Nontuberculous mycobacterial pulmonary disease and the potential role of SPR720

ABSTRACT

Introduction

Nontuberculous mycobacteria infect patients who have structural lung disease or those who are immunocompromised. Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in prevalence. Treatment guidelines for Mycobacterium avium complex (MAC) pulmonary disease involve a three-drug regimen with azithromycin, ethambutol, and rifampin, and those of Mycobacterium abscessus complex (MAB) pulmonary disease involve a combination of three or more antimicrobials including macrolides, amikacin, and a β-lactam or imipenem. However, these regimens are poorly tolerated and generally ineffective.

Areas covered

SPR720 is a novel therapeutic agent that has demonstrated activity against a range of NTM species, including MAC and MAB. Encouraging in vitro and pre-clinical data demonstrate that SPR720 is active both alone and in combination with standard-of-care agents, with no evidence of cross-resistance to such agents. It is generally well tolerated with mainly gastrointestinal and headache adverse events of mild or moderate severity.

Expert opinion

Management of NTM-PD is challenging for many reasons including length of therapy, poor efficacy, drug intolerance, recurrence, and resistance development. The current antimicrobial management options for NTM-PD are limited in number and there exists a large unmet need for new treatments. SPR720 has encouraging data that warrant further study in the context of a multidrug regimen.

KEYWORDS:

• Nontuberculous mycobacteria
• Mycobacterium avium complex
• pulmonary disease
• guidelines
• therapy
• SPR720

1. Introduction

Nontuberculous mycobacteria (NTM) are a diverse group of organisms that are ubiquitous in the environment [1]. More than 200 NTM species and subspecies have been identified to date [2] but only a small percentage are recognized to cause human infection. The vast majority (80–85%) of NTM pulmonary disease (NTM-PD) is caused by Mycobacterium avium complex (MAC), with Mycobacterium abscessus complex (MAB) and Mycobacterium kansasii comprising the remainder [3], and species such as Mycobacterium malmoense and Mycobacterium xenopi prevalent in other regions of the world (namely Europe and Canada) [4,5].

NTM-PD prevalence is increasing worldwide [3,6], and given that risk is greater in older individuals [7–10], it is expected that larger numbers of patients will acquire these infections from the environment as the population ages. Underlying bronchiectasis is the strongest risk factor for NTM-PD, although immunosuppression and underlying architectural lung disease such as chronic obstructive pulmonary disease, pneumonia, and asthma also predispose to disease [8,11–15].

Treatment of MAC pulmonary disease (MAC-PD) is well articulated by guidelines [16,17]; however, success of therapy and tolerability are unsatisfactory. A three-drug regimen with azithromycin, ethambutol, and rifampin is recommended for all patients initiating therapy. ‘Cure’ is elusive, particularly in the setting of bronchiectasis, and only 60–70% of individuals convert their sputum cultures to negative within the first six months of therapy [18,19]. Further, even after treatment success has been achieved (defined as completion of 12 months treatment post-culture conversion to negative), approximately half of those will become culture positive within three years [20]. This return to culture positivity represents both new infection from the environment as well as relapse of the original infection [21–23]. The tolerability of this regimen is poor, and population-based data suggest that less than half of patients who start triple-drug therapy are still using this regimen at six months after treatment initiation [24]; further attrition is evident and early therapy discontinuation is common [24–28].

Replacement for these recommended three drugs is limited, as only clofazimine has observational data supporting its use in this context [29–31]. Additionally, access to this drug is limited in the United States as it is only available within a managed access program offered by the manufacturer. Fluoroquinolones have little to no activity against MAC and are rarely useful in the treatment of MAC-PD [32]. Intravenous (IV) and inhaled forms of amikacin, including amikacin liposome inhalation suspension (ALIS), have good activity against MAC and are used initially in the treatment of cavitary disease (IV amikacin) or after failure of culture conversion (‘refractory disease’) within six months of therapy [16,17]. The need for new therapies against MAC, as well as MAB, for which there are essentially no active oral therapies for most isolates beyond clofazimine, cannot be understated.

