PdCure.org

  Providing resources and ideas for therapies and medical developments for Parkinson's disease:

 

Drugs and Therapies in Trials for Parkinson's Disease:

Cure development of drugs in trials are listed by solution categories including repurposed drugs which are available now for off label use. Unlike the drugs approved and in-use today that only address symptoms, many of the drugs in development and in trials seek to halt the progression or even reverse the course of Parkinson's disease (PD).

Drug Approval Process:

In the United States, the Food and Drug Administration (FDA) drug trials are categorized as "Phase 1", "Phase 2" and "Phase 3" trials:

  • Phase 0: Often skipped. Tests for drug absorption, half life. This phase is often skipped or merged with phase 1.
  • Phase 1: Tests on 20-100 humans to test toxicity and dosage safety.
  • Phase 2: Test on 100-300 humans for efficacy and side effects
  • Phase 3: Large test on 300-3000 patients to determine a drug's therapeutic effect and safety

In Europe the European Medicines Agency (EMA) has four phases:
  • Human Pharmacology: Dose-tolerance studies
  • Therapeutic Exploratory: Explore use for the targeted indication. Dose-response.
  • Therapeutic Confirmatory: Demonstrate/confirm efficacy
  • Therapeutic Use: Refine understanding of benefit/risk relationship in general or special populations and/or environments. Identify less common adverse reactions. Large trials.

Drugs which can show efficacy and safety for the patient, may be approved at the end of the process.

Drugs In Trials And Seeking Approval:

Note that drugs in trials do not have catchy brand names. Also, most do not make it to market and about 40% of drugs in completed trials go unpublished due to poor results (ref).

The approach taken by the various drug companies differs and their efficacy may depend on the patient's root cause of the disease. Each item listed is considered to be a Mechanism Of Action (MOA):
  • target alpha-synuclein aggregation (clean the mess)
    (various pathways include immunotherapy)
  • target neurotrophic factors (repair the mess)
  • gene therapy (drug delivery across BBB to repair the mess)
  • target inflammation pathway (avoid the mess)
  • target the genetic mutation (specific to those who possess LRRK2 or GBA mutations)
  • target the mitochondria health (improve cell health and energy to fight the mess)
  • target dopamine production (traditional, mess remains)

Some drugs are new and specific to curing Parkinson's disease and are categorized as "disease modifying" while others treat symptoms and are considered "symptomatic therapies".

Medicine - Creative Commons

Re-purposed and Off-Label Drugs:

Some drugs are re-purposed drugs already approved by the FDA for treating other ailments but are being tested for efficacy in treating Parkinson's. These are a drug company's dream as development costs are already covered and safety trials are already complete. Re-purposed drugs also have a safety track record with a lot of patients giving them a large statistical sample.

Drugs already FDA approved but for a different purpose can be prescribed "Off-Label" for Parkinson's disease. The FDA regulates drug approval, not drug prescribing which is the domain of the physician. More than one in five outpatient prescriptions written in the U.S. are for off-label use, so the practice is common in the field of medicine, but unfortunately it is not common in the field of neurology. Some physicians feel that off-label prescriptions can raise the risk of lawsuits and can expose patients to risky or ineffective treatments. Off-label prescriptions are also more likely to be challenged by healthcare insurance providers.

See Linked Clinical Trials (LCT) – The Development of New Clinical Learning Studies in Parkinson’s Disease Using Screening of Multiple Prospective New Treatments for a look at drug re-positioning of existing and approved therapies for Parkinson's disease.

Examples of trials of FDA approved drugs in trials to be re-purposed for Parkinson's:
  • Bydureon: type 2 diabetes (available "off-label" prescription)
  • Deferiprone: iron chelator
  • Ambroxol: used in the treatment of respiratory diseases
  • EPI-589: treatment for mitochondrial dysfunction
  • Liraglutide: type 2 diabetes
  • Nilotinib: leukemia
  • Lixisenatide: type 2 diabetes
  • Fasudil: inflammation
  • Simvastatin: high cholesterol treatment
  • Rucaparib: PARP inhibition
  • Nilotinib: cAbl inhibition
  • Nortriptyline: anti-depressant
  • ... and many more from the LCT effort ...

see info below for more details on these drugs.

Also see Therapies which target the gut microbiome.

Ambroxol

Ambroxol is a re-purposed drug to reduce the build-up of alpha-synuclein in neurons by using the GCase protein pathway to trigger exocytosis.
Phase 2 trial (London UK): NCT02941822 - dosage and toxicity study.
Also see: The Ambroxol Trial - The facts
Trial Results: Ambroxol for the Treatment of Patients With Parkinson Disease With and Without GBA Mutations (2020)
See below for more information on Ambroxol (Targeting GBA).

Immunotherapy For Parkinson's:

Prophelactic vacine against toxic mis-folded alpha-synuclein. This mechanism targets toxic (mis-folded, oligamer forms) alpha-synuclein on the move, outside the neuron cell walls by energizing the immune system and the generation of antibodies.

