The Platform and What It Means for Patients

The CDC estimates that every year, at least 2 million people are infected with drug resistant bacteria and that the number of deaths resulting from these infections is equivalent to one fully loaded jumbo jet crashing each week. There are many contributors to these troubling statistics, with one being a lack of novelty in the way such infections are treated.The lack of novelty is by no means due to a lack of effort devoted to this cause. Rather it is predominantly due to the physiology of Gram-negative bacterium, specifically the make-up of the outer-membrane of these bacteria that has hindered innovation. The outer membrane of Gram-negative bacteria poses a challenging physical barrier for antibiotics to cross, limiting the options we have for patients with serious infections. We believe our Potentiator Platform utilizes unique screening methods to identify molecules that interact with this outer membrane to assist microbiological killing, and it does so in a manner well tolerated per our clinical trials.

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We are excited to recently announce positive clinical data for our first Potentiator product candidate, SPR741, and a path to the clinic for our second Potentiator product candidate, SPR206, following positive data from our IND-enabling studies. Both product candidates are IV administered and have the potential to address a major unmet need in hospital-based infections with a novel approach.In the case of SPR741, binding specifically to the lipopolysaccharide (LPS) in the outer membrane results in a weakening of this barrier and enhances entry into the cell for a range of co-administered antibiotics. This allows us to combine SPR741 with existing, commonly used antibiotics to improve their activity against Gram-negative bacteria, including problematic drug-resistant variants. SPR206 represents the next evolution of the Potentiator Platform, where improved tolerability and direct killing of a broad spectrum of bacterial pathogens will be pursued in a single molecule.

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What the Data Mean for the Platform

SPR741 Phase Ib Trial

‍We previously announced tolerability and favorable PK of SPR741 in a Phase 1 trial supporting a fundamental premise of the platform: that we can design molecules that bind the outer membrane to enhance the activity of co-administered antibiotics, while preserving therapeutic index. Data from our recently completed Phase Ib study complements this finding by demonstrating that the PK and tolerability of SPR741 is unaffected when combined with some of the most commonly used antibiotics in the hospital. The data expands the safety profile of SPR741 observed in prior preclinical studies, and support the use of SPR741 in combination with common beta-lactam antibiotics, such as piperacillin-tazobactam, ceftazidime, and aztreonam. This data is important to support potential future efficacy studies of SPR741 in combination with these (and other) antibiotics, and is part of the data supporting a use case for SPR741 as an agent that can enhance and restore the utility of other commonly used agents.SPR206 Path to ClinicSPR206 is the culmination of deep learnings in the optimization of intrinsic bacterial efficacy and safety of Potentiator Platform molecules. SPR206 can kill bacteria as a monotherapy, without the need for a co-administered antibiotic, yet retains the tolerability attributes of SPR741. In addition to the bacterial pathogens addressed by SPR741, SPR206 can combat infections due to drug-resistant Pseudomonas aeurginosa and Acinetobacter baumannii, including variants harboring problematic carbapenem-resistant enzymes, pathogens for which few therapies exist on the market or in development.Additionally, in a manner similar to SPR741, SPR206 has the potential to also enhance the utility of empirically co-administered antibiotics. Our preclinical data recently announced support the program’s entry into clinical evaluation and our positive clinical data for SPR741 and the correlation between that data and preclinical toxicology studies enhances our confidence in the clinical prospects for SPR206 in Phase I and beyond.SPR741 and SPR206 represent novel, complementary advances in the approaches we have to treat resistant Gram-negative infections. We gratefully acknowledge the historical and ongoing support of the NIH, DoD, and the CARB-X initiative in delivering these data and are excited about the options that the Platform can bring to patients in need.

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This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201500014C.The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program under Award No. W81XWH-16-2-0019. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. In conducting research using animals, the investigator(s) adheres to the laws of the United States and regulations of the Department of Agriculture. This publication is supported by the Cooperative Agreement Number IDSEP160030 from ASPR/BARDA and by an award from Wellcome Trust, as administrated by CARB-X. The contents are solely the responsibility of the authors and do not necessarily represent the official views of CARB-X, the HHS Office ofthe Assistant Secretary for Preparedness and Response, the National Institutes of Health or Wellcome Trust. 

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About the Authors:

Ankit Mahadevia, M.D.

Chief Executive Officer of Spero Therapeutics

Troy Lister, Ph.D.

Vice President, Research of Spero Therapeutics