Parkinson’s Disease

Public User Description.  This is the public user homepage for the Parkinson’s Disease (PD) Therapeutic Area.  There are currently numerous drugs approved for the management of PD, but there is room for considerable improvement in drug therapy.  New classes of agents and compounds targeted at the management of levodopa induced dyskinesia are under study.

The STEPh REPORT for Parkinson’s Disease reviews compounds and development programs currently under study from preclinical through NDA submission.  Information is reviewed in multiple formats:

  • mechanism of action
  • phase of development
  • projected year of approval

In addition, each compound has its own monograph that expands on the clinical efficacy and safety information reported during clinical trials.  Where available, links are provided to abstracts of relevant information such as published literature, SEC filings, and press releases.  The Parkinson’s Disease STEPh REPORT is kept current as new information becomes available (e.g., new reports are uploaded every other month).  After downloading the STEPh REPORT, you can select the bookmark function from the PDF file for easy maneurverability through the document.

The Parkinson’s Disease homepage also includes links to relevant resources, daily and archived PD news of interest, mini-reviews of Hot Topics, and a continuously updated Pipeline Table.

Access to the full Parkinson’s Disease STEPh REPORT as well all other information in the PD homepage is available by subscription.  Please feel free to contact us for more information about becoming an active subscriber to this and other services offered by STEPh Inc.

Table of Contents

  • TABLE OF CONTENTS (July 2013)
    • Background
    • Current Treatment
    • Challenges to Treatment
  • OVERVIEW OF PROJECTS IN DEVELOPMENT FOR PARKINSON’S DISEASE
    • Recently Discontinued Products
    • Compounds Available for licensing partnerning
    • Drug Targets
    • New Formulations of Marketed Drugs
    • Novel Dopamine Agonists
    • Adenosine Type 2A Antagonists
    • Neurotrophic Factors
    • Metabotropic Glutamate Receptor Modulators
    • Gene Therapy
    • Stem Cell Therapy
    • Levodopa Induced Dyskinesias
  • INDIVIDUAL DRUG MONOGRAPHS
    • Table 1. Phase of Development of PD Compounds in Development
    • Table 2. Earliest Possible Approval Date for PD Compounds in Development
    • Compounds in all phases of development

OVERVIEW OF PARKINSON’S DISEASE

Background

Parkinsons’ disease (PD) is a chronic neurodegenerative, debilitating disease that was first described nearly 200 years ago.  There are >1 million people afflicted with PD in the US, which makes it the second-most common neurodegenerative disease after Alzheimer’s disease.  PD is characterized by the selective loss of neuromelanin-containing dopaminergic neurons within the substantia nigra and the presence of protein-containing Lewy bodies comprised of multiple substances including α-synuclein.

Numerous theories have been proposed to help explain the etiology of PD and among these include:

oxidative stress (Shukla 2011),

proapoptotic mechanisms (Lev 2003),

mitochondrial dysfunction (Cardoso 2011; Cocksun 2011; Sato 2011), and

accumulation of toxic proteins from dysfunction of the protein degradation system (Olanow 2011).

 

Despite ongoing research, the etiology of PD is not fully understood.  PD is an idiopathic disorder that remains without cure and with only limited pharmacological choices for symptomatic treatment.  Loss of dopaminergic neurons results in depletion of dopamine and the emergence of parkinsonian motor symptoms.  Bradykinesia, tremor, and postural instability occur when a critical threshold amount (~70%) of dopaminergic neurons in the substantia nigra are lost.

Current Treatment

Levodopa has remained the cornerstone of therapy for more than 40 years.  However, despite the availability of various dopaminergic treatments, these are palliative at best and provide control of some symptoms (e.g., tremors, rigidity) but not more troubling ones such as gait freezing and postural instability. Current treatments do not halt the progression of the disease or completely ameliorate later stage symptoms.

It is unfortunate that as PD advances, dopaminergic therapies lose effectiveness over time.  Patients experience oscillations in motor response throughout the day and eventually a troublesome phenomenon of levodopa-induced dyskinesias [LID] (i.e., head bobbing, grimacing, oscillatory movements of the extremities), which can cause significant disability.  There are several theories regarding the development of LID.  Recent preclinical and clinical data have focused on the differential role of presynaptic versus postsynaptic mechanisms, dopamine receptor subtypes, ionotropic and metabotropic glutamate receptors, and non-dopaminergic neurotransmitter systems in the pathophysiology of LID (Calabresi 2010; Fisone 2011).  Discontinuous and intermittent delivery of levodopa to the brain results in non-physiologic pulsatile stimulation of striatal dopamine receptors.  Immediate-release formulations of levodopa have a short half-life of ~90 minutes, and this is thought to be the major causative factor in the pathogenesis of LID.

