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Brilacidin - Innovation Pharmaceuticals

Drug Profile

Brilacidin - Innovation Pharmaceuticals

Alternative Names: Brilacidin tetrahydrochloride; Brilacidin-Ocular; Brilacidin-OM; Brilacidin-Otic; Defensin-mimetic - Innovation Pharmaceuticals; HDP-mimic - Innovation Pharmaceuticals; Host defense protein-mimic - Innovation Pharmaceuticals; PMX-30063

Latest Information Update: 01 Jun 2020

At a glance

  • Originator PolyMedix
  • Developer Innovation Pharmaceuticals
  • Class Amides; Anti-infectives; Anti-inflammatories; Antiacnes; Antibacterials; Antivirals; Foot disorder therapies; Guanidines; Peptidomimetics; Pyrimidines; Pyrrolidines; Skin disorder therapies; Small molecules
  • Mechanism of Action Cell membrane permeability enhancers; Cell membrane structure modulators; Immunomodulators; Type 4 cyclic nucleotide phosphodiesterase inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes
  • Available For Licensing Yes - COVID 2019 infections; Stomatitis

Highest Development Phases

  • Phase II Skin and soft tissue infections; Stomatitis; Ulcerative proctitis
  • Phase I Inflammatory bowel diseases
  • Preclinical Acne; Atopic dermatitis; COVID 2019 infections; Hidradenitis suppurativa
  • No development reported Diabetic foot ulcer; Otitis; Wounds
  • Discontinued Intestinal infections; Ophthalmic infections; Ulcerative colitis

Most Recent Events

  • 26 May 2020 Antimicrobial data from a preclinical study in COVID-2019 infections released by Innovation Pharmaceuticals
  • 19 May 2020 Preclinical trials in COVID-2019 infections in USA (IV)
  • 19 May 2020 Antimicrobial data from preclinical studies in COVID-2019 infections released by Innovation Pharmaceuticals

Development Overview

Introduction

Brilacidin is a non-peptidic, synthetic, amphiphilic, small-molecule, defensin biomimetic, being developed by Innovation Pharmaceuticals (formerly Cellceutix), for the treatment of inflammatory bowel diseases, ulcerative colitis, Crohn's disease, ulcerative proctitis, ulcerative proctosigmoiditis, atopic dermatitis, COVID-2019 infections, acne, hidradenitis suppurativa, pan-staphylococcal infections, including methicillin-resistant strains (MRSA) and for the prevention of stomatitis (oral mucositis). Brilacidin directly lyses the bacterial cell membrane by penetrating into it resulting in disruption of barrier and membrane-associated metabolic functions and subsequent bacterial death. It also induces misfolding of cytoplasmic protein. The drug lessens inflammation and promotes healing. It is effective against both rapid growth phase and stationary phases of bacteria and has the potential to function as a single-dose therapy against multi-drug resistant bacteria or superbugs. Thus, brilacidin is capable of disrupting biofilms and has the potential to be used for biofilm-related infections caused by Staphylococcus aureus. It is active against both gram-positive and gram-negative bacteria. Brilacidin is not intended for mycobacterial infections. The product is designed to offer advantages such as a low probability for drug resistance, broad-spectrum activity, ability for single-dose intravenous administration and inexpensive to produce. Clinical development of intravenous formulation is underway in Canada, Russia, Ukraine and the US for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Clinical development of brilacidin oral rinse (topical formulation) is underway for the prevention and treatment of stomatitis. Clinical development of a retention enema (rectal formulation) of brilacidin is underway in the US and planned for foam and gel formulations for ulcerative proctitis/ulcerative proctosigmoiditis. Preclinical development for the treatment of acne, inflammatory bowel disease (oral formulation), atopic dermatitis and hidradenitis suppurativa is underway in the US. Planned tablet formulation being developed for ulcerative colitis and crohn's disease. Preclinical development for COVID-2019 infections is ongoing in the US.

Innovation Pharmaceuticals was also developing Brilacidin as a vaccine for COVID-2019 infections [See Adis Insight Drug Profile 800057896].

Preclinical development was underway for the treatment of intestinal infections and ophthalmic infections, but development was discontinued. Preclinical development was ongoing for diabetic foot ulcer, otitis and wounds, however, no recent development has been reported.

Brilacidin is the first defensin mimetic antibiotic compound to enter human clinical trials for systemic use. The compound emerged from a PolyMedix research programme [see AdisInsight drug profile 800020520] that focused on anti-infectives, which is now owned by Innovation Pharmaceuticals. The company is developing an oral formulation of brilacidin for the treatment of extensive forms of inflammatory bowel diseases including Crohn's disease, and a topical formulation of brilacidin for inflammation and immunologic conditions, including atopic dermatitis and acne.

In June 2017, Cellceutix changed its name to Innovation Pharmaceuticals [1] .

Innovation Pharmaceuticals is looking for partnership opportunities for the brilacidin in COVID-19 infections [2]

Innovation Pharmaceuticals is exploring potential licensing opportunities with pharmaceutical companies for brilacidin, for prevention of stomatitis [3] .

Company Agreements

In July 2019, Innovation Pharmaceuticals entered into a license agreement with Alfasigma to develop and commercialise locally-administered brilacidin globally, for the treatment of ulcerative proctitis/ulcerative proctosigmoiditis (UP/UPS). Innovation Pharmaceuticals will receive an initial payment from Alfasigma, and will be eligible for additional payments based on certain milestones, totaling over $US 24 million, and receive a 6% royalty (net sales) based on the successful marketing of brilacidin for UP/UPS. The agreement also includes a Right of First Refusal for brilacidin for the treatment of more extensive forms of inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn’s disease, and a right of first negotiation for brilacidin in other gastrointestinal indications. [4]

Innovation Pharmaceuticals, in June 2019, entered into an agreement with Bio-Images Drug Delivery (BDD) Pharma, for the development of tablets for targeted oral delivery of brilacidin to the colon. These tablets will be developed by utilising BDD pharam's proprietary, multi-core timed-release OralogiK™ technology that employs controlled erosion of a time-dependent barrier layer during small intestine transit to provide effective colon targeting. As per the agreement terms, BDD will provide further expertise and resources by collaborating with the Innovation Pharmaceuticals to accelerate initiation of clinical trials.
[5]

In July 2018, Innovation Pharmaceuticals entered into a drug product manufacturing contract with CoreRx to formulate and package brilacidin into granular form in unit dose sachets. The convenient, portable, quick-mixing “instant” brilacidin sachets will be used in clinical trials conducted to treat severe oral mucositis (WHO Grade ≥ 3) in head and neck cancer patients receiving chemoradiation therapy. [6]

In November 2014, Cellceutix reported that it has entered into an agreement with a division of one of the largest US pharmaceutical companies to test whether the use of brilacidin as a component of certain implanted devices can prevent infection. The material transfer agreement does not include the pharmaceutical use of brilacidin for the treatment of infections or other diseases. The final contract is subject of brilacidin getting approved by the US FDA [7] .

Cellceutix reported in February 2014 that it had selected Dr. Reddy's Custom Pharmaceutical Services for the formulation of brilacidin for use in ophthalmic and otitis infections [8] .

In April 2013, PolyMedix filed for Chapter 7 bankruptcy with the Bankruptcy Court for the District of Delaware. In August 2013, Cellceutix made a "stalking horse" offer for the purchase of PolyMedix's assets, following a due diligence process. The asset purchase agreement was approved by the Bankruptcy Court for the District of Delaware in September 2013, which involved a cash payment of $US2.1 million and 1.4 million shares of Cellceutix stock; none of PolyMedix's debt was assumed by Cellceutix [9] .

To design compounds like brilacidin, PolyMedix licensed a proprietary computational drug design technology developed at the University of Pennsylvania.

Key Development Milestones

Cellceutix reported in August 2014 that it had stabilised the formulation of brilacidin, eliminating the need for refrigeration and allowing storage at room temperature. This breakthrough positions the company to proceed with development for the treatment of diabetic foot ulcers, followed by ophthalmic and otic formulations [10] .

Innovation Pharmaceuticals is developing a foam formulation of brilacidin [11] .

COVID-2019 infections

In May 2020, Innovation Pharmaceuticals released preclinical data for brilacidin from antiviral assays in COVID-2019 infections [12] [13] .

In May 2020, Innovation Pharmaceuticals announced that Lab testing conducted at a US based Regional Biocontainment Laboratory (RBL) supported Brilacidin’s antiviral activity in directly inhibiting SARS-CoV-2 in cellular assays, with a molecular screening study of 11,552 compounds also supporting it as a promising novel coronavirus treatment. Additional pre-clinical and clinical data support Brilacidin’s potential to inhibit the production of IL-6, IL-1b, TNF-a and other pro-inflammatory cytokines and chemokines, which have been identified as central drivers in the worsening prognoses of COVID-19 patients [13] . As of March 2020, Brilacidin’s potential inhibitory activity as a small molecule drug against COVID-2019 infections was being evaluated at one of 12 Regional Biocontainment Labs (RBL) in the US. company released the data from the research, demonstrating direct inhibition of SARS-CoV-2. In April 2020, Innovation Pharmaceuticals announced the brilacidin as a promising and unique (a 3 in 1 combinatio'n; antiviral, immune/anti-inflammatory, and antimicrobial) anti-COVID-19 therapeutic candidate [2] [14] [15] [16] .

Inflammatory bowel disease

In February 2020, Innovation Pharmaceuticals completed the phase I trial and announced that the trial met its primary endpoints. The randomised trial, initiated in January 2020 and was designed to assess the safety, tolerability and pharmacokinetics of oral formulation of brilacidin in healthy volunteers (NCT04240223; BC250; EudraCT2019-003367-22). The single-center enrolled 9 healthy volunteers in the UK [17] [18] .

In January 2019, Innovation Pharmaceuticals released favourable pharmacokinetic data from a simulated gastric fluid model, testing the stability of an oral formulation of brilacidin, for the treatment of inflammatory bowel disease [19] .

Skin and soft tissue infections

Following a positive end-of-phase II meeting with the US FDA in July 2015, Innovation Pharmaceuticals plans to advance brilacidin to phase III development in patients with ABSSSIs. The trial is expected to begin in 2017. The trial initiation is dependent on reaching SPA agreement with the FDA [20] [21] . As required by the FDA, the programme will consist of two phase III studies, the first of which will include an interim analysis for early assessment of efficacy and safety. In September 2015, Cellceutix submitted a Paediatric Study Plan to the US FDA with the aim of expanding the use of brilacidin to children. Lab testing of brilacidin which is to be used in the upcoming phase III trials was completed in December 2015. In February 2016, the company announced that it has submitted a Special Protocol Assessment (SPA) request, including information requested by the US FDA to initiate the planned phase III clinical trials of Brilacidin, for the treatment of ABSSSI caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The SPA request includes details of intravenous vancomycin with an option to switch to oral linezolid after three days of therapy as a choice of comparator for the phase III programme [22] [23] [24] [25] [26] [27] .

In August 2014, Cellceutix completed a randomised, double-blind phase IIb trial designed to assess the safety and efficacy of three dosing regimens of brilacidin, compared with daptomycin, in patients with ABSSSIs caused by Staphylococcus aureus (including MRSA) and Streptococcus pyogenes (NCT02052388). The trial was initiated in February 2014 and enrolled 215 patients in the US. The trial demonstrated that a single intravenous dose of brilacidin delivered comparable outcomes to a seven-day dosing regimen of the FDA-approved drug, daptomycin, in patients with ABSSSIs. In October 2014, the company reported top-line data from the trial and additional data from the microbiological intent-to-treat population was released in December 2014. In April 2015, the company reported that it has gathered microbiological data from bacterial pathogens isolated in the trial along with pharmacokinetic and pharmacodynamics data and also in-depth evaluated the safety profile of brilacidin against that of daptomycin in this patient population. The data will determine the appropriate dose of brilacidin for a planned phase III registration-enabling trial [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] .

