The Clinical Development of Levodopa Inhalation Powder

Abstract

Oral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa absorption, contributing to unpredictable control of OFF periods. Inhaled levodopa powder (Inbrija) is approved for on-demand treatment of OFF periods in patients receiving oral levodopa–dopa decarboxylase inhibitors. The 84-mg dose is administered via a breath-actuated inhaler. It provides pulmonary delivery of levodopa to the systemic circulation and is taken when a patient has an OFF period in between doses of regular oral levodopa medication. The pivotal SPAN-PD trial in patients experiencing OFF periods on oral dopaminergic therapy showed that levodopa inhalation powder 84 mg produced significant improvement in Unified Parkinson Disease Rating Scale Part III score, as measured 30 minutes postdose at week 12, and improvement was seen as early as 10 minutes. More patients in the levodopa inhalation powder group turned ON within 60 minutes of treatment and remained ON at 60 minutes than in the placebo group. Levodopa inhalation powder can also be used to treat early-morning OFF periods and, when used for up to 12 months, produced no clinically significant differences in pulmonary function compared with an untreated cohort. Levodopa inhalation powder 84 mg increased plasma levodopa concentration rapidly and with less variability than oral levodopa/carbidopa (25/100 mg). Most common adverse event associated with levodopa inhalation powder is cough, found in ~15% of patients in the SPAN-PD trial; otherwise, reported adverse events were consistent with those known to be associated with oral levodopa.

The neurodegenerative disorder Parkinson disease (PD) is characterized by both motor and nonmotor (autonomic, sensory, behavioral) symptoms. Motor features include bradykinesia, resting tremor, rigidity, gait disturbance, and postural instability and can limit patient function and quality of life. Dopaminergic medications such as oral levodopa have been used for decades to treat the motor symptoms of PD.^1,2 Initially, oral levodopa is highly effective to treat motor symptoms, but over time, many patients experience response fluctuations.^3–6 Symptom fluctuations consist of OFF periods (ie, times when symptoms reemerge despite the provision of antiparkinsonian therapy), which are in contrast to ON periods (ie, periods when symptoms are well controlled with antiparkinsonian therapy).³ The development of OFF periods is thought to be related to the short serum half-life of levodopa and the declining ability of the remaining dopamine neurons in the brain to take up levodopa, convert it to dopamine, and then release it into the synaptic space over many hours.^7–11 The situation is further complicated by worsening PD-associated gastroparesis because oral levodopa must pass through the stomach to be absorbed in the proximal small intestine.¹² Clinically, OFF periods can take the form of return of symptoms toward the end of a dose period (wearing OFF), sudden occurrence of symptoms at any time during a dose period (sudden OFF or unpredictable OFF), early-morning symptoms before a dose is taken (early-morning OFF), delayed benefit after taking a dose (delayed ON), lack of benefit after taking a dose (no ON), or return of symptoms at night (nighttime OFF).^3,5 OFF periods can include return of both motor symptoms (bradykinesia, rigidity, tremor) and nonmotor symptoms (anxiety, depression, “brain fog,” and others).^3,13–15

About half of people with PD will experience OFF periods within 4 to 6 years of oral levodopa treatment initiation, and about two thirds will experience them after 9 years or more.^5,6 For patients experiencing motor OFF periods, pharmacologic approaches may include adjusting the dose, dosing frequency, or formulation of oral levodopa or adding adjunctive, on-demand (intermittent), or infusion medications.⁵ Levodopa inhalation powder (Inbrija; CVT-301, Acorda Therapeutics, Ardsley, NY) and apomorphine are approved for the on-demand, intermittent treatment of OFF periods in patients with PD. Apomorphine is available in 2 formulations: the original subcutaneous injection (Apokyn; US WorldMeds LLC, Louisville, KY) and a newer sublingual formulation (Kynmobi; Sunovion Pharmaceuticals Inc, Marlborough, MA).

Patients with PD and their caregivers report a substantial clinical burden from OFF periods, leading to deterioration in quality of life.^16–18 On-demand therapy to treat OFF periods could help reduce functional and quality-of-life deficits among patients with PD and their caregivers by reducing motor fluctuations. In addition, OFF periods can exacerbate the economic burden of PD owing to factors such as patient functional decline, increased need for health care utilization, the inability to work consistently, and a reduced ability to be productive while working.^19–21 Taken together, these factors suggest that effective control of OFF periods is an unmet medical need for patients with PD, and that effective control of OFF periods would also benefit their caregivers. The purpose of this article is to review the pharmacokinetics, efficacy, and safety of levodopa inhalation powder for the intermittent treatment of OFF periods in patients with PD who are on a standard regimen of oral carbidopa and levodopa.

TREATMENT OF OFF PERIODS

Several pharmacologic approaches have demonstrated clinical utility when used as an adjunct to oral levodopa for treating motor fluctuations in patients with PD.²² These include nonergot dopamine agonists (eg, pramipexole, ropinirole, rotigotine), levodopa extended-release capsules or levodopa intestinal infusion, catechol-O-methyl transferase inhibitors (eg, entacapone, opicapone), monoamine oxidase B inhibitors (eg, selegiline, rasagiline, safinamide), and amantadine extended-release capsules.^22,23 Carbidopa is a dopa decarboxylase (aromatic l-amino acid decarboxylase) inhibitor (DDI) that inhibits the peripheral conversion of levodopa to dopamine, and it is routinely administered with levodopa. However, until 2018, subcutaneous apomorphine was the only treatment with an indication for as-needed relief of OFF periods. Dispersible levodopa tablets (eg, Madopar) that can be dissolved in water are approved in many countries outside the United States and are sometimes used for more rapid treatment of OFF periods, although they have the same disadvantages as other oral medications with respect to levodopa absorption in the gastrointestinal tract.²⁴

Subcutaneous apomorphine injection was approved by the US Food and Drug Administration in 2004 to treat acute, intermittent hypomobility or OFF periods (end-of-dose or unpredictable OFF periods) in advanced PD.²⁵ Apomorphine treats motor symptoms by stimulating postsynaptic dopamine D₂–type receptors.²⁵ Apomorphine is subcutaneously injected and can cause nausea and vomiting, so premedication with an antiemetic is recommended.²⁵ Sublingual apomorphine, approved in 2020, consists of a thin film that is held under the tongue, where it delivers the drug into the circulation across the buccal surface.^26,27 Because it does not require injection, it may be a more practical treatment for many than the subcutaneous route. Premedication with an antiemetic is recommended.

