Study to Evaluate the Efficacy and Safety of TRL1068 for the Treatment of Prosthetic Joint Infection

Phase 2 Study to Evaluate the Efficacy and Safety of TRL1068 for the Treatment of Chronic Prosthetic Joint Infection of the Knee or Hip Without Exchange Arthroplasty

TRL1068 is expected to eliminate the pathogen-protecting biofilm in the prosthetic joint and surrounding tissue, thus making pathogens substantially more susceptible to established antibiotic treatment regimens. This Phase 2 study is designed to assess efficacy and safety of TRL1068 in combination with a DAIR (debridement, antibiotics, and implant retention) procedure for chronic prosthetic joint infections of the knee and hip, specifically, eliminating the need for the standard of care 2-stage exchange surgery, so that the original prosthesis can be retained.

Approximately 75% of all clinically significant human infections are estimated to be biofilm-related. Prosthetic joint infections are a classical example of difficult to eradicate infections associated with biofilm. Most Prosthetic Joint Infection (PJI) cases are caused by staphylococcal species (~70%) with an increasing number being antibiotic-resistant (MRSA). In the US, two-stage revision is the standard of care for replacement of an infected prosthetic joint, and is associated with substantial costs and prolonged immobility. TRL1068 is a fully human antibody that has been shown in pre-clinical studies and in the first-in-human Phase 1 study TRL1068-101 to disrupt biofilm. TRL1068 targets a highly conserved epitope on the DNABII family of bacterial DNA binding proteins that includes histone-like (HU) and integration host factor (IHF) proteins of clinically relevant Gram-positive and Gram-negative bacteria. The DNABII epitope bound by TRL1068 has no homologs in the human proteome.

Inclusion Criteria:

1. Age 18 to 85 years, inclusive

2. Chronic PJI:

   1. Systemic Host Grade of A or B [McPherson 2011] (Appendix 3) and either
   2. First chronic PJI of the hip or knee, confirmed by synovial fluid aspirate culture or
   3. Recurrent chronic PJI of the hip or knee confirmed by synovial fluid aspirate culture

3. Willing to be randomized to either:

   1. Receive TRL1068 and to be scheduled for DAIR between Day 15 + 7 days (i.e., between days 15-22) and 10 weeks of targeted antibiotic treatment or
   2. Participate in an observational study arm that receives SoC (i.e., two-stage prosthetic joint replacement) and

   i. Sonication of the explanted prosthesis and performance of synovial fluid aspirates ii. Consents to conduct of stage 2 (implantation of new prosthesis)

4. At least 1 positive bacterial culture without concomitant fungal infection from the infected joint (a joint aspirate within 28 days prior to Screening is acceptable)

5. All identified pathogen(s) are susceptible to the planned antibiotic regimen

6. Availability of radiology assessments of the affected joint without signs of loosening of the prosthesis or presence of osteomyelitis

7. Willing and able to provide written informed consent

8. Willing to perform and comply with all study procedures, including attending clinic visits as scheduled

9. Men and women of childbearing potential (WOCBP) must be willing to practice a highly effective method of contraception that may include, but is not limited to, abstinence, sex only with persons of the same sex, monogamous relationship with vasectomized partner, vasectomy, hysterectomy, bilateral tubal ligation, licensed hormonal methods, intrauterine device (IUD), or use of spermicide combined with a barrier method (e.g., condom, diaphragm) through Day 365.

Exclusion Criteria:

1. PJI associated with presence of concomitant fungal infection or bacterial pathogens that, even when in planktonic form (i.e., when released from biofilm), cannot be adequately treated with available antibiotics.
2. More than one draining sinus and single draining sinus of > 1 cm
3. Less than 3 years life expectancy based on underlying morbidities
4. Expected to receive chronic suppressive antibiotic therapy
5. Congestive heart failure; New York Heart Association (NYHA) Functional Classification of Heart Failure Grade > 3B
6. Uncontrolled diabetes, defined as hemoglobin A1c > 7.4%.
7. BMI > 45
8. Any acute illness within 14 days of Day 1 that could confound the evaluation of safety evaluation of TRL1068, especially local or systemic fungal and other known or suspected bacterial infections
9. Receiving or recently received another investigational drug (within 30 days of Day 1, or 5 half-lives of the investigational drug, whichever is longer)
10. Received any vaccine within 14 days prior to Day 1
11. Positive serum pregnancy test for WOCBP, or nursing women
12. History of drug or alcohol abuse that, in the opinion of the Investigator, would interfere with the patient's ability to comply with all study requirements
13. Any other comorbidity or condition that, in the opinion of the Investigator would make the patient unsuitable for the study or unable to comply with the study requirements.