Challenges to Treatment

Current challenges to more effective therapy can be divided into 4 major categories and development efforts are ongoing in each of these areas:

Optimize delivery of levodopa

Eliminate and/or manage LID

Identify new treatment targets

Identify effective neuroprotective agents from a vast array of potential etiopathogenic mechanisms:  oxidative stress; mitochondrial dysfunction; neuroinflammation; pathways that regulate protein misfolding and aggregation.

 

What the Future Holds

There are currently ~90 development programs under study across multiple mechanisms of action.

Long-acting formulations of levodopa/carbidopa

Novel long-acting formulations of levodopa/carbidopa are likely to earn approval in the short-term.  They should reduce the occurrence of LID but not all will be available in easy to administer formats.

Dopamine agonists

A number of novel dopamine agonists have undergone initial clinical studies but several have been discontinued from further development as they did not offer significant benefits over pre-existing agents.  Thus, it is unlikely that newer dopamine agonists will impact future treatment strategies.

Adenosine type 2A antagonists

Adenosine type 2A antagonists have been demonstrated to reduce “off” time in patients on chronic levodopa therapy.  In addition, it has been suggested that they may be beneficial in patients early in the course of their disease.  Istradefylline had completed phase III studies but FDA determined that efficacy results from these trials did not merit approval.  It has been filed in Japan.  Initial results of Merck’s preladenant appeared to be promising but the compound was discontinued after disappointing initial efficacy data from 3 phase III studies.

α-synuclein Antagonists

Knowledge of α-synuclein and its potential role in PD has been known for some time yet pharmacological approaches aimed at modulating α-synucelin activity are in their infancy.   There are several ongoing projects but although these agents hold great promise, it remains to be determined if they will prove to be neuroprotective, or ineffective, in the treatment of PD.

Neurotrophic factors

This group of agents holds great promise for the treatment of PD due to their neuroprotective potential but initial enthusiasm has been tempered due to safety concerns and difficulties in administration.  The majority of neurotrophic factor development programs involve direct administration of the agent to specific sites within the brain and results of future studies of this class of agents may be impacted by infusion techniques.

Gene therapy

Several different gene therapy approaches for PD have been studied in patients and they have incorporated the adeno-associated virus (AAV) vector and a lentiviral vector as the gene delivery agent.  Agents are administered locally to the striatum portion of the brain and convert cells into a replacement dopamine factory within the brain that replaces the patient’s own lost source of the neurotransmitter.  Gene therapy offers promise but there are many hurdles to overcome before this approach can be commercialized.

Metabotropic Glutamate Receptor Modulators

The metabotropic glutamate receptor (mGluRs) modulators exert a neuromodulatory role in the control of both glutamatergic and GABAergic neurotransmission and have received attention as a therapeutic target for LID.  Only a handful of these agents are currently under study and it is unlikely that this class will revolutionize therapy.

Stem Cell Therapy

There is little data on the use of stem cell therapy for treatment of adults with PD.  Where reported, stem cell therapy showed a beneficial effect on symptoms in a limited sampling of patients, most often in patients with a disease duration of < 5 years.

There is at least one development program ongoing with neuronal stem cells, which is in preclinical development.

 

REFERENCES

Calabresi P, et al.  Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap.  Lancet Neurol 2010;9:1106-1117.    http://www.ncbi.nlm.nih.gov/pubmed/20880751 .

Coskun P, et al.  A mitochondrial etiology of Alzheimer and Parkinson disease.  Biochim Biophys Acta 2011;[Epub ahead of print].  http://www.ncbi.nlm.nih.gov/pubmed/21871538 .

Cardoso SM.  The mitochondrial cascade hypothesis for Parkinson’s disease.  Curr Pharm Des 2011;[Epub ahead of print].  http://www.ncbi.nlm.nih.gov/pubmed/21902669 .

Lev N, et al.  Apoptosis and Parkinson’s disease.  Prog Neuropsychopharmacol Biol Psychiatry 2003;27:245-50.  http://www.ncbi.nlm.nih.gov/pubmed/12657363 .

Olanow CW, et al.  Parkinson’s disease, proteins, and prions: milestones.  Mov Disord 2011;26:1056-1071.

Sato S, et al.  Genetic mutations and mitochondrial toxins shed new light on the pathogenesis of Parkinson’s disease.  Parkinson Dis 2011;doi:10.4061/2011/979231 .  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153940/pdf/PD2011-979231.pdf .

Shukla V, et al.  Oxidative stress in neurodegeneration.  Adv Pharmacol Sci 2011;2011:572634.   http://www.ncbi.nlm.nih.gov/pubmed/21941533

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