Wed . 19 Apr 2019

Brilacidin

brilacidin phase 3, brilacidin and colitis
Brilacidin formerly PMX-30063 an investigational new drug IND, is a polymer-based antibiotic currently in human clinical trials and represents a completely new class of antibiotics called host defense protein mimetics, host defense peptide mimetics, or HDP-mimetics, which are non-peptide or peptide synthetic small-molecules modeled after host defense peptides HDP HDP, also called antimicrobial peptides, some of which are defensins, are part of the innate immune response and are common to most higher forms of life As brilacidin is modelled after a defensin, it is also called a defensin mimetic

Brilacidin is thus an antibiotic that works by disrupting bacterial cell membranes, mimicking defensins that play a role in innate immunity Several mimics of antimicrobial peptides have been researched, both peptides and non peptides, but none have overcome difficulties to reach the market

Contents

  • 1 Structure and action
  • 2 Potential significance
  • 3 History
  • 4 Other uses
  • 5 Clinical trials
    • 51 Phase 2a clinical trial – ABSSSI
    • 52 Phase 2b clinical trial – ABSSSI
    • 53 Phase 2 clinical trial – oral mucositis
  • 6 The HDP-mimetic pipeline
  • 7 Notes
  • 8 References

Structure and action

Brilacidin, a non-peptide chemical mimic, is an arylamide foldamer designed to replicate the amphiphilic properties of antimicrobial peptides while solving the problems encountered by peptide-based antimicrobials Brilacidin, a broad-spectrum antibiotic, has potent Gram positive activity and Gram negative coverage, and is highly effective in treating the 'superbug' methicillin-resistant Staphylococcus aureus 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 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 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

Other uses

Cellceutix is pursuing other clinical applications of brilacidin and related anti-infective HDP-mimetic compounds, including their prophylactic use on implanted medical devices, having already entered into a material transfer agreement with a division of a large US pharmaceutical company An active clinical trial, brilacidin for oral mucositis is detailed below In pre-clinical research, a mouthwash formulation of brilacidin was well-tolerated and efficacious for oral mucositis, significantly reducing the number of days with ulcerations and significantly reducing the mucositis scores in a dose dependent manner Pre-clinical research has shown potential for brilacidin for ocular, Otic, and diabetic foot ulcers

Clinical trials

PolyMedix advanced brilacidin through early stage human clinical trials to a completed Phase 2a proof-of-concept clinical trial Since acquisition, brilacidin has to date completed a Phase 2b clinical trial with positive results Results, as detailed below, showed brilacidin compared favorably with Daptomycin, though administered in a single-dose as compared to Daptomycin's 7-day dosing regimen Discussions presently are underway between Cellceutix and the FDA to begin a pivotal Phase 3 trial for ABSSSI Plans and trial design for the Phase 3 clinical trails are expected be made public after the post-P2b clinical trial with the FDA expected in June 2015

Brilacidin was granted the Qualified Infectious Disease Product QIDP designation by the FDA under the Generating Antibiotic Incentives Now Act of 2011 GAIN Act Receiving QIDP designation means that brilacidin is now eligible for additional FDA incentives in the approval and marketing pathway, including fast track designation and priority review for development and a five-year extension of market exclusivity

Phase 2a clinical trial – ABSSSI

Initial Treatment for Acute Bacterial Skin Infections ABSSSI Caused by Staphylococcus aureus Randomized, Dose Ranging, Active Controlled Efficacy and Safety Evaluation of PMX-30063 As Initial Treatment for Acute Bacterial Skin and Skin Structure Infections ABSSSI 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 complications, reduce costs such as reduced hospital stays and clinic visits, and can help reduce the emergence of antibiotic resistance through a combination of a quick bacterial kill, shorter duration of treatment, and increased patient compliance As patients may feel better before treatment is complete and discontinue treatment too early, this is a risk for their health and also the development of antibiotic resistance A single one day dosage eliminates the risk of patient non-compliance

Phase 2b clinical trial – ABSSSI

Efficacy and Safety Study of Brilacidin to Treat Serious Skin Infections A Randomized, Double-Blind Study Comparing Three Dosing Regimens of Brilacidin to daptomycin in the Treatment of Acute Bacterial Skin and Skin Structure Infections ABSSSI

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 06 mg/kg; single-dose 08 mg/kg; 12 mg/kg over 3 days or 7 days of once daily daptomycin

