It’s been six years since I last wrote about The Future of Parkinson’s, and a decade since my own diagnosis. Seems like an appropriate time to reflect on just how far we’ve come in the last ten years, and use that to guide how far we can go in the next ten.
Just last Monday I took part in a panel discussion brought together by the NIH titled Advances in Therapeutics Development for Parkinson’s Disease. While I was pleasantly surprised to be invited, I once again found myself to be the only patient in a room full of mostly scientists…sigh.
Why was I chosen? Well, partly due to the recommendations of fellow panelists who recognized the need (thanks Alice!), partly because of the answers I gave to these questions I was sent in advance:
- From your lived experience perspective, what are the most significant gaps in PD therapeutics development, and what are some promising approaches that you have seen?
- Do you have an example for how engaging people with lived experience of PD can accelerate therapeutics development?
- Do you have an example of when this has been successful?
Here are the answers I submitted verbatim:
1. There are three big gaps that I think need to be addressed if we are going to see progress in PD therapeutics:
– Basic research: Frankly, there is a lot of waste in the basic sciences. All of our models are just models, some are useful in answering specific questions, but too often we seem to forget that none recapitulate anything that any human really has. I have been to over a hundred labs and clinics all over the world and have never seen a mouse, monkey or worm with anything that I would call Parkinson’s. I’d start by using some of the latest technology, like Medtronic’s brainsense and wearable technologies, to gain insight from real human beings and use that to guide the development of future therapies.
– Clinical translation: All of our disease modifying therapies aim to paint all or most of us with the same PD brush. We must begin to treat those diagnosed as individuals, and embrace the tough reality that it is likely that there are dozens of factors contributing to each person’s individual disease if we are going to make progress.
– Access to Care: We have some great therapies currently available like DBS, however it is available to too few individuals. We desperately need to train more neurologists and surgeons to be able to deliver this life changing therapy to more people.
2. + 3. My examples may be viewed as slightly self-serving, but that is because I spend my time trying to answer the same questions you have posed. They also answer the second half of question 1.
– Rune Labs: I chair their patient advisory board (PAB) where I work closely with the CEO to advance their wearable solution to help us better track and understand individuals with Parkinson’s disease. The advice the PAB has given has been instrumental in helping them better understand our needs and relate those needs back to the clinicians they work with.
– CCBP: This is similar to the Framingham study that linked high blood pressure and cholesterol to cardiovascular diseases, but for neurodegenerative diseases. I believe that if more institutions had similar programs, that looked at neurodegenerative diseases agnostically, ignoring man-made labels and trying to view participants as individuals with unique drivers of their disease, we’d be much further along than we currently are.
– The PAB at Toronto Western: This body plays a critical role in many important decisions made at the clinic. Key to its success is the buy in had from the outset by the leader of the clinic, Prof. Tony Lang.
Coming back now to the title of this article, what will the future of Parkinson’s look like?
Well, I don’t have a crystal ball, though thankfully some of my fellow people with Parkinson’s have provided the next best thing: Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline by Kevin McFarthing et. al. is as good an overview as there is of what is to come of the 5-10 years. (2023 update coming in the next few weeks.)
Not only has the sheer amount of shots on goal grown rapidly, but the variety has as well. Those points alone should make anyone living with this diagnosis hopeful. But how reliable is any one of them? And the far more important question for those diagnosed, which of them will help me?
Sadly, that is where the optimism that often pervades the halls of pharma and biotech companies begins to lose some of its shimmer. We still cannot say with much certainty which of them is more likely to succeed and which will fail until we get the outcome of each trial.
Also, given the increasing knowledge that pharma is still struggling to come to terms with about the heterogeneity of disease labels such as Parkinson’s Disease, to think that any one drug in that vast pipeline might fit squarely onto your round-peg of a disease may be too difficult a pill for the industry to swallow.
And what about beyond that timeline? How will we care for those diagnosed, how will their outcomes change in the years to come and how will those changes affect the pipeline of drugs shown above?
(Note that I am setting aside medical devices like DBS because I just finished writing a book on that topic along with my neurologist Dr. Alfonso Fasano, which we hope will hit shelves sometime this year. Here though is our current proposed cover and table of contents.)
However, I am still optimistic about the future of drug development because narratives in the field are slowly shifting. I have met several scientists who are open to new ideas and conversations about the process of drug development. These scientists are humble enough to admit the limits of their knowledge and do not exaggerate their claims. Below is an excerpt from a conversation I recently had with one such scientist, Judith Steen, professor of neurology at Harvard, on the topics above and the panel discussion last week from the NIH:
JS: My question to you in general is what aspects of the real world outcomes do you want to communicate to scientists. I agree we live in our little bubbles with blinders on. Btw we are organizing a session for our lab scientists to speak with patients but it is not so easy to get patients to sign up because of privacy concerns. We want our lab members to engage in dialogues to understand what issues patients have and what we should be doing to help.