In September 2015, Cellceutix had developed a population pharmacokinetic model for brilacidin using data from three phase I and two phase II trials in patients with ABSSSI. The model was developed to describe the time-course of brilacidin in plasma and to identify predictor's of pharmacokinetics [45] .

Brilacidin was associated with high and sustained clinical response rates across all dose groups in a phase IIa trial in patients with ABSSSIs caused by either meticillin-susceptible (MSSA) or meticillin-resistant (MRSA) Staphylococcus aureus (PMX63-203; NCT01211470). Patients were randomised to one of three dosing regimens of brilacidin or daptomycin, and were assessed at 48 and 72 hours for clinical and microbiologic response. Brilacidin was administered once-daily for five days followed by two days of placebo. Daptomycin was administered once-daily for seven days. Patients were re-evaluated at day 10 to 15 for test of cure, and again for safety at four weeks. In September 2011, PolyMedix received clearance from European regulatory agencies to conduct the trial in Europe. Enrolment of 215 patients in Canada, Ukraine, Russia and other European sites was completed in January 2012 [46] [47] [48] [49] [50] .

PolyMedix completed a phase I trial (PMX63-103) of brilacidin in healthy volunteers in the US in February 2011. The randomised, double-blind study evaluated the tolerability and pharmacokinetics of intravenous brilacidin, given with an initial loading dose followed by once-daily dosing at its highest anticipated therapeutic dose for up to 14 days, in 16 subjects [51] [52] [53] . Volunteers in this study reported experiencing temporary paraesthesia of the face and fingers during brilacidin, similar to those seen in previous phase I studies. To determine the mechanism of the effect, PolyMedix conducted additional in vitro and in vivo studies, and based on these data, PolyMedix believes that the paraesthesia may be associated with temporary interactions with specific potassium, sodium or acid sensing ion channels located on sensory nerve fibres [54] [55] . After completion of the phase I trial, PolyMedix intended to hold discussions with the FDA concerning further development of the drug in the US [56] .

In March 2010, PolyMedix released final results for its phase Ib trial of brilacidin that assessed the safety of repeated dosing [57] . The study was designed to mimic the expected clinical dosing regimen. Healthy volunteers received brilacidin or placebo twice a day for five days at doses ranging from 0.1-0.6 mg/kg every 12h, 24h or 48h, for a total of 5 to 10 doses. Results showed that the optimal dose for phase II investigation was found to be 0.3 mg/kg/day (0.3 mg/kg every 12 hours or 0.6 mg/kg every 24 hours) [58] [59] [60] [61] [62] [63] .

In May 2008, PolyMedix received a notice of no objection from Health Canada to begin phase I trials for brilacidin. The first phase I trial was subsequently initiated in August 2008 and assessed the safety of brilacidin in a dose-escalation study in approximately 30-50 healthy volunteers who received a single IV dose of brilacidin [64] . The subjects were grouped into different cohorts with different dosage levels which allowed for the study of the effects of increased dosages. Positive results from this phase Ia trial were presented in December 2008 [65] [66] .

In December 2014, the US FDA granted the qualified infectious disease product (QIDP) designation to brilacidin for the treatment of ABSSSI [67] . Innovation Pharmaceuticals also intends to file for fast track designation in this indication, in the US. The company believes it may be possible to market brilacidin before the planned phase III trial has been completed. Brilacidin is eligible for additional FDA incentives in the approval and marketing path, including Fast Track designation and Priority Review for development and a potential five-year extension of market exclusivity under the Generating Antibiotics Incentives Now (GAIN) Act [68] [69] [36] .

Stomatitis (oral mucositis)

In November 2019, the US FDA waived initial Pediatric Study Plan requirement for brilacidin, for the prevention of severe oral mucositis in head and neck cancer patients receiving chemoradiation, in pediatric populations. Innovation Pharmaceuticals will focus on development of brilacidin in for the treatment of oral mucositis in adult patients [70] .

In December 2018, Innovation Pharmaceuticals announced that the US FDA completed an End-of-Phase 2 meeting concerning the continuing development of Brilacidin oral rinse to decrease the incidence of severe oral mucositis (SOM) in head and neck cancer (HNC) patients receiving chemoradiation. In October 2018, the company had reported that the US FDA had granted an End-of-Phase 2 meeting for its clinical development programme of brilacidin oral rinse [71] [72] .

In March 2019, Innovation Pharmaceuticals reported that the documentation for the European Medicines Agency (EMA) March 15, 2019 submission cycle requesting scientific advice to advance brilacidin oral rinse in a phase III programme for the prevention of severe oral mucositis in head and neck cancer patients receiving chemoradiation has been completed. EMA granted a meeting with Innovation Pharmaceutical's subsidiary, IPIX Pharma, in April 2019 [73] [74] .

In November 2015, Cellceutix reported that the US FDA had granted Fast Track Designation to the oral rinse formulation of brilacidin for the treatment of oral mucositis. Additionally, in October 2017, Innovation Pharmaceuticals reported that it intends to apply for FDA Breakthrough Therapy Designation, and follow a similar expedited path in Europe, subject to condition that the CTIX-BRI205 phase II trial of brilacidin [see below] yields comparable safety and efficacy results, to those observed at interim [75] [76] [77] .

A phase II trial of brilacidin met its primary and secondary endpoints, including reduced incidence of severe stomatitis experienced by patients during radiation therapy, in December 2017, and subsequently the trial was completed (CTIX-BRI205; NCT02324335). The trial evaluated the efficacy and tolerability of brilacidin (45 mg/15 ml oral rinse), as compared with a placebo rinse, for the prevention of stomatitis in patients with head and neck cancer undergoing chemoradiation. The primary endpoint was assessed by sequential WHO oral mucositis score at multiple time-points. Innovation had completed the trial in November 2017. Positive preliminary interim efficacy, pharmacokinetics and adverse events data from the trial were released by Cellceutix, in March 2017. Updated results from the trial were reported in January 2018, April 2018 and May 2018. The trial met its primary and secondary endpoints [78] [79] . The randomised 1:1, parallel, double-blind trial was initiated in August 2014 and enrolled 61 patients in the US [80] [81] [82] [76] [83] [84] [85] [20] [86] [87] [88] [89] .

In October 2014, the IND for a phase II trial of brilacidin (brilacidin-OM) for the treatment of oral mucositis became effective, and selected a trial site in the US [32] . Cellceutix submitted IND application with the US FDA in September 2014 [33] . The company received the final IND-enabling toxicology report for brilacidin in this indication in August 2014 [90] . In December 2014, Cellceutix received approval from the Institutional Review Board for initiation of the study for prevention of oral mucositis in patients undergoing chemoradiation for treatment of head and neck cancer [29] [7] [91] [89] .

In preclinical trials, brilacidin demonstrated immunomodulatory, antibacterial, anti-biofilm and anti-inflammatory properties, which support the phase II trial of brilacidin for prevention of oral mucositis [28] [92] .

Brilacidin-OM reduced the occurrence of severe ulcerative oral mucositis by more than 94% as compared with placebo in an animal model [93] . Brilacidin demonstrated the ability to significantly reduce ulcerations in an animal model of radiation-induced stomatitis. The agent was administered as a preventive oral rinse thrice daily for 20 days. No adverse events were reported [94] . Brilacidin has also shown positive results in a 28-day acute radiation model, and a 35-day fractionated radiation model [95] . PolyMedix was working toward filing an IND with the US FDA to initiate a clinical trial in early 2013 in patients with stomatitis. Following its acquisition of PolyMedix, Cellceutix announced that it will prioritise completion of the IND filing to pursue development in the oral mucositis indication [69] [96] .

Cellceutix has filed an application with the US FDA in December 2013 requesting orphan drug status for brilacidin in this indication [97] .

Ulcerative proctitis/colitis

In January 2020, Innovation Pharmaceuticals initiated a phase I trial to assess the safety, tolerability, and pharmacokinetics of delayed release tablets of brilacidin in healthy volunteers. The randomised, double-blind, placebo-controlled trial intends to enrol approximately nine patients in the UK. In the same month, the company completed dosing in the trial. After reviewing the safety findings from the first cohort, the Dose Escalation Committee (DCE) recommended to progress dosing to the second cohort. In December 2019, the United Kingdom’s Medicines and Healthcare products Regulatory Agency granted approval to Innovation Pharmaceuticals to conduct a phase I trial for delayed release tablets of brilacidin in healthy volunteers, for the development in ulcerative colitis [98] [99] [100] [101] [18] [102] .

In June 2017, Cellceutix completed a phase IIb proof-of-concept trial evaluating efficacy, pharmacokinetics, safety and tolerability of brilacidin, as a retention enema at 50 mg, 100 mg, and 200 mg once daily for six weeks, in patients with ulcerative colitis (ulcerative proctitis/ulcerative proctosigmoiditis) (CTIX-BRI-206) [103] . The open label, dose escalation, trial initiated in June 2016 enrolled 17 patients, in Europe. The primary endpoint was to assess the frequency of clinical remission with brilacidin administered per rectum by enema, in patients with active ulcerative proctitis after 6 weeks of treatment. In July 2016, the first patient was enrolled. In October 2016 and November 2016, the company reported pharmacokinetics and efficacy data of patients treated in the first cohort of 50 mg brilacidin, demonstrating a well-tolerated drug safety profile, devoid of measurable systemic absorption. In December 2016, the company initiated the second cohort of brilacidin 100mg once daily, which was administered as a retention enema. In January 2017, enrolment in the second cohort was completed and brilicidin was well tolerated. In February 2017, enrolment was initiated in the third cohort of the trial. Patients received 200mg of brilacidin in this cohort. In January 2017, the company released phase II data showing that brilacidin was well-tolerated with no severe adverse events reported and no detection of measurable systemic absorption. Preliminary review in patients in the first cohort showed meaningful improvements for 5 of the 6 patients, including noticeable reductions in ulceration and bleeding [104] [105] [106] [107] [108] [28] [21] [109] [110] [111] [20] [112] [11] [113] . In March 2017, the company released additional updated results for the first two cohorts from this study. In May 2017, Cellceutix completed ulcerative proctitis patient enrolment in the third and the last cohort [114] [115] .

In November 2014, Innovation Pharmaceuticals announced that IND-enabling studies of brilacidin in ulcerative colitis are underways [7] [113] .

Innovation Pharmaceuticals plans to conduct gastroenterological studies of brilacidin as foam and tablet formulations [108] .

In September 2019, Innovation Pharmaceuticals announced that non-clinical studies for oral formulation for Brilacidin met the in vitro specifications for selective delivery to the colon [116] .

Cellceutix reported in September 2013 of its plans to assess the scientific data showing the potential of brilacidin for the treatment of inflammatory bowel diseases [69] . Since then, the company conducted preclinical studies evaluating immunomodulatory properties of brilacidin in animal models of Crohn's disease, ulcerative colitis and inflammatory bowel disease [32] .

Other indications

In March 2020, Innovation Pharmaceuticals announced that the testing of brilacidin as a novel experimental treatment against the latest coronavirus is scheduled to commence in third week of March 2020. Innovation Pharmaceuticals will research its drug candidate, brilacidin with US based Regional Biocontainment Lab (RBL) to evaluate its potential antiviral and anti-inflammatory properties for novel coronavirus treatment. The company has submitted preliminary summary of brilacidin's potential as a novel coronavirus treatment to the Biomedical Advanced Research and Development Authority (BARDA), which is dedicated to rapidly identifying and funding medical countermeasures to the COVID-19 outbreak [117] [118] . Innovation Pharmaceuticals intends to develop brilacidin, for the treatment of coronavirus infections designated as COVID-2019 infections and potentially Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) [119] [120] .

