Brilacidin

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Brilacidin-.png
Systematic (IUPAC) name
N,N'-bis[3-{[5-(carbamimidoylamino)pentanoyl]amino}-2-[(3R)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)phenyl]pyrimidine-4,6-dicarboxamide[1]
Clinical data
Trade names None as of July 2012[1]
Identifiers
CAS Registry Number 1224095-98-0
ATC code None
PubChem CID: 25023695
ChemSpider 28651526
ChEMBL CHEMBL2219413
Chemical data
Formula C40H50F6N14O6
Molecular mass 936.9 g/mol

Brilacidin (formerly PMX-30063[2]) 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 synthetic small-molecules modeled after host defense peptides (HDP).[3][4][5] 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.[6][7] 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.[8][9] Several mimics of antimicrobial peptides have been researched, both peptides and non peptides, but none have overcome difficulties to reach the market. 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.[10] Brilacidin, a broad-spectrum antibiotic, has potent Gram positive activity and Gram negative coverage,[11] and is highly effective in treating the 'superbug' methicillin-resistant Staphylococcus aureus (MRSA). Brilacidin has low cytotoxicity against mammalian cells 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.[12][13][14][15]

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.[16] None of the recently approved novel antibiotics represent entirely new classes.[17] Novel antibiotics are crucial as antibiotic resistance is 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".[18]

History[edit]

Leveraging advanced computational bioinformatics,[19][20][21] Brilacidin and other defensin-mimetics[22] were first developed by University of Pennsylvania-based researchers.[23][24] Their efforts were consolidated, and officially incorporated, in 2002, under the company name PolyMedix. Nicholas Landekic was appointed the company's Chief Executive Officer.

Scientists who performed pre-clinical work[25][26] for PolyMedix included: William DeGrado, a National Academy of Sciences member now at the University of California, San Francisco, and recipient of The American Peptide Society's 2008 Ralph F. Hirschmann Award and The Protein Society's 2015 Stein and Moore Award.;[27][28] Michael Klein, a National Academy of Sciences member now at Temple University, and current head of the Institute for Computational Molecular Science; Richard Scott, now Vice President of Research at Fox Chase Chemical Diversity Center;[29] Gregory Tew, now Professor of Polymer Science and Engineering at the University of Massachusetts Amherst,[30] and Kenichi Kuroda, now Professor of Biologic & Material Sciences at the University of Michigan.[31]

PolyMedix conducted pre-clinical and clinical research with Brilacidin through a completed Phase 2a human clinical trial with positive results.[32] 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.[33][34]

Other uses[edit]

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 U.S. pharmaceutical company.[35] 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.[36] Pre-clinical research has shown potential for Brilacidin for ocular,[37][38] Otic,[39] and diabetic foot ulcers.[40]

Clinical trials[edit]

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 trail(s) are expected be made public after the post-P2b clinical trial with the FDA expected in June of 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).[41] 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.[42]


Phase 2a clinical trial - ABSSSI[edit]

Initial Treatment for Acute Bacterial Skin Infections (ABSSSI) Caused by Staphylococcus Aureus[43] 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 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.[44]

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.[45] 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,[46] 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[edit]

Efficacy and Safety Study of Brilacidin to Treat Serious Skin Infections[47] 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 0.6 mg/kg; single-dose 0.8 mg/kg; 1.2 mg/kg over 3 days) or 7 days of once daily daptomycin.[48]

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 [49] [50][51]

Phase 2 clinical trial - oral mucositis[edit]

Phase 2 Study to Evaluate the Safety & Efficacy of Brilacidin Oral Rinse in Patients With Head and Neck Cancer[52]

The Brilacidin trial for oral mucositis (Briladidin-OM) is active and recruiting patients. Brilacidin-OM is an oral rinse of Brilacidin in water. A placebo comparator will be used. Approximately 60 patients receiving chemoradiation for head and neck cancer will be enrolled, and randomized to receive either Brilacidin-OM or the placebo comparator 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 chemoradiation.

The HDP-mimetic pipeline[edit]

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.[53] 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.[54] Other HDP-Mimetic analogs have proven effective In Vitro against C. Albicans and other candida species.[55]

Also acquired with Brilacidin and the HDP-mimetic pipeline where 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.[56][57][58]

Notes[edit]

