to read some examples).

For 2021, a new theme will be discussed and it will focus on new experimental therapies for which there is a method of target engagement being developed in parallel.

An example of this is the German biotech company MODAG.

As long time readers will be aware, MODAG is a German biotech company that has been developing their lead compound – an alpha synuclein aggregation inhibitor called Anle138b (Click here to read a previous SoPD post about this). In August last year, the company announced that they had completed their first Phase I clinical study of Anle138b in healthy volunteers (Click here to read more about this), and in December they initiated a Phase Ib study in individuals with Parkinson’s, with support from the Michael J Fox Foundation (Click here to read more about this).

What a lot of readers will be unaware of, however, is that the company has also been very busy developing new methods of assessment for their trials. Early on, the team at MODAG realised that the current tools for assessing target engagement and efficacy of alpha synuclein aggregation inhibitors were… well, “lacking” is not really appropriate, perhaps “non-existent” is probably more apt. So the company started working on imaging agents that would allow them to better quantify the amount of aggregated alpha synuclein in the brain before and after a person is treated with an experimental therapy, like anle138b.

And last year they published some of the research that they have been conducting in this area.

Title: (11) C Radiolabeling of anle253b: a Putative PET Tracer for Parkinson’s Disease That Binds to alpha-Synuclein Fibrils in vitro and Crosses the Blood-Brain Barrier.
Authors: Maurer A, Leonov A, Ryazanov S, Herfert K, Kuebler L, Buss S, Schmidt F, Weckbecker D, Linder R, Bender D, Giese A, Pichler BJ, Griesinger C.
Journal: ChemMedChem. 2020 Mar 5;15(5):411-415.
PMID: 31859430                       (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers described a radiolabeling strategy for the aggregation modulator anle253b. They also demonstrated its high‐affinity binding to aggregated alpha synuclein in cell culture conditions and its successful penetration of the blood‐brain barrier in rats.

Source: PMC

And this study was quickly followed by a second study:

Title: [11C]MODAG-001-towards a PET tracer targeting α-synuclein aggregates.
Authors: Kuebler L, Buss S, Leonov A, Ryazanov S, Schmidt F, Maurer A, Weckbecker D, Landau AM, Lillethorup TP, Bleher D, Saw RS, Pichler BJ, Griesinger C, Giese A, Herfert K.
Journal: Eur J Nucl Med Mol Imaging. 2020 Dec 28. Online ahead of print.
PMID: 33369690                     (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers reported the development of a positron emission tomography (PET) brain imaging tracer based on anle138b, which they called [³H]MODAG-001.

The agent revealed a very high affinity towards aggregated alpha synuclein protein (and moderate affinity to aggregated Tau and beta amyloid), as well as excellent CNS penetrance in mice. It will be interesting to watch the future development of this research – an imaging agent for alpha synuclein is currently considered the holy grail for the assessment of clinical trials focused on disease modification in Parkinson’s.

Conducting this kind of readout research speaks volumes to the ethic of the organisation involved. It suggests that the team is not just focused on making money with a new wonder drug, but also on improving the research field. It also indicates a prudence that investors can appreciate – it says “we want to be certain that our agent is doing what we say it is doing“.

And MODAG is not alone in their efforts. There are lots of other examples of biotech companies developing novel methods of evaluating their clinical candidates.

In December 2020, biotech firm Neuron23 was launched with $113 million in financing, part of which will be used to take their LRRK2 inhibitor programme forward to the clinic for Parkinson’s (Click here to read more about this). And encouragingly, the company is also developing a brain imaging (PET) tracer for LRRK2 that it hopes will be used in future clinical studies.

So my second wish for 2021 is to see more researchers and biotech firms giving more consideration to how their potentially therapeutic agents could be better assessed in clinical trials.

There is an element of “be careful what you wish for” to this particular hope for 2021.

The biotech business model relies on making products that generate profits to reward the investors who took the risk of backing the company. Many recent treatments coming to the market, however, enter at rather eye-popping prices (treatment with the Novartis drug Zolgensma started at $2.1 million for a treatment regime), and it would be rather disastrous if the “tools of assessment” started costing society significant sums as well. Admittedly this concern is exaggerated as over the longer-term the copy cat drug makers bring their wares to the market and this dramatically lowers costs.

 

WISH #3:  Again on the restorative rant

In the recent annual annual “Road ahead” post which looks at what we have scheduled for the next 12 months, we outlined some of the clinical trial work that is being conducted on Parkinson’s. We broke the discussion down into the three components that any curative treatment for Parkinson’s will require:

• A disease halting mechanism
• A neuroprotective agent
• Some form of restorative therapy

Now, while there is a great deal of research being conducted on the first and second component, the third component is still very much centred around cell transplantation-based approaches. Growing cells in culture, and then surgically introducing them into the Parkinsonian brain.

I don’t like having all my eggs in one basket. I prefer to have options.

And we need to have more options when it comes to restorative therapies – not just cell transplantation approaches.

