The Futile Hunt for Disease Modifying Therapies

Disease-modification as a goal of clinical trials is problematic not only because "modification" is an amorphous term, but there is disagreement over the term "disease" itself as we lack a universally accepted definition of Parkinson's disease. Prof. Karl Kieburtz argues that moving to better defined and more objective end points that are easier to comprehend and quantify would give us a clearer target to pursue and hasten the delivery of better therapeutics for PD.

Author: Benjamin Stecher


One of the most thought-provoking moments at the Krembil Knowledge Gaps in Parkinson's Disease Symposium, held in Toronto, Canada in April 2019, came near the very end from Prof. Karl Kieburtz who challenged the audience to do away with the term "disease modifying therapy." Prof. Kieburtz of the University of Rochester Medical Center has a long track record of success in getting therapies from the lab to the clinic and has had close ties to the FDA for decades, so he knows as well as almost anyone what it will take for the field to finally break through and deliver improved therapies for people with Parkinson's disease.

The theme of this symposium was Revision vs Reconstruction. Organized by several members of the Movement Disorders Clinic at Toronto Western Hospital, and supported by the Krembil Institute, the meeting was an attempt to re-evaluate how we are trying to develop new and improved therapies for people with Parkinson's disease. Each presenter was given a topic and asked to give their take on whether we need to simply revise our current methods or reconstruct them from the ground up. While for many of the topics there were mixed or wavering opinions with no firm resolution reached, when it came to the talks on clinical trial design the recommendation was clear – blow it up and start fresh.

This sentiment was expressed by Prof. Christopher Coffey, Director of the Clinical Trials Statistical Data Management Center at the University of Iowa, who spoke just before Prof. Kieburtz and set the tone for reconstruction. Prof. Coffey compared our clinical trial model to the frantic construction of football stadiums before every world cup. He went on to say that the way we currently run clinical trials is analogous to building whole football stadiums for each tournament but, instead of finding ways to put them to use, we tear them down once the tournament is finished only to start building again from scratch in the same spot soon after. This he showed is a big part of the reason why trials are so costly and take such a long time.

Prof. Kieburtz followed up on this discussion by elucidating that not only are we incredibly inefficient and clumsy in the way we design most trials in Parkinson's, but the very terminology we use to mark successful end points in trials makes it unlikely for us to achieve our desired outcomes. He emphasized that the most important determinant of a successful trial is the label that gets put on the package of the drug in question. The specific wording of that label gets heavily scrutinized by regulatory bodies, yet few trial designers have it in mind when constructing their trials.

This year has seen two more phase 3 clinical trials for potential "disease modifying therapies" for Parkinson's fail to meet their end points. Out of the 19 therapies with the potential to be "disease modifying" for PD have made it to a phase 3 clinical trial, all have failed. According to Prof. Kieburtz, one of the biggest impediments has been the term "disease modification", which he believes lacks a coherent and unified definition, making it incredibly difficult both to properly quantify as an outcome measure in a trial, and to place on the label of any medication.

In an email exchange I had with him following the conference he went on to say: "(We must) shift the focus in drug development from 'disease modifying' (which I find to be an ambiguous term) to the very tangible (in my view) delay of disability. Disability reflects a person's un-desired limitations in their daily activities, including walking, dressing, eating, socializing, working, etc. I think we should be most interested in interventions that have the ability to delay disability, in a significant way and for a prolonged length of time." He also noted that "many trials at present target short term symptom improvement (which is fine), but the longer term trials focused on delay of disability should use a more coherent vocabulary and structure."

Another key point in his talk was that often those who design trials spend a great deal of time hypothesizing and trying to verify the mechanism of action and detailing the pharmacokinetic properties of their drug. While this is important in differentiating and understanding an intervention, it should not, though it often does, take precedence over first properly defining the expected outcome.

Another critical point he made is that this shift in focus from disease modification to an easier to define term – such as “delay of disability” – would not only enable trials to more readily hit their end points, it would also give patients and their families a clearer picture of what the drug they eventually end up taking might do for them.

In summary, disease-modification as a goal of clinical trials is problematic not only because "modification" is an amorphous term, but there is disagreement over the term "disease" itself as we lack a clear, universally accepted definition of Parkinson's disease. Prof. Kieburtz argues that moving to better defined and more objective end points that are easier to comprehend and quantify – such as time to onset of falling, rather than obstinately sticking to vague terms like "disease-modifying" – would give us a clearer target to pursue and hasten the delivery of better therapeutics for PD.

The path forward in Parkinson's disease is murky. As of April 15, 2019, there were 487 interventional therapies being clinically tested for Parkinson’s disease around the world (see here). I shudder to think about how much money, resources, and man power might be being spent in the pursuit of a target that we can't even hit. Perhaps, as a step towards increasing the likelihood of getting improved therapies to people in need, we should start by clarifying precisely what we are trying to accomplish in all those trials.

Last comment on by Timothy Welborn...


Submitted by Timothy Welborn... on

Ben Stecher concurs with Prof Kiebulzz in challenging the term "disease modifying therapy" but I disagree. This phrase gives a positive direction for investigators and potential clinical triallists. At this stage of our knowledge, the universal definition of Parkinson's disease is still debated and needs more research to clarify its diverse origins.

Diabetes, some decades ago, was a disease with well recognised symptoms and complications but multiple aetiologies. Insulin controlled the symptoms and reduced the complications. But now with much clearer knowledge of its multiple aetiologies, specific treatments other than insulin have been developed to target the individual disease processes.

It is remarkable that despite all the research into Parkinson's disease, current treatments control the symptoms but do not influence the natural history of the disorder, and there are duration related side effects. It is remarkable also most reports of disease modifying therapy in Parkinson's disease come from serendipitous observation of "pre-purposed drugs" that were developed to treat unrelated conditions. For example, exanatide and liraglutide (glucagon-like peptide or GLP-1 agonists) have been shown in animal models to normalise brain dopaminergic function. Two clinical trials indicate that in moderately advanced disease, significant improvements in rating scales for activities of daily living and motor function, and scales for cognitive function, occur and persist for one year after ceasing the therapy.

Also very recent reports of the benefits of terazosin and related compounds (Alpha-1-adrenergic blocking agents), used for the urinary symptoms of prostate disease and/or for hypertension - slows or prevents neuro-degeneration. A prospective study confirmed benefits in a small number of patients. But the important research came from the Parkinson's Progression Markers Initiative database, showing that this class of drug reduced hospital or clinic visits, disease complications, as well as specific scores for walking/gait/coordination measures, for and neuropsychiatric scores. The diagnosis of new Parkinson's disease was reduced by 38%.

Clearly there is an important role for interrogation of available clinical trial and post marketing databases to explore drugs that may be found fortuitously to impact on the natural history of Parkinson's disease.