The Clinical Trial had positive results, indicating that single dose brilacidin was comparable to 7 days of daptomycin The primary endpoint was clinical success in the intent-to-treat population, defined as reduction of at least 20% in area of the ABSSSI lesion, relative to baseline, when observed 48–72 hours after the first dose of study drug, and no rescue antibiotics administered All three brilacidin treatment arms two single-dose regimens and one three-day dose regimen had clinical success rates comparable to the clinical success rate of the FDA-approved seven-day dosing regimen of daptomycin All brilacidin treatment regimens were generally well tolerated There were six serious adverse events SAEs reported in the study, none of which were considered related to brilacidin by the principal investigator

The results were also positive in the microbiological intent-to-treat population MITT This is an important population, as it consists of patients enrolled in the trial who had cultures obtained at the baseline visit that were positive for common ABSSSI pathogens Most of these cultures grew Staphylococcus aureus, and approximately 40% of these were MRSA This is currently the most important bacterial pathogen in patients with ABSSSI The P2b clinical trial results were reported for peer review by abstract and oral presentation at the 2015 European Congress of Clinical microbiology and Infectious Diseases

Phase 2 clinical trial – oral mucositis

Phase 2 Study to Evaluate the Safety & Efficacy of Brilacidin Oral Rinse in Patients With Head and Neck Cancer

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 are receiving chemoradiation for head and neck cancer are randomized to receive either brilacidin-OM or the placebo three times daily for seven weeks The study design is double blind Various primary and secondary outcome measures will be recorded to assess efficacy of brilacidin-OM to prevent or reduce the severity of oral mucositis in patients receiving chemo-radiation

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, Klebsiella pneumoniae, Escherichia coli 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 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

