SPR719 / Spero Therap - LARVOL DELTA

Intrapulmonary pharmacokinetics of SPR719 following oral administration of SPR720 to healthy volunteers. (PubMed, Antimicrob Agents Chemother) - P1 | "Results from this study of the intrapulmonary disposition of SPR719 support further investigation of SPR720 as a potential oral agent for the treatment of patients with NTM-PD. This study is registered with ClinicalTrials.gov as NCT05955586."

Journal • PK/PD data • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases

Evaluation of the Spontaneous Mutation Frequencies of SPR719 Alone and in Combination with Other Agents Used to Treat Mycobacterium avium Complex Pulmonary Disease (IDWeek 2024) - No abstract available

Combination therapy • Infectious Disease

Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis. (PubMed, Int J Mol Sci) - "The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A Study to Assess the Intrapulmonary Pharmacokinetics (PK) of SPR719 by Comparing the Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations Following the Oral Administration of Multiple Doses of SPR720 in Healthy Volunteers. (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: Spero Therapeutics | Recruiting ➔ Completed

Trial completion

Efficacy of SPR720 in murine models of non-tuberculous mycobacterial pulmonary infection. (PubMed, J Antimicrob Chemother) - "In vitro activity of SPR720 against common NTM pathogens and efficacy in murine infections warrant the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD."

Journal • Nontuberculous mycobacteria • Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases

In Vitro Activity of Benzimidazole (SPR719) Against Clinical Isolates of Nontuberculous Mycobacteria With and Without Clarithromycin or Amikacin Resistance. (PubMed, Ann Lab Med) - "The MIC and MBC values of M. kansasii were relatively lower than those of the other species with little difference between them, demonstrating the bactericidal properties of SPR719. The in vitro activity of SPR719 against major clinical NTM species suggests that SPR719 can serve as a novel treatment option for NTM-pulmonary disease."

Journal • Nontuberculous mycobacteria • Preclinical • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases

A Study to Assess the Intrapulmonary Pharmacokinetics (PK) of SPR719 by Comparing the Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations Following the Oral Administration of Multiple Doses of SPR720 in Healthy Volunteers. (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Spero Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Assess the Intrapulmonary Pharmacokinetics (PK) of SPR719 by Comparing the Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations Following the Oral Administration of Multiple Doses of SPR720 in Healthy Volunteers. (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: Spero Therapeutics

New P1 trial

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus. (PubMed, Antimicrob Agents Chemother) - "Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M. abscessus DNA gyrase, and the compound inhibited DNA supercoiling activity of recombinant M. abscessus enzyme. Further profiling of TPP8 in macrophage and mouse infection studies demonstrated proof-of-concept activity against M. abscessus ex vivo and in vivo."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Respiratory Diseases

In Vitro Resistance against DNA Gyrase Inhibitor SPR719 in Mycobacterium avium and Mycobacterium abscessus. (PubMed, Microbiol Spectr) - "Here, we characterized in vitro resistance against SPR719, a drug candidate for the treatment of lung disease caused by non-tuberculous mycobacteria (NTM). The identified resistance associated mutations and the observed differential resistance behavior of the two characterized NTM species provide a basis for follow-up studies of resistance in vivo to further inform clinical development of SPR719."

Journal • Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections. (PubMed, Antimicrob Agents Chemother) - "However, plasma AUC was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720."

Clinical • Journal • P1 data • PK/PD data • Gastrointestinal Disorder • Infectious Disease • Nontuberculous Mycobacterial Disease • Pain • Pulmonary Disease • Respiratory Diseases • Tuberculosis

In vitro activity of SPR719 against Mycobacterium ulcerans, Mycobacterium marinum and Mycobacterium chimaera. (PubMed, PLoS Negl Trop Dis) - "We show that SPR719 is active against these NTM species with a MIC range of 0.125-4 μg/ml and that this compares favorably with the commonly utilized antimycobacterial antibiotics, rifampicin and clarithromycin. Our findings suggest that SPR720 should be further evaluated for the treatment of NTM infections."

Journal • Preclinical • Infectious Disease • Respiratory Diseases • Tuberculosis

[VIRTUAL] Characterization of Resistance to DNA Gyrase Inhibitor SPR719 in Mycobacterium avium (WMF 2021) - "Recently, the aminobenzimidazole SPR720 entered development for the treatment of M. avium disease...Moxifloxacin and clarithromycin, included as comparators, yielded similar frequencies of resistance of ~10-8/CFU...In conclusion, in vitro resistance analyses of SPR719 in M. avium revealed a frequency of resistance of 10-9 to 10-8/CFU and associated polymorphisms mapped to the ATPase domain of the GyrB subunit of DNA gyrase. These results demonstrate a low propensity for the development of resistance and confirm the mechanism of action of the novel DNA gyrase inhibitor in M. avium."

Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases

Piperidine-4-carboxamides target DNA gyrase in Mycobacterium abscessus. (PubMed, Antimicrob Agents Chemother) - "P4C resistant strains showed limited cross-resistance to the fluoroquinolone moxifloxacin, which is in clinical use for the treatment of macrolide resistant M. abscessus disease, and no cross-resistance to the benzimidazole SPR719, a novel DNA gyrase inhibitor in clinical development for the treatment of mycobacterial diseases. This indicates that P4Cs, similar to fluoroquinolones, cause DNA gyrase-mediated DNA damage. Together, our results show that P4Cs present a novel class of mycobacterial DNA gyrase inhibitors with attractive antimicrobial activities against the M. abscessus complex."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Pipeline of anti-Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities. (PubMed, Med Res Rev) - "We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest in M. abscessus that may be worthy of future drug and adjunct therapeutic development."

Journal • Review • Respiratory Diseases

The benzimidazole SPR719 shows promising concentration-dependent activity and synergy against nontuberculous mycobacteria. (PubMed, Antimicrob Agents Chemother) - "We recorded potential for combination therapy with ethambutol against M. kansasii and M. avium and synergy with clarithromycin against M. abscessus Ethambutol increased the SPR719 kill rate against M. kansasii but only prevented SPR719 resistance in M. aviumSPR719 is active in vitro against NTM; its activity is strongest against M. kansasii, followed by MAC and M. abscessus SPR719 shows promise for combination therapy with ethambutol against MAC and M. kansasii and synergy with clarithromycin against M. abscessus The parent drug SPR720 could have a role especially in MAC pulmonary disease treatment. Further studies in dynamic models and trials are ongoing to advance clinical development."

Journal • Nontuberculous Mycobacterial Disease • Respiratory Diseases

[VIRTUAL] Evaluating the Activity of SPR719, a Novel Aminobenzimidazole, against Nontuberculous Mycobacteria (IDWeek 2020) - "SPR719 and comparators clarithromycin (CLA), amikacin (AMK), moxifloxacin (MXF), rifabutin (RFB), minocycline (MIN), and imipenem (IPM) were evaluated. SPR719 had potent activity by both MIC50/90 and MIC range across the evaluated NTM species. The SPR719 activity against clinically relevant MAC and M. abcessus/chelonae Group isolates was comparable or superior to the evaluated comparators, and SPR719 was active against isolates resistant to currently utilized agents. These results highlight the potential of SPR719 in the treatment of NTM pulmonary disease."

Infectious Disease • Nontuberculous Mycobacterial Disease

"Pharmacokinetics/pharmacodynamics of the Novel Gyrase Inhibitor SPR719/SPR720 and Clinical Dose Selection to Treat Pulmonary Mycobacterium avium-complex Disease #IDWeek2020 https://t.co/yZoh6OHC4r" (@Mwendowagutu)

Clinical • PK/PD data • Infectious Disease

[VIRTUAL] Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections (IDWeek 2020) - "Background: SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned."

P1 data • PK/PD data • Infectious Disease • Nontuberculous Mycobacterial Disease • Tuberculosis

[VIRTUAL] Pharmacokinetics/pharmacodynamics of the Novel Gyrase Inhibitor SPR719/SPR720 and Clinical Dose Selection to Treat Pulmonary Mycobacterium avium-complex Disease (IDWeek 2020) - "SPR720 monotherapy is predicted to achieve exposures associated with bactericidal effect against pulmonary MAC in 95% of patients at doses that have recently been established to be safe and well tolerated. These data support the continued development of SPR720 for the treatment of pulmonary MAC."

Clinical • PK/PD data • Infectious Disease

[VIRTUAL] SPR720, A Novel Benzamidazole Gyrase Inhibitor, Demonstrates Potent Efficacy Against Mycobacterium avium ATCC 700898 in a Chronic C3HeBFeJ Mouse Infection Model (IDWeek 2020) - "Background: SPR719 (the active metabolite of phosphate prodrug SPR720) belongs to a novel class which targets the ATPase subunits of gyrase by a mechanism distinct from fluoroquinolones...Treatment started on day 28 for 8 weeks with: saline, clarithromycin 250 mg/kg (CLR) QD, SPR720 at 10, 30 and 100 mg/kg QD, or SPR720 at 50 mg/kg BID. SPR720 at 30 mg/kg QD was also combined with CLR +/- ethambutol at 100 mg/kg (EMB), or CLR + rifabutin at 100 mg/kg (RFB) +/- EMB... Oral administration of SPR720 demonstrated a statistically significant reduction in the bacterial burden in all tissues with concomitant improvement in lung pathology, both alone and in combination with standard of care agents. These results support the continued development of SPR720 for treatment of NTM pulmonary infections."

Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease