When we talk about “disease modification”

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There is a lot of effort focused on developing therapies that are capable of “disease modification” in Parkinson’s…

…but what do we actually mean by this label?

In today’s post, we will explore the idea in more depth.

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Source: Martech

It is inconceivable, but we live in a world full of words that we don’t really know the meaning of.

For example: Travesty

For the longest time, I thought this word meant a tragedy or something very unfortunate. And I would use it in a sentence like “His death was such a travesty“. But it doesn’t mean tragic at all. Or even unfortunate. Rather, it refers to a mockery or parody; a distorted representation of something.

Another example is the word Peruse

I would use “peruse” in a sentence like “I am going into that bookshop to peruse the shelves“, because I thought that the word meant to skim or browse and that using it might make me sound erudite and sophisticated.

Source: BBC

But it doesn’t mean to skim or browse.

Peruse means to ‘examine or observe in depth“.

Similarly: Nauseous

I have often said “I feel nauseous“, but nauseous describes something that causes a feeling of nausea. It doesn’t refer to the feeling itself (The word nauseated means to be affected with nausea).

And at a recent session of bedtime story reading with my daughter, I noted on p.582 (first page of chapter 36) of the Harry Potter and the Goblet of fire, that Prof McGonagall ‘looked slightly nauseous‘. So I am not alone in making this mistake.

All of this leads me to the topic for today’s discussion: What do we actually mean by the words ‘disease modification’?

It is a label I use almost everyday with my job at Cure Parkinson’s, but it strikes me as one that we (everyone) don’t really fully grasp.

Ok, so what does disease modification mean to you?

The classical definition of a disease modifying treatment is a therapy that alters the underlying pathophysiology of a medical condition, shifting the overall trajectory of the disease.

It is an agent that can slow, stop or reverse the progression of a condition.

The normal trajectory of the condition looks something like this:

An individual will suspect something is not quite right and after a while they will get a diagnosis of Parkinson’s from a neurologist. The doctor will then prescribe symptomatic treatments (such as L-dopa – the red line in the image above) which bring relief from the symptoms, but they do not alter the overall trajectory of the condition.

At present, we only have symptomatic therapies available for Parkinson’s. They address the features of a condition (such as symptoms) without affecting the underlying biology of the condition. They do nothing to alter the long-term trajectory of the disease. They simply offer temporary relief from the symptoms.

Disease modification an important goal for Parkinson’s, because it is a progressive condition – this means that the symptoms are going to get worse over time. In the image below, a disease modifying treatment would be one that changes the downward trajectory of progression to one of the dotted red lines:

It goes without saying, but we really need therapies that are ‘disease modifying’.

Agreed. So what’s the problem?

Well, while the Parkinson’s research community appreciates the desperate need for disease modifying therapies, it is struggling with defining what it actually means (let alone how to measure any change in trajectory).

What do you mean struggling to define it?

In 2019, Ben Stecher wrote a great piece for the Journal of Parkinson’s called “The Futile Hunt for Disease Modifying Therapies“.

Uber advocate. Source: McGill

Ben rightly argued that the term “disease”  in Parkinson’s is itself useless as we lack a universally accepted definition of “what Parkinson’s is“. And he pointed out that “modification” is a too amorphous term to use in this context – what aspects of Parkinson’s are being modified exactly? The motor issues? Or the non-motor issues?

It would be easy to box ‘disease modifying‘ in with similar vague concepts like ‘common sense‘ or ‘the good old days‘. A useful way of representing an ill defined idea.

And the irony here is that ‘disease modifying’ was originally proposed as an alternative for an even more difficult to define indication: neuroprotective.

There are very serious efforts being made, however, to better define what we mean by ‘disease modifying’.

In his write up, Ben provided a nice summary of the presentations and discussions that were had at the “Krembil Knowledge Gaps in PD Symposium” that was held in Toronto (Canada) in 2019. The organisers of the event wanted to tackle some of the fundamental conceptual challenges that the field of Parkinson’s research is facing at present – one of the primary questions being what do we mean by “disease modification“?

