Nontuberculous mycobacterial pulmonary disease and the potential role of SPR720

Figures & data

Table 1. NTM treatments under investigation.

Drug	Indication	Use or usage exploration	Trial phase (ID; status date)
ALIS	Refractory MAC-PD	Treatment for MAC-PD as part of an antibacterial combination regimen when treatment response is not achieved after six months of a multidrug background regimen is a currently approved indication [16,17]. The efficacy of ALIS plus a background regimen compared to a control plus a background regimen for first-line treatment of MAC-PD is being explored.	Completed: Phase 2 (NCT01315236, 2019-08-21) Phase 3 (NCT04677543, 2023-06-02; NCT02628600, 2020-02-10; NCT02344004, 2020-05-07) Recruiting: Phase 3 (NCT04677569, 2023-06-15)
Clofazimine	Leprosy	First-line oral drug for treatment of MAB and an alternative drug for MAC-PD in patients who are intolerant of first-line drugs [16,17]	Completed: Phase 2/3 (NCT00000641, 2021-11-03) Phase 3 (NCT00001047, 2021-11-04) Recruiting: Phase 2 (NCT05294146, 2022-09-10; NCT02968212, 2023-04-04) Active but not recruiting: Phase 3 (NCT04616924, 2023-06-07) Not yet recruiting: Phase 4 (NCT05494957, 2022-08-10)
Omadacycline	Community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections	Efficacy, safety, and tolerability in MAB-PD are being explored	Recruiting: Phase 2 (NCT04922554, 2023-07-03)
Epetraborole	None	Efficacy, safety, and pharmacokinetics in patients with treatment-refractory MAC-PD are being explored	Completed: Phase 1 (NCT04892641, 2022-03-03) Recruiting: Phase 2/3 (NCT05327803, 2023-07-28)
SPR720	None	Efficacy, safety, tolerability, and pharmacokinetics in MAC-PD are being explored. Intrapulmonary pharmacokinetics and pharmacokinetics with azithromycin and ethambutol co-administration are also being explored in healthy volunteers.	Completed: Phase 1 (NCT03796910, 2019-10-28) Recruiting: Phase 1 (NCT05955586, 2023-07-21; NCT05966688, 2023-08-08) Phase 2 (NCT05496374, 2023-07-06)

Abbreviations: ALIS, amikacin liposome inhalation suspension; MAB, Mycobacterium abscessus complex; MAB-PD, Mycobacterium abscessus complex pulmonary disease; MAC-PD, Mycobacterium avium complex pulmonary disease.

Figure 1. Chemical structures of SPR720 and SPR719.

Figure 2. Bacterial DNA gyrase is composed of two GyrA subunits (light blue) and two GyrB subunits, which contain an ATPase (yellow), a transducer domain (green), and a TOPRIM domain (dark blue). A double stranded DNA segment (black) is captured, and, after ATP binding, the ATPase domains dimerize and the DNA strand gets trapped. ATP hydrolysis, double-strand cleavage, and strand translocation follow and then strand religation and dissociation of the ATPase domains occurs to reset the enzyme for future activity (Stokes, Vemula et al. 2020).

Table 2. MIC ranges, MIC₅₀ values, and MIC₉₀ values of SPR719 against different NTM species^a.

