8-K: Spero Therapeutics and GSK Announce Pivotal Phase 3 Trial for Oral cUTI Treatment Stopped Early for Efficacy

• Spero Therapeutics and GSK announced that the pivotal Phase 3 PIVOT-PO trial for tebipenem HBr, an investigational oral treatment for complicated urinary tract infections (cUTIs), including pyelonephritis, met its primary endpoint.
• The trial was stopped early for efficacy following a recommendation from an Independent Data Monitoring Committee (IDMC) after a pre-specified interim analysis of data from 1,690 patients.
• Tebipenem HBr demonstrated non-inferiority compared to intravenous imipenem-cilastatin in hospitalized adult patients with cUTI, including pyelonephritis, on overall response (clinical cure plus microbiological eradication) at the test-of-cure visit.
• The IDMC review did not identify any new safety concerns beyond what has been previously reported, with diarrhea and headache being the two most reported adverse events.
• GSK plans to work with U.S. regulatory authorities to include this data as part of a New Drug Application (NDA) filing in the second half of 2025.

Score: 9

Explanation: The announcement is overwhelmingly positive, with the pivotal Phase 3 trial meeting its primary endpoint and stopping early for efficacy. This significantly de-risks the drug's path to market and addresses a large unmet medical need with a potentially first-in-class oral treatment. The partnership with GSK and existing FDA designations further enhance the positive outlook.

• The pivotal Phase 3 PIVOT-PO trial for tebipenem HBr met its primary endpoint, demonstrating non-inferiority to the current intravenous standard of care.
• The trial was stopped early for efficacy, indicating stronger-than-anticipated positive results.
• No new safety concerns were identified by the Independent Data Monitoring Committee (IDMC) beyond previously reported adverse events.
• Tebipenem HBr has the potential to be the first oral carbapenem antibiotic for US patients with complicated urinary tract infections (cUTIs), offering a significant advantage over current IV-only options.
• The market for cUTIs is substantial, with an estimated 2.9 million cases treated annually in the US, contributing to over $6 billion per year in healthcare costs, indicating a large addressable market for an effective oral treatment.
• The drug has received Qualified Infectious Disease Product (QIDP) and Fast Track designations from the FDA, potentially expediting regulatory review.
• The development is supported in part by federal funds from the U.S. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under contract number HHSO100201800015C.
• The partnership with GSK, a global biopharma company, provides strong development and commercialization capabilities.

• Diarrhea and headache were reported as the two most common adverse events, though no new safety concerns were identified.

• Actual results may differ materially from forward-looking statements due to various factors.
• Uncertainty regarding whether tebipenem HBr will advance through the clinical development process, or at all, taking into account possible regulatory delays, slower than anticipated patient enrollment, manufacturing challenges, clinical trial design, and clinical outcomes.
• Uncertainty regarding whether the results of such trials will warrant submission for approval from the FDA or equivalent foreign regulatory agencies.
• Uncertainty regarding whether the FDA will ultimately approve tebipenem HBr and, if so, the timing of any such approval.
• The FDA may require additional clinical data or place labeling restrictions on the use of tebipenem HBr that would delay approval and/or reduce the commercial prospects of tebipenem HBr.
• Uncertainty regarding whether a successful commercial launch can be achieved and market acceptance of tebipenem HBr can be established.
• Results obtained in preclinical studies and clinical trials may not be indicative of results obtained in future clinical trials.
• Spero's reliance on third parties to manufacture, develop, and commercialize its product candidates, if approved, including, in the case of tebipenem HBr, reliance on GSK pursuant to the Exclusive License Agreement and GSK's right thereunder to determine, in its sole discretion, whether to continue the PIVOT-PO trial or otherwise further develop tebipenem HBr.
• Spero's need for additional funding.
• The ability to commercialize Spero's product candidates, if approved.
• Spero's ability to retain key personnel.
• Impact of Spero's leadership transitions.
• Uncertainty regarding whether Spero's cash resources will be sufficient to fund its continuing operations for the periods and/or trials anticipated.

The company and GSK plan to submit the data from the successful PIVOT-PO trial as part of a New Drug Application (NDA) filing to U.S. regulatory authorities in the second half of 2025. If approved, tebipenem HBr is anticipated to be the first oral carbapenem antibiotic available for US patients with complicated urinary tract infections, potentially changing the treatment landscape by offering an oral alternative to current intravenous options. Full results will be presented at an upcoming scientific congress and published in a peer-reviewed journal.

• "Achieving the primary endpoint in the PIVOT-PO trial marks a significant milestone for tebipenem HBr. If approved, we believe tebipenem HBr is well positioned to change the treatment landscape for patients diagnosed with cUTI, including pyelonephritis. We look forward to working with GSK on next steps for this program, and would like to thank the patients, site investigators and other clinical staff, and Spero employees who worked diligently to help bring the product to this advanced stage." Esther Rajavelu, Chief Executive Officer, Spero.
• "Complicated UTIs can have a profound impact on patients and carry a high risk of clinical complications, including sepsis and septic shock. Currently many need hospital-based intravenous treatment due to limited oral options for drug-resistant infections, contributing to over $6 billion per year in US healthcare costs. These positive results add to our growing anti-infectives portfolio and reinforce the potential of tebipenem HBr as an effective oral alternative taken at home." Tony Wood, Chief Scientific Officer, GSK.

Complicated urinary tract infections (cUTIs) represent a significant healthcare burden, with millions of cases annually in the US, often requiring hospitalization and contributing billions in healthcare costs. A key challenge is the prevalence of multi-drug-resistant pathogens and the current reliance on intravenous carbapenem antibiotics for severe cases, limiting outpatient treatment options. Tebipenem HBr, if approved as the first oral carbapenem, addresses a critical unmet need by potentially enabling patients to receive effective treatment at home, thereby reducing hospitalizations and associated costs. This development aligns with a broader industry trend towards developing more convenient and accessible treatments for infectious diseases, especially those resistant to existing therapies.

• The PIVOT-PO trial directly compared tebipenem HBr to intravenous imipenem-cilastatin, a current standard of care for hospitalized adult patients with cUTI, demonstrating non-inferiority.
• Unlike existing carbapenem antibiotics which are primarily available for IV administration, tebipenem HBr is being developed as an oral treatment. This offers a significant advantage by potentially allowing patients to transition from hospital-based IV treatment to oral therapy at home, reducing hospital stays and healthcare costs.
• The current landscape for drug-resistant cUTIs often necessitates hospital admission due to limited oral options, making tebipenem HBr a potentially transformative alternative compared to the current IV-centric treatment paradigm.

• Shareholders: Highly positive impact due to successful clinical trial results, potential market approval, and significant market opportunity, which could lead to increased share value.
• Patients: Significant positive impact by potentially providing the first oral carbapenem for complicated UTIs, allowing for home treatment and reducing the need for hospitalization, improving convenience and access to care.
• Healthcare System: Positive impact by potentially reducing hospitalizations and associated healthcare costs for cUTI treatment, estimated at over $6 billion annually in the US.
• Employees: Positive impact due to the success of a key development program, potentially leading to increased job security and future growth opportunities.
• Regulatory Authorities: The successful trial and planned NDA filing will be a focus for the FDA, especially given the QIDP and Fast Track designations, indicating a potential new treatment option for a high-need area.

• GSK plans to work with U.S. regulatory authorities to include the data from the PIVOT-PO trial as part of a New Drug Application (NDA) filing in the second half of 2025.
• Full results from the PIVOT-PO trial will be submitted for presentation at an upcoming scientific congress.
• Full results will be submitted for publication in a peer-reviewed journal.

• 2022-09-01: Spero entered into an exclusive license agreement with GSK for the development and commercialization of tebipenem HBr (approximate date).
• 2025-05-28: Date of report and announcement that the pivotal Phase 3 PIVOT-PO trial met its primary endpoint and will stop early for efficacy.
• 2025-09-01: Planned period for GSK to work with U.S. regulatory authorities to include the data as part of a filing (2H 2025, approximate start).