Levodopa inhalation powder was approved by the US Food and Drug Administration in 2018 for the intermittent treatment of OFF periods for patients with PD who are on an oral carbidopa/levodopa regimen,²⁸ and it has also been approved in Europe for those on any DDI/levodopa regimen. Levodopa inhalation powder is indicated for the intermittent treatment of OFF periods, between regular doses of oral carbidopa/levodopa, to be taken on an as-needed basis. The approved dose is 84 mg, consisting of 2 capsules, each containing 42 mg levodopa. The maximum approved number of doses per day is 5 (420 mg).²⁸ Levodopa inhalation powder relieves reemergence of symptoms of PD by crossing the blood-brain barrier, where it is converted to dopamine.²⁸

INTRODUCTION TO LEVODOPA INHALATION POWDER

Chemistry and Use of the Product

Levodopa ([2S]-2-amino-3-[3,4-dihydroxyphenyl] propanoic acid; C₉H₁₁NO₄) is an aromatic amino acid with a molecular weight of 197.19 g/mol. Levodopa inhalation powder is a large-particle dry inhalation powder formulation of levodopa that uses Arcus technology.^28–30 Arcus is an innovative technology platform that allows for the pulmonary delivery of drugs. The technology platform generates engineered, low-density, porous particles by spray drying that are easily dispersible and have an aerodynamic diameter of ~3 μm, which allows for deeper penetration into the lung. The technology allows for delivery of high doses (up to 50 mg) of medication through an inhalation device that is breath-actuated and can achieve delivered doses ranging from 0.05% to >90% drug load.^29–31 Levodopa inhalation powder is supplied in capsules containing 42 mg levodopa as the active ingredient in a spray-dried powder formula. Each dose comprises 2 capsules and is administered using a breath-actuated inhaler. Using the breath-actuated inhaler, each 42-mg capsule delivers a bioavailable dose of 36.1 mg levodopa for patients, with a peak inspiratory flow rate of 20 L/min/1 L to 90 L/min/2 L. This range encompasses the peak inspiratory flow rate observed for patients with mild to moderate PD experiencing an OFF episode (29–98 L/min).²⁸

Patient training is a key to optimizing outcomes with levodopa inhalation powder. To use the inhaler, the patient places a capsule in the inhaler, breathes in slowly and gently, and then holds their breath for a few seconds. A full dose is 2 capsules, each inhaled individually. More than 1 breath can be taken to empty the capsule, if required. Coughing is quite common on initial use. However, most patients have been observed to learn to inhale without coughing when provided with proper instruction and encouragement to practice until they learn the correct breathing pattern. Sipping liquid before and/or after inhalation can also help with cough. In the phase 3 clinical trials, virtually all patients were able to administer levodopa inhalation powder in an OFF state, and fewer than 2% dropped out due to cough.³⁰

Preclinical Pulmonary Study in Rats

In a 6-hydroxydopamine-lesioned rat model of PD, pulmonary (insufflated) administration of levodopa (not the current clinical formulation) demonstrated that inhaled levodopa resulted in a rapid increase in plasma levels of levodopa with peak concentrations (C_max) approximately 2.5 times that of an equivalent oral levodopa dose and with a mean time-to-peak concentration (t_max) of 4.7 minutes for pulmonary administration versus 24 minutes for the oral route. A more rapid improvement in bracing and akinesia motor performance tasks was achieved by pulmonary levodopa compared with oral levodopa.³² The results of this preclinical study provided a rationale for the use of pulmonary administration of levodopa in further studies.

Pharmacokinetics and Metabolism

Levodopa inhalation powder formulation is mostly levodopa with a trace amount of surfactant added. Its metabolism is through the same enzymes that act on the body's own production of levodopa, that is, monoamine oxidase type B, catecholamine-O-methyltransferase, and dopa decarboxylase (aromatic l-amino acid decarboxylase).³³ No isoenzymes are involved, and no glucuronidation or P450 enzymes are involved. Excretion is by the same means acting upon orally administered levodopa, as an O-methylated metabolite renally excreted, or as the byproduct of dopamine metabolism, homovanillic acid, also renally excreted.^33,34

The pharmacokinetics (PK) of levodopa inhalation powder was examined in beagles (n = 6) given both oral levodopa 125 mg and levodopa inhalation powder 50 mg. Carbidopa 25 mg was administered orally before both doses. Levodopa inhalation powder demonstrated a more rapid and sustained absorption versus a single oral dose of levodopa, with peak plasma concentrations achieved in 2.5 minutes with levodopa inhalation powder compared with 30 to 120 minutes with oral levodopa.³⁵

Pharmacokinetics in healthy human volunteers and in patients with PD and OFF episodes, under both fasted and fed conditions, similarly demonstrated more rapid increases and higher peak plasma concentrations for levodopa inhalation powder compared with oral levodopa.^35,36Table 1 shows the major levodopa inhalation powder trials in the clinical development program.

