KSP-1007 / Sumitomo Pharma, The Kitasato Institute - LARVOL DELTA

In vitro and in vivo activities of KSP-1007, a broad-spectrum inhibitor of serine- and metallo-β-lactamases, in combination with meropenem against carbapenem-resistant Gram-negative bacteria. (PubMed, Antimicrob Agents Chemother) - "The MIC90 of MEM/KSP-1007 at 8 µg/mL against Enterobacterales was lower than those of MEM/vaborbactam, ceftazidime/avibactam, imipenem/relebactam, and colistin and similar to those of aztreonam/avibactam, cefiderocol, and tigecycline...MEM/KSP-1007 showed excellent activity against Escherichia coli with PBP3 mutations and New Delhi metallo-β-lactamase compared to aztreonam/avibactam, cefepime/taniborbactam, and cefiderocol...KSP-1007 enhanced the in vivo activity of MEM against carbapenemase-producing Enterobacterales, A. baumannii, and P. aeruginosa in murine systemic, complicated urinary tract, and thigh infection models. Collectively, MEM/KSP-1007 has a good profile for treating carbapenem-resistant Gram-negative bacterial infections."

Combination therapy • Gram negative • Journal • Preclinical • Infectious Disease

KSP-1007, a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases for Combination with Meropenem (ASM Microbe 2023) - "There is no abstract associated with this presentation."

Safety, Tolerability, And Pharmacokinetics Of KSP-1007 After Single And Multiple Ascending Doses Alone Or In Combination With Meropenem In Healthy Subjects (ASM Microbe 2023) - "The most common AEs at the highest dose of KSP-1007 (1500 mg) in combination with 2g of MEPM were nausea, vomiting and transient increases of serum creatinine (peak changes ranged from 0.31-0.74 mg/dl), which recovered during dosing period. These data further support clinical development of KSP-1007/MEPM for treating serious infections due to resistant bacteria.Table 1: Pharmacokinetic parameters for KSP-1007 when administered with and without Meropenem.Parameter (Day 5)KSP-1007 500 mg q8h aloneKSP-1007 500 mg + MEPM 2g q8h (Combo)N=6N=8Cmax (μg/mL) 23.9 (12.4)30.8 (27.3)AUC0-tau (μg·h/mL) 98.2 (15.2)135 (34.8)Clearance (L/h) 5.09 (15.2)3.71 (34.8)Vss (L) 14.1 (11.8)10.2 (29.7)T1/2 (h) 1.91 (5.1)1.84 (9.2)Data reported as Geometric mean (% geo CV)"

Clinical • Combination therapy • PK/PD data • Infectious Disease

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): In vivo Activity in Mouse Model of Systemic and Urinary Tract Infection (UTI) Due to Carbapenemase-Producing Gram-Negative Bacteria (CP-GNB) (ASM Microbe 2023) - "We discovered the bicyclic boronate KSP, a new broad-spectrum BLI, and investigated its in vivo activity in combination with meropenem (MEM) against CP-GNB...In a UTI model, cyclophosphamide-treated neutropenic mice were inoculated with 50 μL of the bacterial suspension into the left renal pelvis, 3 to 5 h before therapy, and were sc treated with MEM and KSP every 3 h for 24 h. The renal bacterial burden was determined 4 and 28 to 29 h after infection. The ED50 of MEM with KSP against KPC-producing Klebsiella pneumoniae (Kp) was comparable to those of MEM with vaborbactam (VAB), avibactam (AVI), or taniborbactam (TAN), and was lower than that of MEM alone... KSP restored the in vivo activity of MEM against CP-GNB.Systemic infectionMICs (μg/mL) of MEMED50s (mg/kg) of MEM (n =10)OrganismsCarbapenemasesMEMwith KSPMEMwith KSPKp ATCC BAA-2344KPC-2160.03*2056.48†Ec ATCC BAA-2469NDM-1320.03*1038.93†Ab CDC-83NDM-1, OXA-23, 691282**>300 [401]16.3‡Ab CDC-303OXA-23,..."

