A technology evaluation of CVT-301 (Inbrija): an inhalable therapy for treatment of Parkinson’s disease

Figures & data

Figure 1. Diagram of the Inbrija Inhaler

A complete dose is 2 capsules (each capsule consists of 42 mg levodopa for a total dose of 84 mg levodopa). The blue cap is removed and the white mouthpiece is twisted off. One capsule is dropped into the opening of the capsule chamber and the white mouthpiece is reattached and aligned with the white arrows on the handle and mouthpiece. The mouthpiece and handle are pressed together until there is a click. This punctures the capsule. The patient exhales and then, while keeping the inhaler level, takes a deep, comfortable breath filling their lungs. When inhaling, the capsule spins and the whirl can be felt and heard. The patient holds their breath for 5 seconds and then exhales. The 2nd capsule is then inhaled the same way to complete the dosing. If there is powder buildup, the inhaler is cleaned between doses using a cotton swab and dry tissue. The inhaler is replaced when the carton of capsules is empty.

Table 1. Published studies in the CVT-301 clinical development program

Study	Design	Subjects/Patients	Duration	Key Findings
Preclinical Studies
Bartus et al. [31]	Comparison of pulmonary/insufflated administration of particulate LD 2 mg to rats (n = 6) or oral gavage of 2 mg LD solution (n = 7) Inhalation formulation of aerodynamic LD particles	13 male Sprague Dawley rats	Plasma LD concentration assessed for 240 min post dose	PK Plasma LD levels elevated faster after inhalable LD than after oral LD. Cmax was higher for pulmonary LD dose than for oral (P = 0.0197) Mean Tmax 4.7 min (pulmonary LD) vs 24 min (oral LD), P = 0.0017 Mean Cmax 4.8 µg/mL (pulmonary LD) vs 1.8 µg/mL (oral LD), P = 0.010
Lipp et al. [32]	Single doses of 50% LD inhalation formulation (mean aerodynamic particle diameter 1.9 ± 0.2 µm) insufflated, mean doses of 3.8 ± 0.4 mg/kg Single oral doses of LD 10.6 ± 0.9 mg/kg	6 beagle dogs	Plasma LD concentration assessed for 120 min post dose	PK Pulmonary delivery showed a more rapid and less variable absorption of LD compared with oral LD Median Tmax for insufflated LD 2.5 min vs 60 min for oral LD Mean Cmax for insufflated LD 3146 ng/mL vs 6517 ng/mL for oral LD
Clinical Studies
Phase 1
Lipp et al. [32]	Ascending dose, crossover study Single doses of oral CD/LD (25/100 mg) in a fed (n = 9) or fasted (n = 9) state 2 ascending CVT-301 doses (FPD 10 and 30 mg (n = 9), 20 and 50 mg (n = 9) in a fasted state) Safety/tolerability assessed	18 healthy males	Plasma LD concentration assessed for 8 hours post dose	PKPulmonary delivery showed more rapid and less variable absorption of LD compared to oral CD/LD for fed and fasted states Median TmaxCVT-301 (FPD 50 mg) 20 min Oral CD/LD 45 min (fasted), 120 min (fed) Mean Cmax,10 minCVT-301 (FPD 50 mg) 729 ng/mL Oral CD/LD 109 ng/mL (fasted), 18 ng/mL (fed) Variability of plasma LD levels (CV, 10 min postdose)CVT-301 (50 mg FPD) 30 Oral CD/LD (fasted) 91 Oral CD/LD (fed and fasted) 13Safety2 CVT-301 well tolerated: 4 AEs (22%) recorded. No pulmonary AEs reported.
Safirstein et al. [36]	Randomized, multi-center, open-label, 2-way crossover PK evaluation of a single inhaled dose of CVT-301 84 mg (FPD 50 mg), administered with oral CD 25 mg, and a single ingested dose of CD/LD 25/100 mg Patients were fed a standardized high-fat, high-protein meal 30 min before dosing (~4–5 hours after administration of morning CD/LD dose) Safety/tolerability assessed	23 patients with PD, on stable oral CD/LD therapy (total daily dose LD ≤800 mg)	2 dosing days separated by 48 hours. Plasma LD concentration assessed for 4 hours post dose	PKPulmonary delivery showed more rapid and less variable absorption of LD compared with oral CD/LD Median TmaxCVT-301 (FPD 50 mg) 15 min (range 5.0, 90.0 min, 25-75% IQR 10-30 min) Oral CD/LD 120 min (range 57.0, 240, 25-75% IQR 10-20 min) Mean CmaxCVT-301 (FPD 50 mg) 628.6 ng/mL Oral CD/LD 916.1 ng/mL SafetyCVT-301 well tolerated: TEAEs reported in 39.1% after CVT-301 dosing and in 9.1% after CD/LD dosing Only AE in more 1 patient was cough, which was reported in 30.4% after CVT-301 dosing and in 4.5% after CD/LD dosing, 1 patient discontinued due to cough