TABLE 1 - Key Levodopa Inhalation Powder Studies

Study	NCT ID	Phase	Study Type	Purpose	No. Randomized Participants	Treatment*	Treatment Duration	Reference
Study in healthy (non-PD) adult subjects
CVT-301-001	—	1	Open-label, single ascending dose	PK of levodopa inhalation powder in single dose (fed or fasted state), and ascending dose (fasted state)	18	• Oral carbidopa/levodopa (Sinemet 25 mg/100 mg) • Levodopa inhalation powder Ascending doses† - 10 mg FPD, 30 mg FPD - 20 mg, 50 mg FPD Single doses† - 40 mg FPD	2-Part study 1: dose escalation 3-period crossover, single ascending dose study 2: 2 single (40 mg FPD) doses with/without carbidopa pretreatment	Lipp et al 35
CVT-301-007	NCT02633839	1	Open-label, parallel group	Characterize the PK, pulmonary safety, and tolerability of levodopa inhalation powder of a single dose in smoking and nonsmoking adults	63	• Single-dose levodopa inhalation powder 84 mg†	72 h for dose administration and observation	Acorda Therapeutics, Data on File 30
CVT-301-008	NCT02633007	1	Double-blind, randomized, placebo-controlled, 2-period, crossover	Pulmonary safety and tolerability of levodopa inhalation powder in adults with asthma	26	• 3 doses 4 h apart† - Levodopa inhalation powder 84 mg - Placebo	2 period crossover: 1 day for each dosing period	Acorda Therapeutics, Data on File 30
Single-dose studies in patients with PD
CVT-301-009	NCT02807675	1	Multicenter, randomized, double-blind, placebo-controlled	Safety and tolerability study of levodopa inhalation powder when administered with the first carbidopa/levodopa oral dose of the day to treat early-morning OFF symptoms	36	• Levodopa inhalation powder 84 mg • Placebo	2-way crossover: 2 dosing days separated by 1- to 7-d interval	Hauser et al 37
CVT-301-012	NCT03887884	1	Multicenter, randomized, open-label	PK evaluation of a single inhaled dose of levodopa inhalation powder administered with oral carbidopa and a single orally administered dose of carbidopa/levodopa, under fed conditions	23	• Levodopa inhalation powder 84 mg + oral 25 mg carbidopa • Oral carbidopa/levodopa (Sinemet 25 mg/100 mg)	2-way crossover: 2 dosing days separated by 48-h interval	Safirstein et al 36
CVT-301-002	NCT01617135	2	Randomized, placebo-controlled	Safety, PK, and pharmacodynamics of levodopa inhalation powder	24	• Oral carbidopa/levodopa (Sinemet 25 mg/100 mg) • Levodopa inhalation powder - 25 mg FPD - 50 mg FPD • Placebo	4 separate in-clinic visits over a 2- to 6-wk period Patients received total of 4 treatments; 1 treatment per visit day	Lipp et al 35
CVT-301-003	NCT01777555	2	Randomized, double-blind, placebo-controlled	Efficacy and safety of levodopa inhalation powder	89	• Levodopa inhalation powder - 35 mg FPD - 50 mg FPD • Placebo	4 wk (2 wk 35 mg FPD, 2 wk 50 mg FPD)	LeWitt et al 38
Multiple-dose studies in patients with PD
SPAN-PD CVT-301-004 Pivotal phase 3 study	NCT02240030	3	Multicenter, randomized, double-blind, placebo-controlled	Efficacy and safety study	339	• Levodopa inhalation powder - 60 mg - 84 mg • Placebo	12 wk	LeWitt et al 39
CVT-301-004E‡	NCT02242487	3	Multicenter, dose-level blinded, long-term extension study	Pulmonary safety, safety	325	• Levodopa inhalation powder - 60 mg - 84 mg	12 mo	Farbman et al 40
CVT-301-005	NCT02352363	3	Multicenter, randomized, open-label, with observational cohort control	Long-term pulmonary safety study	408	• Levodopa inhalation powder 84 mg • None (observational control)	12 mo	Grosset et al 41

*All participants were on a standard oral DDI/levodopa regimen, except in CVT-301-001, 007, and 008.

†For each levodopa inhalation powder dosing, all participants also took 50 mg oral carbidopa every 8 hours on the preceding day and on the dosing day itself.

‡Extension of SPAN-PD study, but also enrolled former patients from CVT-301-005, CVT-301-009, and from an earlier study (CVT-301-003), if eligible.

DDI, dopa decarboxylase inhibitor; FPD, fine-particle dose; PD, Parkinson’s disease; PK, pharmacokinetics.

In one study, 18 healthy male volunteers were randomized to receive a single dose of oral carbidopa 25 mg/levodopa 100 mg in either the fasted or fed state (1:1); then half of them were randomized to receive 2 ascending doses of either levodopa inhalation powder 10 mg and 30 mg or 20 mg and 50 mg in a fasted state.³⁵ These levodopa doses represent the fine-particle dose (FPD), which is the quantity of levodopa estimated to reach the lungs. The mean levodopa plasma concentration 10 minutes after dosing was >6.5 times higher for levodopa inhalation powder than for oral levodopa in the fasted state, and approximately 40 times more than for oral levodopa in the fed state (729 vs 109 and 18 ng/mL, respectively), demonstrating the effect of gastrointestinal impairment of levodopa absorption. Levodopa exposure with levodopa inhalation powder was dose dependent, and it was associated with smaller between-subject variability in plasma levodopa concentrations compared with oral levodopa, as shown by lower percent coefficients of variation (%CV). For example, at 10 minutes postdose, %CVs were 30, 91, and 132 for levodopa inhalation powder, oral levodopa (fasted), and oral levodopa (fasted or fed), respectively.³⁵

Similar findings were reported in an open-label, in-clinic study of 24 patients with PD taking carbidopa/levodopa and experiencing ≥2 h/d OFF time (CVT-301-002, NCT01617135). Patients received a single dose of oral carbidopa 25 mg/levodopa 100 mg followed by placebo, levodopa inhalation powder 25 mg FPD, and 50 mg FPD, in randomized order and on separate days. Levodopa inhalation powder 50 mg was more rapidly and consistently absorbed than was oral carbidopa/levodopa, with a lower median t_max (15 vs 66 minutes). Within 10 minutes postdose, 77% of patients taking levodopa inhalation powder 50 mg demonstrated plasma concentrations >400 ng/mL, versus only 27% of patients taking oral carbidopa/levodopa.

A multicenter, randomized open-label study of 23 patients with PD (study CVT-301-012; NCT03887884) assessed the PK of a single dose of either levodopa inhalation powder 84 mg (50 mg FPD) plus oral carbidopa 25 mg versus oral carbidopa 25 mg/levodopa 100 mg³⁶ administered in the fed state. Patients received levodopa inhalation powder 4 to 5 hours after their regular morning oral dose of carbidopa/levodopa and immediately after consuming a high-fat, high-protein meal. Blood concentrations were measured over a 4-hour postdose period. Levodopa levels increased rapidly (within 5 minutes), and levodopa C_max was reached in a median time of 15 minutes after levodopa inhalation powder dosing, increasing from a mean ~350 ng/mL to ~630 ng/mL, then gradually declining to subbaseline levels by 4 hours postdose (Table 2, Fig. 1).³⁶ In contrast, a single oral dose of carbidopa/levodopa elicited minimal change in plasma levodopa concentrations, increasing from a mean 300 ng/mL predose and only rising to 340 ng/mL by 45 minutes postdose. A C_max of ~915 ng/mL was observed in a median time of 120 minutes postdose. As was observed in healthy volunteers, levodopa inhalation powder was associated with smaller between-patient variability in plasma levodopa levels compared with oral levodopa. This was evidenced by the larger 25% to 75% interquartile range around the median t_max for the orally administered levodopa of90 to 180 minutes versus the shorter 10 to 30 minutes for levodopa inhalation powder. The difference in the rate of uptake of levodopa likely demonstrates the slow rate of levodopa absorption owing to the food effect and/or delayed gastric emptying commonly found in patients with PD.¹²

TABLE 2 - Pharmacokinetics of Levodopa Inhalation Powder in Patients With PD

Variable	Levodopa Inhalation Powder 84 mg (n = 20)
tmax, median (range), min	15.0 (5.0–90.0)
t1/2, geometric mean (%CV), min	142.8 (41.8)
λz, geometric mean (%CV), h−1	0.0049 (41.8)
Cmax, geometric mean (%CV), ng/mL	590.3 (39.4)
AUC0-4h, geometric mean (%CV), ng·h/mL	1495.9 (36.9)

Reprinted from Safirstein BE, Ellenbogen A, Zhao P, et al.³⁶ Pharmacokinetics of inhaled levodopa administered with oral carbidopa in the fed state in patients with Parkinson's disease. Clin Ther 2020;42(6):1034–1046. Used with permission.