Species		MIC	MIC50	MIC90	Authors
MAC and MAC species	M. avium complex	0.002–4	1	2	Pennings, Ruth et al. 2021 [49]; Cotroneo, Stokes et al. 2023 [47]
	M. avium	0.23–2	0.5	2	Locher, Jones et al. 2015 [36]; Brown-Elliott, Rubio et al. 2018 [43]
	M. intracellulare	0.12–2	0.5	2	Brown-Elliott, Rubio et al. 2018 [43]
	M. chimaera	<0.03–2	N/A	N/A	Pidot, Porter et al. 2021 [50]
	MAC-X	0.12–1	1	1	Brown-Elliott, Rubio et al. 2018 [43]
MAB and MAB subspecies	MAB	0.03 – >32	1–2	2–8	Locher, Jones et al. 2015 [36]; Rubio, Stapleton et al. 2018 [48]; Pennings, Ruth et al. 2021 [49]; Cotroneo, Stokes et al. 2023 [47]
	M. abscessus subspecies abscessus	0.25–8	2	4	Brown-Elliott, Rubio et al. 2018 [43]
	M. abscessus subspecies massiliense	0.12–4	2	2	Brown-Elliott, Rubio et al. 2018 [43]
	M. abscessus/ massiliense hybrid	0.06–2	2	2	Brown-Elliott, Rubio et al. 2018 [43]
M. kansasii		0.002–0.25	0.015–0.06	0.03–0.5	Locher, Jones et al. 2015 [36]; Brown-Elliott, Rubio et al. 2018 [43]; Pennings, Ruth et al. 2021 [49]
M. chelonae		2–4	4	4	Brown-Elliott, Rubio et al. 2018 [43]
M. fortuitum		0.06–1	0.25	1	Brown-Elliott, Rubio et al. 2018 [43]
M. immunogenum		4–8	4	8	Brown-Elliott, Rubio et al. 2018 [43]
M. mucogenicum		0.015–0.25	0.06	0.25	Brown-Elliott, Rubio et al. 2018 [43]
M. marinum		0.12–1	0.5	0.5	Brown-Elliott, Rubio et al. 2018 [43]; Pidot, Porter et al. 2021 [50]
M. simiae		0.5–8	1	2	Brown-Elliott, Rubio et al. 2018 [43]; Pennings, Ruth et al. 2021 [49]
M. malmoense		0.06–0.5	N/A	N/A	Pennings, Ruth et al. 2021 [49]
M. xenopi		0.06–0.5	N/A	N/A	Pennings, Ruth et al. 2021 [49]
M. ulcerans		0.125–0.25	N/A	N/A	Pidot, Porter et al. 2021 [50]

Note: ^aAll values shown are in µg/mL.

Abbreviations: MAB, Mycobacterium abscessus complex; MAC, Mycobacterium avium complex; MIC, minimum inhibitory concentration.

Table 3. Incidence of treatment-emergent adverse events following oral administration of single and multiple ascending doses of SPR720 in healthy volunteers.