The treatment armamentarium for NTM-PD includes a very limited number of therapeutic options and regimens are poorly tolerated and generally ineffective. Beyond clinicians, regulatory bodies and industry have realized the need for therapeutic development within the indication of NTM-PD. The FDA convened a workshop in April 2019 to discuss challenges and considerations related to the treatment of NTM-PD and the expert panelists agreed that there was a great need for new treatment options [33]. Limited therapeutic options for specific NTM species and the emergence of multidrug-resistant strains pose challenges in achieving successful treatment outcomes. Addressing these limitations requires ongoing research and development efforts to improve treatment outcomes for NTM-PD. This includes the development of novel oral antimicrobial agents with improved safety, tolerability, spectrum of activity, efficacy over shorter time periods, and minimal drug-drug interactions [34,35]. Drugs that are currently under development for NTM-PD that have reached clinical trials include ALIS, clofazimine, omadacycline, epetraborole, and SPR720 (Table 1). This review focuses on the attributes of SPR720 and a proposed development pathway in the treatment of NTM-PD.

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.

2. SPR720

SPR720 is an oral agent that was granted Qualified Infectious Disease Product (QIDP), fast track, and orphan drug designations by the FDA, and is being developed initially for the treatment of NTM-PD due to MAC. It is a chemically stable phosphate ester prodrug that is converted rapidly in vivo to SPR719, which is the active moiety. The chemical formulae of SPR720 and SPR719 are C₂₁H₂₆FN₆O₆P and C₂₁H₂₅FN₆O₃, respectively, and the structural formulae can be found in Figure 1. SPR719 is a novel aminobenzimidazole antibiotic that inhibits in mycobacteria the ATPase activity of DNA gyrase B (GyrB) [36–39], a subunit of the tetrameric gyrase A₂B₂ bacterial topoisomerase that catalyzes ATP-dependent negative DNA supercoiling and DNA decatenation [40–43]. DNA gyrase (Figure 2) is the sole complex with topoisomerase activity in mycobacteria, so inhibiting ATPase activity can impede the growth of a range of these pathogens [44]. As such, DNA gyrase is recognized as a clinically validated target for NTM infections [38,45].

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).

The mechanism of action of SPR719 is distinct from that of fluoroquinolones, which inhibit DNA gyrase A (GyrA) [38,46]. As such, there is no cross-resistance with fluoroquinolones or other standard-of-care (SOC) agents; this has been corroborated with in vitro surveillance data from NTM clinical isolates [43].

2.1. In vitro activity of SPR719 against clinically relevant mycobacteria

Several studies have shown that SPR719 is active in vitro against isolates from some of the major NTM organisms including MAC and MAB with a MIC range of 0.002–4 µg/mL and 0.03–8 µg/mL, respectively [36,47,48], as shown in Table 2. Its potent antimycobacterial activity is comparable or better than a range of other antimicrobials, however, not all are universally used for NTM infections. The comparator agents were clarithromycin, rifabutin, rifampin, amikacin, doxycycline, linezolid, trimethoprim/sulfamethoxazole, moxifloxacin, and ciprofloxacin across clinically relevant mycobacterial species in vitro, including MAC (M. avium, Mycobacterium intracellulare, Mycobacterium chimaera), MAB (subspecies M. abscessus, Mycobacterium massiliense, M. massiliense hybrid), M. kansasii, Mycobacterium ulcerans, Mycobacterium marinum, and M. chimaera, with no evidence of cross-resistance to other SOC agents [36,43,48,50]. SPR719 demonstrates potent activity against MAC (MIC₅₀ of 0.5–1 µg/mL and MIC₉₀ of 1–2 µg/mL) and M. kansasii (MIC₅₀ of <0.015 µg/mL and MIC₉₀ of 0.03 µg/mL) and good activity against MAB (MIC₅₀ of 2 µg/mL and MIC₉₀ of 2–4 µg/mL) [43]; its activity was concentration-dependent and considered bacteriostatic for MAC and MAB and bactericidal for M. kansasii [49].