PD, Parkinson's disease; λ_z, terminal rate constant; AUC_0-4h, area under the concentration versus time curve from 0–4 hours postdose; C_max, maximum plasma concentration; t_max, time to reach C_max.

FIGURE 1: Plasma levodopa profiles in patients with PD after a single dose of oral carbidopa 25 mg/levodopa 100 mg or carbidopa 25 mg/levodopa inhalation powder 84 mg. A, Mean (SD) plasma levodopa concentrations. B, Individual plasma levodopa concentrations for levodopa inhalation powder. C, Individual plasma levodopa concentrations for oral carbidopa 25 mg/levodopa 100 mg. CD/LD, carbodopa/levodopa. Reprinted from Safirstein BE, Ellenbogen A, Zhao P, et al.³⁶ Pharmacokinetics of inhaled levodopa administered with oral carbidopa in the fed state in patients with Parkinson's disease. Clin Ther 2020;42(6):1034–1046. Used with permission.

CLINICAL EFFICACY

Phase 1 and 2 Studies

A phase 2 study (CVT-301-002 [NCT01617135]) assessed the clinical benefit of levodopa inhalation powder 25 and 50 mg in 47 patients with PD experiencing an OFF episode.³⁵ Parkinson disease assessments included timed finger tapping and changes in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III score. The UPDRS is a 4-part rating tool used to evaluate various aspects of PD including nonmotor and motor experiences of daily living and motor complications. Part III assesses motor function, and a lower UPDRS motor score indicates better function.

After a single dose of levodopa inhalation powder 25 mg FPD or 50 mg FPD, patients showed improvements at the earliest postdose time points (5 and 15 minutes, respectively) for both PD parameters, with improvements lasting 90 to 100 minutes postdose. With the timed tapping test (which provides a quantified and reproducible assessment of motor function in PD), statistically significant improvements over placebo were observed for both dose strengths at 15 minutes postdose (25 mg: +4.6 taps/30 seconds, P = 0.002; 50 mg: +5.2 taps/30 seconds, P = 0.0085) and 30 minutes postdose (25 mg: +4.8 taps, P = 0.0201; 50 mg: +5.0 taps, P = 0.015); for the 50 mg dose, differences versus placebo were also statistically significant for the average change from predose assessment (+5.1 taps, P = 0.0111) and best response (+8.0 taps, P = 0.0041). Levodopa inhalation powder 50 mg also elicited statistically significant improvements in average change (4.4 point difference; P = 0.0157) and best response (5.5 point difference; P = 0.0254) on the UPDRS Part III motor score versus placebo.

The efficacy of levodopa inhalation powder 35 mg FPD and 50 mg FPD versus placebo was assessed over 4 weeks in a phase 2, randomized, placebo-controlled study (CVT-301-003; NCT01777555) in 86 patients with PD and ≥2 h/d of OFF time despite treatment with oral levodopa ≥4 times per day.³⁸ The primary end point was the mean change in the investigator-assessed UPDRS Part III motor score from a predose OFF state to 10, 20, 30, and 60 minutes postdose at week 4. The proportion of patients achieving an ON state at each study visit and the self-rated Patient Global Impression of Change (PGIC) scores was also assessed. The PGIC asks patients to respond to the question, “How has the addition of study drug changed your PD?” The scale offers 7 ratings, from “much improved” to “much worse.” Across both doses of levodopa inhalation powder, onset of action was rapid, with a treatment effect apparent by 10 minutes and sustained throughout the 60-minute assessment period. At week 4, the mean UPDRS Part III motor score was 7.0 points lower (ie, improved) for patients who received levodopa inhalation powder versus those who received placebo (P < 0.001).³⁸ Treatment effects increased consistently over time as the dose increased from 35 to 50 mg. Of patients in the levodopa inhalation powder group, 79% and 58% achieved ≥6-point and ≥11-point reductions in the UPDRS Part III motor score within 30 minutes postdose, respectively, compared with 33% and 28% of patients in the placebo group. Patients reported 0.9 hours less OFF time with levodopa inhalation powder 50 mg versus placebo (P < 0.05). There was, however, no difference in the mean decrease in patient-reported OFF time for the 35-mg dose of levodopa inhalation powder versus placebo. A greater proportion of patients who received the study drug achieved an ON state than did those who received placebo at week 1 (levodopa inhalation powder, 67% [n = 28] vs placebo, 45% [n = 18]), week 2 (levodopa inhalation powder, 74% [n = 29] vs placebo, 41% [n = 16]), and week 4 (levodopa inhalation powder, 78% [n = 29] vs placebo, 36% [n = 13]). Finally, by the end of week 4, 72% of the study drug group and 46% of the placebo group had a PGIC score indicating an improvement in their PD, whereas 18% of levodopa inhalation powder recipients and 54% of placebo recipients had scores indicating no change in their symptoms.³⁸

Phase 3 Studies

Clinical efficacy of levodopa inhalation powder was evaluated in a phase 3 study (CVT-301-004 [SPAN-PD; NCT02240030]), its extension (CVT-301-004E [NCT02242487]), and a further safety study (CVT-301-005 [NCT02352363]). All three phase 3 studies enrolled patients with idiopathic PD, Hoehn and Yahr stages 1 to 3 in an ON state, and ≥2 h/d of OFF time. CVT-301-005 was designed primarily as a pulmonary safety study, and efficacy outcomes were only exploratory (see next section).

SPAN-PD was a pivotal, phase 3, double-blind, placebo-controlled study conducted in 339 patients randomized to receive levodopa inhalation powder 60 mg (35 mg FPD) or 84 mg (50 mg FPD) or placebo.³⁹ The primary end point was change in UPDRS Part III motor score from predose to 30 minutes postdose for levodopa inhalation powder 84 mg versus placebo at week 12, when patients were evaluated in-office during an OFF period. A 5-step hierarchical analysis was used to assess the following key secondary end points at week 12: the proportion of patients achieving and maintaining an ON state at 60 minutes postdose, change in UPDRS Part III motor score at 20 minutes postdose, the proportion of patients reporting improvement in PGIC scores, change in UPDRS Part III motor score at 10 minutes postdose, and change in total daily OFF time from baseline to week 12 (measured as the mean of 3 consecutive days).

The week 12 UPDRS Part III motor score improved by 9.83 points (95% confidence interval [CI], 6.87–12.79) for patients who received levodopa inhalation powder 84 mg (n = 114) and by 5.91 points (95% CI, 2.96–8.86) for patients who received placebo (n = 112; least squares mean difference, 3.92 [95% CI, 1.00–6.84] points; P = 0.0088) (Table 3). Significantly more patients achieved and maintained an ON response through 60 minutes postdose with levodopa inhalation powder 84 mg (56 of 97 patients, 58%) compared with placebo (35 of 97 patients, 36%; P = 0.0027) (Fig. 2). Statistical significance was not reached for the hierarchical step assessing change in UPDRS Part III motor score at 20 minutes postdose for the 84-mg dose (P = 0.06); thus, the subsequent secondary end points in the hierarchical sequence could not be considered statistically significant. Nonetheless, analyses of these secondary end points revealed numerical differences between study groups. Specifically, a larger percentage of patients who received levodopa inhalation powder 84 mg showed an improved PGIC score at week 12 than did patients who received placebo (71% vs 46%, respectively; nominal P < 0.001). Patients who received levodopa inhalation powder 84 mg also demonstrated a greater improvement in 10-minute postdose UPDRS Part III motor score compared with patients who received placebo (6.45-point improvement vs 4.18-point improvement, respectively; nominal P = 0.04). The results of the hierarchical analysis meant that the levodopa inhalation powder 60-mg dose results were not statistically significant compared with placebo, although nominal P values were <0.05 for superiority of levodopa inhalation powder versus placebo for the change in UPDRS Part III at 30 minutes postdose, for the proportion of patients in the ON state at 60 minutes postdose, and also for patients who showed improved PGIC (Table 3). Finally, there was no difference in the decreased total daily OFF time from baseline to week 12 among the 3 study groups (−0.47 hours for levodopa inhalation powder 84 mg and −0.48 hours for placebo).

TABLE 3 - Efficacy Results From SPAN-PD Study

Efficacy Outcome	Hierarchical Step	Measure of Difference	Levodopa Inhalation Powder vs Placebo (95% CI)	P
Levodopa inhalation powder 84 mg vs placebo
Change in UPDRS motor score at 30 min	1	LS mean difference	−3.92 (−6.84 to −1.00)	0.0088
Achieve and maintain ON state at 60 min postdose	2	OR	2.65 (1.48 to 4.76)	0.0027
Change in UPDRS motor score at 20 min	3	LS mean difference	−2.55 (−5.22 to 0.13)	0.062*
Improvement on PGIC	4	OR	2.94 (1.62 to 5.33)	<0.001*
Change in UPDRS motor score at 10 min	5	LS mean difference	−2.26 (−4.48 to −0.04)	0.046*
Change in time spent in OFF state, per PD diary	6	LS mean difference	−0.01 (−0.55 to 0.56)	0.975*
Levodopa inhalation powder 60 mg vs placebo
Change in UPDRS motor score at 30 min	7	LS mean difference	−3.07 (−5.99 to −0.16)	0.039*
Achieve and maintain ON state at 60 min postdose	8	OR	2.30 (1.29 to 4.10)	0.006*
Change in UPDRS motor score at 20 min	9	LS mean difference	−1.98 (−4.65 to 0.70)	0.147*
Improvement on PGIC	10	OR	1.85 (1.05 to 3.28)	0.026*
Change in UPDRS motor score at 10 min	11	LS mean difference	−0.97 (−3.19 to 1.24)	0.387*
Change in time spent in OFF state, per PD diary	12	LS mean difference	−0.10 (−0.66 to 0.46)	0.722*

Reprinted from LeWitt PA, Hauser RA, Pahwa R, et al.³⁹ Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol 2019;18(2):145–154. Used with permission.

*Because the P value for hierarchical step 3 (change in UPDRS motor score at 20 minutes) did not reach statistical significance, all subsequent P values (steps 4–12) are nominal only

LS, least squares; OR, odds ratio; PGIC, Patient Global Impression of Change; UPDRS, Unified Parkinson's Disease Rating Scale.

FIGURE 2: Proportion of patients in the SPAN-PD study who achieved and maintained an ON state at 60 minutes postdose at week 12. *P = 0.0027. Reprinted from LeWitt PA, Hauser RA, Pahwa R, et al.³⁹ Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol 2019;18(2):145–154. Used with permission.

CVT-301-004E was an extension of the SPAN-PD study that used a multicenter, dose-level blinded design to randomize 325 patients to receive levodopa inhalation powder 60 or 84 mg for 12 months.⁴⁰ CVT-301-004E was designed as a long-term safety study; however, achievement and maintenance of an ON state within 60 minutes postdose, the proportion of patients reporting improvements on the PGIC, and duration of OFF time were assessed as secondary outcome measures. During the 52-week study, 67.7% to 83.6% of patients in the levodopa inhalation powder 60-mg group and 70.7% to 79.0% of patients in the levodopa inhalation powder 84-mg group achieved and maintained an ON state within 60 minutes postdose; these proportions were highest at week 24 and remained stable through week 52. Between 65.5% and 89.1% of patients in the 60-mg group and 66.7% and 91.9% of patients in the 84-mg group reported improvements in the PGIC, with the highest proportions observed at week 24 and declining thereafter. By week 52, patients in the 60-mg and 84-mg groups reported a least squares mean reduction in OFF time of 0.7 (95% CI, 0.23–1.17) and 0.88 (95% CI, 0.43–1.34) hours, respectively, relative to baseline.

Exploratory Efficacy Studies

CVT-301-005 was a 12-month open-label, randomized study in which 408 patients were randomized either to an observational cohort or to receive levodopa inhalation powder 84 mg as adjunctive therapy to a stable levodopa regimen.⁴¹ The observational cohort received no study drug and remained on their standard maintenance PD treatment regimen. CVT-301-005 was primarily intended to assess pulmonary safety of levodopa inhalation powder, but changes in UPDRS Part III motor score were also evaluated as exploratory efficacy measurements. Maximum improvement in UPDRS Part III motor scores after levodopa inhalation powder administration was achieved within 30 minutes postdose and maintained at 60 minutes by 80% to 85% of patients, with consistent results observed across all 12 months of the study. Patients who received levodopa inhalation powder reported an increase of 1.01 to 1.49 h/d of ON time without dyskinesia compared with baseline. Patient Global Impression of Change scores also showed improvement among at least 75% of patients at months 3, 6, and 12.

