Neuren Pharmaceuticals (ASX:NEU) has announced top-line results from its Phase 2 clinical trial of trofinetide in moderate to severe traumatic brain injury (TBI).
The INTREPID trial was conducted in collaboration with the US Army Medical Research and Materiel Command. The company said results have been reviewed and interpreted with the assistance of military medical experts and trial investigators.
The safety results from INTREPID, which was the primary endpoint of the trial, identified no treatment related or dose-dependent trends in adverse events or laboratory results.
The trial did not demonstrate a difference between drug and placebo in the 3 core efficacy measures, which were the Extended Glasgow Outcome Scale (GOS-E), the Mayo-Portland Adaptability Inventory (MPAI-4) and mortality.
GOS-E has been used as the primary efficacy measure in previous large TBI clinical trials. MPAI-4 is a validated measure of functioning in activities of daily living following TBI. The overall rate of mortality in the INTREPID trial was lower than was observed in prior trials, but there was no significant difference between drug and placebo.
Superiority of drug over placebo was demonstrated in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which was one of the exploratory efficacy measures in the INTREPID trial.
RBANS is a validated series of tests completed by the patient for assessing cognitive impairment that is commonly used in the diagnosis and tracking of dementia. RBANS has also been validated for use in moderate-to-severe TBI. Further analysis is being conducted to evaluate the clinical implications of this positive RBANS finding and to consider the remaining exploratory efficacy measures, which also assessed cognitive and neuropsychological functioning.
Two factors appear to have contributed to the outcomes in the core efficacy measures. These were the composition of the enrolled patient population and the drug levels that were achieved.
According to the company, a common challenge in clinical trials in TBI is the high degree of variability in the characteristics of injuries and patient populations. The 260 patients enrolled in the INTREPID trial included a higher than expected proportion of patients who were severely injured and, in particular, subjects who had sustained severe injuries to the chest and other parts of the body and were less likely to respond positively to a drug targeting brain injury. Further, the randomisation of patients to either drug or placebo resulted in a higher proportion of severely injured patients being assigned to the drug group rather than placebo in the largest cohort of 200 subjects receiving the highest dose. This imbalance between groups was accounted for in the pre-specified statistical analysis of the results, but the adjustment only partially compensated for the disadvantage in the drug group.
Further detailed analyses of the INTREPID trial data are underway to help inform and define the optimum patient population, dose levels, duration of treatment and efficacy measures should another trial be conducted.
The Phase 2 trial of trofinetide in concussion being conducted by Neuren and the U.S. Army has been placed on hold while the implications and learnings from the INTREPID trial, in particular dose levels, are fully considered.
Neuren’s Chief Science Officer, Larry Glass, said: “Combined with the safety information from the Rett and Fragile X syndrome trials, the results from the INTREPID trial support the use of considerably higher doses in TBI patients. We have also made advances in the use of biomarkers and other measures of baseline severity that would improve the design and analysis of a future trial. After further analysis, we will determine with our U.S. Army colleagues the best way forward for trofinetide in brain injury.”