Innovation Pharmaceuticals plans to initiate clinical trials of brilacidin for the treatment of atopic dermatitis, acne and hidradenitis suppurativa [83] [107] [108] [121] . In January 2018, Innovation Pharmaceuticals reported that the company was in discussion with a leading drug formulator to develop topical formulation/formulations of brilacidin for these three dermatology indications [122] .

Preclinical studies demonstrated good minimum inhibitory concentration values when brilacidin was tested against Propionibacterium species, expressed in acne, as compared with other antibiotics, such as erythromycin, clindamycin, minocycline, doxycycline and metronidazole [123] .

Preclinical trials of an ophthalmic formulation have been conducted by Cellceutix for various ophthalmic infections, including keratitis and conjunctivitis. The studies showed promising pharmacokinetic outcomes and antimicrobial activity [124] . The University of Pittsburgh conducted preclinical safety and tolerability studies and Iris Pharma investigated the pharmacokinetic profile of brilacidin for use in ocular infections. Dr Reddy's Laboratories are involved in the formulation development of brilacidin-ocular.

In December 2015, Innovation Pharmaceuticals plans to start a retinoblastoma program including formulation and toxicity studies, additional ototoxicity studies with brilacidin in different concentrations and proceed with studies in gram- negative and anti-fungal applications for brilacidin. The programme is intended to be initiated by mid-2016 [21] .

In August 2014, Cellceutix reported that it is developing its new room temperature-stable formulation of brilacidin for the treatment of infected diabetic foot ulcers. Innovation Pharmaceuticals intends to conduct clinical trials for infected diabetic wounds [10] . In May 2014, the company released preclinical data demonstrating wound healing properties of brilacidin in a diabetic rat model. Innovation Pharmaceuticals is planning to conduct additional preclinical trials in infected diabetic wound models [125] .

Innovation Pharmaceuticals is also conducting preclinical studies of brilacidin for otitis media and otitis externa [126] . The company will develop its new room temperature-stable formulation for the treatment of otitis media [10] . Dr Reddy's Laboratories are involved in the formulation development of brilacidin-otic.

PolyMedix suspended the preclinical development of brilacidin as topical (ophthalmic infections) and oral (intestinal infections) applications pending further allocation of resources, according to its Form 10-K (filed 12 March 2010).

In June 2015, Cellceutix reported that it is in the process of completing formulation work for brilacidin in treating hidradenitis suppurativa [86] . The company had previously planned a pre-IND meeting with the US FDA for a phase II trial for this indication but decided it will only advance this programme after review of preliminary data from the oral mucositis trial.

Financing information

In October 2018, Innovation Pharmaceuticals secured financing for up to $US10 million, which includes an initial net placement of approximately $US2.2 million over the course of the first 30 days. The company intends to utilise these funds for the continued advancement of brilacidin for oral mucositis, kevetrin [see Adis Insight Drug profile 800028294] for ovarian cancer and prurisol [see Adis Insight Drug profile 800028312] for psoriasis [127] .

In April 2015, Cellceutix entered into a common stock purchase agreement with Aspire Capital Fund. Aspire agreed to purchase upto $US30 million of the company's common stock over 3 years. The proceeds will be used to support brilacidin development and development of other pipeline candidates. Previously, Aspire Capital had completed two similar transactions with the company totalling $US30 million [128] .

In March 2013, PolyMedix announced a proposed public offering of common stock, which was expected to raise approximately $US25 million. Potential proceeds were to be used to conduct clinical trials of brilacidin and general corporate uses [129] .

In November 2010, PolyMedix was awarded two grants totalling $US488 958 under the Qualifying Therapeutic Discovery Project (QTDP) programme, created as part of the Patient Protection and Affordable Care Act of 2010. The maximum grant amount was awarded for two of PolyMedix's programmes, including the development of brilacidin [130] .

PolyMedix developed brilacidin as a topical rinse for the treatment of stomatitis and received a Phase I grant from the NCI to further explore the potential of this compound in addressing this unmet medical need [96] [131] .

In March 2010, PolyMedix closed a debt financing for gross proceeds of $US10 million, and in November 2009, the company closed an equity financing for gross proceeds of $US20.7 million. This provided significant additional financing to fund some of the continued clinical development of brilacidin and delparantag.

PolyMedix secured a $US14 million credit facility with Hercules Technology II, L.P. in April 2010. PolyMedix intended to use proceeds from the facility to fund certain phase III enabling activities for brilacidin and delparantag, including manufacturing and toxicology studies [132] .

Patent Information

In February 2019, Innovation Pharmaceuticals reported that the USPTO had granted patent number 10 206 894, which covers methods for treating and/or preventing mucositis with one or more compounds, or pharmaceutically acceptable salts [133] .

Innovation Pharmaceuticals reported that the USPTO granted the “Issue Notification” of a new patent (projected US patent number 10 166 232) that covers brilacidin in the form of a pharmaceutical composition containing water and Tris-buffered saline. The patent also covers Brilacidin in combination with additional therapeutic agents, including an antibiotic, an anti-inflammatory agent, an anesthetic agent, an anti-allergic agent, an acetylcholine blocking agent, an adrenergic agonist, a beta-adrenergic blocking agent, an anti-glaucoma agent and an anti-hypertensive agent. This patent builds on the “Notice of Allowance” covering oral, buccal and sublingual pharmaceutical compositions of brilacidin [134] .

In November 2018, the USPTO issued a 'Notice of Allowance' to Innovation Pharmaceuticals, covering oral, buccal, and sublingual pharmaceutical compositions of brilacidin, including liquid compositions, such as rinses. Earlier, US patents with patent numbers 8 802 683, 9 155 738, 9 457 027 and 9 795 575 were granted [135] .

Innovation Pharmaceuticals, in December 2017, was granted a European patent by the European Patent Office for brilacidin for the prevention and control of oral mucositis. Similar patents were granted in the US, Asia (Japan, Taiwan, China), Australia and South Africa, all the patents are valid through 2032. The candidate also has pending patent applications in Russia and South Korea [136] .

In September 2009, the University of Pennsylvania was issued US Patent No. 7,590,517 entitled 'Methods, Systems, and Computer Program Products for Computational Design of Amphiphilic Polymers,' which provides protection for the underlying process and implementation of two proprietary computational methodologies, PACE™ (Proteomic Assisted Computational Engine) and GOLDYN™ (Global Optimization of Long-time Dynamics force field). The two methodologies were used by PolyMedix in its development of defensin mimetic antibiotic compounds, including brilacidin [137] .

PolyMedix was issued the US Patent No. 7,173,102 entitled 'Facially Amphiphilic Polymers as Anti-Infective Agents' in February 2007. The patent claims compositions of matter for facially amphiphilic polymers and oligomers. Also claimed are antimicrobial material compositions, methods of killing micro-organisms and processes of producing antimicrobial surfaces [138] .

Drug Properties & Chemical Synopsis

  • Route of administration IV, Ophthalmic, Otic, PO, Rectal, Topical
  • Formulation Controlled release, Enema, Infusion, Liquid, unspecified
  • Class Amides, Anti-infectives, Anti-inflammatories, Antiacnes, Antibacterials, Antivirals, Foot disorder therapies, Guanidines, Peptidomimetics, Pyrimidines, Pyrrolidines, Skin disorder therapies, Small molecules
  • Target Cell membrane structure; Type 4 cyclic nucleotide phosphodiesterase
  • Mechanism of Action Cell membrane permeability enhancers; Cell membrane structure modulators; Immunomodulators; Type 4 cyclic nucleotide phosphodiesterase inhibitors
  • WHO ATC code

    A01A (Stomatological Preparations)

    A07E (Intestinal Antiinflammatory Agents)

    D03 (Preparations for Treatment of Wounds and Ulcers)

    D10 (Anti-Acne Preparations)

    D11 (Other Dermatological Preparations)

    J01X (Other Antibacterials)

    J05A-X (Other antivirals)

    S02A (Antiinfectives)

  • EPhMRA code

    A1 (Stomatologicals, Mouth Preparations, Medicinal Dentifrices etc)

    A7E (Intestinal Anti-Inflammatory Agents)

    D10 (Anti-Acne Preparations)

    D11 (Other Dermatological Preparations)

    D3 (Wound Healing Agents)

    J1X (Other Antibacterials)

    J1X1 (Glycopeptide antibacterials)

    J5 (Antivirals for Systemic Use)

    S2A (Otic Anti-Infectives)

  • Chemical name N4,N6-bis(3-(5-guanidinopentanamido)-2-((R)-pyrrolidin-3-yloxy)-5-(trifluoromethyl)phenyl)pyrimidine-4,6-dicarboxamide tetrahydrochloride
  • Molecular formula C40 H54 Cl4 F6 N14 O6
  • SMILES C1=C(C=C(C(=C1NC(=O)CCCCNC(=N)N)OC1CCNC1)NC(=O)C1=CC(=NC=N1)C(=O)NC1=CC(=CC(=C1OC1CCNC1)NC(=O)CCCCNC(=N)N)C(F)(F)F)C(F)(F)F.Cl
  • Chemical Structure
  • CAS Registry Number 1224095-98-0

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

abscess

Outcome Measure

ATPase inhibitory factor 1

1

methicillin-resistant Staphylococcus aureus infections

Outcome Measure

ATPase inhibitory factor 1

1

post-traumatic infections

Outcome Measure

ATPase inhibitory factor 1

1

postoperative infections

Outcome Measure

ATPase inhibitory factor 1

1

skin and soft tissue infections

Outcome Measure

ATPase inhibitory factor 1

1

staphylococcal infections

Outcome Measure

ATPase inhibitory factor 1

1

streptococcal infections

Outcome Measure

ATPase inhibitory factor 1

1

wound infections

Outcome Measure

ATPase inhibitory factor 1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Brilacidin - Innovation Pharmaceuticals ATPase inhibitory factor 1 Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acne - - Preclinical USA Topical / unspecified Innovation Pharmaceuticals 26 Oct 2016
Atopic dermatitis Eczema - Preclinical USA Topical / unspecified Innovation Pharmaceuticals 01 Nov 2016
COVID 2019 infections - - Preclinical USA IV / unspecified Innovation Pharmaceuticals 19 May 2020
Diabetic foot ulcer - - No development reported (Preclinical) USA unspecified / unspecified Innovation Pharmaceuticals 28 Aug 2018
Hidradenitis suppurativa - - Preclinical USA Topical / unspecified Innovation Pharmaceuticals 01 Nov 2016
Inflammatory bowel diseases - In volunteers Phase I United Kingdom PO / Controlled release Innovation Pharmaceuticals 06 Feb 2020
Inflammatory bowel diseases - - Preclinical USA PO / Controlled release Innovation Pharmaceuticals 14 Jan 2019
Intestinal infections - - Discontinued (Preclinical) USA PO / unspecified Innovation Pharmaceuticals 08 Jan 2018
Ophthalmic infections - - Discontinued (Preclinical) USA Ophthalmic / unspecified Innovation Pharmaceuticals 08 Jan 2018
Otitis - - No development reported (Preclinical) USA Otic / unspecified Innovation Pharmaceuticals 28 Feb 2018
Skin and soft tissue infections Acute bacterial skin and skin structure infections due to Staphylococcus aureus Acute bacterial skin and skin structure infections due to Staphylococcus aureus (including MRSA) and Streptococcus pyogenes - Phase II Canada, Russia, USA, Ukraine IV / Infusion Innovation Pharmaceuticals 18 Feb 2014
Stomatitis In patients with head and neck cancer undergoing chemoradiation Prevention Phase II USA (fast track) Topical / Liquid Innovation Pharmaceuticals 14 Aug 2014
Ulcerative colitis - - Discontinued (Preclinical) USA Topical / unspecified Innovation Pharmaceuticals 08 Jan 2018
Ulcerative proctitis - - Phase II USA Rectal / Enema Innovation Pharmaceuticals 15 Jun 2016
Ulcerative proctitis - In volunteers Phase I USA PO / Controlled release Innovation Pharmaceuticals 17 Jan 2020
Wounds Non-infected - No development reported (Preclinical) USA unspecified / unspecified Innovation Pharmaceuticals 28 Jun 2018