There are two forms of immunotherapy being tested for Parkinson's:
  1. Active immunization: inject a non-active fragment of the pathogen to trigger the immune system to generate resistance. The immune effect tends to be longer lasting.
  2. Passive immunization: artificially generated antibodies. The immune effect tends to be immediate.
Immunotherapies in trials:
  • PD01A/PD03A: AFFITOPE PD01A: phase 2 trials 2014, 2020 Austrian vaccine against alpha-synuclein using Specific Active Immunotherapy (SAIT) to target rogue proteins. Inject inactive alpha-synuclein to instigate the body to generate antibodies (as opposed to Biogen and Prothena approach to inject antibodies). Seek to show a decline in alpha-synuclein levels in the blood.
    Phase 1 trials (5 trial records 2014): NCT01568099, NCT01885494, NCT02618941, NCT02758730, and NCT02216188.
    phase 1 results
    Corporation: AFFiRiS AG Vienna Biocenter in Vienna, Austria and Sympath Research Project
  • PRX002/RG7935/RO7046015 (Prasinezumab): antibody therapy targeting alpha-synuclein. Prasinezumab is designed to block the cell-to-cell transmission of the aggregated, pathogenic forms of alpha-synuclein. Positive results were shown in halting Parkinson's progression and reduced motor function decline 35% after one year of treatment but they weren't good enough to meet the study's objective and is undergoing further development.
    Information: Roche patient information
    Trials conducted by Roche. Works well in transgenic mice: Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models (2014: NIH and Prothena) Reduced alpha-synuclein in the blood. Humanized IgG1 monoclonal antibody that targets aggregated C-terminally truncated form of alpha-synuclein that is considered neurotoxic, as well as alpha-synuclein propagation from cell to cell.
    phase 2 trials (also known as the PASADENA study) NCT03100149 (2017-current)
    phase 1b trials: NCT02157714 (2016)
    Corporation: Prothena Dublin/San Francisco and Hoffmann-La Roche Switzerland
  • Glycerol Phenylbutyrate: repurpose FDA approved drug to see if it can increase the removal of alpha-synuclein from the brain into the bloodstream.
    phase 1 trials NCT02046434 2020
    Institution: University of Colorado, Denver
  • BIIB054 (Cinpanemab): info
    human-derived monoclonal antibody passive vaccination targeting alpha-synuclein. Development discontinued Feb 2021
    phase 2 trials NCT03318523 2018 SPARK study
    phase 1 trials NCT02459886 2015
    Corporation: Biogen (Note: Biogen acquired Neurimmune and former drug NI-202)
  • LU AF82422: info
    monoclonal IgG1 antibody targeting the C-terminal of alpha-synuclein.
    phase 1 trials NCT03611569 2018
    Corporation: H. Lundbeck A/S and Genmab A/S
  • MEDI1341/TAK-341: info
    high-affinity monoclonal antibody to monomeric and aggregated alpha-synuclein. The antibody intercepted cell-to-cell spreading of human alpha-synuclein fibrils in cell culture and in a mouse model of alpha-synuclein pathology propagation in brain.
    phase 1 trials NCT04449484 2020
    Corporation: AstraZeneca and Takeda Pharmaceutical Company
  • PRX003: alpha-synuclein immunotherapy
    phase 1 results
    Research: Sympath Research Project
  • UB-312: enhanced synthetic peptide-based alpha-synuclein immunotherapy
    phase 1 trials NCT04075318 2020
    Corporation: United Neuroscience
  • ABBV-0805: info
    humanized monoclonal antibody targeting alpha-synuclein. Antibodies (PD1601, PD1602) bind oligomeric/protofibrillar alpha-synuclein with nanomolar affinity and high selectivity over monomeric protein. Pre-clinical mouse studies show reduced levels of alpha-synuclein oligomers and protofibrils in the central nervous system, less severe motor abnormalities and a doubling of the life-span after antibody treatment.
    phase 1 trials NCT04127695 2019
    Corporation: AbbVie (licensed from BioArctic AB)

Targeting alpha-synuclein:

There are multiple, fundamentally different approaches being taken in this domain:
  • Target DNA/mRNA so the body reduces the amount of the alpha-synuclein protein generated by cells thus starving any attempts of aggregation
  • Influence the clean-up of alpha-synuclein by neurons using autophagy or bind directly to alpha-synuclein to break-up Lewey bodies, fibrils and oligomers
  • Small molecule drugs to prevent the formation of alpha-synuclein oligomers, fibrils and Lewey bodies

These drugs are targeting the mal-folded protein which damage or kill neurons and is considered to be the fundamental cause of the disease.

