Date: 2018-05-09
Type of
information: Results
phase: 2
Announcement: results
Company: Cellceutix (USA - MA), now Innovation Pharmaceuticals (USA - MA)
Product: brilacidin-OM oral rinse
Action
mechanism:
- antibiotic. Brilacidin is the first of a new class of antibiotics called defensin-mimetics. Modeled after the body’s innate host-defense response, this small, non-peptidic, synthetic molecule penetrates bacterial cell wall membranes. Brilacidin also functions in an immunomodulatory capacity, lessening inflammation and promoting healing.
Disease: oral mucositis in patients undergoing chemoradiation therapy for head and neck cancer
Therapeutic
area: Cancer - Oncology
Country: USA
Trial
details:
- Oral Mucositis (OM) is a painful and debilitating side effect of many of the drug/radiation regimens used to treat cancer. This study examines the investigational drug brilacidin and its possible application in prevention of oral mucositis in patients undergoing chemoradiation for treatment of head and neck cancer. In this trial, head and neck cancer patients self-administered brilacidin (45 mg/15 ml oral rinse—“swish and spit”) or placebo three times daily across 7 consecutive weeks (49 days). Of the 61 patients randomized, 46 patients met the cumulative radiation dose criteria of at least 55 Gy—the minimum treatment threshold for inclusion in the efficacy population—and 39 of these patients met more strict criteria for inclusion in the “per protocol” study population. The trial’s primary endpoint was established as reduced incidence of severe oral mucositis (defined as Grade ? 3 on the WHO Oral Mucositis scale) experienced by patients during radiation therapy. (NCT02324335)
Latest
news:
-
• On
May 9, 2018, Innovation Pharmaceuticals announced that the company has concluded its review of all data outputs and corresponding analyses from the Phase 2 Brilacidin-OM trial for the indication of decreasing the incidence of severe oral mucositis (WHO Grade ? 3) in head and neck cancer patients receiving chemoradiation.
Summary of Brilacidin-OM Phase 2 Study Results
Key Efficacy Outcomes were:
· Reduced Incidence of Severe OM (Primary Endpoint)
o Placebo 60.0%, reduced to Brilacidin 42.9% [Modified Intent to Treat (mITT) Population].
o Placebo 60.0%, reduced to Brilacidin 36.8% [Per Protocol (PP) Population].
· Delayed Onset of Severe OM (Secondary Endpoint)
o For those patients in the Brilacidin group who did experience Severe OM, onset occurred generally later during radiation therapy.
· Reduced Duration of Severe OM (Secondary Endpoint)
o Severe OM median duration was 0.0 days for Brilacidin (mITT and PP Populations), indicating that more than half of all patients on active treatment did not experience Severe OM.
o Overall Severe OM median durations for placebo were 3.0 days and 5.5 days for the mITT and PP Populations, respectively.
Brilacidin was more effective in decreasing the incidence of severe oral mucositis in patients receiving the more aggressive chemotherapy regimen - cisplatin administered in a higher concentration (80-100 mg/m2), approximately every 21 days - as compared to lower concentrations of cisplatin (30-40 mg/m2) administered weekly.
· Reduced Incidence of Severe OM, 21-day Cisplatin Regimen subset
o Placebo 71.4%, reduced to Brilacidin 25.0% [mITT Population] (p=0.048).
o Placebo 72.7%, reduced to Brilacidin 14.3% [PP Population] (p=0.025).
· Delayed Onset of severe oral mucositis, 21-day Cisplatin Regimen subset
o The time to onset of severe oral mucositis was delayed with brilacidin treatment compared to placebo, even more markedly in the 21-day cisplatin regimen subgroup.
A 65.0% (mITT Population) and 80.3% (PP Population) relative risk reduction ([incidence control- incidence active]/incidence control) in the incidence of Severe OM was achieved with Brilacidin compared to placebo, for the approximately every 21 days cisplatin regimen subset. The academic literature
indicates that a once-every-3-weeks cisplatin regimen, versus once-a-week, largely remains the recommended dosing schedule for the treatment of HNC.
• On
April 16, 2018, Innovation Pharmaceuticals reported additional information from the completed Phase 2 clinical trial of brilacidin-OM for the indication of decreasing the incidence of severe oral mucositis (WHO Grade ?3) in head and neck cancer patients receiving chemoradiation. These additional data align with previously released Brilacidin-OM results showing a risk reduction in the incidence of severe oral mucositis, including up to an 80.3% risk reduction in the incidence of severe oral mucositis among patients receiving more aggressive chemotherapy. Other previously released results indicate Brilacidin-OM also delayed onset of severe oral mucositis.
Secondary Endpoint: Duration of SOM
Brilacidin outperformed placebo in both the Initial Instance Duration of severe oral mucositis and the overall suration of severe oral mucositis, as shown below.
Exploratory Endpoint: Unplanned Office Visits, Emergency Department Visits, and/or Hospital Admissions Due to oral mucositis
Positive oral mucositis assessment endpoints are additionally supported by zero (0) of the patients in the Brilacidin-OM group having unplanned office visits, ED visits, or hospital admissions due to oral mucositis, compared to four patients in the placebo group.
Other Study Observations
Regardless of the oral sites irradiated (at least two sites from: buccal mucosa, floor of mouth, ventral/lateral tongue, and soft palate), the incidence by patient of Severe OM on Brilacidin-OM relative to placebo was consistently reduced.