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.

Studies also demonstrate activity against contemporary clinical isolates resistant to current therapeutics such as clarithromycin, fluoroquinolones, amikacin, cefoxitin, and imipenem [36,43,47,51]. Furthermore, the potential for combination therapy with ethambutol against MAC and M. kansasii or synergy with clarithromycin against M. abscessus (mean fractional inhibitory concentration index of 0.8 for each) has been demonstrated [49].

Characterization of in vitro activity is a first step in the profiling of resistance properties of novel drug candidates. Susceptibility studies have confirmed that SPR719 exhibited consistent activity against both MAC and MAB isolates that were resistant to SOC agents. Laboratory studies have identified spontaneous mutants in the ATPase domain of GyrB of MAC displaying resistance to SPR719 at low frequency (10⁻⁸/CFU) at concentrations 2 × MIC of SPR719 but not at higher concentrations. For MAB, but not for MAC, a second resistance mechanism at a frequency of 10⁻⁶/CFU, associated with frameshift mutations in the transcriptional repressor MAB_4384, was observed. Finally, resistant mutants did not exhibit cross-resistance to clarithromycin or moxifloxacin, indicating that resistance is specific to SPR719 and not due to a multidrug-resistance mechanism [51]. In the clinic, this will be further de-risked knowing that NTM-PD is treated with combination agents.

2.2. Various nonclinical models support the efficacy of SPR719/SPR720 in NTM-PD

SPR719 showed significant microbial kill in a hollow fiber system model of pulmonary intracellular MAC using a pharmacokinetic (PK) profile that supports once-daily dosing of SPR720 in humans [52]. Penetration of SPR719 into THP-1 monocytes was demonstrated. Moreover, SPR720 doses that are currently being evaluated in the ongoing Phase 2a clinical trial were predicted to achieve exposures associated with bactericidal effect in 95% of patients.

In a 60-day chronic C3HeBFeJ mouse infection model, SPR720 monotherapy caused a dose-dependent reduction in pulmonary M. avium ATCC 700898 burden at 10–100 mg/kg/day in comparison to the untreated control group. The combination of SPR720, clarithromycin, and ethambutol demonstrated the greatest reduction in the average mycobacterial burden in the lungs, spleen, and liver in this model [53].

SPR720 was also evaluated in a 17-day acute prolonged severe combined immunodeficiency (SCID) mouse model of infection with M. abscessus subspecies boletti 103. SPR720 significantly reduced the mycobacterial burden in the lungs, spleen, and liver after oral dosages of 25–400 mg/kg/day for 16 days. While dose-dependent efficacy was observed, a dose level of 100 mg/kg/day resulted in the greatest reduction in M. abscessus burden in the lungs, spleen, and liver compared with that in the control group [48].

Finally, the efficacy of SPR720 dosed at 25, 50, and 100 mg/kg/day, and comparator agents clarithromycin, amikacin, and clofazimine, dosed both alone and in combination with SPR720, was assessed in a 60-day chronic murine model of pulmonary and systemic infection caused by M. abscessus subspecies bolletii 1513. The SPR720 treatment group of 100 mg/kg/day resulted in the greatest bacterial reduction in the lung when given as a single agent, but the greatest bacterial reduction in the lung was achieved when SPR720 was combined with clarithromycin, amikacin, and clofazimine [47].

2.3. Phase 1 randomized, double-blind, placebo-controlled trial

SPR720 was evaluated in a phase 1, randomized, double-blind, placebo-controlled, single-center, first-in-human study (NCT03796910) to assess safety, tolerability, and PK [54]. A total of 96 healthy males and females aged 18–55 years participated in this two-part, multi-cohort study. Each subject was assigned to only one cohort and each cohort enrolled eight subjects, randomized (3:1) to receive SPR720 or placebo as single ascending doses (SAD) ranging from 100 to 2000 mg daily, including a second 500-mg dose group of healthy elderly subjects aged ≥65 years (n = 56) or multiple ascending doses doses (MAD) ranging from 500 to 1500 mg daily for seven or 14 days (n = 40).