  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. 
  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:10.1021/bk-2013-1135.ch019. 
  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:10.1038/ja.2011.44. PMID 21587262. 
  10. ^ Pucci, Michael J; Bush, Karen (October 2013). "Investigational antimicrobial agents of 2013". Clinical Microbiology Reviews 26 (4): 792–821. doi:10.1128/CMR.00033-13. PMC 3811234. 
  11. ^ "ECCMID poster: brilacidin, host defence peptide mimetic, on 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:10.3390/ijms10093951. 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 10 (9): 3951–3970. doi:10.3134/ehtj.09.001. PMC 3167646. 
  14. ^ Perron, Gabriel; Et. Al. (Jan 22, 2006). "Experimental evolution of resistance to an antimicrobial peptide". Proceedings of the Royal Society Biological Sciences 273 (1583): 251–256. doi:10.1098/rspb.2005.3301. 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". PSC.edu. 
  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:10.1021/ct050298p. PMC 2577386. PMID 18985168. 
  21. ^ "Nicholas Landekic Interview". twst.com
  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". NewScientist. 
  25. ^ Tew, Gregory N.; Richard W. Scott; Michael L. Klein; William F. Degrado (Jan 19, 2010). "De Novo Design of Antimicrobial Polymers, Foldamers, and Small Molecules: From Discovery to Practical Applications". Acc Chem Res 43 (1): 30–39. doi:10.1021/ar900036b. PMC 2808429. PMID 19813703. 
  26. ^ Kuroda, Kenichi N.; William F. Degrado (March 3, 2005). "Amphilic Polymethacrylate Derivatives as Antimicrobial Agents". Journal of the American Chemical Society 127 (12): 4128–4129. doi:10.1021/ja044205. PMID 15783168. 
  27. ^ "American Chemical Society Awards". The American Peptide Society. 
  28. ^ "The Stein And Moore Award". The Protein Society. 
  29. ^ "FCCDC Leadership". Fox Chase Chemical Diversity Center. 
  30. ^ "Tew Research Group". University of Massachuusetts Amherst. 
  31. ^ "Kuroda Lab". University of Michigan School of Dentistry. 
  32. ^ "PolyMedix announces positive results from phase 2 clinical trial with PMX-30063 first-in-class defensin-mimetic antibiotic" (Press release). PolyMedix. 
  33. ^ "Cellceutix Acquires PolyMedix Assets From Bankruptcy Court, Gains Ownership of Two Clinical Stage Drugs, Multiple Compounds, and Equipment Assets" (Press release). Cellceutix. 
  34. ^ Cellceutix. "SEC Form S3 Filing: Cellceutix". 
  35. ^ "December to be momentous month in company's history" (Press release). Cellceutix. 
  36. ^ "ECCMID Poster: Brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications" (PDF). ECCMID. 
  37. ^ "The In Vitro Activity of Three Novel Biomimetics Against Clinically Relevant Ocular Pathogens". 2006 Ocular Microbiology and Immunology Group. 
  38. ^ "The in vitro and in vivo antibacterial evaluation of Brilacidin" (PDF). The Association for Research in Vision and Opthalmology. 
  39. ^ "Brilacidin: Otic". Cellceutix. 
  40. ^ "Brilacidin: Diabetic Fool Infections/Ulcers". Cellceutix. 
  41. ^ "Brilacidin receives QIDP designation from FDA" (Press release). Cellceutix. 
  42. ^ "S.1734 - Generating Antibiotic Incentives Now Act of 2011". 
  43. ^ "ClinicalTrials NCT01211470". ClinicalTrials.gov. 
  44. ^ 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:10.1128/AAC.02955-14. PMC 4135847. PMID 24936592. 
  45. ^ "PolyMedix Announces Positive Results From Phase 2 Clinical Trial With PMX-30063 First-in-Class Defensin-Mimetic Antibiotic" (Press release). Globe NewsWire. 
  46. ^ Marc Bonten, MD; Eijkman-Winkler Institute for Medical Microbiology, Utrecht, the Netherland | Infectious Diseases, and Inflammation
  47. ^ "ClinicalTrials NCT020388". ClinicalTrials.gov. 
  48. ^ "ClinicalTrials NCT020388". ClinicalTrials.gov. 
  49. ^ "ECCMID". ECCMID.org. 
  50. ^ "ECCMID Brilacidin Oral Presentation #O195". eccmidlive.org. 
  51. ^ "ECCMID Brilacidin Oral Presentation #O195 Slides" (PDF). Cellceutix. 
  52. ^ "ClinicalTrials NCT02324335". ClinicalTrials.gov. 
  53. ^ "Synthetic novel host defense protein mimetics for the treatment of Gram-negative bacterial infections". European Society of Clinical Microbiology and Infectious Diseases: 2015. 
  54. ^ "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. 
  55. ^ "In Vitro activity of novel biomimetic compounds against oral Candida strains" (PDF). New Jersey Dental School. 
  56. ^ "Synthetic polymer mimics antimicrobial properties of host-defense proteins". Qmed. 
  57. ^ "Plastics Engineering". February 15, 2011. 
  58. ^ "Data showing effectiveness of PolyCide antimicrobial in surgical suture coatings published in American Chemical Society Journal, Langmuir" (Press release). Globe NewsWire. 

References[edit]