Brilacidin (formerly PMX-30063), an investigational new drug (IND), is a

polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

-based

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

currently in human clinical trials, and represents a new class of antibiotics called host defense protein mimetics, or HDP-mimetics, which are non-

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

synthetic small molecules modeled after

host defense peptides Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for an ...

(HDPs). 158pages HDPs, also called

antimicrobial peptides Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...

, some of which are defensins, are part of the innate immune response and are common to most higher forms of life. Accounts of Chemical Research As brilacidin is modeled after a defensin, it is also called a

defensin mimetic Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct antimicrobial activity, immune sig ...

. Brilacidin is an antibiotic that works by disrupting bacterial

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

s, mimicking defensins that play a role in innate immunity. Several mimics of antimicrobial peptides, both peptides and non-peptides, have been studied, but none have overcome difficulties to reach the market.

Structure and action

Brilacidin, a non-peptide chemical mimic, is an

aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

foldamer In chemistry, a foldamer is a discrete chain molecule (oligomer) that folds into a conformationally ordered state in solution. They are artificial molecules that mimic the ability of proteins, nucleic acids, and polysaccharides to fold into w ...

designed to replicate the amphiphilic properties of antimicrobial peptides while solving the problems encountered by peptide-based

antimicrobials An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...

. Brilacidin, a broad-spectrum antibiotic, has potent

Gram positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

activity and Gram negative coverage, and is highly effective in treating the 'superbug'

methicillin-resistant Staphylococcus aureus Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of ''Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in humans. ...

(MRSA). Brilacidin has low cytotoxicity against mammalian cells while selectively targeting bacteria, directly and rapidly disrupting their membranes, resulting in the bacteria's death. Due to this unique mechanism of action (mimicking the host's natural immune response, proven to be successful in fighting off infections over millions of years of evolution), bacterial

antibiotic resistance Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...

is less likely to develop.

Potential significance

There has not been a new drug approval from a new class of antibiotics since 1987. While six antibiotics have been approved over the last year, they are all adaptations of existing antibiotic classes. None of the recently approved novel antibiotics represent entirely new classes. Novel antibiotics are crucial as antibiotic resistance poses a global health risk. The World Health Organization, warning of a "post-antibiotic era" has stated that antimicrobial resistance (AMR) is a "problem so serious that it threatens the achievements of modern medicine".

History

Leveraging advanced computational bioinformatics, brilacidin and other defensin mimetics were first developed by University of Pennsylvania-based researchers. Their efforts were consolidated, and officially incorporated, in 2002, under the company name PolyMedix. PolyMedix conducted pre-clinical and clinical research with brilacidin through a completed Phase 2a human

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

with positive results. After discontinuing a clinical trial for an unrelated compound PolyMedix filed for Chapter 7 bankruptcy protection on April 1, 2013. Cellceutix acquired the PolyMedix assets and intellectual property, including the licenses and patents for brilacidin and the rest of the HDP-mimetic pipeline, from bankruptcy court which on September 4, 2013 approved Cellceutix's

stalking horse bid A stalking horse offer, agreement, or bid is a bid for a bankrupt firm or its assets that is arranged in advance of an auction to act as an effective reserve bid. The intent is to maximize the value of its assets or avoid low bids, as part of (or be ...

. On June 7, 2017 Cellceutix Announced a Company Name Change to Innovation Pharmaceuticals Inc. On June 9th 2017 the stock ticker name was effectively changed to "IPIX".

Clinical trials

Innovation Pharmaceuticals advanced brilacidin through early stage human clinical trials to a completed Phase 2a proof-of-concept clinical trial. Since acquisition, brilacidin was entered into a Phase 2b clinical trial. Brilacidin was granted the Qualified Infectious Disease Product (QIDP) designation by the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

under the ''Generating Antibiotic Incentives Now Act'' of 2011 (GAIN Act).

Phase 2a clinical trial – ABSSSI

''Initial Treatment for Acute Bacterial Skin Infections (

ABSSSI Skin and skin structure infections (SSSIs), also referred to as skin and soft tissue infections (SSTIs), or acute bacterial skin and skin structure infections (ABSSSIs), are infections of skin and associated soft tissues (such as loose connective ti ...