So I repeat last year’s wish for more novel methods in restorative therapies for Parkinson’s.

As I mentioned above, 2020 gave us a bumper crop of preclinical futuristic/”blue sky” restorative approaches (Click here, here, here and here to read some examples). In addition, we saw biotech companies like NeuExcell Therapeutics launch with the goal of developing direct convertion of cells in the brain into dopamine neurons as a therapy for Parkinson’s.

So the future of restorative therapies looks good, but I am hoping to see more progress towards the clinic of novel restorative approaches in 2021.

 

Wish #4:  More Phase III

I’m adding a 4th wish here.

One of the stark observations on the drug development pipeline for Parkinson’s report that was published last year was the lack of Phase III clinical trials for disease modifying therapies (Click here to read the research report and click here to read an SoPD post about this).

Phase III trials are considered the last step before regulators decide to approve (or reject) a drug for clinical use.

Source: Closerlookatstemcells

The goal of a Phase III trial is to determine the long-term safety and efficacy of the agent in a large group of the patient population of interest (200+ participants). These are huge, expensive trials that will last 1-2 years on average in the case of a slowly progressing condition like Parkinson’s. Positive Phase III results are required by health regulators in order for an agent to be approved for clinical use.

Now, the clinical development pathway is a slow process, and in 2021 while it would be nice to see more Phase III clinical trials being added to the list of disease modifying studies, there are only a limited number of potential Phase III trials lined up to possibly start (The Cure Parkinson’s Trust’s ambroxol study being one of them).

So perhaps my wish should not be a desire to see more trials, but a shift to better streamlining the clinical development system and working on better trial designs that will allow quicker progress to Phase III for therapies that display potential.

In 2020, we discussed an effort to develop a novel clinical trial platform for Parkinson’s that involved a Multi-Arm Multi-Stage (or MAMS) trial design (Click here to read the SoPD post about this topic). Such a initiative would allow for the seamless transition between Phase II and III, thus speeding up the whole process.

So my last wish for Parkinson’s research in 2021 is to see more development in this direction.

 

So what does it all mean?

2020 was a brutal year.

Source: Alliantstudios

It was an experience that has left a mark in so many ways. And I for one am extremely glad it is behind us. It was supposed to be the year that we’d have bases on the moon and be exploring deep space (slight hick up in the 1990 predictions there), but instead we were locked down and seemingly at each others throats. I am grateful to have survived it and it has given me a new sense of appreciation for what we have.

Despite the restrictions and limitation that fate pressed upon us, I was particularly impressed by how much was actually achieved in the field of Parkinson’s research during 2020 (Click here to read the SoPD’s annual review). The amazing efforts that researchers and clinical trial participants made to get data collected and studies finished left me feeling inspired and looking to the future with increased optimism and hope.

2021 is full of opportunity and resources to take significant steps in our lives to make the world a better place. And I’m sure if we asked the little Bar-tailed Godwits (who are currently sitting in New Zealand getting ready to return north in May) they would tell us that there is a lot that can be achieved in 12 months.

Source: PRX

 

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ADDENDUM #1: Updated 3rd February – Unfortunately the communication wish (#2.) is NOT off to a good start in 2021.

Today, the pharmaceutical company Biogen announced the result of their highly anticipated SPARK study (Click here to read a previous SoPD post about this) and… it was a single sentence buried deep in their annual results (PDF).

The results indicate that the Phase II study of BIIB054 (also known as cinpanemab) in Parkinson’s “did not achieve proof-of-concept” – missing both its primary and secondary endpoints (pre-determined measures of assessment/efficacy). In a second sentence, Biogen said it was discontinuing development of this therapy, but “will apply learnings to future efforts in Parkinson’s”.

I appreciate that Biogen has been through some hard times lately and don’t really want to make a lot of noise regarding an immunotherapy candidate for Parkinson’s not reaching its clinical trial endpoints (as in parallel they try to get their Alzheimer’s immunotherapy aducanumab cleared by the regulators). But for a company who prides itself on “Caring Deeply. Working Fearlessly. Changing Lives“, they need to seriously rethink how they communicate trial results to patients and “apply learnings to future ” announcements. 

One hopes that the single sentence in an annual report was not how the 311 courageous participants (and their families) found out about the result of this multi-year study.

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ADDENDUM #2: Updated 5th February – (Big sigh) Yeah, the communication wish (#2.) is off to a disastrous start in 2021.

Today the biotech company Sanofi announced (in a single sentence) of their annual report that “the venglustat Phase 2 trial in Parkinsons with GBA mutations did not meet the primary endpoint (end-January) & the indication was halted” (Click here to read more… although, there isn’t much else regarding the study). 

As I said above, I appreciate the stock market being a factor in the nature of these announcements, but perhaps there is an opportunity for pharmaceutical companies to explore novel methods of delivering clinical trial results to those who are most affected by them.

And again, one hopes that the single sentence in an annual report was not how the 270 courageous participants (and their families) found out about the result of this multi-year study.

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