The primary objective was to investigate the safety and tolerability in both the SAD and MAD cohorts. A full list of treatment-emergent adverse events (TEAEs) can be found in Table 3. TEAEs were reported by 42.9% of subjects who received SPR720 across the SAD cohorts. Higher doses of SPR720 led to higher reporting of TEAEs compared to lower doses (e.g. 2000 mg dose, 100%; 1500 mg, 66.7%; 1000 mg, 33.3%; 100 mg, 16.7%). Across the MAD cohorts, 60.0% of SPR720 recipients reported TEAEs. The proportion of subjects reporting TEAEs in the seven-day dose cohorts (500 mg, 66.7%; 1000 mg, 100%; 1500 mg, 66.7%) was greater than in the 14-day cohorts (500 mg, 16.7%; 1000 mg, 50.0%), which likely represents improved tolerability with continued dosing. All TEAEs were mild or moderate in severity and tended to be either gastrointestinal in nature (nausea, vomiting, and diarrhea) or headaches. No serious TEAEs were reported, and no deaths occurred.

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.

Secondary objectives were to investigate the PK as well as any effects of food or age on PK in the SAD groups. The mean plasma SPR719 concentrations increased with increasing dose of SPR720 (Figure 3). The median SPR719 T_max ranged from 2.8–8.0 hours across cohorts, and the mean t_1/2 ranged from 2.9–4.5 hours. C_max was independent of dose. Dosing with a high-fat meal decreased SPR719 plasma exposure (C_max, AUC_last, and AUC_inf) by approximately 20% compared to the fasting state (Table 4) and there was also a trend toward greater exposure of SPR719 in healthy subjects ≥65 years versus younger subjects.

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.

In the MAD cohorts, SPR719 plasma concentrations increased with increasing dose of SPR720. SPR719 plasma C_max and AUC _0–24 increased in a greater-than-dose-proportional manner with increasing doses of SPR720 (Table 5). SPR719 plasma exposure declined approximately 40% between days 1 and 7, suggesting induction of an elimination pathway. However, this seemed to stabilize after day 7 as AUC_0–24 was comparable between days 7 and 14. SPR719 trough plasma concentrations also stabilized by the end of dosing (Table 6).

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.

SPR720 was rapidly and extensively converted to SPR719 in vivo. Overall, these results suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720 [54].

2.4. Phase 2a dose-ranging clinical trial

SPR720 is currently being evaluated in a phase 2a, randomized, double-blind, placebo-controlled, multicenter, dose-ranging study (NCT05496374) to evaluate the efficacy, safety, tolerability, and PK of SPR720 for the treatment of adult patients with MAC-PD. Double-blind treatment assignments will be SPR720 500 mg, SPR720 1000 mg, or placebo orally once daily for 56 days, in addition to one open-label intensive PK arm with a treatment of SPR720 1000 mg orally once daily for 56 days. The estimated enrollment is 31 patients.

3. Conclusion

NTM infection is increasingly common especially among individuals with structural lung disease or immunocompromised conditions. NTM-PD may be due to a range of mycobacterial species with MAC being the most common. Management of this disease can be difficult due to limited effectiveness, poor tolerability, the long duration of SOC treatment, and the paucity of anti-NTM drugs in development. Currently SPR720 shows promise based on its activity against a range of NTM species including strains resistant to SOC agents. Clinical trials are ongoing.