Hauser et al. [39]	Double-blind, placebo-controlled, randomized, 2-way crossover safety study Primary objective was to investigate the safety and tolerability of CVT-301 84 mg (FPD 50 mg) vs placebo when administered with the first oral dose of CD/LD to treat early morning OFF symptoms Exploratory efficacy objective was to determine the time required to reach an examiner-rated ON state with CVT-301 compared with placebo, when administered with the first oral CD/LD dose of the day Safety and exploratory efficacy assessments made for 3 hours post dose	36 patients with PD, (≥2 hours/day OFF time), on stable oral CD/LD therapy for ≥30 days	2 dosing days separated by 1–7 days (patients on usual CD/LD regimen)	SafetySingle doses of CVT-301 84 mg administered with oral CD/LD for early morning OFF symptoms were well-tolerated, with no notable safety concerns TEAEs reported: 25.0% (CVT-301) and 11.1% (placebo) Most common AE: cough 11.1% for CVT-301 vs 2.8% for placebo, which was typically mild and transient and lasted between 5–11 min Asymptomatic orthostatic hypotension AEs were similar for both groups (CVT-301, 6; placebo, 7) Examiner-rated dyskinesia during 3 hours post dose was similar for both (36–39% mild, 3–6% moderate, 0% severe) Exploratory EfficacyMedian time-to-ON: 25.0 min following CD/LD + CVT-301 and 35.5 min following CD/LD + placebo (P = 0.26) More patients turned ON at 30 min post dose following CD/LD + CVT-301 administration (66.7%), than with CD/LD + placebo (44.5%)(P = 0.040)
Phase 2
Lipp et al. [32]	Double-blind, single doses of placebo or CVT-301 (FPD 25 mg or 50 mg) in randomized order on separate days at least 4 hours after 1st oral CD/LD of day in a fed state (received during an OFF episode) Clinical efficacy assessed through timed finger tapping and UPDRS-III motor score	24 patients with PD (≥2 hours/day OFF time), on regular oral CD/LD therapy	Plasma LD concentration observed for 180 min post dose	PKPulmonary delivery showed more rapid and less variable absorption of LD compared to oral CD/LD Median TmaxCVT-301 (FPD 50 mg) 15 min Oral CD/LD (25/100 mg) 66 min (fed) Mean CmaxCVT-301 (FPD 50 mg) 698 ng/mL Oral CD/LD (25/100 mg, fed) 1465 ng/mL Variability (CV, 10 min postdose)CVT-301 (50 mg FPD) 55 Oral CD/LD (25/100 mg, fed) 162Clinical Benefit/Efficacy Timed finger tapping and UPDRS-III total score improved as early as the first measured time points of 5 min and 15 min post dose, respectively, with CVT-301 vs placeboSafety CVT-301 generally safe and well tolerated: 31 TEAEs in 16 patients Most common CVT-301 TEAE: mild-to-moderate cough (25%) CVT-301 had lower dyskinesia incidence than oral CD/LD
LeWitt et al. [12]	Randomized, double-blind, placebo-controlled, parallel-group dose escalation efficacy and safety study Patients randomized to CVT-301 (FPD 35 mg) or placebo for 4 weeks up to 3 times/day Dose increased to 50 mg after 2 weeks Efficacy assessments: mean change in UPDRS-III total score predose OFF to post dose at 10, 20, 30, 40, and 60 min at weeks 1,2 and 4 PGIC at end of weeks 2 and 4 Examiner rated achievement of ON state Patient diary Safety assessments: AEs and spirometry etc.	86 patients with PD (≥2 hours/day OFF time), on stable oral CD/LD therapy	4 weeks	EfficacyMean change in UPDRS-III total score from predose was statistically significant for CVT-301 for both doses At week 4, UPDRS-III change favored CVT-301 over placebo by −7.0 points (P < 0.001) for FPD 50 mg dose (averaged change from 10 to 60 min post dose) (primary endpoint) Treatment effect was evident at first assessment time (10 min post dose) and sustained for ≥60 min for both doses At week 4, proportion of patients turning ON during 60 min post dose was 78% for CVT-301 FPD 50 mg and 36% for placebo PGIC: 72% of patients on CVT-301 FPD 50 mg and 46% on placebo rated their PD as improved at 4 weeks By patient diary data, mean OFF time change from baseline favored CVT-301 FPD 50 mg by 0.9 hours/day (P = 0.045) at 4 weeks SafetyCVT-301 achieved rapid improvement of OFF states and reduced daily OFF time without an increase in dyskinesia or in severe or serious TEAEs Most frequent AEs for CVT-301 were dizziness, cough, and nausea (7% each). Dyskinesia reported in 1 patient in each treatment group AEs of cough were mild, none led to dose reduction or discontinuation No patient reported dyspnea, wheezing, or bronchospasm.
Phase 3