The purpose of CVT-301-009 (NCT02807675), a multicenter, randomized, double-blind, placebo-controlled phase 1 study of 36 patients with PD, was to evaluate the acute safety and tolerability of levodopa inhalation powder for control of early-morning OFF when given with the first oral dose of carbidopa/levodopa.³⁷ Because levodopa inhalation powder does not contain carbidopa, there was concern that administering levodopa inhalation powder by itself first thing in the morning, when carbidopa levels in some patients might have fallen below therapeutic levels overnight, could induce levodopa-associated adverse events (AEs), such as nausea, vomiting, and orthostatic hypotension. Moreover, the tolerability and safety of levodopa inhalation powder as an adjunct to the first oral dose carbidopa/levodopa for early-morning OFF had not been previously reported, and the combination could potentially have different safety and efficacy characteristics than when taken later in the day when carbidopa plasma levels are likely higher. The efficacy component of the study was underpowered and therefore exploratory only.

Patients in an early-morning OFF state were administered levodopa inhalation powder 84 mg immediately after their first single dose of oral carbidopa/levodopa. Control patients received an inhaled placebo. Regarding the exploratory efficacy outcomes, median time-to-ON was not significantly different between patients taking levodopa inhalation powder versus placebo (mean, 25 vs 35.5 minutes, respectively). However, significantly more patients achieved an ON state within 30 minutes after levodopa inhalation powder compared with those who received placebo (66.7% vs 44.5%, respectively; P = 0.04).³⁷ Patients who received levodopa inhalation powder reported slightly longer duration of ON periods versus those who received placebo (149 minutes vs 144 minutes, respectively) and slightly shorter duration of OFF periods (30 minutes vs 35 minutes).³⁷

SAFETY AND TOLERABILITY

Safety Outcomes From Clinical Trials

The safety profile of levodopa inhalation powder is generally consistent across the clinical development program and is similar to that of oral levodopa, with the exception of mild or moderate treatment-emergent adverse events (TEAEs) related to the pulmonary delivery route (eg, cough). Across the phase 1 to phase 3 studies, cough was the most common pulmonary TEAE associated with levodopa inhalation powder.^37–41 Most AEs of cough in the CVT-301 groups started within the first 30 days of treatment and were generally assessed as mild or moderate in intensity and related to the drug. Cough did not seem to be dose dependent: in SPAN-PD, cough occurred for 15% of patients in both the 60- and 84-mg groups (vs 2% in the placebo group); in CVT-301-004E, cough was reported for 16.3% of patients receiving levodopa inhalation powder 60 mg and 14.5% receiving levodopa inhalation powder 84 mg (Table 4). Educating patients that coughing is a common experience with their initial dosing is important. Typically, with repeated trials of inhaled levodopa, coughing tends to improve over time. Patients should also be instructed that a slow, steady inhalation is sufficient to deliver a therapeutic dose for adequate pulmonary absorption and that a rapid or exaggerated inhalation is likely to induce cough. The authors' clinical experience suggests that taking a few sips of water before and in between inhalations may also be helpful.

TABLE 4 - TEAEs in Phase 3 Studies for Levodopa Inhalation Powder

	SPAN-PD CVT-301-004 39		CVT-301-004E 40		CVT-301-005 41
	Levodopa Inhalation Powder 60 mg (n = 113)	Levodopa Inhalation Powder 84 mg (n = 114)	Levodopa Inhalation Powder 60 mg (n = 153)	Levodopa Inhalation Powder 84 mg (n = 159)	Levodopa Inhalation Powder 84 mg (n = 271)*
Adverse event, n (%)*
Any TEAE	64 (56.6)	66 (57.9)	103 (67.3)	115 (72.3)	192 (70.8)
Serious TEAE	6 (5.3)	2 (1.8)	22 (14.4)	13 (8.2)	42 (15.5)
TEAE leading to withdrawal	3 (2.7)	6 (5.3)	12 (7.8)	14 (8.8)	24 (8.9)
Drug-related TEAEs†	41 (36.3)	40 (35.1)	45 (29.4)	51 (32.1)	102 (37.6)
Severe TEAEs	7 (6.2)	5 (4.4)	19 (12.4)	12 (7.5)	36 (13.3)
TEAEs in ≥4% of patients, n (%)
Cough	17 (15.0)	17 (14.9)	25 (16.3)	23 (14.5)	36 (13.3)
Upper respiratory tract infection	2 (1.8)	7 (6.1)	10 (6.5)	12 (7.5)	13 (4.8)
Nausea	0	6 (5.3)	2 (1.3)	0	10 (3.7)
Sputum discolored	0	6 (5.3)	1 (0.7)	2 (1.3)	9 (3.3)
Dyskinesia	5 (4.4)	4 (3.5)	6 (3.9)	10 (6.3)	17 (6.3)
Fall	5 (4.4)	3 (2.6)	24 (15.7)	17 (10.7)	22 (8.1)
Nasopharyngitis	2 (1.8)	3 (2.6)	8 (5.2)	4 (2.5)	18 (6.6)
Back pain	4 (3.5)	1 (0.9)	8 (5.2)	3 (1.9)	12 (4.4)
Throat irritation	8 (7.1)	1 (0.9)	7 (4.6)	5 (3.1)	9 (3.3)
Dizziness	2 (1.8)	1 (0.9)	5 (3.3)	4 (2.5)	6 (2.2)
Constipation	1 (0.9)	0	5 (3.3)	7 (4.4)	2 (0.7)

*Levodopa inhalation powder safety population

†Adverse events were considered drug related if the event was classified as possibly, probably, or definitely related to study drug by investigators.

TEAEs, treatment-emergent adverse events.