Priority Development Status

Type Region Indication
Fast Track US Stomatitis

Commercial Information

Involved Organisations

Organisation Involvement Countries
PolyMedix Originator USA
Innovation Pharmaceuticals Owner USA
Alfasigma Licensee World
University of Pennsylvania Technology Provider USA
Bio-Images Drug Delivery Collaborator United-Kingdom
Dr Reddys Laboratories Collaborator India

Licensing Availability

Licensing Organisation Available Indication Available Phase Region Date
Innovation Pharmaceuticals Stomatitis Unspecified - 13 Nov 2019
Innovation Pharmaceuticals COVID 2019 infections Unspecified - 20 Apr 2020

Scientific Summary

  • Adverse Events Frequent: Paraesthesia
    Occasional: Blood platelet disorders; Hypertension; Numbness

Pharmacokinetics

Phase II:

Interim results from a phase II study in four patients with ulcerative proctitis, treated with brilacidin at the lowest dose (50 mg), showed that drug concentrations in plasma, across all time points, were below the lower limit of quantification (i.e., <100 ng/mL), which is consistent with very limited systemic exposure from administration per rectum by enema [121] [111] . Updated interim results from the phase II study in ulcerative proctitis demonstrated that drug concentrations in plasma continued to show limited systemic absorption of brilacidin, with all values registering less than 100 ng/mL for all six patients in Cohort A and averaging approximately 215 ng/mL maximum concentrations across the six patients in Cohort B [104] [115] [113] .

Stomatitis

In a preliminary interim analysis of a phase II trial, all concentrations of brilacidin were below the lower limit of quantification (< 10 ng/mL) in plasma samples from six patients. The randomised, double-blind trial is designed to evaluate the safety and efficacy of brilacidin oral rinse in preventing and controlling oral mucositis in 60 patients with head and neck cancer undergoing chemoradiation [85] [89] .

Clinical

In pooled results for two randomised, placebo-controlled, multiple-dose phase I trials of intravenous brilacidin in a total of 77 healthy male volunteers, the terminal elimination half life varied between 16.6 and 23 hours. Pharmacokinetics were dose-dependent [147] .

The pharmacokinetic parameters of IV brilacidin were similar between male and female volunteers in a phase I multiple-dose study [54] .

In a phase I clinical study involving 22 healthy volunteers, simple exponential kinetics were observed, with a distribution and elimination half-life of 1.5 and 15 hours, respectively. Peak plasma levels were consistently found to be about 15 times the dose, so that 0.18 mg/kg resulted in a mean Cmax of 2.7 µg/mL, and the 0.54 mg/kg dose had a mean Cmax of 8 µg/mL. Pharmacokinetic modelling with this data suggested that a single daily dose of 0.18 mg/kg would provide steady-state plasma levels exceeding 2 µg/mL for 12 hours daily and exceeding 1 µg/mL continuously. The same dose twice daily, or a once-daily dose of 0.4 mg/kg, would provide plasma levels exceeding 2 µg/mL for 16 hours and exceeding 1 µg/mL continuously from the first day of treatment [65] .

The mean plasma half-life of intravenous brilacidin was 23 hours, according to results from a phase I trial (PMX63-103) in 16 healthy volunteers. A loading dose of 1mg/kg was followed by 0.35mg/kg daily on days 2-14 [52] . Urinary excretion accounted for <1% of elimination; in males and females, respectively, 0.258 and 0.219mg of drug was recovered unchanged in urine [53] .

Preclinical

efficacy in the neutropenic mouse thigh burden with brilacidin against MRSA and MSSA strains of Staphylococcus aureus was demonstrated to be highly correlated with reaching minimal inhibitory concentration (MIC) levels of free compound in plasma. Full efficacy was achieved with MSSA and MRSA when plasma C0 values of free brilacidin reached MIC levels (0.7 to 1.2 µg/ml, respectively), and AUC values of free brilacidin reached 3 000 to 6 000 h*ng/ml, respectively [150] .

At maximally efficacious doses in preclinical infection models, pharmacokinetic parameters at therapeutic doses were comparable to human subjects at doses more than 0.18 mg/kg [65] .

Following a single 2mg/kg intravenous dose of [14C]-brilacidin, 40.17% and 25.47% of radioactivity was found in faeces of male and female rats, respectively. This indicates that the bile and/or the gut mucosa may be a main route of elimination. Renal excretion is not a significant elimination pathway [53] .

In a study involving a simulated gastric fluid model, brilacidin was minimally degraded across four hours, indicating that orally formulated brilacidin was not susceptible to rapid breakdown in the stomach. These results suggested the likelihood of developing an oral formulation of the drug for the effective treatment of inflammatory bowel disease [19] .

Preliminary top-line results demonstrated that no quantifiable brilacidin concentrations in blood at any timepoint across treatment cohorts and shows containment of Brilacidin within the target location [17] [18] .

Adverse Events

Skin and soft tissue infections

Top-line data from a phase IIb trial in an intent-to-treat population, demonstrated that three dosing regimens of brilacidin was safe and generally well tolerated in patients with acute bacterial skin and skin structure infections (ABSSSI). Six severe adverse events, unrelated to the drug, were reported. Adverse events appeared to be exposure-related. Aside from mild, transient numbness and tingling (for which no patient discontinued treatment), the overall adverse event rates were under 10% in each treatment group (low, medium and high doses of brilacidin and daptomycin). In 3.8% (n = 6/160) of patients treated with brilacidin, transient increases in systolic blood pressure were observed; of these patients, half (n = 3) were in the high-dose group. Previous interim results also showed a case of increased platelets in the low dose group. In this double-blind trial, 215 patients were randomised to one of three dosing regimens of brilacidin (0.4 mg/kg on day 1 then 0.30 mg/kg [low], 0.75 mg/kg on day 1 then 0.35 mg/kg [medium] or 1.0 mg/kg on day 1 then 0.35 mg/kg [high]) once daily for 5 days followed by placebo for 2 days, or daptomycin once daily for 7 days. An approximately 25% of 215 patients were recruited into each treatment arm [46] [144] [146] .

Ulcerative proctitis

Phase II

Interim results from the phase II CTIX-BRI-206 proof-of-concept trial in ulcerative proctitis demonstrated that brilacidin was safe and well tolerated by patients in both cohorts A and B and all patients maintained stable vital signs. A total of 16 adverse events in six patients were reported, none of which were related to the study drug. No serious adverse events were reported [104] [115] [108] [113] .

Stomatitis:

Brilacidin 45 mg/15 ml oral rinse, for prevention and control of stomatitis, was generally safe and well-tolerated in a phase II trial in patients with head and neck cancer undergoing chemoradiation. Safety findings were typical for patients with this indication and all treated patients reported at least one treatment-emergent adverse event (TEAE). At least one serious adverse event (SAE) was reported in 13 patients, 8 from the brilacidin group, and 5 from the placebo group, of the TEAE categorised as SAEs. SAEs were not related to brilacidin treatment. There was no death because of the SAEs. The randomised 1:1, parallel-group, double-blind trial enrolled 61 patients. The oral rinse of brilacidin or placebo was self-administered by patients for three times daily across 7 consecutive weeks in the trial [82] [85] [89] .

Healthy volunteers

Phase I

in pooled results for two randomised, placebo-controlled phase I trials of intravenous brilacidin in a total of 77 healthy male volunteers, the most common adverse events were paraesthesia and increases in blood pressure and heart rate, all of which were transient and required no treatment. No gastrointestinal or renal effects were observed. Brilacidin showed an unremarkable safety profile between 0.1 and 0.3mg/kg once-daily dosing. Increasing the frequency of dosing from once- to twice-daily did not appear to improve the safety profile at comparable dose levels [147] .

The most frequently reported adverse event in a phase I, multiple-dose trial of brilacidin was transient paraesthesias of the lips, face and fingers. In this randomised, double-blind study, 20 male and female volunteers received a loading dose (1mg/kg) of intravenous brilacidin followed by daily dosing (0.35mg/kg) for up to 14 days. The paraesthesias did not worsen over the study period and most cases resolved after withdrawal of brilacidin. Several volunteers were withdrawn from the study after 9-13 days' treatment due to hypertension and increased heart rate, and one subject experienced reversible atrial fibrillation. A few cases of transient elevations in liver enzymes were noted but the changes were not clinically significant [54] . Based on these results, it was concluded that once-daily dosing of brilacidin for 5 days is an appropriate regimen [52] .

Brilacidin was generally well tolerated whether administered every 12h or every 24h in a phase Ib study in healthy volunteers. In the randomised, placebo-controlled study, the maximum tolerated dose of brilacidin for investigation in phase II studies was found to be 3.0 mg/kg (0.3 mg/kg every 12 hours or 0.6 mg/kg every 24 hours). No clinically significant adverse effects at therapeutic dosages were observed [59] [61] .

In a phase Ib study of brilacidin, a dose-limiting toxicity was found at the higher dosages and consisted of paraesthesias. These usually beginning in the oral area and extension to the face, scalp, extremities, upper thorax, and/or perineum, lasting from hours to days. In all cases the effects were temporary and resolved without treatment. Transient increases in ALT and AST were observed in some subjects at higher doses and in all cases resolved without treatment after completion of the study. Healthy volunteers (n = 56) were divided into 8 cohorts and received up to 5 doses of either brilacidin or placebo. The doses ranged from 0.1 mg/kg to 0.6 mg/kg per day and were administered as a single one-hour infusion every 24 or 48 hours. Dosing continued until a threshold was reached where more than one volunteer in a cohort tolerated fewer than 5 doses. There were minimal clinically relevant adverse events at 0.2 mg/kg (total dose of 1.0 mg/kg), and there was no early termination of dosing until the 0.4 mg/kg level. At the 0.5 and 0.6 mg/kg doses (up to 2.5 and 3.0 mg/kg total doses, respectively), the syndrome of subjective effects became more prominent. As also seen in the previous Phase 1a clinical study, there were no objective correlates or clinical measurements associated with the sensations. Five of ten subjects intended to receive 2.5 mg/kg or more total dose tolerated that amount. The data confirmed that a total dose of 3.0 mg/kg, given as 5 doses of 0.6 mg/kg once-daily, was the limiting dosage in this study [62] [55] .

In a phase I clinical study involving 22 healthy volunteers, brilacidin at doses 0.54 mg/kg and above resulted in paresthesias, usually beginning in the oral area and extension to the face, scalp, extremities, upper thorax, and/or perineum. The degrees of extension appeared to correlate with dosage increase, with symptoms lasting from hours to days. No adverse events were classified as serious or severe; however, mild to moderate symptoms suggested that dose escalation could be halted to 2.5 mg/kg [65] [55] .

Animal toxicology

In preclinical studies, brilacidin at 12 and 24 mg/kg/day bid, given as an IV infusion was well-tolerated. Transient reduction in feed consumption and body weight loss was observed in the high dose group. No other acute brilacidin-related effects were observed [152] .

Studies on peripheral nerve function in rats showed that the effect of brilacidin is of a pharmacological nature, without neurotoxicity [156] .

Preliminary top-line results from the phase I trial demonstrated that the trial met its primary endpoints and brilacidin delayed release was well tolerated across all treatment cohorts with no serious adverse events. Two volunteers on brilacidin delayed release and two on placebo experiences atleast one adverse events of mild intensity and not related to study treatment [17] [18] .

