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

 

Parkinson's Disease Drugs and Therapies in Trials:

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 Also, most do not make it to market and about 40% of drugs in completed trials go unpublished due to poor results (ref).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". 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. 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 repositioning of existing and approved therapies for Parkinson's disease.

Examples of re-purposed drugs:
  • Bydureon: type 2 diabetes
  • 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.

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.
    Glycerol Phenylbutyrate: 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) info. 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.
    PRX002/RO7046015: Roche patient information
    Trials conducted by Roche. Works well in transgenic mice.
    Corporation: Prothena Dublin/San Francisco and Hoffmann-La Roche Switzerland
  • BIIB054 (Cinpanemab): info
    human-derived monoclonal antibody passive vaccination targeting alpha-synuclein.
    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: alpha-synuclein immunotherapy
    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 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 propogation, 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
  • 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
  • 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
  • PBT (Phenylbutyrate-triglyceride):
    Glycerol Phenylbutyrate: flushes alpha-synuclein to blood stream.
    trials NCT02046434
    University of Colorado, Denver Curt R Freed, MD
  • UCB0599: Alpha-synuclein Oligomerization (a step in alpha-synuclein aggregation) Inhibitor.
    phase 1b trials
    Corporation: Neuropore teamed with UCB pharma and University of California San Diego
  • ENT-01:
    Squalamine based. Targets removal of alpha-synuclein in the gut.
    phase 2 trials NCT03781791
    Corporation: Enterin
  • K0706: 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.
    phase 2 trials NCT03655236 2018
    phase 1 trials NCT02970019
    Corporation: Sun Pharma Advanced Research Company Limited (SPARC)

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.

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: 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 cells) 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. Weekly injection. Phase 2.
    Also see: Phase 2 trials: NCT04154072
    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. Targets the GLP-1 signalling pathway. Side effects include thyroid cancer and pancreatitis. Weight loss can be extreme.
    Phase 2 trials: NCT04305002
    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.
    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

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

NLRP3:

For more on NLRP3 see:

Other Inflammation Pathways:

  • Inzomelid: developed by startup to commercialize inflammasome blocker
    Corporation: Inflazome Ltd
  • NPT520-34: Neuroinflammation - receptor 2 antagonist small molecule drug that reduces the astrocytic and microglial of markers of neuroinflammation and neuropathology.
    Phase 1 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:

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

  • DNL201, DNL151:
    Phase 1b results published
    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
    Corporation: Biogen

Targeting GBA:

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

  • AiM-PD/Ambroxol:
    phase 2 for Parkinson's. Existing re-purposed drugs NCT02941822
    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. Ambroxol is believed to triggers exocytosis (cell waste removal rather than recycling) by lysosomes (ref).
    Phase 2 trial: NCT02941822
    Also see: The Ambroxol Trial - The facts
  • 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
  • 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: Lysosomal Therapeutics

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.

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
    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:

  • 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
  • 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.
    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
  • 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
  • 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
Medicine - Creative Commons

Pros:

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.