Disease-modifying treatments with breakthrough effectiveness remain a long-term proposition for Parkinson disease (PD). The alleviation of symptoms will continue to be the mainstay of PD therapy for many years because of the lack of disease-modifying options in the near to medium term. No drug has yet proven to be neuroprotective or disease-modifying in PD in clinical trials to date. None has been shown to delay, slow, halt, or reverse the relentless underlying progression of the disease either.
Efforts to develop disease-modifying treatments for PD and other neurodegenerative diseases have been crippled by the lack of understanding of the underlying pathogenesis, which precludes the identification of valid drug targets and effective mechanisms of action. Genetic studies of PD have revealed useful but far from conclusive information about the etiology or pathological mechanisms underlying PD.
Recently, some resources (e.g., Parkinson’s Disease Foundation project) have been shifted toward methods for the identification of early-stage disease and biomarker studies. It is hoped that these research-stage approaches will reveal some of the basic science mysteries of the progressive neurodegeneration of PD and eventually lead to the discovery and development of effective preventive interventions. Clearly, effective prevention or a cure is badly needed. PD patients relentlessly progress to increasingly and eventually unmanageable motor function and other symptoms such as cognitive loss.
Unfortunately, current research suggests that disease-modifying drugs with breakthrough effectiveness remain perhaps 15 years away from routine clinical use. It is also unfortunate that large pharmaceutical companies appear to be backing away from investment in disease-modifying drugs for neurodegenerative diseases because of the lack of validated therapeutic targets, long development timelines, and high risk.
Biotechnology-based approaches such as gene therapy (e.g., growth factor in clinical development) and cellular transplantation (e.g., neuronal stem cells) offer novel, early-stage prospects for treatment of symptoms, although widespread utilization of surgical approaches is, at best, a distant prospect.
It is notable that many if not most of the drugs that have been tested for neuroprotection are already used in the treatment of PD (e.g., MAO-B inhibitors, dopamine agonists). The future demonstration of incremental, but statistically significant, neuroprotective effectiveness of a known PD drug would represent a true advance. Delaying or slowing progression even for a year or two would significantly benefit patients in terms of ability to move, productivity, and overall quality of life. It would also very likely reduce healthcare expenditures. However, a neuroprotective agent that delays or slows progression of PD for a limited period of time would simply delay, not reduce, the need for symptomatic treatment.
More effective drugs are needed to treat the symptoms of PD. Although treating the underlying cause of PD, not only the symptoms, is the ultimate goal of basic science research, the daily realities of the PD patient and unmet clinical needs demand a renewed commitment to the development of symptomatic therapies.
In fact, the development of carbidopa-levodopa, dopamine agonists of other drugs with dopaminergic activities has been a great success story—loss of motor function (sometimes so severe that the patient cannot move or talk) is the symptom, and restoration of motor function (albeit imperfectly) is the result of successful symptomatic treatment.
The lives of patients with PD who progress beyond the mild stage of the disease were dramatically improved by the introductions of levodopa and the dopaminergic agents that followed it. Patients treated with dopaminergic drugs may experience five, ten, or many more years of good motor function and quality of life.
Patients with Alzheimer disease or amyotrophic lateral sclerosis do not have the option to take drugs with a similar degree of effectiveness against the symptoms of their diseases. On the other hand, patients with multiple sclerosis have benefited greatly from new drugs introduced during the last 20 years that hold their symptoms in check, although often not completely or consistently. Unfortunately for the patient with PD, the available drugs become less effective over time and disease symptoms re-emerge and adverse effects occur.
The problem of ineffective management of the symptoms of PD is large and growing. More than one million Americans suffer from PD, and the number might be as high as 1.5 million, according to the Parkinson’s Disease Foundation. Worldwide estimates of the number of people suffering from PD range from 4 to 10 million. As a disease that affects people who are in their 50s or older, the prevalence of PD is increasing rapidly as the population ages in much of the world. The number of people affected in the U.S. will nearly double in the next 20 years as the 65+ population increases from 41 million in 2010 to 73 million in 2030 (UN Population Division), and demographic projections are similar for many other parts of the world. The economic burden in the U.S. will more than double in the next 30 years, from $23 billion in 2010 to $50 billion by 2040.
The loss of effectiveness of dopaminergic drugs and onset of adverse effects has a huge impact on an individual’s motor function, productivity, quality of life, and overall psychological state. Patients experience a frustrating loss of interior locus of control over their lives when motor symptoms that were once well controlled no longer respond to dopaminergic agonists.
Some 65% of all diagnosed and treated PD patients (moderate 50%; severe 15%) are defined as advanced patients who experience hypomobility episodes from once a week to several times a day. The motor deficits may be severe: 25–50% experience severe off-episodes during which they are unable to move or speak. Not all off-episodes are so severe, but all are disabling.
What is being done to help these patients? Innovative biopharmaceutical companies have taken the lead, with R&D ranging from work on biotechnology-based therapeutics and new chemical entities (NCE) to new formulations of well-established therapeutic agents such as carbidopa-levodopa and apomorphine. Development of established (or repurposed) drugs in novel delivery systems for the treatment of motor complications is based on the vast clinical experience with these drugs and pharmacological innovation.
For carbidopa-levodopa, and possibly the commonly used dopamine agonists, clinical experience suggests that continuous drug delivery and continuous dopaminergic stimulation will reduce off-episodes. For apomorphine, a potent dopamine agonist administered by subcutaneous injection for the rescue treatment of off-episodes, the challenge is to develop a fast-acting noninjectable formulation.
An approved drug that has been reformulated to improve delivery characteristics may have a shorter path to FDA and EMA approval, which can reduce development time and make them available to patients sooner than the time frame required to discover and develop an NCE.
The point is to provide more effective and accessible treatments for the motor complications experienced by patients with PD as soon as possible. Today, patients in their 60s with PD, want to live full lives, as free as possible from the symptoms of PD.
The long-term hope is for a preventive treatment or cure for this devastating disease. However, the immediate and foreseeable need for symptom control and maximized restoration of motor function requires deployment of significant R&D resources to speed the introduction of new drugs. Today, innovative biopharma companies focused on these needs are writing new chapters in the story of treating symptoms and improving motor function in the patient with PD.