Pharmacodynamics

Summary

Brilacidin demonstrated in vivo efficacy in the mouse subcutaneous abscess (MSCA) and rat granuloma pouch (RGP) infection models of Staphylococcus aureus skin infections. In the MSCA model, brilacidin demonstrated log CFU reductions of 1.3 - 2.3 for IV dosing regimens (both once and twice daily) between 10-20 mg/kg as compared to untreated controls. In the RGP model, brilacidin effected log CFU reductions in pouch fluid of 1.1-2.5 following single IV doses of 4-20 mg/kg and up to a 5 log reduction at 10 mg/kg twice daily (within 6 hrs of administration) [149] .

Brilacidin demonstrated robust efficacy against MSSA and MRSA in a mouse thigh burden model, and against MSSA in a rat thigh burden model and a mouse peritonitis model [152] .

Brilacidin demonstrated activity in vitro against the New Delhi metallo-beta-lactamase-1 (NDM-1) drug resistant strain of Klebsiella pneumonia [148] .

In a chinchilla model of otitis media, brilacidin treatment greatly reduced Streptococcus pneumonia bacterial counts, with no toxic effects [8] .

Brilacidin suppressed various pro-inflammatory mediators (such as TNF-α, IL-1β, IL-8, IL-6, MMP-9, MCP-1). Preclinical studies showed dose-dependent inhibition of PDE4B2 and PDE3A, in vitro, with brilacidin treatment. Brilacidin may possess good cell membrane permeability property, based on similar IC50 values against both PDE4 (biochemical) and cytokine release in cell-based assays. Localised clinical administration allowed brilacidin concentrations that markedly exceed in vitro IC50 values, thus, providing for increased concentrations of cAMP. The overall effect of Brilacidin’s ability to modulate cAMP levels supports its potential to treat a number of chronic, autoimmune and inflammatory diseases related to issues of innate immunity, such as inflammatory bowel disease, atopic dermatitis and others [140] .

In an acute radiation model in hamsters (n=10), brilacidin (at the three highest doses) significantly reduced peak mucositis scores and daily mucositis scores on 9 to 10 of the 10 evaluation days when stomatitis was evident (p<0.001 vs vehicle). At the three highest doses, brilacidin reduced the number of animal days with ulceration by ≅90%; from 42% in vehicle-treated group to <5% in the active treatment groups (p<0.001). Brilacidin was dosed as a topical rinse three times daily, at 0.03, 1.0, 3.0 or 10.0mg/mL for 28 days, following a single dose of radiation to the buccal cheek pouch (40 Gy). In a fractionated radiation model in hamsters, brilacidin significantly reduced daily mucositis scores prior to peak stomatitis, and during the remaining treatment period (p<0.001 vs vehicle). Brilacidin reduced the number of animal days with ulceration by ≅94%; from 55% in vehicle-treated animals to 3.3% (p<0.001). Radiation was administered at 7.5 Gy/dose on days 0, 1, 2, 3, 6, 7, 8 and 9, targeting the left buccal pouch mucosa. Brilacidin 3mg/mL was dosed three times for 35 days [95] .

Treatment of non-infected wounds with brilacidin for 5 days decreased the time to wound healing, compared with untreated controls, in a diabetic rat model. Complete reduction of the wound area was observed in brilacidin-treated animals [125] .

In VERO cells (a monkey kidney cell line), at 16 hours post-infection, treatment with brilacidin demonstrated a dose-dependent reduction in the SARS-CoV-2 infectious viral titers compared with vehicle-alone control (Dimethyl sulfoxide or DMSO) [14] [15]

Antimicrobial Activity

Summary

Clinical

In two phase Ib dose-escalation trials, intravenous brilacidin had antibacterial activity against both meticillin-susceptible and meticillin-resistant strains of Staphylococcus aureus (MSSA and MRSA) in blood samples taken from healthy male volunteers who had received brilacidin at doses of 0.1 mg/kg or higher. In these randomised trials, 77 subjects received either placebo or brilacidin at doses ranging from 0.1-0.6 mg/kg/day, administered every 12h, 24h or 48h [59] [61] . Bactericidal activity in serum against MSSA and MRSA strains was observed at single doses of 0.1-0.3 mg/kg [147] .

In antimicrobial assays following brilacidin treatment, bacteriostatic and bactericidal activity against methicilin-sensitive Staphylococcus aureus (S. aureus) and MRSA strains were achieved at doses at or above 0.2 mg/kg, and largely correlated with those established in normal medium and in experimental animal studies. Healthy volunteers (n = 56) were divided into eight cohorts and received up to 5 doses of either brilacidin or placebo. The doses ranged from 0.1 mg/kg to 0.6 mg/kg per day and were administered as a single 1h infusion every 24 or 48h. Dosing continued until a threshold was reached where more than one volunteer in a cohort tolerated fewer than 5 doses. Antimicrobial assays were performed with blood samples drawn from the study subjects. In these assays, blood samples were taken from the subjects after they had been dosed with brilacidin. Staphylococcus aureus bacteria was then added to these blood samples, to determine if the brilacidin in the subjects blood would have antimicrobial activity [62] [156] .

Preclinical

Brilacidin demonstrated potent activity against 1000 worldwide strains of Gram-positive staphylococci and streptococci clinical isolates, including those resistant to linezolid, daptomycin and methicillin. These data were presented at the 21st Annual European Congress of Clinical Microbiology and Infectious Disease (ECCMID-2012) in April 2012 [145] .

Brilacidin demonstrated a low incidence for development of resistance in vitro, and high selectivity for bacteria versus mammalian cell types. MIC90 values for brilacidin were 1 µg/mL for S. aureus, 0.5 µg/mL for S. epidermidis, and 1 µg/mL for S. haemolyticus. Brilacidin was bactericidal with a time-kill range between 30 min and 6h. Brilacidin was highly stable in the presence of plasma and isolated hepatocytes from multiple species [151] .

Brilacidin, in an in vitro experiment in COVID-2019 infections using human kidney cell line expressing hACE2, demonstrated an average of 29% inhibition at 0.1ug/ml and 85% inhibition at 100ug/ml. Earlier in vitro results using VERO cells, reduced the viral titer (load) of SARS-CoV-2 by 75 percent after only 1 hour of preincubation prior to infection at a concentration of 10µM as compared to vehicle control. An earlier 16-hour post-infection experiment, in VERO cells, showed Brilacidin exhibited a dose-dependent reduction in SARS-CoV-2 infectious viral titers [12] [13] .

Therapeutic Trials

Top-line data from a phase IIb trial in an intent-to-treat population, demonstrated that three dosing regimens of brilacidin met the primary endpoint of reduction of at least 20% in area of acute bacterial skin and skin structure infections (ABSSSI), compared to baseline, for 48-72 hours, post-first-dosing, without the administration of any rescue antibiotics. The clinical success rate of the three dosing regimens of brilacidin were statistically comparable to that of daptomycin. Brilacidin produced early, high and consistent clinical response in patients with ABSSSI. Clinical response rates at days 2-3, 7-8, 10-14 and 28 were 97.5%, 91.4%, 92.3% and 91.5%; 92.5% 94.3% 97.4% 95.7%; 92.5% 91.4% 97.4% 95.7%; and 87.5% 80.0% 97.4% 93.6%; in the brilacidin low, medium and high dose groups, and the daptomycin group, respectively. The respective 95% confidence intervals around the clinical success rates were 85-100%, 90-100%, 94-100%, and 87-100%. In addition to the intent-to-treat population, similar positive results were obtained in the microbiological intent-to-treat population which consisted of patients who had cultures obtained at the baseline, which were positive for common ABSSSI pathogens. Majority of the cultures grew Staphylococcus aureus, 40% of which included methicillin-resistant Staphylococcus aureus. In this double-blind trial, 215 patients were randomised to one of three dosing regimens of brilacidin (0.4 mg/kg on day 1 then 0.30 mg/kg [low], 0.75 mg/kg on day 1 then 0.35 mg/kg [medium] or 1.0 mg/kg on day 1 then 0.35 mg/kg [high]) once daily for 5 days followed by placebo for 2 days, or daptomycin once daily for 7 days. An approximately 25% of 215 patients were recruited into each treatment arm [154] [46] [144] [146] [44] .

Top line results from a phase II trial demonstrated clear reduction in the incidence of severe stomatitis (OM)(WHO Grade = 3) on treatment with brilacidin 45 mg/15 ml oral rinse as compared with placebo, in patients with head and neck cancer undergoing chemoradiation. Overall reduction was 17.1% (brilacidin: 42.9%; placebo: 60.0%) in modified intent to treat (mITT) population and 23.2% (brilacidin: 36.8%; placebo: 60.0%) in per protocol (PP) population (primary endpoint). The severe OM median duration was 0.0 days for brilacidin in mITT and PP populations (secondary endpoint). Overall Severe OM median durations for placebo were 3.0 days and 5.5 days for the mITT and PP populations. Brilacidin-OM successfully prevented severe oral mucositis from occurring, as well as delayed its onset, in a substantial number of patients compared with placebo, particularly the period from approximately 28-42 days, after the initiation of treatment. 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). Initial instance duration median was 33.5% and overall duration median was 35.5% in modified intent to treat (mITT) population. In mITT population, incidences were reduced by 65% in brilacidin group, when compared with placebo (brilacidin: 25.0%; placebo: 71.4%; P = 0.0480) in patients receiving higher concentration of cisplatin (80-100 mg/m2); in per-protocol population, incidences were reduced by 80.3% in brilacidin group, when compared to placebo (brilacidin: 14.3%; placebo: 72.7%; P = 0.0249). The randomised 1:1, parallel, double-blind trial enrolled 61 patients. The oral rinse of brilacidin or placebo was self-administered by patients for three times daily across 7 consecutive weeks in the trial [80] [82] [78] [79] [85] [89] .

Updated results from the first two cohorts from the phase II CTIX-BRI-206 trial demonstrated that a clinically beneficial response was observed in all patients, as measured by the Modified Mayo Disease Activity Index (MMDAI). The primary efficacy endpoint of clinical remission (stool frequency, rectal bleeding, endoscopy sub-scores) was met by three out of six patients from each cohort. Out of the patients from both the cohorts that did not meet the primary endpoint (n=6), all of the patients achieved a partial response (two out of three criteria met). Rate of clinical remission was 60%, 67%, and 75% in the cohort A, B, and C, respectively. Endoscopy subscore of ≤ 1 was achieved by 80%, 67%, and 75% of patients, from the cohort A, B, and C, respectively. Zero rectal bleeding subscore was observed in 80% and 100% of patients of patients from cohort A and cohort B & C, respectively. All patients achieved stool frequency subscore. In Full MMDAI assessment (Stool Frequency + rectal bleeding + endoscopy findings + Physician’s Global Assessment), 100% reduction in 2 patients in Cohort A and 2 patients in Cohort B, 50-75% reduction in 2 patients in Cohort A and 4 patients in Cohort B and 20% reduction in 1 patient in Cohort A was reported. According to partial MMDAI assessment (Stool Frequency + rectal bleeding + endoscopy findings), 100% reduction in 3 patients in Cohort A and 3 patients in Cohort B and 50-83% reduction in 2 patients in Cohort A and 3 patients in Cohort B was observed. All 12 patients reported an improvement in quality of life as measured by the SIBDQ, with, over 40% of patients reporting significant improvements, ranging approximately from 20 points to more than 50 points higher on the 70-point SIBDQ scale. Interim results in four patients treated with brilacidin for ulcerative proctitis demonstrated clinically meaningful improvements, as measured by the Modified Mayo Disease Activity Index (MMDAI). At Day 42, on the Partial MMDAI (accounting for Stool Frequency, Rectal Bleeding, and Physician’s Global Assessment scores), 2 of 4 patients achieved full response (100% reduction) and the other 2 patients had notable improvement (50% reduction). At Day 42, on the MMDAI (equivalent to Partial MMDAI + Endoscopy score; completed by 3 of 4 patients), 1 of 3 patients achieved full response (100% reduction) and 2 of 3 patients had notable improvement (50% reduction). Patient quality of life, as assessed by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), was improved after 6-weeks of treatment with brilacidin [142] [111] [104] [115] [113] .