Gram negative • Preclinical • Infectious Disease • Nephrology • Pneumonia

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): Bactericidal Activity, Effects of Human Plasma, Serum Albumin, Urine and Medium PH on the In vitro Activity in Combination with Meropenem (MEM) against Carbapenemase-Producing Enterobacterales (CPE) (ASM Microbe 2023) - "Background: The emergence of CPE is a major global health concern as CPE is resistant to β-lactams including carbapenems. MEM/KSP showed bactericidal activity against almost all strains of CPE used in this study. The in vitro activity of MEM/KSP against CPE was unaffected by media variations, except for human urine at pH 8.Drug (µg/mL)MIC range (µg/mL)MBC range (µg/mL)MIC/MBC rangeSerine-carbapenemaseproducing Enterobacterales n = 6MEM/KSP (4)0.015 - 0.060.03 - 0.061 - 2MEM/VAB (8)0.03 - 0.50.03 - 41 - 8CAZ/AVI (4)≤0.12 - 2≤0.12 - 21 - 2Metallo-carbapenemaseproducing Enterobacterales n = 11MEM/KSP (4)0.03 - 0.250.03 - 0.51 - 8*MEM/VAB (8)4 - 1288 - >1281 - ≥2CAZ/AVI (4)>128>128-VAB, vaborbactam; CAZ, ceftazidime; AVI, avibactam; * Ratio 8 is only 1 strainOrganismsMICs of MEM with KSP at 4 μg/mL (μg/mL)AlbuminPlasmaCAMHBHuman urine0%*4%20%50%pH 5pH 6pH 8pH 5pH 6pH 7pH 8Ec ATCC BAA-2340 (KPC-3)0.0150.030.030.0150.120.06≤0.030.250.030.0150.015Kp..."

Combination therapy • Preclinical • Infectious Disease • Pneumonia

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): Biochemical Characterization of Inhibitory Activity against Various β-Lactamases (BL)s (ASM Microbe 2023) - "Background: To identify new treatments in combination with meropenem for infections due to carbapenemase-producing carbapenem-resistant bacteria, we discovered the bicyclic boronate KSP, a new broad-spectrum BL inhibitor... KSP strongly inhibited KPCs with a similar potency as avibactam (AVI) and taniborbactam (TAN) and was superior to the other comparators... KSP was the only compound that inhibited all classes A, B, C, and D BLs used in this study.BLClass Ki app (nmol/L)KSPVABAVIRELTAZTANCTX-M-15A0.066478.10.3690.8410.03870.0245SHV-5A12714202.156.261.845.90TEM-10A6.902190.236.830.93827.3PDC-11C0.79386010748.040.534.6KPC-2A1.4663.73.965.031591.10KPC-3A2.1988.35.707.672700.947OXA-23D4.07ND161564014NDOXA-24D1.09ND112ND1002080OXA-48D0.861ND2.4189.35.32204NDM-1B126NDNDNDND2660NDM-5B31.6NDNDNDND393NDM-7B53.0NDNDNDND704VIM-1B350NDNDNDND271IMP-1B512NDNDNDNDNDVAB, vaborbactam; ND, not detected due to the low inhibitory activity"

Infectious Disease

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): Pharmacokinetics, Distribution, Metabolism, and Excretion in Nonclinical Studies (ASM Microbe 2023) - "Background: In a previous study, we discovered the bicyclic boronate KSP, a new broad-spectrum β-lactamase inhibitor that is a novel treatment for carbapenemase-producing carbapenem-resistant bacteria in combination with meropenem. KSP showed satisfactory PK profiles in non-clinical studies, supporting co-administration of meropenem with a dosing interval of every 8 hours in clinical trials."

PK/PD data • CYP2C9

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): Pharmacokinetics/Pharmacodynamics in Combination with Meropenem (MEM) against Carbapenemase-Producing Klebsiella Pneumoniae (CP-Kp) and Acinetobacter Baumannii (CP-Ab) in a Neutropenic Murine Thigh Infection Model (ASM Microbe 2023) - " Cyclophosphamide-treated neutropenic mice were inoculated into the gastrocnemius muscle with Kp (KPC, NDM, or IMP producer) or Ab (NDM and/or OXA producer) 2 h before therapy and were subcutaneously treated with MEM at 5 to 100 mg/kg every 3 h for 24 h alone or with KSP administered at 3-, 6-, 12-, or 24-h dosing intervals. The in vivo efficacy of KSP in combination with MEM against CP-Kp and Ab was dependent on the %fT>CT."

