Part 4: Today’s Most Promising Drug Targets

(This is part 4 in a series titled The Search for a Cure, click here for Part 1: Back to the future, here for Part 2: Coping with Biology, here for Part 3: A Crash Course in Drug Development)

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To date, there is nothing clinically proven that can slow, let alone stop, the progression of Parkinson’s disease. But, that might not be the case for long. As of November 28, 2018 there are 53 active phase 1, 2, 3 trials, testing a variety of therapies that have the potential to modify the progression of this disease, and many more in the preclinical pipeline. Finding this elusive therapy would be the single biggest step forward in our collective attempt to rid the world of this disease yet. (Go to pdtrialtracker.info to learn more about trials in development and check out their collaboration page for more useful resources.)

Each therapy in development is based on a biological target that some scientists believe play a role in this disease. But, with so many in development, it can be hard to know what the most promising targets are. So, in an attempt to gauge which targets have the most support from the field, I sent out a survey to experts asking each to list their 5 top candidates from the following:

Alpha-synuclein antibodies and vaccines
LRRK2 inhibitors
GBA manipulators
GLP1 agonists
Calcium Channel Blockers
c-Abl Inhibitors
Parkin activators
PARIS inhibitors
Other (please write)

 

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Before I get to the results, a couple notes.

The list above was based on my perception of what the leading drug targets are. The list may also be biased by the representative responders. While I tried to reach out to as diverse a group of experts as I could, there may well have been some innate selection bias.

Additionally, several responders pointed out some important notes to bear in mind when interpreting the results of this survey. I condensed and summarized these points in the paragraph below.

Ideally, the mechanisms that drive and/or accelerate the disease process should dictate which disease-modifying treatments are used. But, since we are still in the process of identifying the underlying mechanisms of PD, all of these strategies are hypothetical. They were derived from hypothesis based on experiments in imperfect models and incomplete epidemiologic data-sets. Some are now being tested in humans under the assumption that we will be able to detect a disease-modifying signal. Identifying which subtype of PD an individual has and then matching that subtype to the appropriate therapeutic target will likely be critical to delivering effective therapies. It may also be that for many people with PD, a disease-modifying therapy will only come from a combination of two or more of these therapies and will be most effective if applied at a relatively early stage of their disease.

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With that said, here are the results…

 

The Big Three

Alpha-synuclein (SNCA) – 35
GBA – 29
LRRK2 – 28

No real surprises here given that these targets have the most solid foundations of evidence and subsequently the most funding. Though, it does lead me to wonder how much this is a case of, as Dr. Simon Stott noted in an interview last year, “the evidence tail wagging the clinical dog scenario”? Still, the case to be made for each of these three is pretty strong, so let’s break down these responses in a little more detail.

Alpha-synuclein – There are currently nine trials testing a variety of strategies targeting the misfolded and accumulated forms of this protein in humans. Perhaps most interesting is that, despite all the evidence, eight responders did not think alpha-synuclein to be among the most promising targets. Also, among the 35 that did list alpha-synuclein, various strategies were mentioned:

25 stated alpha-synuclein vaccine and antibody (likely overstated due to the list I gave)
4 specifically stated antisense oligonucleotides
3 specifically stated alpha-synuclein small molecule inhibitors
2 specifically stated just antibodies
1 specifically stated the inhibitor NPT200-11
1 added that alpha-synuclein immunotherapies would be for cognitive decline

 

GBA manipulators – The ongoing GBA and LRRK2 trials are among the first drug trials tailored for a subset of the PD population. .Click here for an overview of GBA mutation in PD and here for a survey of GBA experts.

 

LRRK2 inhibitors – Prof. Dario Alessi summed up the state of LRRK2 inhibitors succinctly in a recent interview I did with him, “At the moment drug companies are being very secretive about the inhibitors they have, so no one knows what the chemical structure of the various inhibitors are. But they will be distinct, some will be more potent than others, some might penetrate the brain better than others, some might last longer in the body, and each will have different off-target effects that can be quite unpredictable. We will probably end up with 7 or 8 different clinical trials and some might work better for certain LRRK2 mutations. Then the work will shift to finding out which patient might be best suited for which inhibitor.”

For more watch this recent discussion on the latest in therapies targeting GBA and LRRK2…

Next on the List

 

GLP1 agonists – 14
Parkin activators– 13
c-Abl inhibitors – 10
Calcium Channel Blockers – 7
Paris inhibitors – 3

Interesting to note the number of mentions for parkin activators despite, unlike the others listed here (except Paris), it does not have any ongoing human trials. I assume that is because people have more faith in targets with a direct genetic link. GLP1, c-Abl and calcium channel blockers all have ongoing trials in at phase 2 or beyond, the results of each should be released within the next few months, which I imagine will significantly push them either or up or down this list. (Also for GLP1 agonists, one person specifically stated Exenatide, and another person stated a combination GLP1-GIP agonists. For calcium channel blockers one person specified they be used with a MAO blocker.)

 

The ‘Others’

In many ways these responses were the most interesting as they were least likely to succumb to the bias inherent from the list provided. The first thing that stands out is the sheer number of potential targets as 23 different ones were mentioned. They include a hodgepodge of new drug targets, repurposed compounds, and therapies on the horizon.

Targeted anti-inflammatories – 5  (2 specifically stated targeting microglia)
Cell replacement therapy – 4
Pink 1 activators  – 3
DPP4 inhibitors – 3
Enhancing chaperone mediated autophagy – 2
PARP inhibitors – 2
Beta-adrenoreceptor agonists – 2
Anti-TNF – 2 (1 specifying sol TNF, the other TNF-alpha)

A2A receptor antagonists
Oral aporphines
Neuromelanin vaccines
Banisteriopsis caapi
Upregulating PARK7, the DJ-1 gene
Nicotine
D-Serine
Nurr1 agonists
NLRP3 inhibitors
TFEB activators
NAD+ precursors
Senolytics
Gene therapy
Tau-ASOs
Metformin

 

Well, that’s the list. I want to stress that the number of votes received is not necessarily a good predictor of whether a therapy will be effective. I also wanted to reiterate that in all likelihood no single therapy is going to be disease-modifying for everyone. My suspicion is that almost everything on this list would be partially beneficial for some subset of the population. Going forward it will be critical that we identify which therapy, or therapies, should be administered to which subset of people.

 

 

Got anything else you think deserves to be on the list? Write it in the comments below or send it to me here.

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Almost all of the therapies listed above aim to either slow or possibly stop disease progression. In Part 5 of this series we will look at therapies that have the potential to reverse disease progression or restore lost function. Please let me know if there are any you think I should make sure to mention.

The Search for a Cure

 

Part 1: Back to the Future 

Part 2: Coping with Biology

Part 3: A Crash Course in Drug Development

Part 4: Today’s Most Promising Drug Targets

Coming up in this series...(tentative schedule)

Part 5: Restorative treatments on the horizon

Part 6: Obstacles to Overcome

Part 7: The Bigger Problems

Part 8: Technology to the Rescue

Part 9: The Promise of Precision Medicine

Part 10: The Role of Patients

Part 11: Where Hope Springs 

Part 12: The End of PD – Not with a bang, but a whimper

 

 

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