Future Events

Expected Date Event Type Description Updated
30 Sep 2020 Trial Update Innovation Pharmaceuticals plans a phase II trial for Ulcerative colitis (PO, Controlled release tablet) in USA by September 2020 (700319549) [139] 17 Mar 2020
30 Jun 2020 Trial Update Alfasigma plans multiple clinical trials for Ulcerative proctitis/ulcerative proctosigmoiditis in mid-2020 [101] 30 Dec 2019
16 Mar 2020 Trial Update Regional Biocontainment Labs plans to commence testing of brilacidin for COVID-2019-infections in March 2020 [119] 03 Apr 2020
17 Jan 2020 Trial Update Innovation Pharmaceuticals and BDD Pharma plan a phase I trial for Ulcerative colitis (In volunteers) in United Kingdom in (PO,Tablet) in January 2020 [99] 21 Jan 2020
31 Oct 2018 Regulatory Status Innovation Pharmaceuticals plans an end-of-phase II meeting with the FDA in October 2018 [141] 17 Nov 2018

Development History

Event Date Update Type Comment
26 May 2020 Scientific Update Antimicrobial data from a preclinical study in COVID-2019 infections released by Innovation Pharmaceuticals [12] Updated 01 Jun 2020
19 May 2020 Phase Change - Preclinical Preclinical trials in COVID-2019 infections in USA (IV) [13] Updated 26 May 2020
19 May 2020 Scientific Update Antimicrobial data from preclinical studies in COVID-2019 infections released by Innovation Pharmaceuticals [13] Updated 26 May 2020
22 Apr 2020 Licensing Status Brilacidin is available for licensing as of 20 Apr 2020 for the treatment of COVID-19 infections http://www.ipharminc.com/collaborations [2] Updated 22 Apr 2020
06 Apr 2020 Trial Update Innovation Pharmaceuticals plans a clinical trial for COVID-2019 infections in the US and Europe [14] [13] Updated 14 Apr 2020
01 Apr 2020 Scientific Update Pharmacodynamics data from early research phase in COVID-2019 infections released by Innovation Pharmaceuticals [15] Updated 03 Apr 2020
17 Mar 2020 Phase Change Early research in COVID-2019 infections in USA (IV) [16] Updated 23 Mar 2020
10 Mar 2020 Trial Update Regional Biocontainment Labs plans to commence testing of brilacidin for COVID-2019-infections in March 2020 [119] Updated 03 Apr 2020
05 Mar 2020 Trial Update Innovation Pharmaceuticals plans a phase II trial for Ulcerative colitis (PO, Controlled release tablet) in USA by September 2020 [139] Updated 17 Mar 2020
24 Feb 2020 Company Involvement Innovation Pharmaceuticals submits preliminary summary of brilacidin's potential for COVID-2019-infections to the Biomedical Advanced Research and Development Authority (BARDA) [118] Updated 28 Feb 2020
13 Feb 2020 Scientific Update Top-line adverse events and pharmacokinetics data from the phase I trial in Inflammatory bowel diseases released by Innovation Pharmaceuticals [17] Updated 20 Feb 2020
12 Feb 2020 Trial Update Innovation Pharmaceuticals completes a phase I trial in Inflammatory bowel diseases (In volunteers) in United Kingdom (PO) (NCT04240223) Updated 28 Feb 2020
06 Feb 2020 Phase Change - I Phase-I clinical trials in Inflammatory bowel diseases (In volunteers) in United Kingdom (PO) [17] Updated 20 Feb 2020
17 Jan 2020 Phase Change - I Phase-I clinical trials in Ulcerative proctitis (In volunteers) in USA (PO, Controlled release) [99] [102] Updated 21 Jan 2020
17 Jan 2020 Trial Update Innovation Pharmaceuticals and BDD Pharma plan a phase I trial for Ulcerative colitis (In volunteers) in United Kingdom in (PO,Tablet) in January 2020 [99] Updated 21 Jan 2020
26 Dec 2019 Regulatory Status Medicines and Healthcare products Regulatory Agency approves a Clinical Trial Application for a phase I trial of brilacidin in Ulcerative Colitis in United Kingdom (PO,Tablet) [100] Updated 30 Dec 2019
10 Dec 2019 Trial Update Alfasigma plans multiple clinical trials for Ulcerative proctitis/ulcerative proctosigmoiditis in mid-2020 [101] Updated 30 Dec 2019
10 Dec 2019 Regulatory Status Innovation Pharmaceuticals submits regulatory documents to the respective health authority for Ulcerative colitis for planned clinical trial [101] Updated 17 Dec 2019
25 Nov 2019 Regulatory Status The US FDA waives Paediatric Investigation Plan for Stomatitis in patients with Head and neck cancer [70] Updated 28 Nov 2019
13 Nov 2019 Licensing Status Brilacidin is available for licensing for Stomatitis (Prevention) as of 13 Nov 2019. www.ipharminc.com Updated 26 Nov 2019
16 Sep 2019 Phase Change - Preclinical Preclinical trials in Ulcerative colitis in United Kingdom (PO, Tablet) before September 2019 [116] Updated 18 Sep 2019
22 Jul 2019 Licensing Status Innovation Pharmaceuticals signs a license agreement with Alfasigma for the development and commercialisation of brilacidin in Ulcerative proctitis/Ulcerative proctosigmoiditis [4] Updated 25 Jul 2019
30 Jun 2019 Trial Update Innovation Pharmaceuticals plans a phase III trial for Stomatitis [68] Updated 06 May 2020
06 Jun 2019 Licensing Status Innovation Pharmaceuticals collaborates with BDD pharma for the developing oral tablets for Inflammatory bowel disease [5] Updated 12 Jun 2019
19 Feb 2019 Patent Information Innovation Pharmaceuticals has patent protection for brilacidin in USA [133] Updated 22 Feb 2019
14 Jan 2019 Phase Change - Preclinical Preclinical trials in Inflammatory bowel diseases in USA (PO) [19] Updated 17 Jan 2019
14 Jan 2019 Scientific Update Pharmacokinetics data from a simulated gastric fluid model in Inflammatory bowel disease released by Innovation Pharmaceuticals [19] Updated 17 Jan 2019
14 Jan 2019 Trial Update Innovation Pharmaceuticals plans a phase III trial in Stomatitis (PO) [19] Updated 17 Jan 2019
14 Jan 2019 Trial Update Innovation Pharmaceuticals plans clinical development in Ulcerative colitis and Crohn's disease (PO) and Ulcerative proctitis (Foam/gel) [19] Updated 17 Jan 2019
02 Jan 2019 Patent Information Innovation Pharmaceuticals receives "issue notification" for a new US patent from the USPTO [134] Updated 07 Jan 2019
17 Dec 2018 Regulatory Status The US FDA completes an End-of-Phase 2 meeting for clinical development programme of brilacidin in Stomatitis (Prevention, in head and neck cancer patients receiving chemoradiation) [71] Updated 21 Dec 2018
01 Nov 2018 Patent Information Innovation Pharmaceuticals has patent protection for brilacidin in USA [135] Updated 09 Nov 2018
01 Nov 2018 Patent Information USPTO issues Notice of Allowance for oral, buccal, and sublingual pharmaceutical compositions of brilacidin [135] Updated 09 Nov 2018
24 Oct 2018 Regulatory Status The US FDA grants an End-of-Phase 2 meeting for clinical development programme of brilacidin in Stomatitis (Prevention, in head and neck cancer patients receiving chemoradiation) [72] Updated 30 Oct 2018
12 Oct 2018 Scientific Update Pharmacodynamics data from preclinical studies released by Innovation Pharmaceuticals [140] Updated 22 Oct 2018
20 Sep 2018 Regulatory Status Innovation Pharmaceuticals plans an end-of-phase II meeting with the FDA in October 2018 [141] Updated 17 Nov 2018
05 Sep 2018 Trial Update Innivation Pharmaceuticals plans a clinical trials for Atopic dermatitis and Acne Updated 07 Sep 2018
28 Aug 2018 Phase Change - No development reported No recent reports of development identified for preclinical development in Diabetic-foot-ulcer in USA Updated 28 Aug 2018
28 Jun 2018 Phase Change - No development reported No recent reports of development identified for preclinical development in Wounds in USA Updated 28 Jun 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
09 May 2018 Scientific Update Updated efficacy data from a phase II trial in Stomatitis released by Innovation Pharmaceuticals [80] Updated 16 May 2018
09 May 2018 Trial Update Innovation Pharmaceuticals completes a phase II trial in Stomatitis (Prevention) in USA [80] (NCT02324335) Updated 16 May 2018
28 Feb 2018 Phase Change - No development reported No recent reports of development identified for preclinical development in Otitis in USA (Otic) Updated 28 Feb 2018
08 Jan 2018 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Intestinal infections in USA (PO) (Innovation pipeline, January 2018) Updated 08 Jan 2018
08 Jan 2018 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Ophthalmic infections in USA (Ophthalmic) (Innovation pipeline, January 2018) Updated 08 Jan 2018
08 Jan 2018 Phase Change - Discontinued(Preclinical) Discontinued - Preclinical for Ulcerative colitis in USA (Topical) (Innovation pipeline, January 2018) Updated 08 Jan 2018
03 Jan 2018 Scientific Update Updated efficacy data from a phase II trial in Stomatitis (Prevention) released by Innovation Pharmaceuticals [79] Updated 08 Jan 2018
28 Dec 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Ophthalmic-infections in USA (Ophthalmic) Updated 28 Dec 2017
12 Dec 2017 Patent Information Innovation Pharmaceuticals has patent protection for Brilacidin in Europe, Japan, Taiwan, China, Australia and South Africa [136] Updated 15 Dec 2017
12 Dec 2017 Patent Information Innovation Pharmaceuticals has patents pending for Brilacidin in Russia and South Korea [136] Updated 15 Dec 2017
11 Dec 2017 Scientific Update Top line efficacy and adverse events data from a phase II trial in Stomatitis (Prevention) released by Innovation Pharmaceuticals [82] Updated 15 Dec 2017
22 Nov 2017 Trial Update Innovation Pharmaceuticals completes a phase II trial in Stomatitis (Prevention) in USA (Topical) [76] Updated 01 Nov 2017
16 Nov 2017 Regulatory Status Innovation Pharmaceuticals plans to follow expedited approval procedure for Stomatitis in Europe [75] Updated 22 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Intestinal-infections in USA (PO) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Ulcerative-colitis in USA (Topical) Updated 04 Nov 2017
26 Oct 2017 Regulatory Status Innovation Pharmaceuticals plans to apply for FDA Breakthrough Therapy Designation for Stomatitis [76] Updated 01 Nov 2017
26 Oct 2017 Trial Update Innovation Pharmaceuticals plans a pivotal phase III trial in Stomatitis [76] Updated 01 Nov 2017
07 Aug 2017 Trial Update Cellceutix plans a clinical trial for Atopic dermatitis [83] Updated 08 Aug 2017
07 Aug 2017 Trial Update Innovation Pharmaceuticals completes enrolment in its phase II trial for Stomatitis (Prevention) in USA [83] Updated 08 Aug 2017
13 Jul 2017 Scientific Update Additional efficacy data from a phase II trial in Ulcerative colitis released by Innovation Pharmaceuticals [142] Updated 19 Jul 2017
26 Jun 2017 Trial Update Innovation pharmaceuticals completes a phase II trial in Ulcerative colitis in USA [103] Updated 04 Jul 2017
07 Jun 2017 Company Involvement Cellceutix is now called Innovation Pharmaceuticals Updated 09 Jun 2017
18 May 2017 Trial Update Cellceutix Corporation completes enrolment in its phase II trial for Ulcerative colitis [114] Updated 25 May 2017
27 Mar 2017 Scientific Update Preliminary interim efficacy, pharmacokinetics and adverse events data from a phase II trial in Stomatits released by Cellceutix [85] Updated 04 Apr 2017
08 Mar 2017 Scientific Update Interim efficacy, pharmacokinetics and adverse events data from a phase II proof-of-concept trial in Ulcerative colitis released by Cellceutix [115] Updated 19 Mar 2017
17 Jan 2017 Trial Update Cellceutix completes enrolment in the second cohort in its phase II trial for Ulcerative colitis in USA (Rectal) [107] Updated 23 Jan 2017
