An Inhaled PI3Kδ Inhibitor Improves Recovery in Acutely Exacerbating COPD Patients: A Randomized Trial

Figures & data

Figure 1 Study schematic (Panel A) and trial profile (Panel B).

Abbreviation: HRCT, high resolution computed tomography.

Table 3 Placebo Corrected Changes in Secondary LD-HRCT Endpoints

Endpoint	Parameter	Region	Placebo (Baseline vs D28, Treatment Ratio (95% Cr I))	Nemiralisib (Baseline vs D28, Treatment Ratio (95% Cr I))	Nemiralisib vs Placebo (Baseline vs D28, Treatment Ratio (95% Cr I))	Probability (θ>1) or (θ<1)^a
siRaw	Specific imaging airway resistance	Distal	0.99 (0.75, 1.30)	0.91 (0.71, 1.19)	0.93 (0.64, 1.36)	66%
siVaww	Specific imaging airway wall thickness	Distal	1.02 (0.97, 1.08)	0.98 (0.93, 1.03)	0.96 (0.89,1.03)	87%
LAS	Low attenuation score	Total	1.01 (0.85, 1.20)	0.93 (0.78, 1.11)	0.92 (0.73, 1.17)	75%
		Upper	1.02 (0.84, 1.23)	0.95 (0.79, 1.15)	0.94 (0.72, 1.21)	69%
		Lower	1.01 (0.85, 1.20)	0.90 (0.75, 1.07)	0.89 (0.70, 1.13)	83%
IALD	Internal airflow lobar distribution	Upper	1.04 (0.99, 1.09)	0.98 (0.93,1.03)	0.94 (0.88, 1.01)	96%
		Lower	0.97 (0.93,1.02)	1.05 (1.00,1.10)	1.08 (1.01, 1.16)	99%
BVD	Blood vessel density	Upper	0.96 (0.91, 1.02)	1.01 (0.95, 1.06)	1.05 (0.97, 1.13)	87%
		Lower	0.98 (0.92, 1.05)	1.00 (0.94,1.07)	1.02 (0.93, 1.11)	63%
Endpoint	Parameter	Region	Placebo (Baseline vs D28, Treatment Difference (95% Cr I))	Nemiralisib (Baseline vs D28, Treatment Difference (95% Cr I))	Nemiralisib vs Placebo (Baseline vs D28, Treatment Difference (95% Cr I))	Probability (θ<0)
AT^b	Air trapping	Upper	−0.59 (−3.73, 2.51)	0.17 (−2.99, 3.25)	0.73 (−3.44, 5.02)	36%
		Lower	−1.04 (−4.12, 2.03)	−0.41 (−3.52, 2.66)	0.60 (−3.54, 4.79)	38%

Notes: Scans conducted at FRC (functional residual capacity) for siRaw and AT, TLC (total lung capacity) for siVaww and LAS, N/A for IALD. All data presented as untrimmed data other than siRaw, presented as trimmed data for the screening: day 28 pair. ^aθ represents the true treatment ratio to placebo. ^bAT data presented as treatment difference rather than treatment ratio, with θ representing the true treatment difference vs placebo, as data were not log normally distributed and therefore were not log-transformed.

Table 1 Baseline Characteristics

Demographics	Placebo	Nemiralisib
n [%]	63 (50)	63 (50)
Age in Years [Mean (SD)]	64.9 (7.88)	65.6 (7.14)
Sex [n (%)]
Female:	17 (27)	17 (27)
Male:	46 (73)	46 (73)
BMI (kg/m^2) [Mean (SD)]	25.45 (4.336)	25.93 (4.904)
Height (cm) [Mean (SD)]	170.6 (6.90)	169.6 (8.67)
Weight (kg) [Mean (SD)]	74.24 (14.350)	74.78 (16.208)
Hospitalized for the primary exacerbation? [n (%)]
Yes	27 (43%)	26 (41%)
No	36 (57%)	37 (59%)
Concurrent maintenance therapy^a, n (%)
LAMA	4 (6)	2 (3)
LABA	0	1 (2)
LAMA and LABA	3 (5)	3 (5)
ICS	3 (5)	3 (5)
ICS and LAMA	3 (5)	5 (8)
ICS and LABA	15 (24)	20 (32)
ICS, LAMA and LABA	35 (56)	27 (43)
No ICS, LAMA or LABA specified	0	2 (3)

Note: ^aPost-hoc summary.

Abbreviations: BMI, body mass index; ICS, Inhaled corticosteroids; LABA, Long-acting beta agonists; LAMA, long-acting muscarinic antagonists.

Table 2 Summary of Adverse Events

	Placebo (N=63)	Nemiralisib (N=63)
Adverse Events	n (%)	n (%)
Subjects with any AE(s), n (%)	41 (65%)	49 (78%)
Most common AEs^a
Cough	2 (3%)	22 (35%)
Worsening COPD	9 (14%)	4 (6%)
Headache	5 (8%)	7 (11%)
Dry mouth	5 (8%)	2 (3%)
Hypertension	4 (6%)	0
Diarrhea	3 (5%)	3 (5%)
Constipation	3 (5%)	1 (2%)
Nasopharyngitis	2 (3%)	3 (5%)
Pneumonia	2 (3%)	3 (5%)
Infestations and Infections	n (%)	n (%)
Any Event	6 (10%)	10 (16%)
Nasopharyngitis	2 (3%)	3 (5%)
Pneumonia	2 (3%)	3 (5%)
Respiratory tract infection	1(2%)	0
Respiratory tract infection (viral)	0	1 (2%)
Upper respiratory tract infection	1 (2%)	0
Lower respiratory tract infection	1 (2%)	0
Candida infection	0	1 (2%)
Oral Candidiasis	0	1 (2%)
Oral fungal infection	1 (2%)	0
Cystitis	0	1 (2%)
Clostridium difficile infection	0	1 (2%)
Conjunctivitis	0	1 (2%)

Notes: ^aMost common AEs were defined as ≥ 5% in at least one of the treatment arms.

Figure 2 Median % change from baseline in distal region siVaw at FRC after 28 days.

Abbreviations: siVaw, specific imaging airway volume; FRC, functional residual capacity.

Figure 3 Placebo-corrected change in siVaw at FRC after 12 and 28 days of treatment with nemiralisib.

Figure 4 Change from baseline in FEV₁ (Panel A) and sGaw (Panel B) in relation to the severity of the index exacerbation (FEV₁ and sGaw measured at clinical visits at baseline, Day 28 and Day 84). Data presented as median ± 95% Cr I. Analyses of FEV₁ data excludes data for one subject (281) due to erroneously large FEV₁ recorded at baseline.

Abbreviations: FEV₁, forced expiratory volume in 1 sec; sGaw, specific airway conductance; Cr I, credible interval.

Figure 5 Number of patients (out of 63 per arm) with any new exacerbation events^a during treatment and of the observed total number of severe exacerbations^b (28 in the placebo arm and 21 in the nemiralisib arm) the proportion requiring hospitalization. ^aNew exacerbation event based on observed treatment for an exacerbation; a new prescription for corticosteroids and/or antibiotics. ^bSevere exacerbations based on investigator-reported exacerbations resulting in hospitalization.