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Parkinson’s Disease Research Rajeev Kumar, MD Rocky Mountain Movement Disorders Center
Parkinson’s Disease Research
Rajeev Kumar, MD Rocky Mountain Movement Disorders Center
The Drug Development Timeline
Post-Marketing and
Life Cycle
Full Development
Exploratory Discovery
Full Discovery
Exploratory Development
Target ID Lead Discovery
Pre-IND toxicology and pharmacology
File IND – PHASE 1
Phase 2a Phase 2b/3
File NDA Phase 3b/4
Life Cycle
2-3 Years 3-7 Years 10+ Years 2 Years 2 Years
The average cost is $500 million to $800 million dollars. *
It takes 10 to 15 years for a drug to get from “bench to bedside.”
*Source: www.emedonline.com
Clinical research cannot not take place and new knowledge and therapies are not
possible without study volunteers!
• The majority of clinical studies have difficulty in enrolling participants, this leads to delays in study completion.
• More people with PD and those who know and love them need to participate in clinical studies.
• If this where to happen more studies would be completed sooner.
Parkinson’s Disease--Symptoms
motor non-motor
–cognitive & dementia
–depression & anxiety
–sleep
–autonomic
–sensory
Dopminergic neurons are vulnerable and have autonomous pacemaking mediated by calcium channels causing increased energey demands and oxidant stress.
Blocking L type calcium channels with isradipine is neuroprotective in animals models of PD
Epidemiological evidence of reduced risk of PD and slowed progression of PD in those taking calcium channel blockers.
Isradipine may slow progression of PD
Three year multicenter NIH-sponsored double-blind placebo controlled study
Newly diagnosed patients not yet on symptomatic therapy
Goal is to slow progression of PD
During the course of the trial, we expect that most patients will also require and will receive standard PD medication in addition to study medication
Isradipine as a Disease Modifying Agent in Early PD
Motor Complications
With advancing disease the L-dopa threshold for production of dyskinesias becomes less, while the antiparkinson threshold remains constant. The duration of effect of levodopa shortens causing motor fluctuations (wearing off).
Adenosine A2a receptors are found in the striatum on neurons of the indirect pathway.
Adenosine Receptor Antagonists
Dysfunctional Motor Control in Parkinsonism
Lang and Lozano, NEJM
Istradefylline improved motor fluctuations without increasing dyskinesias and reduced off time about 2 hours per day in prior studies. It is an approved drug in Japan.
Istradefylline for Motor Fluctuations
We are conducting an international phase 3 study
–12 week, double blind placebo controlled
–Patients must have at least 2 hours of off time per day
–Study drug will be added to current levodopa and other PD medications
–2 different drug doses vs. placebo
Istradefylline
This is another adenosine A2a receptor antagonist and in phase 2 studies also reduced off time by more than 2 hours without increasing dyskinesias.
We are conducting an international phase 3 double-blind placebo controlled study followed by an open-label extension
Tozadenant
Taking levodopa orally results in slow absorption and may result in unpredictable efficacy resulting in off-episodes
Injectable apomorphine is approved by the FDA for treatment of off-episodes, but is difficult to use for many patients
Inhaled levodopa results in rapid and predictable absorption
Inhaled Levodopa
In Phase 2 trials, inhaled levodopa improved off-episodes in about 10 minutes and reduced off time on average by 1.6 hours per day with patients taking on average 2 doses per day
We will be conducting phase 3 studies assessing the safety and efficacy of inhaled levodopa for treatment of off-episodes in patients with motor fluctuations
Inhaled Levodopa
Amantadine is a highly effective drug for treatment of levodopa-induced dyskinesias in PD.
Adverse effects from amantadine are very common including hallucinations, swelling of the feet, dry mouth, and constipation
Amantadine
Dissociation of dyskinesias and parkinsonism with amantadine
NMDA antagonists such as amantadine (300-400 mg/day) and significantly reduce LID without affecting L-dopa’s antiparkinson effect.
In phase 2 studies, extended release amantadine was well tolerated, significantly reduced dyskinesias in 75% of patients (reduced troublesome dyskinesias an average of 3 hours per day).
We are about to conduct a phase 3 double-blind placebo controlled multicenter study of extended release amantadine
Patients must have troublesome dyskinesias and cannot have previously discontinued use of standard amantadine due to side effects
Extended Release Amantadine
Parkinson’s Disease--Symptoms
motor non-motor
–cognitive & dementia
–depression & anxiety
–sleep
–autonomic
–sensory
Constipation is present in up to 80% of PD patients and it is often troublesome. The mobility of the gut is affected early in PD.
We are conducting a phase 2 proof of concept study of RM-131.
–This is a synthetic analog of the naturally occurring hormone ghrelin which promotes gut mobility.
–Highly effective in phase 2 studies of non-PD patients with chronic constipation and patients of diabetes affecting the gut causing constipation.
MOVE-PD
Double-blind placebo controlled 4 week study of once per day drug administration vs. placebo.
Patients must have bothersome constipation and are able to have only 3 or fewer bowel movements per week.
PD medication must remain stable during the study.
MOVE-PD
Skin Biopsy Study We hope to develop a new diagnostic tool for PD
There is preliminary evidence supporting the presence of alpha-synuclein deposits in skin. The results have been highly variable from study to study possibly based on skin sampling and analysis techniques.
We hypothesize that alpha-synuclein is present in the skin of patients with Parkinson’s disease (PD), which is not evident in patients with multiple systems atrophy (MSA), progressive supranuclear palsy (PSP), and healthy individuals.
Potential eligible subjects must have a diagnosis of PD, MSA, or PSP, and must be 50 years of age or older.
After a telephone pre-screen visit, potential subjects will be asked to come into the clinic for a screening visit and skin biopsy.
The field of Parkinson’s disease research is advancing extremely quickly and there is great hope that we will be able to deliver more effective therapies soon.
We need your help and participation to make this a reality.