Commonly reported TEAEs (in addition to cough) that occurred more frequently with levodopa inhalation powder 84 or 60 mg than with placebo in SPAN-PD included upper respiratory tract infection (6% vs 2% vs 3%, respectively), nausea (5% vs 0% vs 3%), sputum discoloration (5% vs 0% vs 0%), dyskinesia (4% vs 4% vs 0%), fall (3% vs 4% vs 2%), and throat irritation (1% vs 7% vs 0%).³⁹ Treatment-emergent AEs led to study withdrawal for 9 patients receiving levodopa inhalation powder (60 mg, 3% [n = 3]; 84 mg, 5% [n = 6]) and 3 (3%) receiving placebo. Three patients (60 mg, 1% [n = 1]; 84 mg, 2% [n = 2]) withdrew from the study owing to a TEAE of cough. Serious TEAEs were reported for 11 (3%) patients (60 mg, 5.3% [n = 6]; 84 mg, 1.8% [n = 2]; placebo, 2.7% [n = 3]). Serious TEAEs of hypotension (60 mg, 0.9% [n = 1]) and atrial fibrillation (84 mg, 0.9% [n = 1]) were the only events considered possibly related to levodopa inhalation powder. One patient receiving the 60-mg dose committed suicide; the study investigator considered this outcome to be unrelated to the study drug.³⁹

In the extension study CVT-301-004E, TEAEs of cough, fall, and upper respiratory tract infection were the most commonly occurring in patients receiving levodopa inhalation powder, with frequencies in the 84-mg groups of 14.5%, 10.7%, and 7.5%, respectively. Serious TEAEs were reported for more patients in the levodopa inhalation powder 60-mg group (14.4% [n = 22]) than the levodopa inhalation powder 84-mg group (8.2% [n = 13]), but only 1 serious TEAE was considered possibly related to the study drug (impulse control disorder for 1 patient receiving the 84-mg dose).⁴⁰

In study CVT-301-005, the most common TEAEs related to levodopa inhalation powder were cough, dyskinesia, throat irritation, and discolored sputum.⁴¹ Serious TEAEs were reported for 15.5% of patients receiving levodopa inhalation powder 84 mg, and 10.2% of patients in the observational cohort, but only 2 serious TEAEs (pulmonary embolism and dopamine dysregulation syndrome, 0.8% each) were considered possibly related to levodopa inhalation powder treatment. Nearly 9% of patients who received levodopa inhalation powder (n = 24) experienced a TEAE that led to study withdrawal. One death (drowning) occurred during the study; the patient was in the levodopa inhalation powder 84-mg treatment group, but the death was considered unrelated to study drug.

In CVT-301-009, one quarter of patients taking the study drug (n = 9) experienced TEAEs, compared with 11% taking placebo (n = 4). The most common AE was mild cough (13.9%). Nine patients (25%) experienced orthostatic hypertension after carbidopa/levodopa plus levodopa inhalation powder or placebo, but all cases were asymptomatic, nonserious, and not considered clinically significant. No serious AEs, deaths, or AE-related discontinuations were reported.³⁷

Finally, in CVT-301-002, the most frequently reported TEAE was cough (25%) that was transient and resolved spontaneously. No deaths were reported.³⁵

Carbidopa-levodopa administration can cause hallucinations as a dose-related adverse effect; this has been well-reported in the scientific literature.^42–44 Levodopa inhalation powder administration in its phase 3 clinical trial had a very low incidence of hallucination (2 events [1.8%] in the 60 mg dose group and 2 events [1.8%] in the 84 mg dose group).³⁰ The supplementary effect of levodopa inhalation powder should not change any cardiac effects of levodopa (especially considering the levodopa concentrations reported in the PK section of the article), and there were no notable changes from baseline to 12 weeks in electrocardiogram interval values (heart rate; respiratory rate; PR, QRS, and QT interval; and QTcB or QTcF) in any treatment group.³⁹ Levodopa inhalation powder has not been studied for possible interactions with quetiapine or pimavanserin in causing alteration of QTc, although oral levodopa intake has been investigated in clinical development preceding the approval of pimavanserin.⁴⁵

Examiner-Assessed Dyskinesia

All 3 phase 3 studies evaluated examiner-assessed dyskinesia occurring ≤60 minutes postdose at each clinic visit. Levodopa-induced involuntary movements are largely choreic and sometimes are intermingled with dystonic or athetotic components.⁴ Patients with preexisting severe dyskinesia that would significantly interfere with the ability to participate in the studies were not enrolled. In the SPAN-PD trial, dyskinesia, recorded as a TEAE, occurred in 9 patients receiving levodopa inhalation powder (60 mg, 5 patients [4%]; 84 mg, 4 patients [3%]) compared with none in the placebo group, but all were mild or moderate in severity. Overall examiner-rated dyskinesia showed only a slight increase over 12 weeks for 84 mg, from 14.9% at baseline to 16.7% at week 12, and this increase was due to dyskinesia of mild severity.³⁹

In the CVT-301-004E study, no clear trend was found for dyskinesia, and it was observed in 11.2% to 17.0% of patients (n = 35–53) overall during the 60 minutes after dosing with levodopa inhalation powder on the 6 treatment visits. However, dyskinesia was less common among patients receiving the lower levodopa inhalation powder dose of 60 mg; for example, at 1 month, the observed rate was 12.4% versus 21.4% for the 84-mg dose group. No severe dyskinesia was reported.⁴⁰

The occurrence of 60-minute postdose dyskinesia generally decreased over time in study CVT-301-005, from 20.3% of patients at 1 month to 12.9% at 12 months, and cases were largely mild or moderate. By 12 months, the UPDRS Part IV score (which measures dyskinesia) was similar to baseline (2.1 and 2.0, respectively). Severe dyskinesia was reported for 0.4% to 1.1% (n = 1–3) of patients at any study visit.⁴¹

In CVT-301-009, examiner-rated mild or moderate dyskinesia within 3 hours postdose was present in about one third of both the study drug population (n = 12 [33.3%]) and the placebo population (n = 13 [36.1%]). No severe dyskinesia was reported.³⁷

Pulmonary Safety

Because levodopa inhalation powder is an inhaled dry powder that delivers active treatment via the lungs, its pulmonary safety was evaluated in patients with PD in 2 phase 2 studies (CVT-301-002 and CVT-301-003) and all phase 3 studies (SPAN-PD, CVT-301-004E, and CVT-301-005).^40,41,46 Each study used spirometry to assess changes in forced expiratory volume in 1 second (FEV₁), forced vital capacity (FVC), the FEV₁/FVC ratio, and carbon monoxide diffusion capacity (DL_co).⁴⁰ CVT-301-004E and CVT-301-005 were specifically designed to evaluate the pulmonary safety of levodopa inhalation powder, and CVT-301-005 assessed pulmonary safety like CVT-301-004E, but with a different set of patients and with the ability to compare with an observational cohort of patients with PD who were not taking levodopa inhalation powder.

Two specific phase 1 safety studies (CVT-301-007 and CVT-301-008) were performed in smokers and asthmatics. Smoking is known to have effects on drug metabolism as well as adverse effects on lung function and has been shown to enhance systemic exposure of inhaled compounds.^47,48 Furthermore, smoking may lead to compromised lung function, which could trigger adverse reactions in people who receive inhaled medication. Chronic pulmonary diseases can adversely affect the systemic bioavailability of inhaled compounds, and inhaled administration of any compound can also affect lung function. Therefore, subjects with asthma were excluded from the phase 3 studies of levodopa inhalation powder to avoid variability that could confound the study data.