BS: Great to hear about that initiative to engage more with patients, sorely needed, hoping others follow suit. The call yesterday I think went really well, I did have several specific asks of the group and will see in the months to come what if any real world impact my words had.
JS: Thanks Ben, I totally agree with your points but what if lowering asyn results in the slowing disease progression in the long term? Immediate effects on bradykinesia can be modulated by other drugs but the long term effect is to improve quality of life.
BS: Possible, but I’m not convinced you can show that without a direct symptomatic impact as well. Afterall, all the measures we use of this disease are symptomatic. And need to be checked against those.
JS: Agreed, but I think we need to use multiple drugs. Manage immediate symptoms and prevent progression. We observe two different biochemical pathways. Initiation of disease and progression. (Not to say that I am proposing reducing asyn levels for any of these target pathways)
BS: But if a drug that targets the disease pathway can’t, at least within a year, have a noticeable effect on symptoms (whether it stops them from getting worse or alleviates existing ones) then it won’t pass a trial because all of our outcome measures are symptomatic. And, it will be very hard to convince patients to take a new drug, on top of everything they already take, and not be able to tell if it works for them. I wonder how this works in the abeta AD trial?
JS: I was at Genentech and UCSF last week and am in D.C. tomorrow for a drug target-trial meeting. In SF, we (scientists and medics) discussed the beta-amyloid trials and the results (statistics and side effects). When I suggested that the outcomes were poor, I kept hearing that it was better than most cancer trials! I think all of us should be aiming higher. People like you need to keep us honest. Also, pricing is another aspect, that needs to be reconsidered. Perhaps, we need not for profit drug companies!
BS: Oy vey, the fact that this field thinks that Cancer is in anyway analogous to neurodegenerative disorders is itself scary. A few of the panelists on Monday got slightly upset with me when I asked directly after they listed the similarities in therapeutic approaches (between cancers and NDDs) if they had ever bothered to count up the differences. Still waiting for an answer.
JS: I mentioned you (at the D.C., NIH sponsored target and trials meeting)! I talked about my friend who doesn’t care about a 0.05% decrease in tau unless he observes quality of life changes. I was told we have to start somewhere.
BS: Oy vey. Starting from the wrong starting point is not the same thing as starting somewhere.
Which all leads me to the biggest revelation I have had over the last ten years. Science is a collection of stories we agree to tell each other about the truth of our world. In physics and chemistry the stories are rooted in ground truths that have been codified into the laws of physics, the periodic table of elements, etc. These truths have thus far defied our collective attempts to disprove them.
Unfortunately, medical science doesn’t have the same kinds of rigorous laws needed to know which of our stories are true and which are false. We are very much still in pre-history with only one tool by which the entire pharmaceutical industry uses to test which stories about us to believe in – clinical trials.
However, technological advances are pushing clinical trials forward. Companies like Rune Labs are making arcane clinical scales, which can only give companies snapshots of how patients are doing while in a doctor’s office, a thing of the past and replacing them with continuous real-world monitoring of symptoms. They are also enabling, for the first time in human history, the recording of vital data from deep inside the brains of real human beings.
In addition, artificial intelligence is enabling individuals to scower through millions of lines of written human text and emerge with profound new insights into connections between them. We can now begin to tell where these stories come from, and which are more likely to be grounded in truth and which are not. As a newly released article titled A publication-wide association study (PWAS), historical language models to prioritise novel therapeutic drug targets states:
“Most biomedical knowledge is published as text, making it challenging to analyse using traditional statistical methods...Our findings underscore the potential for extracting yet-to-be-discovered relationships through data-driven approaches, leading to generalised biomedical literature mining for potential therapeutic drug targets. The Publication-Wide Association Study (PWAS) enables the prioritisation of under-explored targets and provides a scalable system for accelerating early-stage target ranking, irrespective of the specific disease of interest.”
However, to aid these efforts patients will need pharma companies to enter into many more pre-competitive frameworks and begin sharing the data they have with the rest of the world. We will also need many more longitudinal data sets from humans that can take in device data and couple it with biochemical data from blood draws such as those being done in the Cincinnati Cohort Biomarker Program.
For anyone interested to learn more about how some of the latest advances in machine learning might help biomedical science, especially those with the resources to help, please contact me as I am working with a great group now eagerly building this future.
And for those wondering, the banner image was itself created by an AI drawing tool which was given the prompt The Future of Parkinson’s Research.