Imipenem

On December 2, 2024, Merck's combination antibiotic injection, Imipenem/Cilastatin/Relebactam (containing 500mg imipenem, 500mg cilastatin, and 250mg relebactam), received marketing approval from China's National Medical Products Administration. Based on the latest advances in clinical trials, the approved indications may include ventilator-associated bacterial pneumonia (VABP) and hospital-acquired bacterial pneumonia (HABP). Imipenem/Cilastatin/Relebactam contains three active ingredients with different mechanisms of action: imipenem, a carbapenem antibiotic; relebactam, a β-lactamase inhibitor; and cilastatin, a membrane dipeptidase inhibitor. The drug was first approved in the U.S. in July 2019 under the trade name Recarbrio for treating adult patients with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) who have limited treatment options or no alternative therapies. In June 2020, the indications for this drug were expanded to include VABP and HABP. According to public records, Merck initiated a global Phase III clinical trial (N=478) for Imipenem/Cilastatin/Relebactam in September 2018 in the EU, Japan, and China. This trial aimed to evaluate the efficacy, safety, and tolerability of Imipenem/Cilastatin/Relebactam compared to Piperacillin/Tazobactam (produced by Pfizer) in treating patients with HABP and VABP. The primary endpoint of the study was all-cause mortality related to treatment by day 28. The study successfully concluded in July 2022. Results from the Phase III RESTORE-IMI 2 study conducted in the U.S., EU, and Japan indicated that Imipenem/Cilastatin/Relebactam could reduce all-cause mortality in patients with HABP and VABP by 15.9%, demonstrating non-inferiority to Piperacillin/Tazobactam (which reduced mortality by 21.3%). Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are common types of bacterial pneumonia among hospitalized patients. HABP refers to pneumonia that develops within 48 hours of hospitalization in patients who have not received invasive mechanical ventilation and are not in the latent phase of a pathogenic infection. VABP refers to pneumonia occurring in patients who have undergone intubation or tracheostomy and were mechanically ventilated for 48 hours, as well as pneumonia that arises within 48 hours after extubation or ventilator removal. Both types of pneumonia can lead to symptoms such as fever, chills, cough, chest pain, and increased oxygen demand.

Spero’s SPR729 is a prodrug that converts into an active form that targets ATPase site of DNA gyrase B in mycobacteria. Image credit: Lemonsoup14 / Shutterstock. Spero Therapeutics has suspended the development of its antibiotic SPR720, after the therapy failed to meet the primary endpoint in a Phase IIa trial in patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD). The company was quick to note that whilst SPR720 showed antimicrobial activity, “the interim analysis did not show sufficient separation from placebo.” Spero also noted that it plans to lay off 39% of its staff. Following the announcement, the company’s stock was down by over 17% in premarket trading today. Spero reported that it has enough cash reserves to fund operations into mid-2026. The Phase IIa trial (NCT05496374) enrolled 25 non-refractory patients with SPR720. The interim analysis of 16 patients showed no differentiation in antimicrobial effect from placebo evaluated using the rate of change in log10 colony forming units per millilitre (CFU/mL), the study’s primary endpoint. Potential dose-limiting “safety issues”, including three cases of Grade 3 hepatotoxicity, were seen in patients receiving 1,000mg orally once daily dose. Spero plans to complete the data analysis of all 25 enrolled patients and “determine the next steps for the SPR720 program over the next several months.” The company plans to funnel its resources into two of its antibiotic programmes – an oral carbapenem antibiotic, tebipenem HBr, and SPR206, a next-generation polymyxin. Spero has out licenced tebipenem HBr to GSK, with the latter having global marketing rights to the therapy, except in certain Asian countries. Spero has received $143.5m from GSK as part of the partnership to date and is eligible to receive up to $400m in additional milestone-based payments along with tiered royalties on sales. The Phase III PIVOT-PO trial (NCT06059846) will compare oral tebipenem HBr with the two carbapenem antibiotics combination, intravenous imipenem and cilastatin, in hospitalised adult patients with complicated urinary tract infections (cUTI). The study is expected to recruit about 2,648 patients with cUTI, with enrolment planned for completion in the second half of 2025. Antibiotic development has seen mixed results in recent months. Last week, the US FDA approved Iterum Therapeutics’s Orlynvah (sulopenem etzadroxil and probenecid) for treating uncomplicated UTIs (uUTIs) caused by E. coli, Klebsiella pneumoniae or Proteus mirabilis in adult women who have limited or no alternative antibacterial treatment options. Whilst AN2 Therapeutics suspended development for its lead antibiotic, epetraborole, after it failed to show efficacy in Phase II/III trial (NCT05327803). AN2 was evaluating epetraborole as a treatment for refractory mycobacterium avium complex (MAC) lung disease. Spero plans to evaluate SPR206 as a treatment for multidrug-resistant (MDR) gram-negative pathogens in patients with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). The company has received clearance from the US Food and Drug Administration (FDA) to start a Phase II trial. However, Spero noted that trial initiation is “contingent on availability of non-dilutive funding.” Following the recent round of lay-offs, Spero joins the list of pharmaceutical companies such as Aerovate Therapeutics , Sage Therapeutics and Shattuck Labs that have fired workers in the l to funnelmoney into their clinical development pipelines.