LeWitt et al. [13]	Randomized, double-blind, placebo-controlled, multicenter, international study (SPAN-PD) Randomized (1:1:1) to 60 mg (FPD 35 mg), 84 mg (FPD 50 mg), placebo 12-week treatment period (baseline, 4, 8, and 12 week assessments) Efficacy Change in UPDRS-III up to 60 min post dose Examiner rated achievement of ON state PGIC improvement Safety Safety assessments: AEs and spirometry etc.	339 patients with PD (≥2 hours/day OFF time), on stable oral CD/LD therapy (total daily dose LD ≤1600 mg)	12 weeks	Efficacy At week 12, UPDRS-III change favored CVT-301 84 mg over placebo by −3.92 points (P = 0.0088) at 30 minutes post dose (primary endpoint) 58% of CVT-301 84 mg patients achieved an ON state by 60 min vs 36%, (P = 0.0027) PGIC rating scores showed 71% of CVT-301 84 mg patients reported improvement vs 46% placebo at week 12 (nominal P < 0.001) UPDRS-III scores showed greater improvement for CVT-301 84 mg vs placebo at other timepoints. Nominally significant at 10 min (P = 0.046). This was not declared as significant due to a prespecified testing sequence. Safety Treatments safe and well tolerated Cough most common CVT-301 TEAE: 15% in 84 mg group. Most events were mild or moderate in severity and transient Severe AEs 4% in CVT-301 84 mg and 2% in placebo group. No severe AE in more than one patient in any group AEs consistent with known LD/DDI use
Farbman et al. [38]	52-week extension study of the phase 3 SPAN-PD study (above) A 12-month, dose-level blinded, multicenter study of CVT-301 (60 mg or 84 mg) Placebo-treated patients from SPAN-PD and patients who had not participated in SPAN-PD randomized in a 1:1 to receive 60 mg or 84 mg CVT-301 to use as needed up to 5 times/day Primary objective was to characterize the effects of CVT-301 on pulmonary safety as assessed by spirometry over a 12-month period Exploratory efficacy endpoints included UPDRS-III, proportion of patients achieving ON within 60 minutes and remaining ON at 60 minutes, total daily OFF time, and PGIC	325 patients (≥2 hours/day OFF time), on regular oral CD/LD therapy (total daily dose LD ≤1600 mg)	12 months	Safety CVT-301 (60 mg and 84 mg) was well tolerated Most frequent TEAEs (≥5%) were cough (15.4%), fall (13.1%), upper respiratory tract infection (7.1%), and dyskinesia (5.1%) Severe TEAEs (>1 event) were cough (1.9%) and dyskinesia (0.6%) 12-month decline in pulmonary function was consistent with PD control group (see Grosset et al below) Exploratory Efficacy CVT-301 maintained improvement in achieving an ON state in patients experiencing OFF periods, decreasing daily OFF time, and maintaining improvement in PGIC At 12 months, 73.0% of patients on 84 mg achieved an ON state within 60 min Total daily OFF time was reduced by 0.55 hours at month 1 and 0.88 hours at month 12 for the 84 mg dose Percentage of patients reported as improved by PGIC was maintained at 65.5–91.9% over 12 months
Grosset et al. [37]	Open-label, randomized, controlled study characterized the safety, including pulmonary safety, of CVT-301 84 mg Patients randomized 2:1 to CVT-301 or an observational cohort receiving oral standard of care. Pulmonary safety assessed using spirometry and carbon monoxide diffusion capacity. Exploratory efficacy endpoints, assessed only for CVT-301, included UPDRS-III, proportion of patients achieving ON and remaining ON at 60 minutes, PGIC, and total daily OFF time	398 patients with PD (≥2 hours/day OFF time), on regular oral CD/LD therapy (total daily dose LD ≤1600 mg)	12 months	Safety CVT-301 84 mg induced no clinically significant differences in pulmonary function compared with the observational cohort. Most frequent CVT-301-related TEAEs were cough (13.3%), dyskinesia (6.3%), throat irritation and discolored sputum (3.3% each). 88.4% of cough AEs were mild with 1 severe. 3 patients discontinued due to cough.Exploratory Efficacy Improvements in motor scores, OFF time, and patient-reported outcomes support clinical efficacy for up to 12 months UPDRS-III scores improved from predose to 60 minutes post dose at all assessments 80–85% of patients switched ON within 60 min and remained ON over 12 months >75% reported improvement in PGIC over 12 months OFF time decreased by 1.32–1.42 hours/day over 12 months

AE, adverse event; CD, carbidopa; C_max, maximum observed concentration; CV, coefficient of variation; DDI, dopa decarboxylase inhibitor; FPD, fine particle dose; IQR, interquartile range; LD, levodopa; PD, Parkinson’s disease; PGIC, Patient Global Impression of Change; PK, pharmacokinetic; TEAE, treatment-emergent adverse event; T_max, time to maximum observed concentration; UPDRS-III, Unified Parkinson Disease Rating Scale Part III (motor).

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