Preferred term	Number (%) of subjects
	Placebo, overall (n = 14)	Cohort 1, 100 mg (n = 6)	Cohort 2, 250 mg (n = 6)	Cohort 3, 500 mg (n = 6)	Cohort 4, 1000 mg, fasted (n = 6)	Cohort 4, 1000 mg, fed (n = 6)	Cohort 5, 1500 mg (n = 6)	Cohort 6, 2000 mg (n = 6)	Elderly, 500 mg (n = 6)	SPR720, overall, SAD (n = 42)
SAD
Any TEAE	3 (21.4)	1 (16.7)	2 (33.3)	1 (16.7)	1 (16.7)	0	4 (66.7)	6 (100)	3 (50.0)	18 (42.9)
Nausea	0	0	0	0	0	0	4 (66.7)	5 (83.3)	0	9 (21.4)
Headache	1 (7.1)	0	0	0	1 (16.7)	0	3 (50.0)	3 (50.0)	0	7 (16.7)
Vomiting	0	0	0	0	0	0	3 (50.0)	5 (83.3)	0	8 (19.0)
Diarrhea	0	0	0	1 (16.7)	0	0	0	2 (33.3)	0	3 (7.1)
Abdominal discomfort	0	0	1 (16.7)	0	0	0	0	0	0	1 (2.4)
Amylase increased	0	0	0	0	0	0	0	0	1 (16.7)	1 (2.4)
Dyspepsia	0	0	0	0	0	0	0	0	1 (16.7)	1 (2.4)
Neuralgia	0	0	0	0	0	0	0	0	1 (16.7)	1 (2.4)
Rhinorrhea	0	0	0	0	0	0	0	0	1 (16.7)	1 (2.4)
Skin abrasion	0	1 (16.7)	0	0	0	0	0	0	0	1 (2.4)
Toothache	0	0	1 (16.7)	0	0	0	0	0	0	1 (2.4)
	Placebo, overall (n = 10)	Cohort 1, 500 mg, 7 days (n = 6)	Cohort 2, 1000 mg, 7 days (n = 6)	Cohort 3, 1500 mg (750 mg q12h), 7 days (n = 6)	Cohort 4, 500 mg, 14 days (n = 6)	Cohort 5, 1000 mg, 14 days (n = 6)	SPR720, overall, MAD (n = 30)
MAD
Any TEAE	1 (10.0)	4 (66.7)	6 (100)	4 (66.7)	1 (16.7)	3 (50.0)	18 (60.0)
Diarrhea	1 (10.0)	2 (33.3)	4 (66.7)	4 (66.7)	0	3 (50.0)	13 (43.3)
Headache	0	2 (33.3)	3 (50.0)	2 (33.3)	1 (16.7)	0	8 (26.7)
Nausea	0	2 (33.3)	1 (16.7)	3 (50.0)	0	1 (16.7)	7 (23.3)
Vomiting	0	1 (16.7)	2 (33.3)	1 (16.7)	0	0	4 (13.3)
Abdominal pain	0	0	2 (33.3)	1 (16.7)	0	0	3 (10.0)
Back pain	0	0	1 (16.7)	0	0	1 (16.7)	2 (6.7)
Abdominal discomfort	0	0	1 (16.7)	0	0	0	1 (3.3)
Abdominal pain upper	0	0	0	0	0	1 (16.7)	1 (3.3)
Contusion	0	0	1 (16.7)	0	0	0	1 (3.3)
Gastroesophageal reflux disease	0	0	0	0	0	1 (16.7)	1 (3.3)
Insomnia	0	1 (16.7)	0	0	0	0	1 (3.3)
Lipase increased	0	0	0	0	0	1 (16.7)	1 (3.3)
Oropharyngeal pain	0	0	1 (16.7)	0	0	0	1 (3.3)
Pancreatic enzymes increased	0	0	0	1 (16.7)	0	0	1 (3.3)
Rash	0	0	0	1 (16.7)	0	0	1 (3.3)
Syncope	0	1 (16.7)	0	0	0	0	1 (3.3)

Abbreviations: MAD, multiple ascending dose; SAD, single ascending dose; TEAE, treatment-emergent adverse event.

Figure 3. Geometric mean plasma SPR719 concentration-time curves following single ascending doses of SPR720.

Table 4. Food effect on the PK of SPR719 following single oral 1000 mg doses of SPR720 in healthy volunteers^.a

Parameter	Geometric LS mean		Geometric LS mean ratio % (90% CI)	Within-subject CV (%)
	1000 mg, fasted (n = 6)	1000 mg, fed (n = 6)
Cmax (ng/mL)	4,730	4,000	84.6 (69.9–102.4)	16.6
AUClast (h s^2 ng/mL)	56,500	45,100	79.9 (68.5–93.0)	13.2
AUCinf (h s^2 ng/mL)	56,800	45,200	79.6 (68.3–92.8)	13.2

Note: ^aResults were obtained using a fixed-effects ANOVA with fixed effects of treatment and subject.

Abbreviations: AUC_inf, area under the concentration-time curve (AUC) extrapolated to infinity; AUC_last, AUC from time of dosing to time of the last measurable concentration; CI, confidence interval; C_max, maximum plasma concentration; CV, coefficient of variation; LS mean, least-squares mean.

Table 5. Summary of SPR719 PK parameters following oral administration of multiple ascending doses of SPR720 in healthy volunteers.

