Parkinson’s disease: Unmet needs to be fulfilled by novel therapies and reformulations

LeachThe current global Parkinson’s disease market is characterized by a number of unmet needs, which include addressing the motor complications of dyskinesia and off-episodes. The recent approval of novel therapies and reformulations of existing drugs has the potential to fulfill some of these unmet needs, particularly in patients with advanced disease.

Related: FDA approves generic Comtan tablets for Parkinson's

Parkinson’s disease is the second most common neurodegenerative condition in the world, affecting 3.4 million people in the 8 major markets (8MM; United States, France, Germany, Italy, Spain, United Kingdom, Japan, Brazil) in 2014. According to GlobalData’s recent report, PharmaPoint, Parkinson’s Disease – Global Drug Forecast and Market Analysis to 2022, the prevalence of the disease is expected to increase to 4.3 million people by 2022.¹ This is due, in part, to an aging global population, as Parkinson’s is more prevalent in the elderly population.

In patients with Parkinson’s disease, a combination of risk factors, including age as well as environmental and genetic factors, leads to the loss of dopaminergic neurons within the substantia nigra and the accumulation of proteins known as Lewy bodies. The most frequent initial symptom is resting tremor. Other symptoms may include bradykinesia, a hunched gait, and loss of the sense of smell. As the disease progresses, bradykinesia, rigidity, and instability become more pronounced, causing moderate-to-severe disability in the later stages.^2,3

Current management

Initially, Parkinson’s disease is controlled by monotherapy, most frequently with levodopa, a dopamine agonist, or a monoamine oxidase B (MAO-B) inhibitor, such as Azilect (rasagiline, Teva Pharmaceuticals) and Eldepryl (selegiline, Somerset Pharmaceuticals) or Zelapar (selegiline, Valeant Pharmaceuticals). Combination therapy with levodopa and carbidopa is central to the management of Parkinson’s disease and is administered between 3 and 10 times per day. Most of the drugs used to treat Parkinson’s disease act on the dopamine pathway, either by increasing the concentration and bioavailability of the neurotransmitter, or by directly stimulating the dopamine receptors. The treatment of advanced Parkinson’s disease typically requires polypharmacy-the use of multiple classes of medications in combination-and more frequent doses of levodopa.^2,3

NEXT: New drug approvals

Polypharmacy: standard of care for motor complications in advanced Parkinson’s disease

Advanced Parkinson’s disease is difficult to manage due to the significant loss of dopamine receptors. The optimal concentration of dopamine is narrowed, and the pulsatile administration of levodopa leads to alternating periods of dyskinesia and off-episodes. Dyskinesia refers to uncontrolled movements caused by levodopa, and off-episodes are periods of bradykinesia that occur between doses of levodopa. Both are common motor complications in Parkinson’s patients and represent a major unmet need. In addition to the use of the drugs mentioned previously as monotherapies for early Parkinson’s disease, a catechol O-methyltransferase (COMT) inhibitor or an adenosine 2A (A2A) inhibitor may be added.^3,4 An alternative strategy to pulsatile levodopa administration is continuous administration of the drug, which holds promise for both early- and late-stage patients by preventing or delaying the emergence of motor complications and by offering superior control of these symptoms once they set in.

New drug approvals

January 2015 was a notable month for Parkinson’s disease, as 2 levodopa-based products gained FDA approval: Impax Pharmaceutical’s Rytary (carbidopa/levodopa extended-release capsule) and AbbVie’s Duopa (carbidopa/levodopa enteral suspension). The extended-release carbidopa/levodopa capsule is suitable for all patients requiring levodopa therapy. The carbidopa/levodopa enteral suspension is a gel that is delivered by a pump into the small intestine. This is only suitable for advanced patients, however, because it requires a medical procedure to make a stoma (small hole) in the small intestine to place a gastrojejunostomy tube for drug delivery.⁵

Related: FDA approves Rytary for Parkinson's disease

NEXT: Extended-release carbidopa/levodopa capsule improvement

New extended-release carbidopa/levodopa capsule improvement over immediate-release levodopa but reimbursement challenges

This carbidopa/levodopa extended-release capsule was approved for patients with both early and advanced Parkinson’s disease, with a lower starting dose recommended for patients who are naïve to levodopa. The APEX-PD trial enrolled 381 levodopa-naïve patients and used the Unified Parkinson’s Disease Rating Scale to assess the performance of activities in daily life and the control of motor symptoms, with patients randomized to the extended-release carbidopa/levodopa capsule showing significant improvements over those taking placebo.⁶ In a separate randomized trial, ADVANCE-PD, the extended-release capsule showed significant improvements over immediate-release carbidopa/levodopa in 471 patients with advanced Parkinson’s disease. The extended-release capsule showed a mean reduction in off-time of 1.17 hours and the additional benefit of less time with “troublesome dyskinesia,” compared with immediate-release carbidopa/levodopa.⁷

This new carbidopa/levodopa extended-release formulation has been shown to benefit both early and advanced Parkinson’s patients, and physicians agree that continuous levodopa therapy could theoretically prevent the emergence of off-time and dyskinesia when used as an early treatment. Its initial use, however, will primarily be for advanced patients. For early patients, the prohibitive cost of roughly $2500 per patient per year, compared with $450 per patient per year for a generic form of the immediate-release formulation, will discourage its use. Although this extended-release formulation is more expensive for advanced patients, who will use the drug more frequently, at an estimated cost of $5000 per patient per year, there are obvious benefits that outweigh the cost. In addition to the positive clinical trial data cited previously for the new extended-release capsule, patients on extended-release formulations may need fewer doses per day, which is a significant advantage for patients who require medications every 2 hours.

