Inhaled levodopa for threatening impending OFF episodes in managing Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that leads to the degeneration of dopaminergic neurons resulting in a widespread pathology of motor and non-motor symptoms. Oral levodopa remains the most effective symptomatic treatment of PD, but motor complications such as Off episodes occur over time. The spectrum of manifestation of OFF episodes varies, e.g., early morning akinesia, end-of-dose wearing OFF, delayed ON, suboptimal ON and dose failure. The functional disability substantially impacts the quality of life for PD patients. An innovative on-demand therapy to treat Off episodes was approved for patients receiving oral levodopa/dopa deacarboxylase inhibitor: inhaled levodopa powder (Inbrija®). The pulmonary delivery of inhaled levodopa powder provides a predictable and fast treatment effect, independent of gastrointestinal dysfunctions or food intake, which could affect levodopa absorption. Levodopa is administered with a breath-actuated inhaler device and the approved dose is 84 mg per Off episode. During the pivotal SPAN-PD phase III trial, significant improvement in Unified Parkinson Disease Rating Scale III score was measured 30 min post-dose at week 12. Improvement was already seen for the first measured time point 10 min post-dose. No differences in pulmonary function was observed when using inhaled levodopa powder regularly for up to 12 months. Inhaled levodopa powder was also approved for early morning Off episodes. The aim of this review article is to give an overview of the different clinical studies of the innovative inhaled levodopa powder, a new on-demand therapy to treat Off episodes in PD.

High-dose versus low-dose inhaled levodopa (CVT-301) in patients with Parkinson disease for the treatment of OFF episodes: a meta-analysis of randomized controlled trials.

BACKGROUND: Levodopa is the most commonly used first-line drug for Parkinson's disease. However, during the period of medication, the generation of motor fluctuations affects the life quality of patients. CVT-301, as an inhaled levodopa for the treatment of OFF episodes, rose in response to this condition. METHODS: We systematically searched Medline, EMBASE, Cochrane Library, and Clinicaltrials.gov for relevant randomized controlled trials, from the earliest available date to February 12, 2022, to evaluate the efficacy of high and low dose of inhaled levodopa in patients with Parkinson's disease. RESULTS: A total of six multicenter, randomized controlled trials with 1166 patients were included. Compared with placebo, CVT-301 has a statistically significant effect on the treatment of Parkinson's patients with OFF episodes of medication interval. The UPDRS Part III score decreased more significantly in the high-dose group 30 minutes after administration than the low-dose group (WMD = - 4.51; 95% CI, - 7.34 to - 1.68; p = 0.002). More patients in the high-dose group achieved and maintained an on state up to 60 min after receiving study medication (RR = 1.17; 95% CI, 1.08 to 1.27; p < 0.001). And more patients were proved with improved PGIC scores in the high-dose group (RR = 1.13; 95% CI, 1.05 to 1.21; p = 0.001). CONCLUSIONS: High doses CVT-301 can improve the motor function of the patient to some extent. There seems no risk of increasing adverse reactions.

Indirect comparison of apomorphine sublingual film and levodopa inhalation powder for Parkinson's disease 'OFF' episodes.

Aim: To compare efficacy of apomorphine sublingual film (APL) and levodopa inhalation powder (CVT-301) for 'on-demand' treatment of Parkinson's disease 'OFF' episodes. Patients & methods: Patient-level data from an APL pivotal study were re-weighted to match average baseline characteristics from a CVT-301 study (SPAN-PD). Placebo-adjusted treatments were compared at week 12. Results: Improvements in predose Unified Parkinson's Disease Rating Scale Part III scores were significantly larger for APL versus CVT-301 at 60 min postdose (least squares mean difference-in-difference: -8.82; p = 0.002); difference at 30 min favored APL but was not statistically significant (-4.46; p = 0.103). Total daily 'OFF' time reductions were significantly larger for APL versus CVT-301 (-1.31 h; p = 0.013). Conclusion: Results suggest APL treatment may lead to improved efficacy versus CVT-301.

An evaluation of the efficacy and value of CVT-301 for the treatment of Parkinson's disease.

Introduction: Levodopa is the most effective drug in the treatment of Parkinson's disease, but its chronic treatment is linked to the occurrence of motor complications with fluctuations of motor performance and dyskinesia. Unpredictable OFF episodes can be severe and disabling and current rescue medications cannot always be used safely. Rescue therapy is characterized by a rapid and predictable ON response and the safety profile of levodopa will represent a major advantage for patients affected by unresponsive OFF episodes.Areas covered: CVT-301 is a new inhaled formulation of LD recently developed as a self-administered treatment for OFF periods. Herein, the pharmacodynamic and pharmacokinetic properties, efficacy, and safety of CVT-301 are reviewed.Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism, and less plasma level variability. It should be noted that the delivery device used has been described as relatively simple to use, but the few steps required to prepare and self-administer the dose can be challenging for PD patients during their OFF state. Additionally, resolution of an OFF episode requires the administration of two capsules of CVT-301, which further complicates the use of the device.

Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease.

PURPOSE: Levodopa (LD) is the most effective oral pharmacotherapy for the management of motor symptoms in Parkinson's disease. However, LD use is complicated by a progressive shortening of the duration of efficacy of a dose, resulting in episodes of inadequate responsiveness, or OFF periods. OFF periods may also occur unpredictably, partly due to the pharmacokinetic (PK) variability of oral LD, resulting from gastrointestinal dysfunction and from the effects of food on absorption. CVT-301 is a levodopa inhalation powder for the treatment of OFF period symptoms in patients on oral dopa-decarboxylase inhibitor/LD. PK and safety profiles of single dose CVT-301, administered with oral carbidopa (CD) and oral CD/LD, were examined in patients with Parkinson's disease in the fed state. METHODS: Eligible patients were aged 30-85 years, with a clinical diagnosis of Parkinson's disease and a body mass index of 18-32 kg/m2, and were receiving treatment with a stable regimen that included oral CD/LD (25/100 mg) (total LD, ≤800 mg/d). A high-fat/protein meal was eaten 4-5 h after the administration of the morning oral CD/LD dose. Blood samples for predose PK analysis were obtained after the meal, followed by a single inhaled dose of CVT-301 84 mg (+25 mg of oral CD) or oral CD/LD (25/100 mg) or vice versa in 2 dosing periods in a crossover design. Blood was sampled at 0, 5, 10, 15, 30, and 45 min and at 1, 1.5, 2, 3, and 4 h postdose. Tolerability assessments included treatment-emergent adverse events. FINDINGS: Twenty-three patients were enrolled (65.2% male; 87.0% white; mean age, 69.3 years; mean body mass index, 26.9 kg/m2; mean Parkinson's disease duration, 8.2 years; mean baseline LD dosage, 460.9 mg/d; 73.9% at Hoehn and Yahr stage <2.5). PK analyses were based on LD concentrations without baseline adjustment. Median Tmax values with CVT-301 and oral CD/LD were 15 and 120 min (P < 0.001). Cmax with CVT-301 was lower than with oral CD/LD (590.3 vs 844.3 ng/mL). C10min and C30min values with CVT-301 were approximately twice those with CD/LD (522.9 and 531.5 ng/mL vs 247.3 and 300.9 ng/mL, respectively). %CV for C5min to Cmax with CVT-301 was lower than that with oral CD/LD. The most common treatment-emergent adverse event was cough (CVT-301, 7 patients [30.4%]; oral CD/LD, 1 patient [4.5%]). IMPLICATIONS: PK properties showed that CVT-301 was more rapidly absorbed, with higher plasma LD concentrations in the first 45 min, and demonstrated lower interpatient variability, than was oral CD/LD in the fed condition. The study findings suggest that CVT-301 can be used without regard to food intake. ClinicalTrials.gov identifier: NCT03887884.

CVT-301 for the treatment of Parkinson's disease.

Introduction: For patients with Parkinson's disease (PD), the treatment of motor and nonmotor fluctuations is tantamount to maintaining quality of life. Subcutaneous apomorphine has been the only commercially available rescue therapy for the treatment of OFF episodes. In December 2018, CVT-301 (Inbrija), an inhaled formulation of levodopa (LD), was approved by the FDA for this indication. Areas covered: In this review, the authors summarize the armamentarium available to address motor fluctuations in PD, including medications in development. The authors discuss the pharmacological properties of CVT-301 as well as its efficacy and safety as reported in phase I, II, and III studies. Expert opinion: More than 20 medications or surgical procedures are available or in development to address motor fluctuations in PD. Deep brain stimulation (DBS) is an invasive but effective intervention at the end of the treatment spectrum. Less invasive therapies are used in combination to ameliorate motor fluctuations. Rescue therapies can help patients taking oral medications who experience delayed onset symptom relief (delayed ON), and unexpected wearing OFF by providing rapid and durable symptoms relief. CVT-301, an inhaled LD formulation, provides a safe and effective delivery mechanism that may be preferred by patients over subcutaneous injections.

Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson's disease.

