Introduction

Levodopa was the first main, and arguably still the best, treatment for Parkinson’s disease. Being similar in structure to tyrosine, it is absorbed through the gut by an amino acid transporter – its half life in the blood is short, namely 0.7 to 1.4 hours. This has advantages in terms of avoiding peripheral dopaminergic effects and dopa decarboxylase inhibitors further reduce this latter effect.

The fact that the clinical action of levodopa is far longer than its half life is presumably due to presynaptic storage and control of release as dopamine and so it is no wonder that, as the disease progresses and there is increasing loss of the remaining presynaptic terminals, PD control from oral levodopa becomes more brittle and the clinician resorts to frequent dosing, longer acting agonists, delayed release preparations and even continuous intrajejunal delivery.

This review article, Profile of inhaled levodopa and its potential in the treatment of Parkinson’s disease, describes a further new delivery method, namely inhaled levodopa. This avoids the variability of gastric emptying and competing with the amino acids of food for absorption.

CVT301 inhaled levodopa is a complex of molecules in a large low density porous particle that can aerosolise and avoid phagocytic destruction in the lungs. The particles are readily absorbed through the alveolar membranes. The Arcus inhaler works by delivering the particles in dry powder form and requires the patient only to breathe in rather than also to activate a pump.

Phase I study

In a Phase I study, following safety trials in animals, plasma levodopa concentrations rose within 10 minutes of inhalation (they also took oral carbidopa) by healthy volunteers.

Phase II Study

Ini this study, patients with Parkinson’s disease and significant off periods had a median T max (time to max concentration ) of 15 minutes vs 66 minutes for oral, and clinical improvement (finger tapping) within 5 minutes and lasting 90-100 minutes.

Side effect of cough occurred in 25% which often settled after initial dose and was described as mild. There was less dyskinesia giving 50 mg than for oral 100 mg – but the study did not quantify the relative benefits of finger tapping tasks, so perhaps the oral was simply a bigger dose with more benefit and more side effects.

There were no differences in lung function between oral and inhaled groups after 4 weeks.

Phase III Study

There was a 12 week double blind, placebo controlled study in 339 patients with motor fluctuations randomised to placebo, 35 mg dose and 50 mg dose. Chronic lung disease was a contraindication.

Mean change on motor UPDRS at 12 weeks from pre treatment versus 30 minutes after treatment was -9.83 versus -5.91 for placebo (p = 0.009). There was no reduction in off time according to patient diaries; 85% of subjects completed the study. There were side effects of cough (14.5% versus1.9% placebo), URTI (6.1% v 2.7%), nausea (5.3% v 2.7%), sputum discolouration (5.3% v 0%), and dyskinesia (3.5% v 0%). Only two subjects discontinued due to cough. No statistically significant differences in FEV1 or diffusion capacity of lungs were found (but is this evidence for no effect on the lungs rather than no evidence for effect?).

Long-term studies

In a longer term open label study of 408 subjects, the treatment arm used a mean of 2.3 doses a day. After dosings at four weeks into the study, they experienced a mean UPDRS III change of -5.7 at 10 min, -12.0 at 20 min, -15.5 at 30 min and -16.1 at 60 min at 4 weeks and at 60 weeks the equivalent changes were -5.0, -11.5, -15.3, -14.8.

In another study, FEV1 and diffusion of carbon monoxide were not statistically different (!). Dyskinesia was worse; 5.5% versus 3.1% in the group with standard of care. Two of I think 100 subjects discontinued due to cough.

In a study of other subjects having morning off, subjects getting 50 mg inhaled levodopa came on in 25 mins vs 35 on placebo, and an on event was 35% more likely than after placebo.

The C max of the higher strength (50 mg) is 500 ng/ml while 100 mg oral achieves 700-1000 ng/ml. As the authors comment, there are no head to head comparisons of inhaled versus oral.

The authors conclude that inhaled levodopa is an option for rescue therapy.

Journal Club discussion

The data demonstrate only biological efficacy, and it does seem fast acting. There are not data on the quantitative effect versus oral levodopa or even the speed of action versus oral levodopa, dispersible levodopa or subcutaneous apomorphine. There appears to be no carbidopa or benserazide, so patients are going to be needing to take oral levodopa at around the same time or at least have had a decent amount fairly recently.

On a google search in March 2023, the cost is $1223 for 60 capsules of what is stated to be 45 mg but I think this is equivalent to 35 mg in the study. This might seem about a 1 month supply but no – one dose is two capsules. Patients had an average of 2 doses a day and the company specifies a maximum of 5 doses a day or ten capsules which is $204 a day!

In comparison, oral levodopa is $13 for 90 100 mg tablets. The 100 mg appears to be up to double the strength of the higher strength inhaled, which we presume is 2 capsules. So the cost of inhaled levodopa is over 500x greater than standard treatment. It does seem almost provocative not to attempt a comparison with standard care so much cheaper. We can surmise that perhaps inhaled might work about 15 minutes more quickly. The magnitude of benefit is demonstrated biologically but there is no comparison with oral. Measurements were made when the patients were rendered off to maximise the benefit rather than in a real world scenario dealing with unpredictable sudden off. Would the plasma concentrations as little as half that of 100 mg of oral really rescue such patients?

Regarding safety there are one year data. No worsened lung function was demonstrated but this does not mean there is evidence of no side effects unless the study was powered and the type B error quantified. We have many examples of preliminary data not showing the dangers revealed subsequently on post- marketing surveillance.