Across cumulative radiation dose intervals, patients in the Brilacidin-OM group consistently reported less often feeling the sensation “swollen” (approximately half of that reported for the placebo group). “Burning” sensation also was reported consistently less frequently in the Brilacidin treatment group.
Patients in the Brilacidin-OM group appeared to trend more favorably over the course of chemoradiation treatment according to Eastern Cooperative Oncology Group (ECOG) Performance Status—a common set of criteria used in oncology trials to assess debility.
• On
April 9, 2018, Innovation Pharmaceuticals reported further data analysis from its completed Phase 2 clinical trial of brilacidin-OM (
see NCT02324335) for the indication of decreasing the incidence of Severe Oral Mucositis (SOM) in Head and Neck Cancer (HNC) patients receiving chemoradiation.
Brilacidin-OM Subgroup Analysis (by Chemotherapy Regimen)
Brilacidin-OM was more effective in decreasing the incidence of SOM in HNC patients receiving the more aggressive chemotherapy regimen—cisplatin administered in a higher concentration (80-100 mg/m2), every 21 days—as compared to lower concentrations of cisplatin (30-40 mg/m2) administered weekly.
For the Modified Intent-to-Treat (mITT) population, Brilacidin-OM in the aggressive chemotherapy regimen reduced the incidence of SOM by 65.0% ([incidence control- incidence active]/incidence control) as compared with placebo (Brilacidin: 25.0%; placebo: 71.4%; p=0.0480). For the Per Protocol (PP) population, Brilacidin-OM in the aggressive chemotherapy regimen similarly reduced the incidence of SOM by 80.3% as compared with placebo (Brilacidin: 14.3%; placebo: 72.7%; p=0.0249). Treatments appeared well-tolerated with good safety.
• On
January 3, 2018, Innovation Pharmaceuticals presented additional secondary endpoint topline results from the company's randomized, double-blind, placebo-controlled, Phase 2 clinical trial of brilacidin for the prevention and control of oral mucositis in patients receiving chemoradiation for treatment of head and neck cancer.
- Summary of Key Secondary Endpoints Analysis
- · Onset of Severe Oral Mucositis: Based on Kaplan-Meier curves, Brilacidin-OM oral rinse showed a clear separation from placebo in delaying the onset of severe oral mucositis —particularly the period from approximately 28-42 days, after the initiation of treatment, during which the incidence of severe oral mucositis rose strikingly in the placebo group while not in the group being treated with Brilacidin. The delay of onset of severe oral mucositis data further support the positive primary endpoint findings that showed a clear reduction in the incidence of severe oral mucositis in patients receiving Brilacidin-OM treatment.
- Duration of Severe Oral Mucositis: Given that Brilacidin-OM successfully prevented severe oral mucositis from occurring, as well as delayed its onset, in a substantial number of patients, data comparisons aimed at assessing potential reduction in the duration of severe oral mucositis were constrained by the fewer number of Brilacidin-OM treated patients that could be included in such analysis. While Brilacidin-OM appeared to decrease the initial duration of severe oral mucositis (time from the initial WHO Grade ? 3 to the first WHO Grade ? 2 OM assessment), detailed interpretation of this and other duration data comparisons were limited.
- The company is now working to complete the Clinical Study Report (CSR). The CSR is central for engaging with the FDA to further discuss program development, and is also an important component for informing already advanced oral mucositifs partnership discussions.
- • On December 11, 2017, Innovation Pharmaceuticals presented topline results from the double-blind, placebo-controlled, Phase 2 clinical trial of brilacidin for the prevention and control of oral mucositis in patients receiving chemoradiation for treatment of head and neck cancer. These results showed the use of brilacidin met its primary endpoint with a clearly reduced incidence of severe oral mucositis (WHO Grade ? 3) compared to placebo.
- Summary of Topline Results from the Placebo-Controlled Phase 2 Trial
- · Brilacidin met primary endpoint of reduced incidence of severe OM experienced by patients during radiation therapy.
- · Incidence of severe OM in Modified Intent to Treat (mITT) Population: Brilacidin 42.9%, Placebo 60.0%.
- · Incidence of severe OM in Per Protocol (PP) Population: Brilacidin 36.8%, Placebo 60.0%.
- · Trial results support continued and expedited development of Brilacidin-OM.
- Primary Efficacy Results: Incidence of severe OM (WHO Grade ? 3)
- Active (Brilacidin) Control (Placebo)
Modified Intent to Treat 9 of 21 patients (42.9 %) 15 of 25 patients (60.0%)
(mITT) Population (n=46)
Per Protocol
(PP) Population (n=39) 7 of 19 patients (36.8%) 12 of 20 patients (60.0%)
- Overall reduction in observed severe oral mucositis (WHO Grade ? 3) in the Brilacidin-OM treatment group from that seen in the control group ([incidence control - incidence active]/incidence control) was: 28.5% (mITT population) and 38.7% (PP population).
- Safety and Tolerability Profile
- Brilacidin administered as an oral rinse was generally well-tolerated by patients. Safety findings were typical for patients with head and neck cancer being treated with chemoradiation, with all treated patients reporting at least one Treatment-Emergent Adverse Event (TEAE). Of the TEAEs categorized as serious (SAEs), 13 patients (8 in the Brilacidin group, and 5 in the Placebo group) experienced at least one SAE. No SAEs reported led to death. None of the SAEs were classified by the Investigator as related to brilacidin.
Is
general: Yes
