First-Ever Anti-Biofilm Drug Enters Phase 2/3 Trial for Prosthetic Joint Infections

(This article first appeared on our sister brand, Medical Economics.)

A clinical trial testing a first-in-class drug designed to combat infections from medical devices has enrolled its first patient at the University of Cincinnati Medical Center, Peptilogics announced.

The RETAIN Phase 2/3 registration trial, led by Toan Le, is evaluating PLG0206 in patients with prosthetic joint infection following knee replacement surgery. The drug candidate represents a new approach to treating medical device-related infections by targeting biofilm, a protective bacterial matrix that shields pathogens from antibiotics and the immune system.

Approximately 5 million joint replacements are performed annually across the US, UK, and Europe. In 2% of cases, biofilm forms on implant surfaces, resulting in prosthetic joint infection. The condition can develop quickly after surgery or years later.

Current standard treatment requires two-stage revision surgery to remove the infected prosthesis, which carries a 15 to 25% failure rate and subjects patients to multiple procedures. The condition is associated with a 25% five-year mortality rate. The estimated annual economic burden in the US alone is $20 billion.

"I'm excited about the promise of PLG0206 as a first-in-class treatment for patients with PJI, and as a potential solution for all medical device-related infections in the future," said Javad Parvizi, professor of orthopedic surgery at Acibadem University in Istanbul and past president of the American Association of Hip and Knee Surgeons.

The randomized, double-blind, placebo-controlled trial is designed to assess whether the drug is superior to standard care. The primary endpoint is treatment failure at 12 months, with a key secondary endpoint of infection-related surgical intervention at the same time point. The trial plans to enroll up to 240 patients across up to 50 clinical sites.

An earlier Phase 1B study demonstrated preliminary efficacy, with only one of 13 PLG0206-treated patients experiencing recurrent infection by 12 months, representing a 7% failure rate. Current standard care has shown 12-month failure rates of 35 to 55%.

PLG0206 has received a Qualified Infectious Disease Product designation from the FDA, which provides five additional years of market exclusivity upon approval, as well as Orphan Drug and Fast Track designations for the treatment of prosthetic joint infections.

More than 55 million people in the U.S. live with medical devices and implants, including joint replacements, cardiovascular devices, spinal hardware, hernia mesh, and vascular grafts. Bacterial biofilms are the primary drivers of serious device-related infections across these categories.

Recent advances in medical device infection prevention and treatment

The medical community has made significant progress in understanding and addressing device-related infections over the past decade, moving beyond traditional reliance on systemic antibiotics alone.

Researchers have developed antimicrobial coatings that can be applied directly to implant surfaces, using materials such as silver ions, antibiotics, and antimicrobial peptides. These coatings aim to prevent bacterial adhesion during the critical early hours after implantation, when devices are most vulnerable to colonization.

Surface modification technologies have also advanced, with manufacturers creating implants featuring nano-structured surfaces that mechanically disrupt bacterial attachment. These textured surfaces can reduce biofilm formation without relying on chemical agents, potentially lowering the risk of antimicrobial resistance.

Diagnostic tools have improved substantially, enabling earlier detection of device-related infections. Advanced imaging techniques, including specialized PET scans and molecular imaging, can identify low-grade infections that traditional methods might miss. Biomarker panels and molecular diagnostics now enable clinicians to detect bacterial DNA and distinguish infection from normal inflammatory responses to implants.

Surgical techniques have also evolved, with enhanced debridement protocols and single-stage revision approaches showing promise in select patient populations. These methods aim to reduce the burden of multiple surgeries while maintaining infection control.

Research into biofilm biology has revealed new potential therapeutic targets. Scientists now better understand the complex signaling systems bacteria use to coordinate biofilm formation and the unique metabolic states of bacteria within biofilms. This knowledge has informed the development of agents designed to disrupt bacterial communication, disperse established biofilms, or target the specialized persister cells that survive conventional antibiotic treatment.

Clinical practice has also shifted toward more aggressive prevention strategies, including standardized preoperative screening protocols, refined surgical sterility measures, and optimized perioperative antibiotic prophylaxis tailored to patient risk factors and local resistance patterns.

Despite these advances, medical device-related infections remain a significant clinical challenge, with outcomes that have not substantially improved in recent years for established infections. The focus has increasingly turned to developing therapies that specifically address the biofilm environment, representing a fundamental shift from attempting to optimize existing antibiotics toward creating entirely new classes of anti-biofilm agents.