07 Dec 2016 Scientific Update Interim adverse events data from a phase II proof-of-concept trial in Ulcerative colitis released by Cellceutix [108] Updated 13 Dec 2016
07 Dec 2016 Trial Update Cellceutix plans clinical trials for hidradenitis suppurativa [108] Updated 13 Dec 2016
07 Dec 2016 Trial Update Cellceutix plans gastroenterological studies for foam and tablet formulations of brilacidin (Cellceutix website) Updated 13 Dec 2016
01 Nov 2016 Phase Change - Preclinical Preclinical trials in Atopic dermatitis in USA (unspecified route) (Cellceutix website) Updated 13 Dec 2016
01 Nov 2016 Phase Change - Preclinical Preclinical trials in Hidradenitis suppurativa in USA (unspecified route) (Cellceutix website) Updated 13 Dec 2016
26 Oct 2016 Phase Change - Preclinical Preclinical trials in Acne in USA (unspecified route) [121] Updated 13 Dec 2016
26 Oct 2016 Trial Update Cellceutix plans clinical trials for Acne [121] Updated 28 Oct 2016
10 Oct 2016 Scientific Update Interim pharmacokinetics and efficacy data from a phase II trial in Ulcerative colitis released by Cellceutix [111] Updated 14 Oct 2016
15 Jun 2016 Phase Change - II Phase-II clinical trials in Ulcerative proctitis in USA (Rectal) [11] [143] Updated 22 Jun 2016
26 Feb 2016 Regulatory Status Cellceutix submits Special Protocol Assessment (SPA) to the US FDA for its planned phase III clinical trial Updated 02 Mar 2016
09 Feb 2016 Regulatory Status Cellceutix announces intention to submit Special Protocol Assessment (SPA) to the US FDA for its planned phase III clinical trial [22] Updated 11 Feb 2016
25 Nov 2015 Regulatory Status Brilacidin receives Fast Track designation for Stomatitis [Topical,Liquid] (Prevention) in USA [77] Updated 29 Nov 2015
15 Sep 2015 Regulatory Status Cellceutix submits Paediatric Study Plan (PSP) to the US FDA for Skin and soft tissue infections [24] Updated 15 Oct 2015
31 Aug 2015 Active Status Review Brilacidin is still in phase-II development for Skin and soft tissue infections in Canada, Russia, Ukraine and USA Updated 31 Aug 2015
20 Jul 2015 Regulatory Status The US FDA recommends advancing the brilacidin programme to phase III development [25] Updated 22 Jul 2015
01 Jun 2015 Phase Change Early research in Hidradenitis suppurativa in USA (unspecified route) Updated 06 Jul 2015
21 Apr 2015 Trial Update Cellceutix plans a phase II trial for Ulcerative colitis in Europe (Topical) [28] Updated 27 May 2015
21 Apr 2015 Trial Update Cellceutix plans a phase III trial for Skin and soft tissue infections in USA [28] Updated 26 May 2015
08 Dec 2014 Trial Update Cellceutix plans to initiate a phase II trial in Stomatitis in USA Updated 14 Mar 2015
08 Dec 2014 Regulatory Status Brilacidin receives Qualified Infectious Disease Product (QIDP) designation from the FDA for Acute bacterial skin and skin structure infections [67] Updated 09 Dec 2014
24 Nov 2014 Licensing Status Cellceutix enters into an agreement with a division of one of the largest US pharmaceutical companies to test brilacidin for the prevention of infection in certain implanted devices [7] Updated 03 Dec 2014
11 Nov 2014 Licensing Status Brilacidin is available for licensing in World as of 11 Nov 2014. http://cellceutix.com/ Updated 13 Nov 2014
23 Oct 2014 Scientific Update Top-line efficacy and adverse events data from a phase IIb trial in Skin and soft tissue infections released by Cellceutix [30] Updated 14 Nov 2014
13 Oct 2014 Regulatory Status US FDA approves IND application for phase II trial of brilacidin in Stomatitis [32] Updated 15 Oct 2014
09 Sep 2014 Regulatory Status Cellceutix files an IND application with the US FDA for Stomatitis [33] Updated 12 Sep 2014
31 Aug 2014 Trial Update Cellceutix completes a phase IIb trial in Skin and soft tissue infections in USA [31] (NCT02052388) Updated 30 Oct 2014
19 Aug 2014 Trial Update Cellceutix completes enrolment in a phase IIb trial for Skin and soft tissue infections in USA (NCT02052388) Updated 21 Aug 2014
14 Aug 2014 Phase Change - II Phase-II clinical trials in Stomatitis (Prevention) in USA (Topical) (NCT02324335) Updated 27 May 2015
14 Jul 2014 Phase Change - Preclinical Preclinical trials in Diabetic foot ulcer in USA (unspecified route) Updated 14 Aug 2014
19 May 2014 Scientific Update Pharmacodynamics data from a preclinical study in Wounds (non-infected) released by Cellceutix [125] Updated 26 May 2014
01 May 2014 Phase Change - Preclinical Preclinical trials in Wounds in USA (unspecified route) Updated 26 May 2014
24 Feb 2014 Scientific Update Pharmacodynamics data from a preclinical trial in Otitis media released by Cellceutix [8] Updated 25 Feb 2014
18 Feb 2014 Phase Change - II Phase-II clinical trials in Skin and soft tissue infections in USA (IV) Updated 19 Feb 2014
01 Jan 2014 Phase Change - Preclinical Preclinical trials in Otitis in USA (Otic) Updated 24 Jan 2014
20 Dec 2013 Regulatory Status Cellceutix applies for orphan drug status for briliacidin for oral mucositis in USA [97] Updated 24 Dec 2013
04 Nov 2013 Phase Change - Preclinical Preclinical trials in Ophthalmic infections in USA (Ophthalmic) Updated 06 Nov 2013
16 Sep 2013 Phase Change - Preclinical Preclinical trials in Ulcerative colitis in USA (Topical) Updated 04 Dec 2014
16 Sep 2013 Phase Change - Preclinical Preclinical trials in Intestinal infections in USA (PO) Updated 06 Nov 2013
04 Sep 2013 Licensing Status Cellceutix acquires brilacidin from PolyMedix [9] Updated 11 Sep 2013
01 Apr 2013 Company Involvement PolyMedix files for Chapter 7 bankruptcy [9] Updated 11 Sep 2013
20 Sep 2012 Company Involvement PolyMedix receives a Phase I grant from the National Cancer Institute for preclinical development of brilacidin in Stomatitis [96] Updated 24 Sep 2012
12 Sep 2012 Scientific Update Pharmacokinetics data from a preclinical study & a phase I trial in Healthy volunteers presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC-2012) [53] Updated 10 Oct 2012
11 Sep 2012 Scientific Update Final efficacy and adverse event data from a phase II trial in acute bacterial Skin and soft tissue infections released by PolyMedix [46] Updated 14 Sep 2012
04 Jun 2012 Scientific Update Pharmacodynamics data from preclinical studies in Stomatitis presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO-2012) [95] Updated 05 Jun 2012
23 Apr 2012 Scientific Update Final efficacy and adverse events data from a phase II trial in Skin and soft tissue infections released by PolyMedix [144] Updated 24 Apr 2012
02 Apr 2012 Scientific Update Antimicrobial data from preclinical trials in Bacterial infections presented at the 21st Annual European Congress of Clinical Microbiology and Infectious Disease (ECCMID-2012) [145] Updated 04 Apr 2012
01 Mar 2012 Trial Update PolyMedix completes its phase II trial for Skin and soft tissue infections in Canada, Russia and Ukraine (NCT01211470) Updated 11 Sep 2013
04 Jan 2012 Trial Update PolyMedix completes enrolment in its phase II trial for Skin and soft tissue infections in Canada, Russia and Ukraine (NCT01211470) Updated 06 Jan 2012
07 Dec 2011 Scientific Update Interim efficacy and adverse events data from a phase II trial in Skin and soft tissue infections released by PolyMedix [146] Updated 08 Dec 2011
20 Sep 2011 Scientific Update Pharmacokinetics & adverse events data from a phase I trial in Healthy volunteers presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC-2011) [52] Updated 27 Sep 2011
12 Sep 2011 Phase Change - II Phase-II clinical trials in Skin and soft tissue infections in Russia (IV) Updated 14 Sep 2011
12 Sep 2011 Phase Change - II Phase-II clinical trials in Skin and soft tissue infections in Ukraine (IV) Updated 14 Sep 2011
19 May 2011 Phase Change - Preclinical Preclinical trials in Stomatitis in USA (Topical) Updated 23 May 2011
10 May 2011 Scientific Update Pharmacokinetics, antimicrobial & adverse events data from two phase I trials in Healthy volunteers presented at the 21st European Congress of Clinical Microbiology and Infectious Diseases and the 27th International Congress of Chemotherapy (ECCMID-ICC-2011) [147] , [55] Updated 17 Jun 2011
28 Apr 2011 Scientific Update Pharmacodynamics data from a preclinical study in Bacterial infections released by PolyMedix [148] Updated 29 Apr 2011
25 Feb 2011 Scientific Update Final adverse events data from a Phase I trial in Healthy volunteers released by PolyMedix [54] Updated 28 Feb 2011
25 Feb 2011 Trial Update PolyMedix completes a phase I dose-escalation trial in Healthy volunteers in USA [54] Updated 28 Feb 2011
11 Nov 2010 Phase Change - I Phase-I clinical trials in Bacterial infections (in volunteers) in USA (IV) Updated 15 Nov 2010
11 Nov 2010 Regulatory Status US FDA approves IND application for brilacidin in Bacterial infections [56] Updated 15 Nov 2010
29 Sep 2010 Phase Change - II Phase-II clinical trials in Skin and soft tissue infections in Canada (IV) Updated 29 Sep 2010
31 Mar 2010 Trial Update PolyMedix completes phase I trials in Bacterial infections Updated 13 Jul 2010
31 Mar 2010 Scientific Update Final adverse events and antimicrobial data from a phase Ib trial in Staphylococcal infections released by PolyMedix [59] Updated 01 Apr 2010
12 Mar 2010 Phase Change - Suspended(Preclinical) Suspended - Preclinical for Intestinal infections in USA (PO) Updated 09 Nov 2010
12 Mar 2010 Phase Change - Suspended(Preclinical) Suspended - Preclinical for Ophthalmic infections in USA (Topical) Updated 09 Nov 2010
12 Mar 2010 Scientific Update Interim safety and antimicrobial data from a phase I trial in Bacterial infections released by PolyMedix [61] Updated 15 Mar 2010
19 Dec 2009 Scientific Update Adverse events and antimicrobial data from a phase I trial in Bacterial infections released by PolyMedix [62] Updated 22 Dec 2009
15 Sep 2009 Scientific Update Pharmacodynamics and pharmacokinetic data from a preclinical trial in Bacterial infections presented at the 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC-2009) [149] , [150] Updated 07 Oct 2009
06 Jun 2009 Trial Update PolyMedix initiates patient dosing in a phase I trial in healthy volunteers in USA Updated 09 Jun 2009
26 May 2009 Trial Update PolyMedix receives regulatory clearance from Health Canada to commence a second phase I clinical trial of brilacidin in healthy volunteers Updated 26 May 2009
11 Dec 2008 Scientific Update Adverse events and pharmacokinetics data from a phase I trial in Healthy volunteers released by PolyMedix [65] Updated 12 Dec 2008
28 Oct 2008 Scientific Update Antimicrobial, adverse events, and pharmacodynamics data from preclinical trials in Bacterial infections presented at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th Annual Meeting of the Infectious Diseases Society of America (ICAAC/IDSA-2008) [151] , [152] Updated 10 Nov 2008
22 Aug 2008 Phase Change - I Phase-I clinical trials in Bacterial infections in Canada (IV) Updated 25 Aug 2008

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  95. PolyMedix Receives Grant From National Cancer Institute to Study Brilacidin for Oral Mucositis

    Media Release
  96. Cellceutix Files Orphan Drug Designation Application for Brilacidin for Oral Mucositis With US FDA.