4. Expert opinion

NTM-PD is increasing in prevalence, especially among those with underlying structural lung disease such as bronchiectasis, COPD, or cystic fibrosis, and those with compromised immune systems. Expert Societies have published guidelines on the management of this disease. Treatment for MAC-PD involves a three-drug regimen including a macrolide and ethambutol for a minimum of 12 months after sputum cultures convert from positive to negative, whereas treatment of MAB-PD involves a combination of three or more antimicrobials including macrolides, amikacin, and a β-lactam or imipenem. Despite treatment guidelines, only half of diagnosed patients begin guideline-based therapy with only 18% continuing at 12 months. Adherence rates decline further at 18 months. The occurrence of a wide range of adverse events have been reported by patients with NTM-PD. The complexity of the regimen can lead to challenges identifying which drug incites these events. It is also important to note that the occurrence of these events is often a factor of age. Further, several of the currently available drugs are metabolized in such a way that drug-drug interactions can be common and manifest as other adverse effects.

In addition to the physiological and mental burden associated with NTM-PD, it is not surprising that patients struggle with therapeutic strategies. Over-arching these individual complexities, resistance to some of the recommended agents is emerging which can lead to uncertainty regarding empirical management. Moreover, even in patients who receive ‘appropriate’ therapy, the clinical success of multidrug therapy can be unpredictable. Among those patients with susceptible strains, sputum conversion can occur in less than two-thirds of patients, while in those with resistant isolates conversion occurs in less than 20%. Recurrence can occur even in those whose sputum converted with two subgroups of recurrence, genuine relapse and reinfection.

In summary, the current antimicrobial management options for NTM-PD are limited in number, with poor tolerability, adherence, and efficacy contributing to the challenges of therapy. There exists a large unmet need with regard to NTM therapeutics, as NTM-PD continues to increase in prevalence. The aminobenzimidazole, SPR720, has demonstrated potential activity in in vitro and pre-clinical models and is currently in phase 2 proof-of-concept study with MAC-PD. If a clinically meaningful signal is detected, then further study incorporating this agent in the context of a multidrug regimen should be undertaken.

Article highlights

• Nontuberculous mycobacteria, including MAC and MAB, can cause pulmonary infections that are increasing in prevalence.

• Underlying lung disease such as bronchiectasis or chronic obstructive pulmonary disease, immunosuppression, and older age are the biggest risk factors.

• Management of NTM-PD is clinically challenging due to the long duration of complex multidrug antibiotic regimens, poor efficacy, recurrence, and resistance development.

• Current therapies are poorly tolerated, which often leads to early treatment discontinuation.

• SPR720 is a novel oral aminobenzimidazole that inhibits in mycobacteria the ATPase activity of DNA gyrase B.

• This agent has demonstrated activity against MAC and MAB both alone and in combination with standard-of-care agents in vitro and in pre-clinical models.

• SPR720 was well tolerated in a phase 1 randomized, double-blind, placebo-controlled trial with mainly mild or moderately severe gastrointestinal or headache adverse events.

• SPR720 is currently in phase 2 clinical studies.

Declaration of interest

KL Winthrop has received research support from AN2 Therapeutics, Insmed, Paratek Pharmaceuticals, RedHill Biopharma, Renovion, and Spero Therapeutics, and is a consultant for AN2 Therapeutics, Insmed, Paratek Pharmaceuticals, RedHill Biopharma, Renovion, and Spero Therapeutics. P Flume has received grant support from AbbVie, AN2 Therapeutics, Armata Pharmaceuticals, AstraZeneca, Cystic Fibrosis Foundation Therapeutics, Insmed, Janssen Pharmaceuticals, National Institutes of Health, Novovax, RedHill Biopharma, Sound Pharmaceuticals, Spero Therapeutics, Synchrony Bio, and Vertex Pharmaceuticals; and is a consultant for AN2 Therapeutics, Chiesi Farmaceutici, Eloxx Pharmaceuticals, Insmed, Ionis Pharmaceuticals, Janssen Research & Development, McKesson, Sionna Therapeutics, Spero Therapeutics, and Vertex Pharmaceuticals. KA Hamed is an employee of Spero Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.