Combination therapy • PK/PD data • Preclinical • Infectious Disease • Pneumonia

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): In vitro Activity in Combination with Meropenem (MEM) against Gram-Negative Bacteria (GNB) Including Carbapenemase Producers (ASM Microbe 2023) - "The MIC90 of MEM/KSP at 8 μg/mL (MEM/KSP8) against 207 Ent was lower than those of MEM/vaborbactam (VAB), ceftazidime/avibactam (CAZ/AVI), imipenem/relebactam (IMP/REL), and colistin (CST), and comparable to those of aztreonam/avibactam (AZT/AVI), cefiderocol (FDC), and tigecycline (TGC)...MEM/KSP8 showed excellent activity against Ent with NDM and PBP3 mutations compared to AZT/AVI, cefepime/taniborbactam (FEP/TAN), and FDC... KSP restored MEM activity against GNB including CP-isolates. MEM/KSP was a potent BL/BLI combination.DrugsEnt (n = 207)Serine-CP Ent (n = 80)Metallo-CP Ent (n = 74)Ab (n = 55)Pa (n = 96)MIC50MIC90MIC50MIC90MIC50MIC90MIC50MIC90MIC50MIC90MEM4324328>3232>12816>128MEM/KSP (4)≤0.068≤0.060.12≤0.06324328128MEM/KSP (8)≤0.061≤0.06≤0.06≤0.068488128MEM/KSP (16)≤0.060.25≤0.06≤0.06≤0.06124864MEM/VAB (8)0.2532≤0.0618>3232>1288>128CAZ/AVI (4)2>320.52>32>3232>324>32IMP/REL (4)0.5160.2528>3232>322>32AZT/AVI..."

Combination therapy • Gram negative • Preclinical • Infectious Disease

The Broad-Spectrum β-Lactamase Inhibitor KSP-1007 (KSP): In vivo Activity against Carbapenemase-Producing Acinetobacter Baumannii (CP-Ab) in a Mouse Lung Infection Model (ASM Microbe 2023) - "Cyclophosphamide-treated neutropenic mice were intranasally inoculated with an Ab CDC-277 (OXA-24 and 65 producer) suspension at 2 h before therapy and subcutaneously (sc) treated with MEM at 100 mg/kg every 3 h for 24 h alone or with KSP administered at 3-, 6-, 12-h dosing intervals (240 and 480 mg/kg/day)...Colistin at 30 mg/kg was sc administered every 12 h. The pulmonary bacterial burden was determined 2 and 26 h after infection... KSP restored the activity of meropenem against CP-Ab lung infection and demonstrated penetration in the lung.MICs (μg/mL) against Ab CDC-277MEM alonewith KSP at 4 μg/mLwith KSP at 8 μg/mLwith KSP at 16 μg/mLColistin1284411Change in log10 CFU/lung relative to the start of treatmentControl+2.96+KSP 30 mg/kg q3h-3.86+KSP 60 mg/kg q3h-4.17Colistin 30 mg/kg q12h-0.48+KSP 60 mg/kg q6h-3.96+KSP 120 mg/kg q6h-4.08MEM 100 mg/kg q3h+0.11+KSP 120 mg/kg q12h-4.17+KSP 240 mg/kg q12h-4.21q3h, every 3 h; q6h, every 6 h; q12h, every 12 h"

Preclinical • Infectious Disease • Respiratory Diseases

Study of the Safety and Pharmacokinetics of KSP-1007 Alone and Coadministered With Meropenem in Healthy Subjects (clinicaltrials.gov) - P1 | N=123 | Completed | Sponsor: Sumitovant Biopharma, Inc. | Recruiting ➔ Completed

Trial completion • Infectious Disease