Spero Therapeutics has achieved a significant milestone in antibiotic development by enrolling the first patient in PIVOT-PO, a global pivotal Phase 3 clinical trial evaluating tebipenem HBr for complicated urinary tract infections (cUTI), including acute pyelonephritis (AP). If approved, tebipenem HBr would become the first oral carbapenem antimicrobial to receive marketing approval in the United States.
"First patient visit, in the PIVOT-PO Phase 3 clinical trial, is an important milestone in our tebipenem HBr program," said Sath Shukla, President and CEO of Spero Therapeutics. "We are developing Tebipenem HBr to potentially be the first oral broad-spectrum carbapenem in the U.S. for use in patients with cUTI. Oral administration may provide physicians with an alternative to hospital-based IV therapy, for appropriate patients, with potential value to the broader healthcare system."
Trial Design and Endpoints
PIVOT-PO is designed as a global, randomized, double-blind, pivotal Phase 3 clinical trial comparing oral tebipenem HBr versus IV imipenem cilastatin in hospitalized adult patients with cUTI/AP. The trial employs a 1:1 randomization scheme, with patients receiving either tebipenem HBr (600 mg) orally every six hours or imipenem cilastatin (500 mg) IV every six hours for seven to ten days.
The primary efficacy endpoint will be overall response, defined as a composite of clinical cure plus microbiological eradication at the test-of-cure visit. The primary analysis will assess non-inferiority in the microbiological intention-to-treat population, based on a 10% non-inferiority margin. The trial is designed to enroll approximately 2,648 patients, with randomization stratified by age, baseline diagnosis (cUTI or AP), and the presence or absence of urinary tract instrumentation.
Regulatory Pathway and FDA Guidance
The FDA has provided encouraging guidance regarding the regulatory pathway for tebipenem HBr. The agency has indicated that positive and persuasive results from PIVOT-PO, supported with confirmatory evidence of efficacy, could be sufficient to support approval of tebipenem HBr as a treatment for cUTI, including pyelonephritis, for a limited use indication.
Tebipenem HBr has been granted Qualified Infectious Disease Product (QIDP) and Fast Track designations by the FDA for the treatment of cUTI and AP, which may expedite the development and review process.
Drug Profile and Mechanism
Tebipenem HBr (tebipenem pivoxil hydrobromide; formerly SPR994) represents Spero's novel late-stage development asset, an oral formulation of tebipenem pivoxil, a carbapenem antibiotic of the β-lactam class. The drug is based on a compound already marketed by Meiji Seika Pharma Co. Ltd. in Japan as Orapenem® since 2009 for pediatric infections limited to pneumonia, otitis media and sinusitis.
Carbapenems are an important subclass of antibiotics because they have been observed to be safe and effective in the treatment of drug-resistant Gram-negative bacterial infections. Tebipenem HBr is being developed specifically for the treatment of complicated urinary tract infections, including AP, caused by certain microorganisms in adult patients who have limited treatment options.
Financial Terms and Commercial Potential
Under the terms of its license agreement with GSK, Spero is entitled to receive $95 million in development milestone payments, payable in four equal installments over two years. The company is also eligible for additional milestone and royalty payments including an additional $25 million in development milestones, up to $150 million in potential commercial milestones based on first commercial sale, up to $225 million in potential sales-based milestones, and low-single digit to low-double digit tiered royalties on net product sales of tebipenem HBr in all territories, except Japan and certain other Asian countries.
Research Support and Development
Select tebipenem HBr studies have been funded in part with federal funds from the U.S. Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under contract number HHSO100201800015C.
Spero Therapeutics, headquartered in Cambridge, Massachusetts, is a multi-asset, clinical-stage biopharmaceutical company focused on identifying, developing, and commercializing novel treatments for bacterial infections, including multi-drug resistant bacterial infections and rare diseases. The company is also developing SPR720 as a novel oral therapy candidate for non-tuberculous mycobacterial infections and SPR206, an IV-administered next generation polymyxin product candidate for MDR Gram-negative infections in the hospital setting.