SPR720 treatment (n)	Day	Mean (% CV)^a
		Cmax (ng/mL)	Tmax (h)	t1/2 (h)	^AUC0–12 (h s^2 ng/mL)	^AUC0–24 (h s^2 ng/mL)	AUCinf (h s^2 ng/mL)	Accumulation ratio
500 mg QD, 7-day dose group (n = 6)	1	2,470 (40.8)	4.0 (4–8)	NC	14,700 (41.5)	16,800 (47.2)	NC	NA
	7	2,420 (39.9)	4 (1.5–4)	1.67 (11.8)	9,480 (25.8)	9,970 (24.7)	10,900 (19.7)	0.593 (52.8)
1000 mg QD, 7-day dose group (n = 6)	1	5,610 (20.1)	4 (4–4)	NC	43,200 (24.5)	57,000 (34.9)	NC	NA
	7	5,110 (21.4)	4 (1.5–4)	2.87 (14.3)	27,400 (34.3)	30,600 (40.7)	33,300 (40.2)	0.537 (44.4)
1500 mg total daily dose (750 mg q12h),	1	4,690 (24.0)	4 (4–4)	NC	31,300 (26.0)	54,700 (39.7)	NC	NA
7-day dose group (n = 6)	7	2,520 (34.8)	4 (4–4)	4.28 (70.8)	17,300 (41.2)	19,300 (44.0)^b	19,700 (42.1)	0.386 (17.8)
500 mg QD, 14-day dose group (n = 6)	1	1,410 (48.5)	4 (1–8)	NC	8,140 (68.4)	9,420 (75.7)	NC	NA
	7	1,140 (72.8)	4 (1.5–8)	NC	5,680 (97.0)	6,260 (100.6)	NC	NC
	14	967 (78.6)	4 (1–8)	5.05 (81.0)	5,040 (93.8)	5,640 (94.1)	9,720 (50.8)	0.599 (103.9)
1000 mg QD, 14-day dose group (n = 6)	1	3,500 (28.6)	4 (4–8)	NC	27,500 (30.6)	35,700 (25.8)	NC	NA
	7	3,490 (56.0)	4 (4–4)	NC	19,400 (63.6)	21,600 (68.7)	NC	NC
	14	2,500 (51.6)	4 (4–8)	3.67 (53.0)	13,300 (42.5)	14,500 (43.1)	19,900 (24.9)	0.405 (67.3)

Note: ^aC_max and AUC are expressed as geometric means, T_max values are expressed as medians (ranges), and half-life values are expressed as arithmetic means. Dosing of SPR720 in the 7-day dose groups was administered in the fasting state; dosing in the 14-day dose groups was administered without regard to meals.

^bThe AUC_0–24 cannot be compared between day 1 and day 7 for cohort 3 (750 mg q12h) since the subjects received two doses (750 mg q12h = 1500 mg) on day 1 but only one dose (750 mg once in the morning) on day 7.

Abbreviations: AUC_0–12, area under the concentration-time curve from time zero to 12 h; AUC_0–24, area under the concentration-time curve from time zero to 24 h; AUC_inf, area under the concentration-time curve from time zero to infinity; C_max, maximum concentration; t_1/2, elimination half-life; T_max, time of maximum observed concentration; NC, not calculatable.

Table 6. Trough concentrations of SPR719 by dose following oral administration of multiple ascending doses of SPR720 in healthy volunteers.

Dose group	Geometric LS mean trough concentration (ng/mL) at day
	2	3	4	5	6	7	8	9	10	11	12	13	14
500 mg x 7 days	20.8	9.7	7.1	5.7	5.0	5.0	NA	NA	NA	NA	NA	NA	NA
1000 mg x 7 days	306	100	34.7	18.1	21.1	18.7	NA	NA	NA	NA	NA	NA	NA
750 mg q12h x 7 days	2,370	1,510	1,430	1,300	662	406	NA	NA	NA	NA	NA	NA	NA
500 mg x 14 days	12.4	8.5	7.2	7.0	6.6	7.2	8.6	5.7	8.1	11.5	8.3	5.0	7.4
1000 mg x 14 days	176	85	42.7	50.2	54.4	25.5	25.3	22.1	18.7	20.4	14.2	10.0	12.0

Abbreviations: MAD, multiple ascending dose; NA, not applicable.

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