Parkinson’s Disease: How close are we to a cure?

Neurological disorders are the leading source of disability globally, and Parkinson’s is the fastest-growing neurological condition. It could be due to several factors ranging from an increase in geriatric population, longevity, improved diagnostics methodologies, a better understanding of the disease to the specific use of some pesticides, and industrialization. The number of individuals with Parkinson’s disease increased by 118% to 6.2 million globally (Global Burden of Disease, 2015) from 1990 to 2015. The total diagnosed prevalence is exponentially rising; and as per DelveInsight’s epidemiological estimates, the total diagnosed prevalent population of Parkinson’s disease in the 7MM (the US, EU5 (the UK, Germany, France, Italy, and Spain) and Japan) expected to reach 3,284,084 in 2030. 

However, there is still no cure for Parkinson’s. However, medications are at the place to improve the main symptoms of Parkinson’s disease, such as shaking (tremors) and movement problems. The present treatment options for Parkinson’s disease consists of medication, surgery, complementary therapies, and supportive therapies (such as diet, exercise, physical therapy, occupational therapy, and speech therapy). The approved Parkinson’s disease therapies are categorized into seven groups that include Levodopa, Carbidopa-levodopa infusion (Duodopa), Dopamine agonists (Mirapex, Requip, Neupro), MAO B inhibitors (Zelapar, Azilect, Xadago), Catechol O-methyltransferase (COMT) inhibitors (Tasmar, Comtan), Anticholinergics (Cogentin, Artane), and Amantadine. 

The choice of the treatment regimen to opt for varies with the stages of the disease, symptoms expressed, and ongoing medication course. Taking into consideration the stages of Parkinson’s disease, it can be either early-stage or late-stage. For the treatment of early-stage Parkinson’s disease (in patients who have been diagnosed with the disease for less than 5 years or those who have not developed motor complications from levodopa use), treatment with monoamine oxidase-B (MAO-B) inhibitors, amantadine (Symmetrel), or anticholinergics may modestly improve mild symptoms; however, most patients need levodopa or a dopamine agonist. 

In cases of late-stage Parkinson’s disease (patients already receiving carbidopa/levodopa treatment who have developed motor complications). It has been observed that after 5 years of treatment with levodopa, about 40% of patients develop motor fluctuations and dyskinesia. Some patients can undergo a “wearing-off” effect characterized by a shorter duration of benefit from each levodopa dose, causing parkinsonian symptoms to reemerge. On the other hand, others can experience an “on-off” effect characterized by unpredictable, abrupt fluctuations in the motor state from when the medication is effective, and symptoms are controlled (“on”) to when parkinsonian symptoms worsen (“off”). These motor complications are addressed with the help of a dopamine agonist, MAO-B inhibitor, or catechol O-methyltransferase (COMT) inhibitor.

Surgery is also an option in cases where Parkinson’s disease has advanced to extreme levels. Surgery may help in reducing the dependence of patients on drugs and medications. Majorly three types of surgeries are performed, namely lesion surgery (burning of tissue), deep brain stimulation (DBS), and neural grafting or tissue transplants. Approved in 2002, Deep brain stimulation is the most commonly performed surgical treatment. 

Depending upon the motor symptoms a Parkinson’s disease patient exhibits, the treatment regimen can also vary. Depression, dementia, and psychosis are common psychiatric problems associated with Parkinson’s disease. For depression, patients receiving levodopa, experiencing the wearing-off effect are given a selective serotonin reuptake inhibitor. Tricyclic antidepressants can also be used; however, it requires careful supervision and extra caution owing to their ability to exacerbate orthostatic hypotension and anticholinergic adverse effects. To manage drug-induced psychosis, Clozapine (clozaril) can be administered. However, in some cases, it has shown to result in causing potentially fatal agranulocytosis. Quetiapine (seroquel), albeit not evaluated extensively in a clinical setting, is commonly prescribed as it has reduced likeness to cause drug-induced parkinsonism.

The year 2020, however, witnessed several pharmaceutical companies coming up with their novel molecules to minimize the global burden of Parkinson’s disease. Recently, oral opicapone (Ongentys), a potent, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor of Neurocrine Biosciences embraced the Parkinson’s disease market as an adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults. Besides this, Sunovion announced the commercial launch of its sublingual film, KYNMOBI (apomorphine HCl) as a prescription medicine for short-term (acute), intermittent “off” episodes in people with Parkinson’s disease (PD).  

The most frequently prescribed combination drugs are carbidopa/levodopa (cocareldopa [sinemet, pharmacopa, atamet]) and benserazide/levodopa (co-beneldopa [Madopar]). Levodopa with a DOPA decarboxylase inhibitor is usually a first-line treatment option for Parkinson’s. According to a market assessment by DelveInsight, levodopa occupies the major chunk of the Parkinson’s disease market. Besides, other classes are also grabbing the market share nicely. Other than levodopa, dopamine agonists followed by amantadine, MAO-B inhibitors, and others (COM-T inhibitors, anticholinergic inhibitors, etc.) accounted for the major market share in the US in 2017. 

Undoubtedly, enormous progress has been made over the past half-century; nonetheless, levodopa remains the most potent drug for controlling Parkinson’s disease symptoms. It has helped patients living with Parkinson’s disease to upgrade their quality of life. However, despite the availability of a number of therapies, several concerns and issues remain unaddressed. While many promising candidates are there in preclinical studies, no drug or treatment strategy has proven to be neuroprotective or disease-modifying. The Parkinson’s disease therapeutics market lacks a curative approach and the burden continues to rise. To tread ahead in the road, there is a call out for novel therapies and advanced surgical management; and that will be possible only with the advanced research and investment into the domain. 

Looking at the current situation, pharmaceutical and biotech companies like Prevail Therapeutics, Axovant Gene Therapies, Neurocrine Biosciences/Voyager Therapeutics, Denali Therapeutics, International Stem Cell Corporation, Living Cell Technologies, and others have come up with their candidates that might prove to be a turning point in the Parkinson’s disease therapy market. Further, the market size of Parkinson’s Disease is estimated to surge during the forecasted period (2020–2030). DelveInsight believes that emerging therapies such as NBIb-1817 (Neurocrine Biosciences/ Voyager Therapeutics), P2B001 (Pharma Two B), LY03003 (Luye Pharma), LY30990 (Luye Pharma), and ABBV-951 (AbbVie) are expected to make the mark in the coming future. 

Stem cell therapies, gene therapies, growth factors, and various others are in the clinical trials underway for the treatment of Parkinson’s disease. The launch of upcoming therapies might prove to be a piece of bad news for the presently approved therapies as the pipeline therapies that target other aspects of pathology, namely genetic mutations, and Lewy bodies and are neuroprotective are anticipated to snatch quite a fruitful share of the Parkinson’s disease market. In the meantime, the Parkinson’s disease market has no other option but to rely on therapies that effectively manage symptoms.