August 22, 2016
CorMedix has completed a multi-center Phase 3 clinical trial in hemodialysis patients with central venous catheters in the U.S. named, LOCK-IT-100. The trial is a randomized, double-blind, active control, parallel arm trial designed to demonstrate the efficacy and safety of Defencath™ as a catheter lock solution for preventing catheter-related bloodstream infections, or CRBSI, in subjects receiving hemodialysis therapy as treatment for end stage renal disease.
In January 2019, CorMedix announced the topline results from the interim analysis of the study, which was terminated in August 2018 following the recommendation of the independent Data Safety Monitoring Board (DSMB), because efficacy had been demonstrated and the pre-specified level of statistical significance had been achieved with no safety concerns. Efficacy data were available from 653 subjects at the time of the interim analysis, including the first 28 cases of catheter-related blood stream infection (CRBSI). However, because the study continued enrolling and treating subjects until study termination, the final efficacy analysis was based on a total of 795 subjects.
In the analysis of the full data set, a total of 41 CRBSI events was determined by the Clinical Adjudication Committee (CAC). There was a 71% reduction in the risk of occurrence of CRBSIs compared with the active control of heparin, which is well in excess of the study’s assumed treatment effect size of a 55% reduction. In the Defencath™ arm, the CRBSI event rate was 0.13 per 1000 catheter days, which is significantly lower than the event rate of 0.46 per 1000 catheter days in the control arm. The statistical significance of the primary endpoint in the full data set (p=0.0006) was even more impressive than that of the interim analysis (p=0.0034).
There were no statistically significant differences between the results in the Defencath™ arm compared with the control arm in the final analysis for the secondary endpoints. The event rate for one of the secondary endpoints, catheter removal for any reason, was 3.48 per 1,000 catheter-days (236 out of 397 subjects) in the Defencath™ arm and 3.23 per 1,000 catheter-days (224 out of 398 subjects) in the control arm (p=0.39).
The loss of catheter patency, which was defined either as catheter removal due to loss of catheter patency or the administration of tissue plasminogen activating factor (tPA), was also a secondary endpoint. The event rate for loss of catheter patency was 0.99 per 1,000 catheter-days (64 out of 397 subjects) in the Defencath™ arm and 0.74 per 1,000 catheter-days (48 out of 398 subjects) in the control arm (p=0.10).
During the clinical trial, there were no serious treatment-emergent adverse events (TEAE) with Probable or Definite Relationship to the study drug as determined by the investigator. The proportion of subjects with any TEAE was similar between the Defencath arm and the control arm.
In January 2019, CorMedix began its initial discussions with the FDA regarding using the LOCK-IT-100 study to support regulatory approval for Defencath™. The Company agreed at the meeting to provide FDA a detailed analysis of the full data set including secondary endpoints from the LOCK-IT-100 study to facilitate FDA’s consideration of CorMedix’s request to file the New Drug Application (NDA) for Defencath™ on the basis of the LOCK-IT-100 study results. Also, at the meeting, the FDA agreed that the Company could request consideration of Defencath™ for approval under the LPAD (Limited Population Pathway for Antibacterial and Antifungal Drugs) pathway. The LPAD pathway was established by the 21st Century Cures Act and is intended to encourage the development of certain antibacterial and antifungal drugs to help address the critical public health and patient care concern that has resulted from the current decline in antibacterial drug research and development as serious antibacterial and antifungal drug-resistant infections increase.
In July 2019, CorMedix announced that it received feedback from the U.S. FDA regarding the submitted statistical analyses of data and additional information requested by the FDA for the primary and secondary efficacy endpoints of the Company’s LOCK-IT-100 clinical study. In its feedback, the FDA did not raise any additional questions regarding the analyses provided and indicated that it would conduct a thorough review of all of the clinical data when the clinical study report is submitted for LOCK-IT-100. Additionally, in FDA’s response to the Company’s question on whether LOCK-IT-100 is adequate as a single study to support a New Drug Application (NDA), the FDA stated that while the data from LOCK-IT-100 and supporting information may be sufficient, it cannot confirm that the data from LOCK-IT-100 are adequate to support an indication for prevention of CRBSI in hemodialysis patients until it has completed its review of the NDA. The Company will continue discussions with the FDA concerning all the information that will be needed to support Defencath™’s NDA.
Recently, CorMedix announced that it had submitted all of the modules for the Defencath™ NDA to the FDA. The NDA was granted rolling submission and review by FDA as announced previously, and there was ongoing dialogue with FDA as it reviewed the submitted modules. The Company requested priority review of the NDA, based on the Fast Track and Qualified Infectious Disease Product Designations granted by FDA to Defencath™. The FDA has 60 days to review the submission for completeness to make a filing decision and grant a priority or standard review. FDA will have a goal of a 6 month review period for priority review, compared to 10 months for a standard review.