Advances Broaden Treatment Options for Parkinson’s Disease Motor Symptoms

NAPLES, FL—Although levodopa remains the standard treatment for managing motor symptoms in patients with Parkinson’s disease, many new options are available, and others are in the pipeline. These options include novel modes of carbidopa–levodopa delivery, new adjunctive medications, and innovations in deep brain stimulation (DBS) therapy.

Stanley P. Fisher, MD

“The explosion of different therapies for Parkinson’s disease is quite exciting,” said Stanley P. Fisher, MD, at the 45thAnnual Meeting of the Southern Clinical Neurological Society. “However, the key is to address individualized management considerations, such as age, cognitive/psychiatric profile, and caregiver status.” Dr. Fisher is Codirector of Saint Luke’s Marion Bloch Neuroscience Institute and Associate Professor of Neurology at the University of Missouri in Kansas City.

Clinical factors to consider include fluctuations in symptom control as the disease progresses—specifically, wearing off (ie, re-emergence of symptoms prior to the next scheduled levodopa dose), on and off time (ie, unpredictable periods of good or poor symptom control), delayed on response (ie, dose takes longer to improve symptoms than previously), dose failure, and levodopa-induced dyskinesia, Dr. Fisher noted. Risk factors for developing dyskinesia include increasing doses of levodopa beyond 400 mg, female gender, low body weight, and earlier age of Parkinson’s disease onset, independent of how many years a patient has been taking levodopa.

Levodopa Preparations

“Levodopa has been used to treat Parkinson’s disease since the early ’70s, and its efficacy is well established,” Dr. Fisher said. “There has been an attempt over the years to create a perfect long-lasting levodopa.” In 1988, the FDA approved Sinemet, an immediate-release combination carbidopa–levodopa oral treatment. Carbidopa prevents the breakdown of levodopa before it crosses the blood–brain barrier, allowing lower doses of levodopa to be used. Sinemet CR (controlled release) has an unpredictable time of onset, Dr. Fisher said. “It should not be used during the day. But it may be helpful to prescribe this drug for use at night, when the time of onset is not critical.”

Parcopa, a carbidopa–levodopa preparation in the form of orally disintegrating tablets, was approved in 2004. “Clinically, it is not much different from Sinemet,” Dr. Fisher said. “However, it is expensive and should be used strictly by people who have difficulty swallowing.”

Duopa, which was approved in 2015, is a carbidopa–levodopa enteral solution delivered by a programmable pump via a transgastric jejunal tube. “It is an intestinal gel that is delivered continuously for at least 16 hours a day,” Dr. Fisher said. “The treatment effect tends to wear off at night, so if the patient does not have a caregiver to help them with the early morning akinesia, using this drug may be quite difficult.”

Rytary is a carbidopa–levodopa extended-release capsule approved in 2015. “The capsules have different beads that allow immediate, intermediate, and long-term release of levodopa, with a half-life of about five hours,” Dr. Fisher said. “Issues related to delayed on and lack of peak-dose effect have limited its widespread use. In addition, the dosing conversion from Sinemet is not intuitive.”

Phase III study results are anticipated for the experimental drug ND0612, a novel liquid carbidopa–levodopa formulation for subcutaneous administration via a pump patch. In a randomized double-blind placebo-controlled parallel group study, investigators are assessing a high dose and a low dose of ND0612 as adjunctive treatment to oral levodopa. Previous research had shown greater bioavailability of the drug with subcutaneous versus oral administration. One study found significantly reduced off time with treatment, with 42% of patients having no off time, Dr. Fisher said.

An inhaled levodopa, CVT-301 (Inbrija), has been submitted to the FDA. The treatment’s novel inhalation system “requires the patient to have intact pulmonary function and certain manual skills. It also requires that oral carbidopa be taken separately,” Dr. Fisher added.

Adjunctive Therapy

“When we started using dopamine agonists and other levodopa-sparing therapies in 1999, it changed the way we treat Parkinson’s disease,” Dr. Fisher said. “Generally, these agents are not as effective as levodopa and potentially have more adverse effects. However, there are some patients with tremor-dominant disease who may respond to dopamine agonists better than to levodopa. Also, for younger patients on 300 mg of levodopa who are not well controlled, prescribing additional dopamine agonists may be the way to go.”

Approved by the FDA in 2004, subcutaneous apomorphine (a non-ergoline dopamine agonist) is delivered via injector pen. Another mode of apomorphine delivery—infusion via injection pump—has been available in Europe for more than 25 years and is being assessed for use in the US. Studies have found that apomorphine infusion may significantly reduce off time and increase on time. The most common adverse effect was skin nodules at the infusion site. In addition, sublingual apomorphine has been studied in a phase III trial and may be available soon, Dr. Fisher said.

Safinamide (Xydago) is a monoamine oxidase type B inhibitor approved in March 2017 indicated for patients who experience off episodes. “While I do not see any dramatic benefit of using this drug, it has two-year data to show that it is safe and effective,” Dr. Fisher noted.

Immediate-release amantadine, an N-methyl-D-aspartate antagonist, has been used to treat Parkinson’s disease since 2003. However, its treatment effect is not well sustained, and multiple doses of the drug throughout the day are not well tolerated, Dr. Fisher said. Extended-release amantadine (Gocovri), approved in August 2017, confers a significant reduction in the Unified Parkinson’s Disease Rating Scale score when given at night. Adverse effects include dizziness, edema, and orthostatic hypotension. “Hallucination is particularly a problem in patients older than 65,” Dr. Fisher said. “The good news is that 57% of hallucination problems resolve within two weeks as patients adjust to the medication. So, it may be worth giving it a try.”

Deep Brain Stimulation

Approved in 2002, the implantable Activa DBS system by Medtronic is indicated for idiopathic Parkinson’s disease of at least four years’ duration in patients who have disabling motor symptoms despite being on an optimized medication regimen but continue, even if briefly, to respond to levodopa, Dr. Fisher said. Used as adjunctive therapy, it provides bilateral stimulation of the internal globus pallidus or the subthalamic nucleus. In one study, patients had significant improvements in on and off time after six months of surgery.

Similar benefits were found for the St. Jude Medical Infinity DBS system, which was approved by the FDA in 2015. The system includes directional lead technology designed to allow physicians to precisely steer current towards the desired structural areas, thereby maximizing symptom management and potentially reducing adverse effects.

The newest DBS system on the market is the Vercise system by Boston Scientific. “This is the only platform that allows independent current delivery to each of the 16 electrodes on the implanted leads,” Dr. Fisher said. “The rechargeable system has a battery life of more than 15 years.” Although the technology has been available in Europe for the last five years, the Vercise system was approved for use in the US in December 2017. Its approval was based on the results of the INTREPID study, the first multicenter, prospective, double-blind, randomized sham-controlled study of DBS for Parkinson’s disease in the US.

“The technology is truly amazing,” Dr. Fisher said. “How the systemperforms in clinical practice remains to be seen.”

—Adriene Marshall

Suggested Reading

Borgohain R, Szasz J, Stanzione P, et al. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord. 2014;29(2):229-237.

Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351(24):2498-2508.

Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord. 2005;20(2):190-199.

Pahwa R, Tanner CM, Hauser RA, et al. ADS-5102 (Amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): a randomized clinical trial. JAMA Neurol. 2017;74(8):941-949.

Schuepbach WM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610-622.