  1. ^ a b "Statement on a nonproprietary name adopted by the USAN council" PDF American Medical Association July 25, 2012 
  2. ^ "Fact Sheet" PDF PolyMedix 
  3. ^ Palermo, Edmund Francis 2011 "Antimicrobial Polymers: peptide-mimetic design and mechanism of action" PDF University of Michigan Library 
  4. ^ Palermo, Edmund Francis 2011 "The convergence of peptide and polymer science toward novel antibiotics" PDF University of Michigan Library  158pages
  5. ^ Sgolastra, Dr Frederica "Design and synthesis of biomimetic compounds with pharmacological activity" PDF Universita' Politecnica Delle Marche 
  6. ^ Kuroda, Kenichi; Caputo, Gregory 2013 "Antimicrobial polymers as synthetic mimics of host-defense peptides" Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 5 1: 49–66 doi:101021/bk-2013-1135ch019 
  7. ^ "Designing mimics of membrane active proteins" PDF  Accounts of Chemical Research
  8. ^ "brilacidin formerly PMX-30063" BioCentury BCIQ BioCentury Publications Retrieved 2013-09-19 
  9. ^ Butler, Mark S; Cooper, Matthew A 18 May 2011 "Antibiotics in the clinical pipeline in 2011" The Journal of Antibiotics 64 6: 413–425 doi:101038/ja201144 PMID 21587262 
  10. ^ Pucci, Michael J; Bush, Karen October 2013 "Investigational antimicrobial agents of 2013" Clinical Microbiology Reviews 26 4: 792–821 doi:101128/CMR00033-13 PMC 3811234  PMID 24092856 
  11. ^ "ECCMID poster: brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications" PDF Celleutix 
  12. ^ Steinstraesser, Lars; Et Al 2009 "Host defense peptides as effector molecules of the innate immune response: a sledgehammer for drug resistance" Int J Mol Sci 10 9: 3951–3970 doi:103390/ijms10093951 PMC 2769137  PMID 19865528 
  13. ^ Nijnik, A; Hancock, REW Feb 24, 2009 "Host defence peptides: antimicrobial and immunomodulatory activity and potential applications for tackling antibiotic-resistant infections" Emerging Health Threats 2: e1 doi:103134/ehtj09001 PMC 3167646  PMID 22460279 
  14. ^ Perron, Gabriel; Et Al Jan 22, 2006 "Experimental evolution of resistance to an antimicrobial peptide" Proceedings of the Royal Society B: Biological Sciences 273 1583: 251–256 doi:101098/rspb20053301 PMC 1560030  PMID 16555795 
  15. ^ "Key to antibiotic resistance Is to leave no enemies behind, says expert" Press release PolyMedix 
  16. ^ Theuretzbacher, Ursula "Recent FDA antibiotic approvals: good news and bad news" The Center for Disease Dynamics, Economics & Policy 
  17. ^ Dryden, Mathew S "Novel antibiotic treatment for skin and soft tissue infection" Current Opinion in Infectious Diseases 
  18. ^ WHO "Antimicrobial resistance: global report on surveillance 2014" World Health Organization ISBN 978 92 4 156474 8 
  19. ^ "NewWeapons for the Germ Wars" PSCedu 
  20. ^ Lopez, Carlos F; Et Al May 2006 "Probing Membrane Insertion Activity of Antimicrobial Polymers via Coarse-grain Molecular Dynamics" J Chem Theory Comput 2 3: 649–655 doi:101021/ct050298p PMC 2577386  PMID 18985168 
  21. ^ "Nicholas Landekic Interview" twstcom
  22. ^ "Chemical mimetics of host defense proteins" PDF PolyMedix 
  23. ^ "The Genius Chemist And His Assault On Mutant Killer Bacteria" Forbes Jan 28, 2011 
  24. ^ "Man-made 'defensin' rips resistant bacteria apart" New Scientist 
  25. ^ "PolyMedix announces positive results from phase 2 clinical trial with PMX-30063 first-in-class defensin-mimetic antibiotic" Press release PolyMedix 
  26. ^ "Cellceutix Acquires PolyMedix Assets From Bankruptcy Court, Gains Ownership of Two Clinical Stage Drugs, Multiple Compounds, and Equipment Assets" Press release Cellceutix 
  27. ^ Cellceutix "SEC Form S3 Filing: Cellceutix" 
  28. ^ "December to be momentous month in company's history" Press release Cellceutix 
  29. ^ "ECCMID Poster: Brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications" PDF ECCMID 
  30. ^ "The In Vitro Activity of Three Novel Biomimetics Against Clinically Relevant Ocular Pathogens" 2006 Ocular Microbiology and Immunology Group 
  31. ^ "The in vitro and in vivo antibacterial evaluation of Brilacidin" PDF The Association for Research in Vision and Ophthalmology 
  32. ^ "Brilacidin: Otic" Cellceutix 
  33. ^ "Brilacidin: Diabetic Fool Infections/Ulcers" Cellceutix 
  34. ^ "Brilacidin receives QIDP designation from FDA" Press release Cellceutix 
  35. ^ "S1734 - Generating Antibiotic Incentives Now Act of 2011" 
  36. ^ "ClinicalTrials NCT01211470" ClinicalTrialsgov 
  37. ^ Mensa, B; Howell, GL; DeGrado, WF September 2014 "Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16" Antimicrob Agents Chemother 58 9: 5136–5145 doi:101128/AAC02955-14 PMC 4135847  PMID 24936592 
  38. ^ "PolyMedix Announces Positive Results From Phase 2 Clinical Trial With PMX-30063 First-in-Class Defensin-Mimetic Antibiotic" Press release Globe NewsWire 
  39. ^ Marc Bonten, MD; Eijkman-Winkler Institute for Medical Microbiology, Utrecht, the Netherland | Infectious Diseases, and Inflammation
  40. ^ a b "ClinicalTrials NCT020388" ClinicalTrialsgov 
  41. ^ "ECCMID" ECCMIDorg 
  42. ^ "ECCMID Brilacidin Oral Presentation #O195" eccmidliveorg 
  43. ^ "ECCMID Brilacidin Oral Presentation #O195 Slides" PDF Cellceutix 
  44. ^ a b Clinical trial number NCT02324335 for "Study of the Effects of Brilacidin Oral Rinse on Radiation-induced Oral Mucositis in Patients With Head and Neck Cancer Brilacidin" at ClinicalTrialsgov
  45. ^ "Synthetic novel host defense protein mimetics for the treatment of Gram-negative bacterial infections" European Society of Clinical Microbiology and Infectious Diseases: 2015 
  46. ^ "ECCMID Presentation: Synthetic Novel Host Defense Protein Mimetics for the Treatment of Gram-Negative Bacterial Infections" PDF European Society of Clinical Microbiology and Infectious Diseases 
  47. ^ "In Vitro activity of novel biomimetic compounds against oral Candida strains" PDF New Jersey Dental School 
  48. ^ "Synthetic polymer mimics antimicrobial properties of host-defense proteins" Qmed 
  49. ^ "Plastics Engineering" February 15, 2011 
  50. ^ "Data showing effectiveness of PolyCide antimicrobial in surgical suture coatings published in American Chemical Society Journal, Langmuir" Press release Globe NewsWire 

References

  • "PolyMedix Receives USAN Approval for Generic Name of Brilacidin for PMX-30063" Globe NewsWire June 12, 2012 Retrieved 2013-09-19 

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