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SPR206

Novel Intravenous (IV) Product Candidate for Treating MDR Gram-Negative Infections

There has been a significant decrease in the number of novel IV antibiotics in development and approved over the past 40 years for the treatment of gram-negative infections.

The physiology of gram-negative bacteria – specifically the make-up of the outer membrane of these bacteria – is one of the primary roadblocks hindering scientific advancement and innovation.[1-4] While gram-positive bacteria possess a single phospholipid cell membrane, gram-negative bacteria have a phospholipid inner membrane (akin to the gram-positive membrane), plus an outer membrane bilayer composed primarily of phospholipid at the inner surface and lipopolysaccharide (LPS) at the outer leaflet. It is this layer of highly polar, negatively charged LPS that excludes many excellent target-based inhibitors, including a trove of clinically useful gram-positive antibiotics from entering gram-negative bacteria to do their work.[1] Unfortunately, a distinct incongruence between chemical properties required for gram-negative penetration (both membranes), and those imposed by many of the known (and novel) bacterial targets, means that simple (or complex) medicinal chemistry tactics have not been able to provide a solution.

Some compounds that can competitively displace the divalent cations and/or “occupy” the extensive negative charge in the outer membrane such as the polymyxins became available in the 1950s.[1]

The clinical use of this antibiotic class has recently grown, often assuming an important role in salvage therapy for otherwise untreatable gram-negative infections.  However, it is common that these antibacterial membrane active molecules also exhibit off-target activities resulting in undesirable toxicology, most notably, nephrotoxicity. It has been shown that balancing kidney cytotoxicity and kidney exposure of polymyxin derivatives plays a key role in a preclinical animal model of nephrotoxicity, and that structure-kidney exposure relationships exist for this class and can be optimized.[3]

a closeup of a patient's hand with an IV
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molecule for SPR206

Our Focus on Gram-Negative Membrane Disruption

Developed within our potentiator platform program, SPR206 is an innovative, investigational direct acting IV antibiotic designed to interact with the LPS to disrupt the outer membrane and possesses antibiotic activity as a single agent.  In preclinical studies, SPR206 has shown activity against MDR gram-negative pathogens, including carbapenem-resistant Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa. 

Spero Therapeutics completed non-clinical, IND-enabling studies supporting its advancement as a potential clinical candidate designed to treat MDR and extensively drug-resistant (XDR) bacterial strains. Based on microbiological and in vivo testing, we believe that SPR206 has the potential to offer a broad-spectrum of activity, including against XDR bacterial strains. A Phase 1 clinical trial designed as a double-blind, placebo-controlled, ascending dose, multi-cohort study in healthy subjects was conducted and results were published in September 2021.

Spero Therapeutics also completed three SPR206 Phase 1 clinical studies: (1) a first-in-human Phase 1 study in which SPR206 was generally well tolerated and demonstrated no evidence of nephrotoxicity at anticipated therapeutic doses; (2) a bronchoalveolar lavage (BAL) study that assessed the intrapulmonary pharmacokinetics of SPR206; and (3) a renal impairment study.

The Latest

Spero received clearance by the US FDA for its IND application to evaluate SPR206 in a Phase 2 clinical study.
The planned Phase 2 study will be a randomized, double-blinded, controlled, multicenter study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of SPR206 in combination with select antibiotics for the treatment of patients diagnosed with hospital-acquired and ventilator-associated bacterial pneumonia ("HABP/VABP"), caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex or carbapenem-resistant Pseudomonas aeruginosa. Approximately 60 adult hospitalized patients are expected to be enrolled. Patients will receive treatment for 7−14 days and will be evaluated through assessment of post-baseline clinical outcomes.

Spero was awarded Fast Track designation for SPR206 in May 2024.
The Phase 2 trial is supported by preclinical data and the results of multiple Phase 1 clinical trials. These Phase 1 trials have demonstrated SPR206's ability to achieve mean lung epithelial lining fluid (“ELF”) exposures above the MIC for targeted gram-negative pathogens, when administered three times daily at 100 mg. The initiation of the Phase 2 trial is contingent on availability of non-dilutive funding.
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Check out the latest posters and publications on SPR206:

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References for SPR206
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  1. Zabawa TP, et al. Treatment of Gram-negative bacterial infections by potentiation of antibiotics. Curr Opin Microbiol. 2016; 33:7-12.
  2. Hancock RE. Peptide antibiotics. Lancet. 1997; 349(9049):418-22.
  3. Brown P, et al. Design of next generation polymyxins with lower toxicity: the discovery of SPR206. ACS Infect Dis. 2019; 5(10):1645-1656.
  4. Akhoundsadegh N, et al. Outer membrane interaction kinetics of new polymyxin B analogs in Gram-negative bacilli. Antimicrob Agents Chemother. 2019; 63(10):e00935-19.

[Last updated July 2024]

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