The open-label, parallel-group study (CVT-301-007, NCT02633839) investigated the effect of a single 84-mg dose of levodopa inhalation powder in healthy nonsmoking and smoking adults (≥10 cigarettes/d for ≥12 months). Carbidopa 50 mg was administered orally to provide sufficient decarboxylase inhibition to minimize peripheral dopamine adverse effects. None of the differences in PK (area under the concentration vs time curve parameters, C_max) observed between smokers and nonsmokers seemed to be clinically relevant. In addition, there was no evidence for an effect of levodopa inhalation powder on FEV₁ on smokers or nonsmokers, nor was there evidence for an effect on the safety profile in smokers compared with nonsmokers.³⁰

CVT-301-008 (NCT02633007) was a double-blind, placebo-controlled, crossover study that investigated the effect of 3 doses of levodopa inhalation powder 84 mg or placebo administered at intervals of approximately 4 hours in healthy adults with mild to moderate asthma. As in CVT-301-007, carbidopa 50 mg was also administered every 8 hours during the treatment period, with the first dose being administered approximately 1 hour before the first dose of levodopa inhalation powder. The thrice-daily dose was consistent with average daily use (5 doses are the maximum indicated per day). Overall, the PK of levodopa was similar between participants in previous studies and subjects with asthma in this study.³⁰ However, certain subjects with asthma seemed to have pronounced bronchoconstriction, and based on the results of the 007 and 008 studies, the use of levodopa inhalation powder is not recommended in patients with concomitant lung disease, especially asthma or chronic obstructive pulmonary disease. This warning is included in both the US prescribing information²⁸ and the European Summary of Product Characteristics⁴⁹ for levodopa inhalation powder. Patients with chronic underlying pulmonary disease were not permitted to be enrolled into the phase 3 efficacy and safety studies.

For the phase 2 studies, no notable changes in lung function were observed from baseline to week 4 of treatment with levodopa inhalation powder 25 or 50 mg or between levodopa inhalation powder and placebo.⁴⁶ Similarly, the phase 3 studies reported no consistent or notable changes in spirometry parameters, suggesting pulmonary safety of up to 12 months of treatment with levodopa inhalation powder 84 mg (CVT-301-005) or up to 15 months of treatment with levodopa inhalation powder 60 and 84 mg (CVT-301-004E). Declines in 12-month pulmonary function in CVT-301-004E and CVT-301-005 were comparable. CVT-301-004E reported overall changes from baseline to month 12 of −0.092 L (FEV₁), −0.097 L (FVC), 0.4% (FEV₁/FVC), and −0.922 mL/min/mm Hg (DL_CO), with no meaningful differences between levodopa inhalation powder doses (60 or 84 mg) at any time during the study.⁴⁰ In CVT-301-005, levodopa inhalation powder was associated with a mean (SD) change in FEV₁ from baseline to month 12 of −0.105 (0.209) L, compared with −0.117 (0.214) L in the observational cohort (Fig. 3).⁴¹ Both the 4-week phase 2 efficacy trial (CVT-301-003)³⁸ and the 12-week phase 3 efficacy study (SPAN-PD)³⁹ included pulmonary testing immediately after inhalation of the first dose of levodopa inhalation powder to evaluate the potential risk of immediate bronchoconstriction after inhalation. Overall, the results from the phase 2 and 3 studies suggest that levodopa inhalation powder does not affect pulmonary function when compared with patients in an observational cohort or patients receiving placebo for up to 12 months.³⁹ In patients without concomitant lung disease, there was no evidence of immediate pulmonary bronchoconstriction after inhalation, and any long-term declines in pulmonary function were considered likely related to underlying disease and aging factors and not to levodopa inhalation powder.

FIGURE 3: Mean changes from baseline in lung function over 12 months in the CVT-301-005 study. Error bars represent standard deviation. Time points are staggered for clarity. DL_CO, diffusing capacity of the lungs for carbon monoxide; FEV₁, forced expiratory volume in 1 second. Reprinted from Grosset DG, Dhall R, Gurevich T, et al.⁴¹ Inhaled levodopa in Parkinson's disease patients with OFF periods: a randomized 12-month pulmonary safety study. Parkinsonism Relat Disord 2020;71:4–10. Used with permission.

REGULATORY STATUS OF LEVODOPA INHALATION POWDER

As of November 2021, levodopa inhalation powder is approved for the intermittent treatment of OFF periods in patients with PD treated with carbidopa/levodopa in the United States, and for the intermittent treatment of episodic motor fluctuations (OFF periods) in adult patients with PD treated with a DDI/levodopa in the European Union, Iceland, Norway, and Liechtenstein.

CONCLUSIONS

Levodopa inhalation powder is an orally inhaled dry powder formulation of levodopa that allows levodopa to rapidly enter the blood via the lungs.²⁸ As an inhaled medication, levodopa inhalation powder does not depend on the digestive tract for absorption. Pharmacokinetics data suggest that an inhaled delivery system provides consistent, measured pulmonary delivery of levodopa inhalation powder to the systemic circulation. Plasma concentrations of levodopa increased more rapidly and with less between-subject variability compared with intake of oral levodopa.^35,36

In phase 2 and 3 studies of patients with PD experiencing OFF periods, levodopa inhalation powder was associated with significant improvements in motor symptoms, as assessed using the UPDRS Part III (motor scale).^38–41 Patients may begin to experience improvement in motor symptoms as quickly as 10 minutes postdose.³⁸ More patients receiving levodopa inhalation powder versus placebo achieved, and continued to remain in, an ON state by 60 minutes postdose.^39–41 On-demand treatment with levodopa inhalation powder may also be used for patients with early-morning OFF periods, given that the inhaled dose does not seem to induce levodopa-associated TEAEs such as orthostatic hypotension, vomiting, and nausea.³⁷

Levodopa inhalation powder is well tolerated at various dose levels (up to the approved 84-mg dose), and its safety profile is generally consistent across studies. Cough is the most common AE associated with levodopa inhalation powder, reported for approximately 15% of patients in the SPAN-PD study.^39–41 Other AEs reported for patients treated with levodopa inhalation powder are generally consistent with AEs associated with oral levodopa. No significant differences in pulmonary safety risk have been noted for levodopa inhalation powder compared with patients in an observational cohort or those receiving placebo.^40,41

Levodopa inhalation powder is intended as an on-demand medication, to be taken when PD symptoms begin to reappear, up to a maximum of 5 doses per day.²⁸