Nemiralisib in Patients with an Acute Exacerbation of COPD: Placebo-Controlled, Dose-Ranging Study

Figures & data

Table 1 Baseline Demographic and Clinical Characteristics

	Placebo (N=276)	Nemiralisib (µg)
		12.5^a (N=22)	50 (N=91)	100 (N=92)	250 (N=90)	500 (N=89)	750 (N=278)
Age in Years, mean (SD)	65.4 (7.94)	67.8 (7.20)	63.1 (7.61)	65.1 (7.43)	66.0 (6.94)	64.9 (8.04)	64.8 (7.61)
Sex, n (%)
Female:	86 (31)	6 (27)	35 (38)	29 (32)	31 (34)	22 (25)	100 (36)
BMI (kg/m^2), mean (SD)	26.3 (4.53)	27.4 (5.42)	25.6 (4.40)	26.8 (4.73)	26.3 (3.98)	26.5 (4.45)	26.9 (4.83)
Race, N (%)
American Indian/Alaskan native	2 (<1)	0	2 (2)	1 (1)	2 (2)	2 (2)	6 (2)
Asian	19 (7)	4 (18)	7 (8)	3 (3)	9 (10)	8 (9)	20 (7)
Black or African American	2 (<1)	1 95)	2 (2)	1 (1)	0	2 (2)	6 (2)
White	253 (92)	17 (77)	80 (88)	87 (95)	79 (88)	77 (87)	246 (88)
Smoking history
Current smoker, n (%)	114 (41)	5 (23)	45 (49)	37 (40)	30 (33)	39 (44)	101 (36)
Former smoker, n (%)	162 (59)	17 (77)	46 (51)	55 (60)	60 (67)	50 (56)	177 (64)
Pack years, mean (SD)	45.9 (23.94)	54.3 (27.42)	41.3 (22.25)	51.4 (28.23)	49.2 (25.44)	48.4 (25.14)	44.8 (25.28)
Duration of COPD, n (%)
< 5 years	80 (29)	7 (32)	32 (35)	23 (25)	26 (29)	25 (28)	82 (29)
5 to <15 years	165 (60)	11 (50)	43 (47)	57 (62)	51 (57)	53 (60)	156 (56)
15 to <25 years	29 (11)	4 (18)	15 (16)	12 (13)	12 (13)	10 (11)	40 (14)
> 25 years	2 (<1)	0	1 (1)	0	1 (1)	1 (1)	0
Baseline lung function mean (SD)
Pre-bronchodilator FEV1 (L)	1.23 (0.538)	1.29 (0.601)	1.32 (0.614)	1.28 (0.520)	1.13 (0.453)	1.24 (0.545)	1.27 (0.570)
Post-bronchodilator FEV1 (L)	1.31 (0.566)	1.33 (0.482)	1.41 (0.633)	1.39 (0.548)	1.24 (0.489)	1.32 (0.555)	1.37 (0.594)
Pre-bronchodilator % predicted FEV1/FVC  ratio (%)	59.0 (16.66)	61.4 (19.35)	60.7 (17.95)	59.1 (18.27)	57.1 (13.50)	57.6 (16.71)	59.5 (17.30)
Post-bronchodilator % predicted FEV1/FVC  ratio (%)	59.8 (17.01)	61.3 (18.86)	61.2 (17.44)	60.3 (18.12)	57.7 (13.92)	59.0 (17.28)	61.0 (18.15)
Moderate/severe exacerbation history in last 12 months, n (%)
0	71 (26)	8 (36)	17 (19)	18 (20)	26 (29)	18 (20)	67 (24)
1	95 (34)	10 (45)	38 (42)	38 (41)	29 (32)	35 (39)	113 (41)
2	66 (24)	2 (9)	22 (24)	15 (16)	16 (18)	19 (21)	48 (17)
3	30 (11)	0	4 (4)	13 (14)	7 (8)	8 (9)	24 (9)
≥4	14 (5)	2 (9)	10 (11)	8 (9)	12 (13)	9 (10)	25 (9)

Note: ^aThe 12.5 µg dose was added following a protocol amendment, to characterize the lower portion of the dose response curve.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; SD, standard deviation.

Figure 1 Patient flow through the study.

Notes: ^aIncludes participants not randomized due to sponsor decision to stop the study; ^bProtocol stopping criteria: clinically significant lab value; pneumonia; Qtc withdrawal criteria.

Table 2 Change from Baseline in Trough FEV₁ (L) at Day 84

	Placebo (N=276)	Nemiralisib (µg)
		12.5 (N=22)	50 (N=91)	100 (N=92)	250 (N=90)	500 (N=89)	750 (N=278)
n^a	215	16	72	75	69	58	216
Posterior adjusted median change from baseline	0.052	0.031	0.026	0.014	0.058	0.049	0.049
SD	0.0186	0.0615	0.0306	0.0302	0.0309	0.0330	0.0189
95% HPD Crl	0.018–0.091	-0.090-0.149	-0.036-0.084	-0.044-0.073	-0.002-0.118	-0.017-0.113	0.012–0.086
Active – placebo
Posterior adj. median difference		−0.022	−0.027	−0.038	0.005	−0.003	−0.004
SD		0.0632	0.0339	0.0333	0.0341	0.0354	0.0236
95% HPD Crl		-0.143-0.103	-0.098-0.036	-0.102-0.028	-0.064-0.071	-0.075-0.061	-0.051-0.042

Note: ^aNumber of patients with data contributing to the analysis.

Abbreviations: Crl, credible interval; HPD, highest posterior density; SD, standard deviation.