  • Anle 138b: more info, more info on phase 1 trial
    Reduce intra-cellular oligomers and targeted specifically to processing toxic misfolded alpha-synuclein aggregations into smaller non-toxic variants of the protein to halt prion-like propagation, University of Cambridge
    phase 1 trials NCT04208152 (2020) and NCT04685265 2021 (UK trials)
    Corporation: MODAG GmbH (Germany)
  • ATV: aSyn high affinity antibody
    Corporation: Denali Therapeutics
  • MEDI1341: info
    phase 1 trials 2017
    Corporation: AstraZeneca (Partnered with Takeda)
  • NPT200–11: Three prong approach for this small molecule drug:
    • Inhibit aggregation of mis-folded proteins
    • Inhibit brain inflammatory processes
    • Rectify defects in the cellular mechanisms for clearing aggregates of mis-folded proteins
    phase 1b trials NCT02606682 2016
    Corporation: Neuropore
  • Nilotinib: re-purpose of a blood cancer leukemia drug FDA approved in 2010 as a therapy for Lewy body clean-up by enhancing autophagic clearance of alpha-synuclein.
    News release
    phase 1 trials NCT02281474
    phase 2 trials NCT02954978
    Corporation: Novartis
  • Radotinib/IY5511: re-purpose of a blood cancer leukemia drug FDA approved. A c-Abl inhibitor which exhibits improved pharmacokinetic properties and BBB penetration compared to nilotinib and other c-Abl inhibitors, was tested in a preclinical alpha-synuclein preformed fibrils (PFF) model of sporadic Parkinson's disease. Prevents dopamine neuron loss and behavioral deficits following alpha-synuclein PFFs-induced toxicity.
    phase 2 trials NCT04691661 (2021)
    Corporation: Il-Yang Pharm Co Ltd
  • Nortriptyline: re-purpose of an FDA approved anti-depressant as a therapy to combat the aggregation of alpha-synuclein. Nortriptyline does not clear toxic alpha-synuclein aggregates but interferes with the aggregation process and renders alpha-synuclein effectively more soluble and hence easier to clear within the cell. Part of a larger study of antidepressants in the treatment of Parkinson's disease (ADepT-PD). It is also hoped that it will help with depression and motor function.
    News description
    phase 3 trials NCT03652870 (2018)
    Institution: University College, London
  • PBT (Phenylbutyrate-triglyceride):
    Glycerol Phenylbutyrate: flushes alpha-synuclein to blood stream.
    trials NCT02046434
    University of Colorado, Denver Curt R Freed, MD
  • K0706 / SCC-138: an oral compound that acts as a suppressor of an enzyme called Abl tyrosine kinase which has been associated with oxidative stress and alpha-synuclein-induced neurodegeneration. PROSEEK study.
    phase 2 trials NCT03655236 2018
    phase 1 trials NCT02970019
    Corporation: Sun Pharma Advanced Research Company Limited (SPARC)
  • ANVS-401:
    alpha-synuclein aggregation inhibitor.
    Also see pipeline
    Corporation: Annovis Bios
  • NPT088: Antibodies. NPT088 is their first GAIM candidate targeted for Alzheimer’s but also hopefully useful for Parkinson's. Completed phase 1B.
    GAIM: General Amyloid Interaction Motif is a technological approach to break apart mis-folded protein aggregates.
    Corporation: Proclara Biosciences
  • UCB0599: Alpha-synuclein Oligomerization (a step in alpha-synuclein aggregation) Inhibitor. The Orchestra Study.
    phase 1b trials
    Corporation: Neuropore teamed with UCB pharma and University of California San Diego
  • ENT-01:
    Squalamine based. Targets the nerve cell membranes of the gut to prevent the aggregation of (and to displace) alpha-synuclein to treat constipation and improve bowel motility. One tablet daily.
    phase 2 trials NCT03781791 2021 "KARMET" study
    phase 2 trials NCT04483479 2021 "Roll-over" study
    Corporation: Enterin
  • IkT-148009:
    selective c-Abl kinase inhibitor that uniquely inhibits c-Abl and the closely related Abl2/Arg enzyme without inhibition of other members of the Abl-kinase family. C-Abl is a clinically validated target that is activated once plaques of alpha-synuclein are internalized by the affected neurons in the brain and gut. C-Abl drives biochemical pathways and processes that lead to degradation of the neurons affected in Parkinson's disease.
    phase 1 trials NCT04350177
    Corporation: Inhibikase Therapeutics Inc

Also see Ambroxol as it targets alpha-synuclein but is listed under the GBA pathway as it increases the production of the GCase enzyme defined by the GBA gene.
See "Targeting GBA" for more information on Ambroxol.