    Media Release
  97. Innovation Pharmaceuticals Completes Dosing in Phase 1 Trial for New Oral Ulcerative Colitis Drug.

    Media Release
  98. Innovation Pharmaceuticals Announces Dose Escalation.

    Media Release
  99. Innovation Pharmaceuticals: Patient Screening for Phase 1 Trial of Oral Brilacidin in Ulcerative Colitis Program On Track for Early January.

    Media Release
  100. Innovation Pharmaceuticals Provides Update on Clinical Trials and Revenue Potential of Brilacidin in Inflammatory Bowel Diseases.

    Media Release
  101. Innovation Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Trial of Oral Brilacidin in Ulcerative Colitis Program; Topline Results Anticipated Early Q1 2020.

    Media Release
  102. Innovation Pharmaceuticals Completes Treatments in Phase 2 PoC Trial for Induction of Remission in Inflammatory Bowel Disease; Topline Results with Endoscopic Response to Be Presented July 13, 2017.

    Media Release
  103. Cellceutix Releases Favorable Topline Findings as Part of Interim Analysis of Phase 2 Drug Candidate Brilacidin for the Treatment of Inflammatory Bowel Disease.

    Media Release
  104. Cellceutix Phase 2 Brilacidin Trial Progresses to Highest Dose Cohort for the Induction of Remission of Mild-to-Moderate Ulcerative Colitis.

    Media Release
  105. Cellceutixs Brilacidin Demonstrates Promise in Treating Ulcerative Colitis Supported by Endoscopic Assessment, Patient-Reported Outcomes.

    Media Release
  106. Cellceutix Completes Enrollment in Second of Three Planned Cohorts in Phase 2 Clinical Trial of Brilacidin for Inflammatory Bowel Disease.

    Media Release
  107. Cellceutix Phase 2 Trial Dose Escalates in 2nd Cohort for Brilacidin as a Novel Anti-Inflammatory Drug Candidate for Ulcerative Colitis.

    Media Release
  108. Cellceutix Receives Preliminary Approval for Clinical Trial of Brilacidin for Ulcerative Proctitis.

    Media Release
  109. Novocure Presents Interim STELLAR Results at IASLC Suggesting Treatment with Tumor Treating Fields Plus Chemotherapy may Extend Survival of Patients with Mesothelioma.

    Media Release
  110. Cellceutix Phase 2 Trial Initial Data Shows Potential of Brilacidin as a Novel Anti-Inflammatory Drug Candidate for the Induction of Remission of Mild-to-Moderate Ulcerative Colitis.

    Media Release
  111. Cellceutix Receives Update on First Patient Enrolled in Phase 2 Proof-of-Concept Study of Brilacidin for Ulcerative Proctitis.

    Media Release
  112. Phase II study of brilacidin for the treatment of Ulcerative Proctitis/Ulcerative Proctosigmoiditis (UP/UPS)

    ctiprofile
  113. Cellceutix Completes Patient Enrollment of Final Cohort in Phase 2 Trial of Brilacidin for Inflammatory Bowel Disease; Topline Results Anticipated in July.

    Media Release
  114. Cellceutix Releases Preliminary Efficacy and Safety Data in Interim Analysis of First Two Cohorts in Phase 2 Trial of Brilacidin for the Induction of Remission of Mild-to-Moderate Ulcerative Colitis.

    Media Release
  115. Innovation Pharmaceuticals Announces Successful Formulation of Oral Brilacidin Tablets; Upcoming Clinical Trial to Target Delivery to the Colon.

    Media Release
  116. Innovation Pharmaceuticals Provides Scientific Rationale and Clinical Development Perspectives for Brilacidin as a Potential Novel Coronavirus COVID-19 Treatment.

    Media Release
  117. Innovation Pharmaceuticals Submits Material Transfer Agreement to Study Lead Defensin Mimetic Brilacidin for Coronavirus (COVID-19).

    Media Release
  118. U.S. Regional Biocontainment Lab to Begin Testing of Brilacidin Against Coronavirus (COVID-19) Next Week.

    Media Release
  119. Innovation Pharmaceuticals Exploring Lead Defensin Mimetic Drug Candidate Brilacidin as Potential Novel Coronavirus Treatment.

    Media Release
  120. Cellceutix Novel Anti-Inflammatory Phase 2 Drug Candidate Brilacidin Builds Momentum Across Multiple Clinical Indications.

    Media Release
  121. Innovation Pharmaceuticals Brilacidin Franchise Anchored in Three Clinical Indications Oral Mucositis, Inflammatory Bowel Disease and Serious Skin Infections; Expands into Dermatologic Diseases.

    Media Release
  122. Innovation Pharmaceuticals Phase 2b Psoriasis Study On-Track for Completion in December 2017; Company a Sponsor at Upcoming Symposium on Hidradenitis Suppurativa.

    Media Release
  123. Cellceutix to Pursue Significant Conjuctivitis and Kerititis Ocular Markets With Novel Antibiotic Brilacidin.

    Media Release
  124. Cellceutix Plans for Entry in Diabetic Foot Wound and Ulcer Market.

    Media Release
  125. Cellceutix Provides Updates on Clinical Trials and Developments of Its Anti-Cancer, Anti-Psoriasis, and Antibiotic Compounds.

    Media Release
  126. Innovation Pharmaceuticals Secures Up to $10 Million in Additional Financing to Advance Clinical Pipeline.

    Media Release
  127. Cellceutix Enters Into a $30 Million Common Stock Purchase Agreement.

    Media Release
  128. PolyMedix Announces Proposed Public Offering of Common Stock.

    Media Release
  129. PolyMedix Awarded Therapeutic Discovery Credits for Two Lead Programs.

    Media Release
  130. PolyMedix Antibiotic Studies Accepted for Presentation at ICAAC.

    Media Release
  131. PolyMedix Secures $14 Million Credit Facility and Files Shelf Registration Statement.

    Media Release
  132. Innovation Pharmaceuticals Receives New Patent for Compounds for Use in Treatment of Oral Mucositis.

    Media Release
  133. Innovation Pharmaceuticals Receives New Brilacidin Patent, Further Expanding Intellectual Property Estate.

    Media Release
  134. Innovation Pharmaceuticals Expands Brilacidin Patent Portfolio.

    Media Release
  135. Innovation Pharmaceuticals Granted European Patent for Brilacidin in the Prevention of Oral Mucositis.

    Media Release
  136. PolyMedix Receives U.S. Patent Protection for Licensed Computational Methods to Design Antimicrobial Polymers.

    Media Release
  137. PolyMedix Receives Issuance of Patent for Antimicrobial Compounds.

    Media Release
  138. Innovation Pharmaceuticals Plans for Phase 2 Trial of New Treatment for Ulcerative Colitis.

    Media Release
  139. Innovation Pharmaceuticals Brilacidin as a Novel Inhibitor of Phosphodiesterase 4 (PDE4) Supports its Potential to Treat Autoimmune and Inflammatory Diseases; Company Invited to Present at Upcoming Crohns & Colitis Foundation Conference.

    Media Release
  140. Innovation Pharmaceuticals Provides Corporate Update Highlighting Upcoming Milestones and Events.

    Media Release
  141. Innovation Pharmaceuticals Phase 2 PoC Trial for Inflammatory Bowel Disease Achieves Induction of Remission in a Majority of Patients Treated with Brilacidin.

    Media Release
  142. Innovation Pharmaceuticals Announces Clinical Development Plans for Oral Brilacidin for Inflammatory Bowel Disease.

    Media Release
  143. PolyMedix Announces Positive Results From Phase 2 Clinical Trial With PMX-30063 First-in-Class Defensin-Mimetic Antibiotic.

    Media Release
  144. PolyMedix's PMX-30063 First in Class Defensin-Mimetic Antibiotic Demonstrates Activity Against Drug-Resistant Bacterial Pathogens.

    Media Release
  145. PolyMedix Announces Encouraging Interim Results From Multinational Phase 2 Clinical Trial With PMX-30063 Defensin-Mimetic Antibiotic.

    Media Release
  146. Korczak B, McAllister E. A phase 1 trial to evaluate the tolerability, safety and pharmacokinetics of multi-dose intravenous regiments of PMX30063. 21st-ECCMID-27th-ICC-2011 2011; abstr. N/A.

    Available from: URL: http://www.eccmid-icc2011.org
  147. PolyMedix Defensin-Mimetic Antibiotic PMX-30063 Active Against NDM-1 Drug-Resistant Bacteria.

    Media Release
  148. Pulse ME. Efficacy of PMX30063 in Experimental Staphylococcal Skin and Skin Structure Infection Models. 49th-ICAAC 2009; abstr. F1-2013.

    Available from: URL: http://www.icaac.org
  149. Scott R W. Pharmacokinetic-Pharmacodynamic Relationships for PMX30063 in the Mouse Thigh Burden Model. 49th-ICAAC 2009; abstr. F1-2014.

    Available from: URL: http://www.icaac.org
  150. Scott RW, Liu D, Xu Y, Clements D, DeGrado WF. In vitro antimicrobial activities of a novel host defence protein mimetic, PMX30063, against multiple isolates of Saphylococci with defined susceptibility phenotypes. 48-ICAAC-46-IDSA-2008 2008;328 (plus poster) abstr. F1-3993.

    Available from: URL: http://www.icaacidsa2008.org
  151. Scott RW, Korczak B, Clements D, Xu Y, Liu D. In vivo efficacy and safety of a novel host defecse protein mimetic, PMX30063: a candidate IV agent to treat Staphylococcal infections. 48-ICAAC-46-IDSA-2008 2008;328 (plus poster) abstr. F1-3994.

    Available from: URL: http://www.icaacidsa2008.org
  152. Innovation Pharmaceuticals Clinical Trial of Oral Brilacidin in Ulcerative Colitis Program Expected to Commence in December; Top-Line Data in Q1 2020.

    Media Release
  153. Cellceutix Releases Confidence Interval Statistics Showing Clinical Success Rates for Brilacidin in Treatment of ABSSSI.

    Media Release
  154. Innovation Pharmaceuticals Plans for Clinical Trial of Oral Brilacidin for Ulcerative Colitis Program in 4th Quarter 2019.

    Media Release
  155. PolyMedix Presents PMX-30063 Antibiotic Data at the 49th Annual Meeting of the Infectious Disease Society of America.

    Media Release
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