Source: Ben’s blog

What was the outcome of that meeting?

Well, as Ben suggested, “the organizers have bitten off more than they can chew” by trying to address too many grand topics in just one conference, but it sounds like it was a very interesting and constructive discussion from what I have heard from some of the other attendees.

To be fair, Rome was not built in one scientific research conference.

For those interested, a very good report on the meeting was published though. Here is that report:

Title: Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?
Authors: Espay AJ, Kalia LV, Gan-Or Z, Williams-Gray CH, Bedard PL, Rowe SM, Morgante F, Fasano A, Stecher B, Kauffman MA, Farrer MJ, Coffey CS, Schwarzschild MA, Sherer T, Postuma RB, Strafella AP, Singleton AB, Barker RA, Kieburtz K, Olanow CW, Lozano A, Kordower JH, Cedarbaum JM, Brundin P, Standaert DG, Lang AE.
Journal: Neurology. 2020 Feb 26. Mar 17;94(11):481-494.
PMID: 32102975                 (This report is OPEN ACCESS if you would like to read it)

We have reviewed this report in a previous SoPD post (Click here to read that post).

And it has also led to other opinion pieces and viewpoints on this topic. A very good, easy to approach read on this topic is this review:

Title: A New Approach to the Development of Disease-Modifying Therapies for PD; Fighting Another Pandemic.
Authors: Kieburtz K, Katz R, McGarry A, Olanow CW.
Journal: Mov Disord. 2021 Jan;36(1):59-63.
PMID: 33026697                        (This report is OPEN ACCESS if you would like to read it)

The authors start by referencing Jonathan Swift’s book Gullivers Travels, and they discuss the story where Lemuel Gulliver visits to the island kingdom of Luggnagg, where some of the inhabitants – the Struldbrugs – are immortal but not ageless, which leaves them vulnerable to various diseases of aging. It is an apt beginning because it nicely illustrates the demographic problem we currently face in the western world.

The authors then shift to discussing the issues associated with developing disease modifying therapies for neurodegenerative conditions, before proposing a possible alternative two‐pronged approach.

First, without rocking the boat too much, they propose that a simple double‐blind, placebo‐controlled, parallel‐group trial design could be used, with a focus on the change in Unified Parkinson’s Disease Rating Scale (or UPDRS) score or in “ON” time without troublesome dyskinesia as an endpoint.

Second, rather than trying to argue ‘disease modification’ has occurred based on any outcome, the authors propose that “a simple and clear description of relevant basic science and specific clinical findings could be described in the product label” (under section 14 of the label).

“Simply report what was found in the clinical trial(s) and the relevant basic science findings in the label”

And they note that this is what occurs in fields such as infectious disease and cancer. The important feature of this approach is that while the treatment in question would not be labelled as ‘disease modifying’, it would at least be approved for clinical use – doctors would be able to prescribe it to patients.

And get new treatments to patients quicker? Sounds like a step in the right direction.

Perhaps, but this report was published before the aducanumab debacle (click here to read a SoPD post on this topic), and the proposition is more of a sticky plaster approach than addressing the actual problem.

And it may not be so easy in reality.

What do you mean?

Let me explain by using an example:

In June of this year, Anavex Life Sciences announced the results of a Phase 2, double-blind, randomized, placebo-controlled study in which they were evaluating the safety, tolerability, and efficacy of ANAVEX2-73/Blarcamesine on cognitive impairment in 132 individuals with Parkinson’s Disease Dementia (Click here to read an SoPD post about this).

According to their press release (we are still waiting to see the full results), Anavex reported that 14 weeks of ANAVEX2-73 treatment resulted in a statistically significant 11 points improvement Parkinson’s symptoms over the 14 week study.

This is rather jaw dropping stuff.