Neurotrophic Factors:

The goal of these drugs is to inhibit the progression and development of Parkinson's by restoring neurons and by inducing growth of new neurons by using neurotrophic factors. Early work in this area inserted tubes in the brain to deliver GDNF neurotrophic factors directly to the putamen with positive results including a 39% improvement in off-medication motor function and a 64% reduction in dyskinesias (ref: Gill). The effects were shown to be long lasting (3 yrs+) in a follow-up study (ref: Patel). Current efforts include drug development with techniques to pass through the blood-brain-barrier including small molecule development and gene therapy. GDNF is not the only neurotrophic factor as there is also neurturin, persephin, and artemin, all with positive/neuroprotective effects. Each also has a respective receptor which when bound will activate another surface protein called Ret proto-oncogene (RET) to result in cell growth and survival.
Also see the association of exercise and Brain Derived Neurotrophic Factors (BDNF) to neuron health.

Gene Therapy:

Gene Therapy attempts to treat Parkinson's by modifying DNA to correct genetic errors. Gene therapy is also used as a delivery mechanism for drugs which can not pass the blood-brain-barrier. This methodology uses a non-replicating virus which does not produce an immune response or illness (typically AAV: adeno-associated viruses) to carry the DNA instructions to manufacture a protein (the medication like a neutrophic factor) to a specific type of cell (dopamine neuron cells). In this way the medication is manufactured at the delivery location as opposed to performing a complex brain surgery to deliver the medication to Parkinson's affected regions of the brain.

Targeting Inflammation Response:

Drugs in this category are targeted at various inflammation pathways. Inflammation is usually a by-product of immune system activation and is meant to have a duration long enough to process a pathogen or heal tissue. When the inflammation becomes chronic it usually has harmful side-effects including cell death, specifically dopaminergic neurons in the substantia nigra in the case of Parkinson's disease.

Inflammation is a signalling mechanism whereby proteins or protein segments (peptides) are released to communicate with the immune system. The signal pathways are identified by their respective proteins or peptides (eg. GLP-1, Nurr1, CCR3, NLRP3, ...).

GLP-1:

Several GLP-1R agonists are approved for treating Type 2 diabetes, in which they ease insulin resistance and normalize glucose metabolism. In the brain, GLP-1R agonists improve glucose metabolism too, while also stimulating neurogenesis and neuron survival, and quelling inflammation. Weight loss may be problematic for some.

For more see:
  • details on GLP-1 and inflammation
  • Does Taming Killer Astrocytes Spare Neurons in Parkinson’s Disease? - how a GLP-1R agonist worked in mouse models of Parkinson’s disease
  • Clinical Trial Highlights – GLP-1 agonists (McFathing et al. Apr 2020)
    "Activation of the GLP-1R can reduce inflammation by preventing cytotoxic microglial responses and suppressing production of pro-inflammatory cytokines."
    "GLP-1R activation has also demonstrated multiple beneficial actions on mitochondria across a range of experimental models, resulting in reduced apoptosis and oxidative stress."
    "There are currently four GLP-1 agonists in clinical trials for PD. The most advanced molecule in this repurposing approach is exenatide." - study conclusions range from 2020 to 2024
    DOI: 10.3233/JPD-200002
  • The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action (2016)
    "GLP-1R stimulation is associated with an impressive array of positive actions that are relevant to PD pathogenesis, such as enhancing mitochondrial biogenesis, suppressing microglial activation and inflammation, enhancing autophagy, and clearance of aggregated proteins, and it is probably that it is this combination of actions that accounts for its positive effects in models of not only PD, but also AD, Huntington's disease, TBI, and ALS."
    DOI: 10.1016/j.drudis.2016.01.013

Insulin Resistance: Patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share a dysregulated insulin inflammation pathway in which insulin influences neurodegeneration.

Drugs targeting Glucagon Like Peptide-1 (GLP-1): hormone which signals the body to produce insulin and blocks glucose release.