Carbidopa/levodopa enteral suspension meets needs of advanced patients but high price

FDA’s approval of the carbidopa-levodopa enteral suspension is a long-awaited win for Parkinson’s disease patients in the United States. Originally developed by Solvay, this formulation was approved in Europe in 2004, where it is marketed as Duodopa. In January 2015, it was approved in the United States as an orphan drug for late-stage Parkinson’s disease. In a phase 3 clinical trial, patients with late-stage Parkinson’s disease were randomized to this enteral suspension or an immediate-release oral formulation of carbidopa/levodopa. Patients treated with the enteral suspension had 1.91 fewer hours of off-time during the day compared with those treated with the oral drug. Furthermore, the enteral suspension was shown to increase the number of functional hours during the day without disability, as measured by on-time without dyskinesia.⁸ As well, because the enteral suspension is delivered via a pump, it frees patients from the significant pill burden and frequent drug administrations to which they have grown accustomed, although this was not measured in the clinical trials of the drug.

Although this enteral suspension is likely to change patients’ lives for the better, it is only expected to be used to treat a small subset of the Parkinson’s population due to its high price and the invasive nature of the therapy. With a price point of roughly $88,000 per patient per year in the United States, it far exceeds the cost of the next highest-priced Parkinson’s drugs on the market-US World Meds’ Apokyn (apomorphine hydrochloride injection) at $13,000 and Novartis’ Stalevo (carbidopa, levodopa, entacapone) at $10,500. In the European Union, reimbursement for the drug was met with roadblocks by the UK’s National Health Service (NHS). The NHS initially refused routine commissioning for the drug, a decision that was met with criticism, and as a result, was later reversed.⁹ One of the main criticisms of the NHS’ initial decision was that enteral suspension is typically reserved as a last line of therapy for patients who have exhausted all other options. It is often prescribed after deep brain stimulation, which involves the surgical implantation of electrodes in patients with late-stage Parkinson’s disease to control impairments in motor function.¹ The enteral suspension may face similar reimbursement issues with insurance companies in the United States. GlobalData expects that it will only be used for a small number of patients in the US, and will have a moderate impact on the US Parkinson’s disease market.

NEXT: Parkinson's disease market growth expected

Parkinson’s disease market growth expected through 2022

In addition to these major developments in the US Parkinson’s disease market, in February 2015, the European Medicines Agency approved Newron and Zambon’s Xadago (safinamide), which is a “me-too” MOA-B inhibitor. In March 2015, Newron and Zambon submitted a New Drug Application (NDA) to FDA for this product; a decision is expected in December 2015.¹⁰ Other drugs in the late-stage Parkinson’s disease pipeline include Acorda’s CVT-301, a phase 3 rescue therapy for off-episodes; Biotie’s tozadenant (SYN115), a phase 3 A2A inhibitor; and Bial’s opicapone (BIA 9-1067), a phase 3 COMT inhibitor. GlobalData expects the Parkinson’s disease market in the 8MM to grow from $3.3 billion in 2014 to $4.7 billion in 2022, due to novel product launches and an aging global population.¹

Read next: Study: Reduce long-term care use among patients with Parkinson's disease psychosis

References

GlobalData. PharmaPoint: Parkinson’s Disease – Global Drug Forecast and Market Analysis to 2022 – Event-Driven Update. June 2015.

Davie CA. A review of Parkinson’s disease. Br Med Bull. 2008;86:109–127.

National Collaborating Centre for Chronic Conditions. Parkinson’s disease. National clinical guideline for diagnosis and management in primary and secondary care. NICE Clinical Guidelines, No. 35. London, United Kingdom: Royal College of Physicians; 2006.

American Academy of Neurology. Treatment of parkinson disease with motor fluctuations and dyskinesias. Current guideline. April 2006. https://www.aan.com/Guidelines/Home/ByTopic?topicId=17. Accessed July 22, 2015

Duopa [prescribing information]. North Chicago, IL: AbbVie; 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203952s000lbl.pdf. Accessed July 22, 2015.

Pahwa R, Lyons KE, Hauser RA, et al; APEX-PD Investigators. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(2):142–148.

Hauser RA, Hsu A, Kell S, et al; IPX066 ADVANCE-PD Investigators. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol. 2013;12(4):346–356.

Olanow CW, Kieburtz K, Odin P, et al; LCIG Horizon Study Group. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141–149.

Newron Pharmaceuticals. Xadago (safinamide) New Drug Application (NDA) accepted for filing by the U.S. Food and Drug Administration (FDA). March 2, 2015. http://www.newron.com/user/download.aspx?FILE=OBJ00570.PDF&TIPO=FLE&NOME=FDA_FILING. Accessed July 22, 2015

NHS England. NHS England announces annual investment decisions for certain specialised services. July 2, 2015. http://www.england.nhs.uk/2015/07/02/annual-investment-decisions/. Accessed July 22, 2015.

Heather Leach is an analyst at GlobalData in New York City, covering immunology and neurology.