Table 3 Subsequent Moderate/Severe Exacerbation Rate During Treatment

	Placebo (N=276)	Nemiralisib (µg)
		50 (N=91)	100 (N=92)	250 (N=90)	500 (N=89)	750 (N=278)
n^a	276	91	92	90	89	278
Posterior median moderate/severe exacerbation rate (84 days)	0.31	0.29	0.28	0.32	0.20	0.36
95% HPD Crl	0.25–0.39	0.20–0.39	0.20–0.38	0.23–0.43	0.13–0.29	0.29–0.43
Active vs placebo
Ratio		0.92	0.89	1.01	0.63	1.13
95% HPD Crl		0.60–1.40	0.57–1.35	0.65–1.50	0.37–1.02	0.85–1.52

Notes: ^aNumber of participants with data contributing to the analysis; patients randomized to the nemiralisib 12.5 µg were excluded from this analysis due to the small size of the group.

Abbreviations: Crl, credible interval; HPD, highest posterior density.

Table 4 Proportion of Responders in Patient-Reported Outcomes (EXACT-Defined Recovery, CAT Total Score and SGRQ Total Score) and EXACT-Defined Time to Recovery

	Nemiralisib (µg)
	PBO (N=276)	12.5 (N=22)	50 (N=91)	100 (N=92)	250 (N=90)	500 (N=89)	750 (N=278)
EXACT
Responder^a	110 (40)	9 (41)	47 (52)	40 (43)	38 (42)	24 (27)	116 (42)
Active vs placebo^b
Posterior median odds ratio		1.21	1.53	1.16	1.12	0.56	1.08
95% HPD Crl		0.36–2.69	0.82–2.33	0.67–1.79	0.63–1.74	0.28–0.88	0.72–1.49
Time to EXACT-defined recovery^c
No. of patients with event, n (%)	142 (51)	11 (50)	54 (59)	50 (54)	45 (50)	34 (38)	149 (54)
Active vs placebo
Posterior median hazard ratio		1.053	1.200	1.060	1.030	0.751	1.149
95% HPD Crl		0.48–1.77	0.84–1.60	0.73–1.43	0.72–1.41	0.49–1.06	0.90–1.43
CAT
Responder^d	88 (32)	8 (36)	31 (34)	36 (39)	34 (38)	30 (34)	69 (25)
Active vs placebo^b
Posterior median odds ratio		1.22	1.11	1.41	1.28	1.11	0.70
95% HPD Crl		0.35–2.70	0.63–1.77	0.77–2.17	0.71–2.00	0.61–1.75	0.46–0.99
SGRQ-C
Responder^e	58 (21)	3 (14)	17 (19)	24 (26)	29 (32)	21 (24)	69 (25)
Active vs placebo^b
Posterior median odds ratio		0.51	0.87	1.37	1.78	1.24	0.95
95% HPD Crl		0.03–1.41	0.42–1.47	0.69–2.24	0.95–2.91	0.61–2.08	0.60–1.40

Notes: ^aResponse was defined as a decrease in the rolling average EXACT Total Score ≥ 9 points from the maximum observed value, sustained for ≥ 7 days with the first of the 7 days defined as the recovery day; ^bAnalysis performed using a separate Bayesian logistic regression for each time point; ^cTime to EXACT-defined recovery from index exacerbation was defined as time from the date of randomization until date of the first EXACT-defined recovery day during the 12-week treatment period. Patients who did not experience EXACT-defined recovery during the 12-week treatment period were censored at the date of their last dose of study treatment. Analysis was performed using a Bayesian Cox proportional hazards model; ^dResponse was defined as a decrease from baseline in CAT Total Score ≥ 2; ^eResponse was defined as a decrease from baseline in SGRQ Total Score ≥ 4.

Abbreviations: CAT, COPD Assessment Test; Crl, credible interval; EXACT, Exacerbations of Chronic Pulmonary Disease Tool; HPD, highest posterior density; SGRQ-C, St George’s Respiratory Questionnaire for COPD.

Table 5 Summary of Most Commonly Reported Adverse Events (AE) and AEs Assessed as Drug-Related

	PBO (N=276)	Nemiralisib (µg)
		12.5 (N=22)	50 (N=91)	100 (N=92)	250 (N=90)	500 (N=89)	750 (N=278)
Any treatment-emergent AE, n (%)	129 (47)	10 (45)	44 (48)	55 (60)	54 (60)	56 (63)	172 (62)
Most commonly reported AE^a, n (%)
Cough	13 (5)	0	10 (11)	11 (12)	23 (26)	31 (35)	96 (35)
Headache	23 (8)	1 (5)	6 (7)	8 (9)	4 (4)	2 (2)	15 (5)
COPD	8 (3)	1 (5)	6 (7)	4 (4)	4 (4)	3 (3)	17 (6)
Pneumonia	4 (1)	1 (5)	2 (2)	2 (2)	5 (6)	1 (1)	3 (1)
Oropharyngeal pain	2 (<1)	0	0	2 (2)	3 (3)	5 (6)	2 (<1)
Dehydration	0	2(9)	0	0	0	0	0
Drug-related adverse events^b, n (%)
Any event	22 (8)	0	10 (11)	17 (18)	26 (29)	32 (36)	100 (36)
Cough	8 (3)	0	10 (11)	9 (10)	21 (23)	28 (31)	89 (32)
Throat irritation	1 (<1)	0	0	0	0	0	5(2)
Bronchospasm	0	0	0	0	0	1(1)	3(1)
Dry mouth	1 (<1)	0	0	1 (1)	0	0	2 (<1)
Headache	3 (1)	0	1 (1)	2 (2)	1 (1)	0	1 (<1)
Chest discomfort	0	0	0	0	0	0	2 (<1)
Mucosal inflammation	0	0	0	0	0	0	2 (<1)

Notes: ^a≥ 5% of patients in any treatment group; ^bIn ≥ 2 patients in any treatment group.

Abbreviation: AE, adverse event.