  • NLY01: FDA approved for use in treating type 2 diabetes and shown to slow Parkinson's progression in transgenic mice. Neuroprotective and inhibits secretion of neuroinflammatory cytokines by microglial cells by targeting the GLP-1 signalling pathway. NLY01 was shown to have a neuroprotective property by mediating the behavior of microglia (immune system macrophage cells in the brain which act as immune sentinels orchestrating an inflammatory response) and their effect on astrocytes (cells that bridge nutrients from capillaries to neurons). Activation of microglia can cause them to release inflammatory agents which in turn cause astrocytes to shift to a dysfunctional reactive state which in turn leads to neuron cell death. NLY01 prevents the microglia from being reactive and making the astrocytes dysfunctional, thus NLY01 saves neurons. Half-life of 88 hours in primates which is an improvement over its predecessor Exenatide which had a half life of 2.5 hours. NYL01 is a pegylated version of exenatide with the advantage of increased blood-brain-barrier penetration and thus increased target engagement of central GLP-1 receptors, which in turn could prove more efficacious than its un-pegylated counterpart. Weekly injection.
    Also see: Phase 2 trials: NCT04154072 Dosage: 2.5 mg or 5 mg weekly injection for 36 weeks
    Trial study enrollment PRISM study - tweaked second round (no usage of levodopa medications allowed)
    Corporation: Neuraly, Inc
  • Exenatide (Byetta, Bydureon): FDA approved (2005) for use in treating type 2 diabetes and obesity. Not yet approved for Parkinson's but available as an "off-label" prescription. Not insulin but a GLP-1 agonist which increases the amount of insulin the pancreas releases. Targets the GLP-1 signalling pathway. Side effects include nausea, loss of appetite and weight loss. Weight loss can be extreme. FDA black box warning: increased incidence in thyroid C-cell tumors in rats (> 2 x clinical dose in male rats and 27 x clinical dose in female rats).
    Also see: Phase 2 trials: NCT04305002 Dosage: Injections, 2 mg once weekly for 18 months
    Institution: Center for Neurology, Stockholm Sweden
  • Lixisenatide: re-purposed FDA approved type 2 diabetes drug. Has neuroprotective properties in animal models of PD.
    Phase 2 trials: NCT03439943
    Corporation: University Hospital, Toulouse (France)
  • PT320: an ultrasonic spray drying technology that produces sustained release of Exenatide, an FDA approved drug to treat patients with Type 2 Diabetes and obesity. Injection once every two weeks.
    Phase 2a trials: NCT04269642
    Corporation: Peptron Inc (South Korea)
  • Liraglutide (Victoza, Saxenda): FDA approved (2010) for use in treating type 2 diabetes and obesity. For use by patients with a high body mass index (BMI) greater than 30 kg/m2 (overweight). Targets the GLP-1 signalling pathway with a longer half-life than exenatide (once daily injection). Side effects include thyroid cancer and pancreatitis. Daily injection.
    Information: study description: "There is reason to believe that liraglutide may prove superior to exenatide in treating PD."
    Phase 2 trials: NCT02953665
    Corporation: Novo Nordisk
  • Lixisenatide (Adlyxin): re-purposed FDA approved drug. Increases neurogenesis and decreased microglial activation. Daily injections.
    Phase 2 trials: NCT03439943
    Institution: University Hospital, Toulouse
  • Semaglutide: a weekly injectable dosage form branded as Ozempic by Novo Nordisk and approved by the FDA in 2017. An oral form of semaglutide, to be called Rybelsus, was approved by the FDA towards the end of 2019 and by the EMA in January 2020.
    Phase 2 trials: NCT03659682
    Institution: Oslo University Hospital
Bydureon BCise auto-inject

Bydureon BCise auto-inject pen: re-purposed type 2 diabetes drug in phase 2 trials as a treatment for Parkinson's: NCT04305002. Also available with an "Off-Label" prescription for Parkinson's treatment. It's a GLP-1 agonist (insulin signaling) acting to suppress inflammation. Expected to be more effective for high BMI patients with undiagnosed insulin resistance. Bydureon is an Exenatide based drug with a history of some success for Parkinson's: History of Exenatide and Parkinson's For more on insulin resistance, GLP-1 agonists, Bydureon and its derivative NLY01, see below.

Nurr1:

For more see details on Nurr1 and inflammation.
  • prostaglandin A1 and E1: increases Nurr1 effectiveness leads to an increase in dopamine levels, which then results in the treatment of Parkinson's disease. Nurr1 also limits inflammatory responses in the central nervous system and specifically protects dopaminergic neurons. The hormone like compound prostaglandin A1 and E1 bind to and activated the Nurr1 protein to protect dopamine neurons against neurotoxins. This research lead to the finding that three existing drugs (Chloroquine, Amodiaquine and Glafenine) activate Nurr1. This has not lead to human clinical trials but is the subject of a funded study by the MJF Foundation.
    Also see PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function

CCR3:

CCR3 is expressed on multiple leukocytes (shite blood cells) important to the allergic inflammatory response.
  • AKST4290-211: is a CCR3 inhibitor with two approach vectors, a broad anti-inflammatory mechanism and an immune modulatory mechanism through the body's innate immune cells. Convenient small molecule pill taken twice a day.
    Also see Alkahest: AKST4290: targeting Eotaxin
    Phase 2 trials: NCT04369430
    Corporation: Alkahest

NLRP3:

For more on NLRP3 see:

Other Inflammation Pathways:

  • NE3107: Neuroinflammation - an oral small molecule compound that is blood-brain permeable and may have the potential to inhibit neuroinflammation and insulin resistance. Nonclinical studies in marmoset monkeys have shown NE3107 administered alone to be as pro-motoric as levodopa.
    Phase 2 trials: NCT05083260
    Corporation: BioVie
  • NPT520-34: Neuroinflammation - receptor 2 antagonist small molecule drug that reduces the astrocytic and microglial of markers of neuroinflammation and neuropathology.
    Phase 1 trials: NCT03954600 completed 2019
    Corporation: Neuropore
  • NPT1220-312: Neuroinflammation & Autophagy: (TLR2 Antagonists) Toll-like receptor 2 (TLR2) antagonist that reduces markers of inflammation and neurotoxic protein burden including Parkinson’s disease patient-derived iPS neurons.
    Pre-clinical
    Corporation: Neuropore
  • Protein kinase-C (PKC5) inhibitor: info PKC plays a critical role in a number of functions from cell growth to death. Inappropriate activation contributes to the development and progression of cell death and neurodegenerative disorders. PKC5 offers a neuroprotective effect.
    Corporation: PK Biosciences Corp
  • 1R43NS110129-01: novel anti-neuroinflammatory agents for treating neurodegenerative disorders
    Corporation: PK Biosciences Corp
  • Sargramostim (Leukine): FDA approved (1991) for use in bone marrow transplantation treatment for immunomodulation and to stimulate the growth of white blood cells in your body.
    Phase 1 trials: NCT03790670
    Corporation: Partner Therapeutics, Inc
  • Fasudil:
    potent Rho-kinase inhibitor and vasodilator approved by the FDA to treat cerebral vasospasm and stroke, re-purposed to treat Parkinson's. Fasudil is highly active under conditions of inflammation and injury, and target inhibition by fasudil enhances axonal growth, regeneration, and promotes neurological recovery following spinal cord injury, making fasudil a promising therapeutic drug for neurological diseases.
    Research: Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease (2016)
    Trials: anouncement 2017
    Institution: Michael J Fox Foundation

Targeting LRRK2 Mutation:

These drugs are targeting patients with the gene LRRK2, identified as having a genetic link to Parkinson's.

  • DNL151:
    Phase 1b results published
    Phase 1b trials: NCT04056689
    Corporation: Denali Therapeutics
  • DNL201:
    Phase 1b trials: NCT03710707
    Corporation: Denali Therapeutics
  • BIIB094: antisense oligonucleotide (ASO) designed to bind to LRRK2 mRNA and mediate its degradation, reducing LRRK2 protein levels. Antisense oligonucleotide that targets the RNA that makes LRRK2
    Phase 1 trials: NCT03976349
    Corporation: Biogen

Targeting GBA Mutation:

These drugs are targeting patients with the GBA gene mutation, identified as having a genetic link to the levels of the lysosomal enzyme glucocerebrosidase (GCase) and Parkinson's disease. Generally the research shows an inverse correlation between GCase and alpha-synuclein but some research shows no statistical correlation at all (see references below).

  • AiM-PD/Ambroxol:
    Ambroxol: repurposed drug. Ambroxol breaks up phlegm, used in the treatment of respiratory diseases and indicated that it may reduce the build-up of alpha-synuclein in neurons for those with the single GBA gene mutation which interferes with GCase protein production. GCase is an enzyme found in lysosomes used to break down and recycle alpha-synuclein proteins and when deficient, alpha-synuclein aggregate within the neuron cell, making the neuron dysfunctional leading to the pathogenesis of Parkinson's disease. While Ambroxol targets the GCase protein pathway, Ambroxol is hoped to be effective for those who possess the GBA mutation and for those who don't. Ambroxol is believed to triggers exocytosis (cell waste removal rather than recycling) by lysosomes (ref).
    Phase 2 trial (London UK): NCT02941822 (targets alpha-synuclein aggregation via the GBA/GCase protein pathway)
    Phase 2 for treatment of Lewy body dementia (London ONT): NCT02914366 (see cognitive treatments below)
    Also see: The Ambroxol Trial - The facts
    Trial Results: Ambroxol for the Treatment of Patients With Parkinson Disease With and Without GBA Mutations (2020)
    "Ambroxol therapy has potential for study as a neuroprotective compound for the treatment of patients with Parkinson disease both with and without glucocerebrosidase (GBA) gene mutations."
    "In the acidic lysosome, ambroxol is eluted, allowing normal catalysis to resume and restoring lysosomal function." - upregulates alpha-synuclein recycling and exocytosis (eviction of alpha-synuclein from brain cells).
    "Evidence also suggests that ambroxol corrects posttranslational folding, mitigating unfolded protein response."
    "Mean scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (standard deviation: 7.1) points. These changes were observed in patients with and without GBA1 mutations."
  • S-181:
    Attempts to reduce the build-up of alpha-synuclein in neurons for those with the GBA gene mutation.
    Also see: A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease
  • BIA28-6156/LTI-291:
    Using pharmacological activation of the GCase enzyme to provide therapeutic benefits. LTI-291 is designed to target the GCase enzyme to increase activity and improve glycosphingolipid metabolism in the lysosome. Pre-clinical studies have shown that LTI-291 easily crosses the blood-brain-barrier and accesses the GCase enzyme within the brain and central nervous system. Phase 1 trials.
    Corporation: Bial bought Lysosomal Therapeutics
  • GZ/SAR402671 (Venglustat): repurposed drug. Showed promise in treating Gaucher’s disease. Development halted Feb 2021.
    Phase 2 trials: NCT02906020 (MOVES-PD study)
    Corporation: Sanofi Genzyme
  • Quetiapine:
    repurposed antipsychotic drug. Binds to the GCase enzyme, and increase levels of the enzyme in cells carrying a GBA-associated Parkinson’s mutation (c.84dupG frame-shift mutation). In a 15 day study with a GBA1 mutated mouse model, quetiapine raised GCase levels, reduced levels of alpha-synuclein accumulation in the brain and reduced levels of oxidized dopamine which is believed to contribute to lysosomal dysfunction. Further studies are needed to examine potential problems with quetiapine blocking dopamine receptors (D2 in particular), effects on blood pressure, constipation and mortality risks.
    Also see:

References:

The research does not agree on a common conclusion on GCase.

  • Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease Brain (Murphy et al, 2014)
    "This study suggests that glucocerebrosidase is reduced in association with the early abnormal accumulation of α-synuclein in sporadic Parkinson’s disease, leading to substantial alterations in lysosomal chaperone-mediated autophagy pathways and altered lipid metabolism."
    "The reduced glucocerebrosidase is likely to contribute to lysosomal dysfunction by altering lysosomal contents and membrane properties, exacerbating any age-related diminished lysosomal capacity."
  • Glucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity (Omer et al, 2021)
    "... no genotype–phenotype correlations were detected between GCase activity and disease severity measures."
    "... demonstrating a correlation between GCase activity and GBA genotype, but not between GCase activity and PD phenotype."
    "GCase activity does not seem to hold promise as a biomarker for disease risk or severity in PD but is rather an endophenotype of mutations in the GBA gene."
Ambroxol

Ambroxol is a re-purposed drug to reduce the build-up of alpha-synuclein in neurons by using the GCase protein pathway to trigger exocytosis.

Targeting Mitochondria:

Mitochondria are the energy source and metabolism for cells and if impaired, it increases the risk of alpha-synuclein mis-folding and aggregation. It has also been shown that alpha-synuclein mis-folding and aggregation impair mitochondria function. These drugs hope to help mitochondria health, neuron cell energy and protein processing and thus decrease alpha-synuclein mis-folding and aggregation.

Therapy for Cognitive Decline with Parkinson's:

  • AiM-PD/Ambroxol:
    Ambroxol: repurposed drug. Ambroxol breaks up phlegm, used in the treatment of respiratory diseases.
    Phase 2 for treatment of Lewy body dementia (London ONT): NCT02914366
    Phase 2 trial (London UK): NCT02941822 (see "Targeting GBA" above)
  • ANAVEX2-73 (blarcamesine):
    this drug is a protein and a Sigma-1 receptor agonist which serves as a molecular chaperone (assists with the folding of other proteins) and functional modulator involved in restoring homeostasis. The Sigma-1 receptor is located in the endoplasmic reticulum (ER) mitochondria-associated membrane. Sigma-1 acts as a chaperone to the IP3R protein and helps facilitate calcium flow from the ER under stress. Increasing Sigma-1 lowers ER stress, promotes synaptic plasticity and increase neurotrophic factors. When ER stress is high, misfolded proteins start to accumulate. The drug ANAVEX2-73 is expected to be neuroprotective and restorative. Study for Patients With Parkinson's Disease With Dementia.
    Information: drug mechanics
    phase 2 trials NCT04575259 2020 (Spain, Australia)
    Corporation: Anavex Life Sciences Corp
  • GRF6021: proprietary plasma-derived product, administered by intravenous (IV) infusion. Designed to replenish regenerative positive chronokines (circulating proteins that increase or decrease with age).
    Phase 2 trials: NCT03713957 completed 2020
    Corporation: Alkahest
  • Ceftriaxone:
    repurposed drug for the treatment of mild to moderate Parkinson's disease dementia (PDD). Found to have functions in reducing glutamatergic hyperactivity and excitotoxicity and may exhibit neuro-protective functions as the mechanism in PDD treatment.
    phase 2 trials NCT03413384
    Institutions: Chung Shan Medical University Hospital, National Taiwan University Hospital,Taichung Veterans General Hospital, Kaohsiung Medical University Hospital and Tungs' Taichung MetroHarbor Hospital
  • LY3154207:
    potential treatment for Parkinson’s disease dementia (PDD) (Lewy Body Dementia) by enhancing dopamine receptor D1, a dopamine receptor involved in cognition.
    phase 1 trials NCT02562768 2015
    phase 2 trials NCT03305809 2017
    Corporation: Eli Lilly and Company
  • SAGE-718:
    For Parkinson's patients with cognitive impairment.
    phase 2 trials NCT04476017 2020
    Corporation: Sage Therapeutics

Dopamine Therapy for Parkinson's Symptoms:

Drugs trying to improve on Levodopa and its variants by improving the side effects.