BACKGROUND: CVT-301 (Inbrija) is a self-administered orally inhaled levodopa approved for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa. Prior studies only evaluated CVT-301 after the first ON of the day. OBJECTIVE AND METHODS: The objective of this study was to evaluate the safety and tolerability of CVT-301 for early morning OFF. Using a randomized, double-blind, 2-way crossover design, eligible patients in the morning OFF state (having not received PD medication overnight) received a single dose of CVT-301 84 mg or placebo on 2 dosing days, immediately after their first morning oral carbidopa/levodopa dose. Safety assessments included treatment-emergent adverse events, vital signs, and patient- and examiner-reported dyskinesia. An exploratory efficacy assessment was examiner-rated time-to-ON with carbidopa/levodopa + CVT-301 vs carbidopa/levodopa + placebo. RESULTS: Of the 36 patients (mean age 62.9 years) who enrolled and completed the study, 9 (25.0%) reported treatment-emergent adverse events following CVT-301 administration; 4 (11.1%) reported treatment-emergent adverse events following placebo. The most common adverse event was cough (4 [11.1%] for CVT-301 vs 1 [2.8%] for placebo), which was typically mild and transient. Incidence of asymptomatic orthostatic hypotension (CVT-301, 6; placebo, 7) and examiner-rated dyskinesia were similar for both (36-39% mild, 3-6% moderate, and 0% severe). Median time-to-ON was 25.0 min following carbidopa/levodopa + CVT-301 and 35.5 min following carbidopa/levodopa + placebo (P = 0.26). At 30 min, more patients had turned ON following carbidopa/levodopa + CVT-301 administration (66.7%), compared with carbidopa/levodopa + placebo (44.5%) (P = 0.040). CONCLUSION: Single doses of CVT-301 84 mg administered with oral carbidopa/levodopa for early morning OFF symptoms were well-tolerated, with no notable safety concerns.

Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson's disease.

INTRODUCTION: Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability. List of Abbreviations: PD: Parkinson's disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson's Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration.

Prospective evaluation of pulmonary function in Parkinson's disease patients with motor fluctuations.

BACKGROUND: Spirometry patterns suggesting restrictive and obstructive pulmonary dysfunction have been reported in Parkinson's disease (PD). However, the patterns' precise relation to PD pathophysiology remains unclear. Purpose/Aim. To assess ON- versus OFF-state pulmonary function, the quality of its spirometric evaluation, and the quality of longitudinal spirometric findings in a large sample of PD patients with motor fluctuations. METHODS: During a placebo-controlled trial of an inhaled levodopa formulation, CVT-301, in PD patients with ≥2 h/d of OFF time, spirometry was performed by American Thoracic Society (ATS) guidelines at screening and throughout the 4-week treatment period. RESULTS: Among 86 patients, mean motor impairment during an OFF state at screening was moderately severe. However, mean spirometry results at screening were within normal ranges, and in a mixed model for repeated measures (MMRM), the results at screening were not dependent on motor state (ON vs. OFF). In the placebo group (n = 43), 76% of ON-state and 81% of OFF-state examinations throughout the study met ATS quality metrics, and in an MMRM analysis, mean findings at these patients' arrivals for treatment-period visits showed no significant 4-week change. Across all 86 patients, flow-volume curves prior to any study-drug administration showed only a 3% incidence of "sawtooth" morphology. CONCLUSIONS: In PD patients with motor fluctuations, longitudinal spirometry of acceptable quality was generally obtained. Although mean findings were normal, about a quarter of spirograms did not meet ATS quality criteria. Spirogram morphology may be less indicative of various forms of respiratory dysfunction than has previously been reported in PD.

A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson's disease.

BACKGROUND: Although levodopa is the most effective oral PD therapy, many patients experience motor fluctuations, including sudden loss of dose effect and delayed benefit. CVT-301 is a levodopa inhalation powder with the potential for rapid onset of action. The objective of this study was to evaluate CVT-301 self-administered by PD patients to relieve OFF episodes. METHODS: PD patients with ≥2 hours per day of OFF time despite oral levodopa ≥4 times per day were randomized to CVT-301 or placebo for 4 weeks, to be used up to 3 times per day for OFF episodes. After 2 weeks, the study-drug dose was escalated from 35 to 50 mg. The primary end point was mean change in UPDRS Part III score from a predose OFF state to the average of postdose scores obtained at 10, 20, 30, and 60 minutes, as assessed in-clinic at the end of week 4. Home diaries were recorded. RESULTS: Eighty-six patients used the study drug at an average frequency of 2.1 times per day for CVT-301 and for placebo. At 4 weeks, least-squares mean change in UPDRS Part III score favored CVT-301 by 7.0 points (P < 0.001). A treatment effect was evident at 10 minutes. At 4 weeks, least-squares mean OFF-time change from baseline favored CVT-301 by 0.9 hours per day (P = 0.045). The most frequently reported adverse events in the CVT-301 group were dizziness, cough, and nausea, each in 7% (3 of 43 patients). CONCLUSIONS: CVT-301 self-administered during OFF episodes provided rapid improvement of motor function, and daily OFF time was significantly reduced at the higher dose. CVT-301 was generally safe and well-tolerated. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.