Additional findings based on review of Brilacidin phase II COVID-19 trial results.- Innovation Pharma
Innovation Pharmaceuticals reported findings from a data review of the Company’s Brilacidin Phase II COVID-19 study and compassionate use of Brilacidin in critically-ill COVID-19 patients.
Summary of Brilacidin COVID-19 Trial Design and Results : The Phase II trial (see NCT04784897) was a randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of Brilacidin treatment in addition to current standard-of-care (SoC) compared to SoC alone, in 120 hospitalized patients with moderate-to-severe COVID-19. Study treatment, Brilacidin IV or saline IV (placebo), was administered as 3 doses or 5 doses. For efficacy analyses, the main comparison was between the Brilacidin 5-dose group and the pooled placebo group. Even with randomization—stratified by age (<= 65 yrs,>65 yrs) and severity (moderate, severe)—patients allocated to the Brilacidin treatment groups exhibited a greater degree of disease burden at baseline, as reflected by higher, on average, elevated biomarker levels (e.g., CRP, viral load), in contrast to the pooled placebo group.</=>
As previously released, Brilacidin did not show a difference compared to placebo in reducing Time to Sustained Recovery Through Day 29, the study's primary endpoint based on clinical status. There was also no difference in mortality between active and placebo, with both groups experiencing low mortality rates (7 percent) compared to other studies that evaluated patients with moderate-to-severe COVID-19. Beneficial Brilacidin treatment effects, however, were observed in NEWS2 secondary endpoints, as well as on the primary endpoint in patient subgroups,, as summarized below.
Pharmacokinetic (PK) analysis (from measured plasma sample concentrations) provided comparable estimations to those seen previously in the Brilacidin IV program, although exposure was generally greater than observed prior (when comparing patients on similar treatment regimens for the indication of acute bacterial skin and skin structure infections [ABSSSI]). These new PK data will help inform any future Brilacidin IV dosing strategies.
Brilacidin was generally well-tolerated by patients, with an overall safety profile in COVID-19 patients consistent with previous clinical studies. The incidence of patients with at least one treatment-emergent adverse event (TEAE) was higher for Brilacidin treatment compared to placebo. However, the proportion of patients with TEAEs is similar across groups (72 percent on active, 65 percent on placebo) after excluding the Brilacidin-related adverse events of tingling (paresthesia) and hypoesthesia (numbness), which are known, transient, mostly mild, non-serious adverse events related to Brilacidin IV treatment. The incidence of serious adverse events was the same (12 percent on active, 12 percent on placebo), and no serious adverse events were reported as related to study treatment.
Secondary Endpoint Analysis : NEWS2 Scores (Intent-to-Treat Population) : More patients in the Brilacidin 5-dose group achieved and maintained, for at least 24 hours, a National Early Warning Score 2 (NEWS2) of <=2. by 10 days (from randomization), 97 percent of the brilacidin 5-dose group had achieved this news2 endpoint compared to 84 percent of patients in the pooled placebo group. a news2 score of 2 or less is clinically meaningful as an aggregate score of 4 or less translates to low clinical risk, per news2 criteria. the mean change from baseline in news2 was greater for the brilacidin treatment groups than for the pooled placebo group, at all assessment timepoints (study days 3, 5, 8, 11, 15, and 29). news2 is an ordinal scale developed by the u.k.’s royal college of physicians to identify patients at risk for rapid clinical deterioration requiring critical care intervention and is considered a valuable tool for management of covid-19. news2 is based on certain physiological parameters—respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse, level of consciousness, and temperature. news2 has been used as an endpoint for several covid-19 clinical trials.></=2.>
Post-Hoc Analysis : Inflammatory Biomarkers: Patient Subgroup with Highest Quartile Baseline Values (Per Protocol Population); For those patients with baseline values for C-Reactive Protein (CRP) in the highest quartile (4th quartile), all patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29, compared to 77 percent of patients in the pooled placebo subgroup. Time to sustained recovery was on average shorter in the Brilacidin 5-dose subgroup compared to placebo. Additionally, for those patients with baseline values for Interleukin-6 (IL-6) in the highest quartile, more patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29 (89 percent compared to 67 percent on placebo). Time to sustained recovery also was on average shorter in the Brilacidin 5-dose subgroup compared to placebo for this quartile of patients. Both CRP and IL-6 levels, when elevated at baseline, have been shown to predict worse outcomes in COVID-19 patients and our data was consistent with this. These two biomarkers have been used by other pharmaceutical companies as enrollment criteria to target COVID-19 patient populations most likely to benefit from treatment. The NIH-sponsored clinical evaluation of Humanigen’s drug, lenzilumab (ACTIV-5/BET-B), was updated to include, as the trial’s primary endpoint, survival without ventilation by 28 days in patients with baseline CRP levels under 150mg/l. Viral Load Biomarker: Patient Subgroup with Highest Quartile Baseline Values (Per Protocol Population):For those patients with baseline values for viral load in the highest quartile, more patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29 (92 percent compared to 82 percent on placebo). Time to sustained recovery was also on average shorter in the Brilacidin 5-dose subgroup compared to placebo for this quartile of patients. This is notable given median time from symptom onset to treatment randomization averaged 9.53 days in the Brilacidin COVID-19 trial, and thus likely occurred after peak viral load in most patients. Time from Onset of Symptoms to Randomization (Per Protocol Population) : If a patient started study treatment within fewer than 7 days of onset of COVID-19 symptoms, patients in the Brilacidin 5-dose group achieved sustained recovery more quickly compared to the pooled placebo group (p=0.03). For this patient population, early treatment with Brilacidin from onset of symptoms appeared to have a potential positive impact on time to sustained recovery (the study’s primary endpoint), suggesting cases that can be treated close to initial onset of disease may be an attractive population to target.
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