  • CVN424: anticipated to induce positive therapeutic effects similar to current Levodopa treatments for Parkinson’s while avoiding side effects such as dyskinesia. Selectively targets the dopamine D2 receptor-dependent, indirect pathway. Phase 2 trials
    Corporation: Cerevance
  • ND0612: Continuous Subcutaneous Infusion of Carbidopa and Levodopa. BouNDless Study.
    Phase 3 trial: NCT04006210
    Corporation: Xenoscience
  • Tavapadon: partial agonist used to balance signalling of neurons from the direct motor pathway (thalamus to the cortex D1/D5 receptors), and indirect motor pathways (D2/D3 receptors) to allow for proper motor control and avoid dyskinesias. Phase 3
    Phase 3 trial: NCT04223193
    Corporation: Cerevel
  • P2B001: contains low doses of the dopamine agonists pramipexole, and the monoamine oxidase-B inhibitor rasagiline.
    Phase 3 trial: NCT03329508
    Corporation: Pharma Two B Ltd.
  • JP-1730/Fipamezole: antagonist of an adrenergic receptor for the potential treatment for levodopa-induced dyskinesia
    Trial: NCT01140841
    Corporation: Bausch Health Americas, Inc.

Other Therapies:

  • Isradipine:
    approved by the FDA to treat high blood pressure. Isradipine may block the damage caused by the flow of certain chemicals through specialized channels that are present in the types of brain cells that are affected in PD patients.
    phase 3 trials NCT02168842 2020
    Institution: University of Rochester
  • Deferiprone:
    iron chelator approved by the FDA to treat iron overload, re-purposed to treat Parkinson's. Addresses high iron and oxidative stress that have been implicated in the neurodegenerative process of Parkinson's.
    phase 2 trials NCT01539837 2020
    Institution: Imperial College London
  • Nilotinib:
    Tyrosine kinase inhibitor antineoplastic agent approved by the FDA to treat leukemia, re-purposed to treat Parkinson's. Found to increase alpha-synuclein clearance and improve motor function.
    phase 2 trials NCT03205488 2020
    Institution: Northwestern University
  • Simvastatin:
    Neuroprotective Treatment for Parkinson's Disease. FDA approved treatment for cholesterol and triglyceride levels, re-purposed to treat Parkinson's.
    phase 2 trials NCT02787590 2020
    Institution: University Hospital Plymouth NHS Trust
  • Rucaparib: PARP inhibition
    a protein called PARP-1 is a key mediator of cell death via Parthanatos, supporting the potential therapeutic benefits of PARP inhibitors for halting Parkinson’s progression. Rucaparib is FDA approved as a treatment for ovarian cancer, re-purposed to treat Parkinson's.
    Press release: Road to cell death more clearly identified for Parkinson's disease 2018
    Institution: Johns Hopkins University School of Medicine
  • Nilotinib:
    FDA approved to treat leukemia, re-purposed to treat Parkinson's.
    phase 2 trials NCT03205488 2020
    Institution: Northwestern University
  • Pridopidine:
    this drug is a protein and a Sigma-1 receptor agonist being evaluated as a treatment for Levodopa-induced dyskinesias in Parkinson’s.
    phase 2 trials NCT03922711 2020
    Corporation: Prilenia
  • ITI-214:
    PDE-1 inhibitor
    phase 2 trials NCT03257046 completed 2018
    Corporation: Intra-Cellular Therapies Inc
  • Terazosin:
    Stimulates glycolysis via PGK-1
    phase 2 trials NCT03905811 2018
    Institution: University of Iowa
  • KM819:
    FAF-q inhibitor
    phase 1 trials NCT03022799 completed 2018
    Corporation: Kainos Medicine Inc
  • Leukine (Sargramostim):
    Recombinant GM-CSF. Potential motor control and mobility improvements.
    phase 1 trials NCT01882010 completed 2016
    Institution: University of Nebraska
  • TD-9855 (Ampreloxetine):
    For Parkinson's patients with symptomatic Neurogenic Orthostatic Hypotension (nOH) showing primary autonomic failures. Treatment for those displaying symptoms of low blood pressure where one feals dizy of faint from standing up from a seated or prone position. SEQUOIA study.
    phase 3 trials NCT03750552 2020
    Corporation: Theravance Biopharma

Clinical Trials:

One can participate or research trials at the following websites:

Pros:
  • Universities, biotechs and big pharmacological corporations are all trying to develop drugs to mitigate the effects of neurodegenerative diseases like Parkinson's disease. Registering to participate in a trial drug is a way to contribute to a cure and also, if not fed the placebo, a chance to experience improvement or even to potentially be cured. Repurposed and off-label use offers some immediate hope for existing drugs that have shown efficacy in Parkinson's disease modification.

Cons:
  • Not much progress is being made. While drugs exist to treat symptoms, little success has been found in halting the progression of neurodegenerative diseases or in reversing the neuron destruction. It's a very difficult problem.