PdCure.org

  Providing resources and ideas for cures 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.
  • 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.

The approach taken by the various drug companies differs and their efficacy may depend on the patient's root cause of the disease:
  • target inflammation pathway (avoid the mess)
  • target alpha-synuclein aggregation (clean the mess)
    (various pathways include immunotherapy)
  • target neutrophic factors (repair the mess)
  • target the genetic mutation (specific to those who possess LRRK2 or GBA mutations)

Immunotherapy For Parkinson's:

Prophelactic vacine against mis-folded alpha-synuclein aggregation.

Targeting alpha-synuclein:

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

  • ATV: aSyn high affinity antibody
    Corporation: Denali Therapeutics
  • MEDI1341: info
    phase 1 trials 2017
    Corporation: AstraZeneca (Partnered with Takeda)
  • Nilotinib: repurpose 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
  • 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
  • NPT200–11: Three prong approach:
    • Inhibit aggregation of mis-folded proteins
    • Inhibit brain inflammatory processes
    • Rectify defects in the cellular mechanisms for clearing aggregates of misfolded proteins

    phase 1b trials NCT02606682 2016
    Corporation: Neuropore
  • 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
  • Anle 138b: more info, more info on phase 1 trial
    Reduce accumulation of alpha-synuclein (Lewy bodies), University of Cambridge
    Corporation: MODAG

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.
Also see the association of exercise and Brain Derived Neurotrophic Factors (BDNF) to neuron health.

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:

For more see details on GLP-1 and inflammation.
  • 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 capilaries 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. Phase 2.
    Also see: Phase 2 trials: NCT04154072
    Corporation: Neuraly, Inc
  • 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. Side effects include thyroid cancer and pancreatitis.
    Phase 2 trials: NCT02953665
    Corporation: Novo Nordisk
  • 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.
    Phase 2 trials: NCT04305002
    Institution: Center for Neurology, Stockholm Sweden

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 - reduces the expression of markers of neuroinflammation and neuropathology. Phase 1 completed 2019
    NPT1220-312: Neuroinflammation & Autophagy: (TLR2 Antagonists) Reduces markers of inflammation and neurotoxic protein burden including Parkinson’s disease patient-derived iPS neurons.
    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 transplatation treatment for immunomodulation and to stimulate the growth of white blood cells in your body.
    Phase 1 trials: NCT03790670
    Corporation: Partner Therapeutics, Inc

Targeting LRRK2:

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

  • DNL201, DNL151:
    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. Preclinical 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:

Gene Therapy:

Gene Therapy attempts to treat Parkinson's by modifying DNA to correct genetic errors.

  • CERE-120: a gene therapy product designed to deliver the neurotrophic factor neurturin, for Parkinson's disease. Phase 2 fail
    Corporation: Ceregene Inc
  • AAV2-GDNF: glial cell line-derived neurotrophic factor (GDNF) gene therapy using the AAV gene therapy platform to slow or reversing Parkinson's disease progression.
    Phase 1 trial: NCT04167540
    Corporation: Brain Neurotherapy Bio, Inc and UCSF
  • OXB-102: a virus that modifies neurons so that they produce dopamine.
    Phase 2 trial: NCT01856439
    Corporation: Oxford Biomedica

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.
Medicine - Creative Commons


Pros:
  • Universities, biotechs and big pharmacological corporations are all trying to develop drugs to mitigate the effects of neurodegenerative diseases. One can participate or research trials at Fox Trial Finder

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.