Two scientific review articles – "The Road from Host-Defense Peptides to a New Generation of Antibiotics" (Feb 2018) and “Membrane Active Antimicrobial Peptides: Translating Mechanistic Insights to Design” (Feb 2017) -- recently were published. Both articles summarize the therapeutic potential of various drugs in development, which leverage the biophysical properties of Antimicrobial Peptides (AMPs)/Host-Defense Proteins (or Peptides) (HDPs) (see the embedded video below).
Brilacidin (PMX-30063), the Company’s novel defensin-mimetic drug candidate benefiting from multiple immunomodulatory properties -- and a successful example of de novo drug design first pioneered by Dr. William DeGrado and colleagues -- is referenced in these reviews.
Nonpepeptidic mimetic drugs, such as Brilacidin, are considered especially attractive antibiotic candidates given favorable characteristics, including being: (i) highly selective (potent against target while leaving host cells unaffected); (ii) not prone to resistance mechanisms; (iii) relatively easy to produce at low costs; (iv) and stable during storage or upon administration.
Given its broad therapeutic profile, Brilacidin is being developed not only to treat serious skin infections, but also oral mucositis and inflammatory bowel disease, with planned extension as topical agent into dermatologic diseases.
Unique Antibacterial Properties of Defensins
Mechanistically, as to bacterial invasion, defensins -- upon which Brilacidin is modeled as a mimic of (pdf) -- are thought to target the structural plasticity/thermodynamic instability of invading toxins, thus increasing their susceptibility to proteolysis and degradation (for more information on this process, refer to this commentary and corresponding study).
Intra-cellular mechanisms, beyond just their membrane-lytic properties -- a distinctive “capacity for acting on multiple targets, at low dose, and by means of a variety of mechanisms” -- may also play (pdf) an important role in contributing to the overall antibacterial efficacy of AMP-based therapies (recent developments), such as Brilacidin via a “multiple-hit model” (pdf).
The Need for Newer and Better Antibiotics
As noted above, Brilacidin, as well as other similar AMP mimics or analogs -- given their broad “functional promiscuity” and “the increasing evidence” of their beneficial applications -- are being advanced (pdf) (and further optimized) as promising infectious disease agents in a world that is in need of newer and better antimicrobial drugs, toward Stopping the Superbugs.
A 2018 World Health Organization report reveals widespread antibiotic resistance among an estimated 500,000 people worldwide.
Regulatory agencies, as well as not-for-profit initiatives, such as Access to Medicine Foundation (see the Antimicrobial Resistance Benchmark project), and CARB-X, also have started to work collaboratively, proposing incentives to spur development, to get more antibiotics to market. Interest in phage therapy is experiencing a resurgence, though this anti-infective approach faces unique regulatory hurdles. Synthetic versions of Teixobactin, a small molecule antibiotic active against gram-positive bacteria, are being studied, if still years away from testing in humans.
Brilacidin-ABSSSI
Innovation Pharmaceuticals has successfully completed a Phase 2b trial of Brilacidin for Acute Bacterial Skin and Skin Structure Infection (ABSSSI). Delivered in a single intravenous dose, it performed comparably to a seven-day dose of Daptomycin (see ECCMID 2015 presentation: audio; slide deck, pdf), which generated over $1 billion in sales for both 2015 and 2016. In the United States, Brilacidin has received Qualified Infectious Disease Product (QIDP) designation from the FDA, which qualifies it both for Fast Track and Priority Review, as well as exclusivity provisions, pending approval.
“The host-defence peptides have been identified as some of the most important leads for the next generation of antibiotics as they typically exhibit broad spectrum antimicrobial ability, low toxicity toward human cells and little susceptibility to currently known mechanisms of bacterial resistance. ”
“Brilacidin, Host Defense Peptide Mimetic, One of a New Class of Immunomodulatory Agents That Can Target Multiple Disease Indications” (ECCMID 2015) (pdf)
Source: “A Randomized, Double-Blind Study Comparing Single-Dose and Short-Course Brilacidin to Daptomycin in the Treatment of Acute Bacterial Skin & Skin Structure Infections”
(ECCMID 2015)
Source: “Chemical Mimetics of Host Defense Proteins” (ICAAC 2011; Company Presentation, 2012) (PDF); note: PMX-30063 is the former name assigned to Brilacidin.