It corresponds to a relative improvement of almost 20% over 14 weeks (18.9% to be exact).

And what is really remarkable about this outcome is that this result was achieved while the participants were on their standard medication. That is to say, the participants were on their standard PD medication (e.g. L-dopa, etc) during the clinical assessments – so the improvement in total UPDRS score was on top of the response to standard medication.

Now (I’ll be honest) the first thing thought that popped into my mind upon reading the press release was “it must be a symptomatic effect” (and I am not alone in thinking this). For such a rapid response, the assumption is that it must be some kind of symptomatic effect.

So if this was a Phase III study and the data went to the regulator for clinical approval, what exactly would the regulator write on the label?

You think it is just a symptomatic effect?

Not necessarily.

I think the differentiation between disease modifying and symptomatic is not cut and dry. Like all things in life there is going to be a lot of grey. It may be that ANAVEX2-73 is somehow cleaning up cells (improving protein folding, etc) and making them healthier, which could result in a rapid improvement in function…

…but would that only be improving the performance of the symptomatic therapies? Could it be considered a disease modifying effect?

By no means am I picking on Anavex Life Sciences here – I think their results are really interesting. I am simply using this situation as an example to show that deciding on what to write on the label of a treatment may be difficult.

The proof of biology is going to be difficult to determine – as we simply don’t have the tools.

So what does it all mean?

At the top of this post is a cartoon image of a group of blind folded individuals trying to work out what they are dealing with. The common joke is that each of them has a different answer (the guy touching the trunk may say ‘snake’ for example). I have often wondered what the elephant must make of it all. Perhaps it is having an crisis of identify and wondering “dude, seriously, what am I?

And this conundrum is relevant to the discussion that we have just had, because ultimately ‘disease modification’ has to be clinically relevant for the patient. Perhaps a novel therapy will be developed for PD, but it will carry debilitating side effects for patients which impact quality of life. Yes, you may be slowing the progression of the condition, but are we actually making things better? My point is: any disease modifying therapy has to be relevant to the individual being treated.

While I appreciate that a discussion about the definition of the term ‘disease modifying’ probably does not carry much weight with many readers (most are simply channeling Margaret Thatcher: “Don’t tell me the what. I know the what. Tell me the how“), but this discussion is important. Medical regulators want to work with black and white definitions, measures and boundaries, but they exist in a world of grey. Biotech companies and research scientists come to the regulators with novel therapies seeking approval as disease modifying therapies. But in the absence of clarity, most of these remedies are probably going to run into trouble. And this will only slow development.

Not knowing how to define ‘disease modification’ is a serious problem. Certainly one that needs more discussion.


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3 thoughts on “When we talk about “disease modification”

  1. English is not my first language, but I don’t like the term “disease modifying,” because to me that includes the possibility of making the disease worse. In this sense, for example, taking paraquat could be called a “disease modifying treatment” since it could alter the trajectory of PD by making it worse.


  2. If the only measure is peripheral parameters – gait etc- then grapefruit juice could be regarded as disease-modifying. It blocks gut CYP3A4 that metabolises levodopa ( and a host of other drugs) and improves its action.. The recent demonstration that carbidopa therapy results in increased levels of serum AADC could also be regarded as disease-modifying, but not in a direction that I find encouraging.. Espay’s ” Brain Fables” reveals how far we are from understnading non-genetic forms of sporadic PD. Myself I place great store upon natural experiments such as the observation that the elderly in rural Kenya do not suffer any sPD. The most likely reason is their daily exposure to sunlight and hence their far better D3 status than most nations. Paradoxically I find that reassuring but then I have made an effort to understand the extensive ramifications of D3 signalling.And many actions of D3 fit with D3 correcting suspected injurious pathways in PDs. But there’s no profit in D3.

    Liked by 1 person

  3. I’m with the views in the Clintrex paper. It needs a courageous, small biopharma to pioneer this approach.


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