) Caused by

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'' ''Randomized, Dose Ranging, Active Controlled Efficacy and Safety Evaluation of PMX-30063 As Initial Treatment for Acute Bacterial Skin and Skin Structure Infections (

) Caused by Staphylococcus aureus'' The study started in October 2010 and had a primary completion date of December 2011 for final data collection for the primary outcome measure. Overall, 215 patients were randomized into either one of the three brilacidin arms or the active comparator Daptomycin arm. There were three dosing regimens for brilacidin, a low, medium and high dose administered for three days, and one dosing regimen for Daptomycin administered for seven days. The clinical trial was successful, demonstrating safety and clinical efficacy for all evaluated doses of brilacidin, with three-day brilacidin cure rates of all dosing regimens comparable with seven days of Daptomycin. The results indicated the potential for a shorter brilacidin dosing regimen. Shorter dosing regimens are important as they reduce the risks from

Intravenous therapy Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...

complications, reduce costs such as reduced hospital stays and clinic visits, and can help reduce the emergence of

through a combination of a quick bacterial kill, shorter duration of treatment, and increased patient compliance.

Phase 2b clinical trial – ABSSSI

''Efficacy and Safety Study of Brilacidin to Treat Serious Skin Infections'' The study started February 2014 and announced completed enrollment August 19, 2014. Overall, 215 patients were randomized to one of three dosing regimens of brilacidin (single dose 0.6 mg/kg; single-dose 0.8 mg/kg; 1.2 mg/kg over 3 days) or 7 days of once daily daptomycin. finding that a single dose brilacidin was comparable to 7 days of daptomycin. The primary endpoint was clinical success in the

intent-to-treat In medicine an intention-to-treat (ITT) analysis of the results of a randomized controlled trial is based on the initial treatment assignment and not on the treatment eventually received. ITT analysis is intended to avoid various misleading artifac ...

population, defined as reduction of at least 20% in area of the

lesion, relative to baseline, when observed 48–72 hours after the first dose of study drug, and no rescue antibiotics administered.

Phase 2 clinical trial – oral mucositis

The brilacidin trial for oral mucositis (Briladidin-OM) has started in May 2015 and is expected to be completed in December 2017. Brilacidin-OM is an oral rinse of brilacidin in water. Approximately 60 patients who received

chemoradiation Chemoradiotherapy (CRT, CRTx, CT-RT) is the combination of chemotherapy and radiotherapy to treat cancer. Synonyms include radiochemotherapy (RCT, RCTx, RT-CT) and chemoradiation. It is a type of multimodal cancer therapy. Chemoradiation can be ' ...

for

head and neck cancer Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms ...

were randomized to receive either brilacidin-OM or the placebo three times daily for seven weeks. Various primary and secondary outcome measures were recorded to assess efficacy of brilacidin-OM to prevent or reduce the severity of oral mucositis in patients receiving chemo-radiation.

Phase 2 clinical trial – Covid-19 / SARS-CoV-2

The Brilacidin trial for the treatment of Covid-19 infection has started in February 2021 and is expected to be completed in July 2021. The study is a randomized, blinded, placebo-controlled, parallel group design and will accept 120 patients. The placebo or drug will be administered via IV infusion to patients with moderate to severe COVID-19, SARS-CoV-2 infection confirmed by positive standard polymerase chain reaction test (or equivalent/ other approved diagnostic test) within 4 days prior to starting study treatment, and hospitalized with respiratory distress but not yet requiring high-level respiratory support.

The HDP-mimetic pipeline

Development is ongoing for numerous brilacidin analogs, selected by laboratory testing of the various HDP mimetics and defensin-mimetic compounds in the antibiotic pipeline. Pre-clinical research has been shown select brilacidin analogs effective in killing a variety of important Gram-negative pathogens (the so-called superbugs), such as

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

, Klebsiella pneumoniae,

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

and Acinetobacter baumannii as well as highly multi-drug resistant ndm-1-producing K. pneumoniae. An abstract update on these efforts was presented at the European Congress of Clinical Microbiology and Infectious Disease
ECCMID
2015 annual conference. The footnote links to the full presentation. Other HDP-Mimetic analogs have proven effective ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' against ''C. albicans'' and other ''Candida'' species. Also acquired with brilacidin and the HDP-mimetic pipeline were the rights to the related PolyCide family of compounds, polymeric formulations that function as antimicrobial agents. These compounds are similar to brilacidin in that they are also synthetic mimics of HDPs. These compounds have superior bacterial killing activity over triclosan and silver nitrate, common biocidal agents. PolyCide compounds could be used as additives to paints, plastics, textiles and other materials to create self-sterilizing products and surfaces.

Notes

References

* {{Antibiotics Antibiotics Experimental drugs Trifluoromethyl compounds Guanidines Pyrrolidines Pyrimidines