Background

This dopamine replacement therapy is the mainstay of treatment for motor symptoms of Parkinson’s disease. Levodopa eases tremors, stiffness, and slowness of movement caused by loss of dopaminergic neurons. A prodrug, levodopa crosses the blood-brain barrier, where dopamine decarboxylase converts it to dopamine. Levodopa is formulated with carbidopa, a decarboxylase inhibitor that prevents the conversion to dopamine in peripheral tissues. This helps prevent the nausea and vomiting produced by levodopa alone, and enables delivery of higher doses to the brain.

Besides nausea, other common side effects are low blood pressure, confusion, and involuntary movements known as dyskinesias. Levodopa can also cause sudden onset of sleep, hallucinations, and increased risk-taking behavior. 

Over time, many patients on levodopa experience the intermittent return of symptoms. These periods are known as motor fluctuations or OFF periods, when the medication stops working between doses. This may be due to the progressive loss of dopamine neurons, or impaired absorption of drug as the disease advances. As patients require increasing doses, dyskinesias also increase, associated with peak drug concentrations. 

Levodopa does not improve non-motor symptoms of PD, or slow disease progression.

Findings

In 1975, the U.S. FDA approved the levodopa/carbidopa LD/CD pill, sold under the name Sinemet. Formulations include disintegrating tablets, and immediate or extended-release tablets, and are available as generics. Dosing is three or four times daily.

In 2015, the FDA approved two new LD/CD formulations, both aimed at smoothing out fluctuations in plasma concentration to lengthen the time of drug action and shorten OFF time (Jan 2015 news). Rytary (Amneal Pharmaceuticals) is an extended-release capsule, containing both immediate and slow-release levodopa. In a Phase 3 trial, it halved OFF time compared to oral LD/CD, with fewer doses needed per day (Hauser et al., 2013). An LD/CD intestinal gel (Duopa, Abbvie), delivered by continuous infusion into the small intestine via a feeding tube and portable pump, likewise reduced daily OFF time by almost two hours compared with immediate-release oral tablets (Olanow et al., 2014). Duopa requires surgical implantation of a feeding tube, and is used for advanced PD patients with severe motor fluctuations. Rytary was approved in Europe in 2015; Duopa has been available there since 2004.

In 2018, the FDA approved an inhaled powder formulation of levodopa as a rescue treatment for OFF episodes occurring between oral levodopa doses. Inbrija (previously known as CVT-301, Acorda Therapeutics), delivers LD/CD to the blood stream in minutes, compared to up to an hour for the pill form (Safirstein et al., 2020). In a Phase 3 trial, an 84 mg inhaled dose outperformed placebo at improving motor symptoms 30 minutes after dosing during an OFF period in patients using oral LD/CD. The most common side effect was cough (LeWitt et al., 2019).

AbbVie is developing a new LD/CD formulation for continuous subcutaneous infusion. ABBV-951 contains foslevodopa and foscarbidopa, which are modified with phosphate groups to render them more water-soluble. A portable infusion pump delivers this combination under the skin of the abdomen. The goal is to smooth out the peaks and valleys of oral dosing, thus minimizing OFF time. In Phase 1 trials in healthy volunteers, the infusion produced consistent and stable plasma levels of levodopa (Rosebraugh et al., 2021; Rosebraugh et al., 2023). Delivery of drug was comparable to that of Duopa intestinal gel (Rosebraugh et al., 2022).

Between May 2017 and June 2019, AbbVie conducted two Phase 1 studies in people with PD. The first study assessed safety of single 24- or 72-hour infusions in 29 people in the lab. The second evaluated four weeks of continuous infusion at home in 20 people. In the single infusion trial, blood levodopa concentrations quickly reached steady state and remained stable over 72 hours (Rosebraugh et al., 2021). Results of the second study were presented at the October 2020 Movement Disorders Society conference. According to news reports, the continuous infusion improved symptoms during waking hours, most noticeably early in the morning. Infused patients had significantly less OFF time compared to a pre-infusion observation period (Aug 2021 Medscape news).

Phase 3 began in April 2019. An open-label study in 240 PD patients assessed safety and tolerability of continuous infusion for one year via a portable external pump. The primary outcomes are 48 clinical measures of safety; secondary outcomes include daily ON and OFF times, PD symptoms, and quality of life. The study was completed in August 2022; no results have been made public. A 96-week safety extension is planned to run until 2025.  

In October 2020, AbbVie began a 12-week Phase 3 study comparing ABBV-951 continuous infusion to oral LD/CD in 130 advanced PD patients. Half the participants received ABBV-951 plus placebo pills; the other half had a placebo infusion and active pills. The primary outcome is change in ON time without troublesome dyskinesias, based on patient diary reports. Secondary outcomes measure other symptoms and quality of life. In October 2021, AbbVie announced positive topline results (press release), and complete trial data were later published (Soileau et al., 2022). Patients taking ABBV-951 had significant increases in ON time without troublesome dyskinesia, and reductions in OFF time, compared to oral levodopa. The main side effects were non-serious infusion site complications. This trial has a 96-week open label extension, running until August 2023.

From January 2022 to March 2023, AbbVie ran an additional Phase 1 pharmacokinetic analysis in 16 patients to assess bioavailability from different infusion sites on the arm, thigh, flank, or abdomen.

In May 2022, AbbVie submitted a new drug application to the FDA (press release). The agency rejected it in March 2023, requesting more information about the pump device used to administer ABBV-951 (press release). The agency did not request additional trials.

For details on ABBV-951 trials, see clinicaltrials.gov.