Antimicrobial resistance (AMR) is a topic that just won’t go away, and for good reason. Despite the plethora of threats facing humankind, including thousands of diseases in need of therapies or cures, many scientists worry that the biggest risk of extinction comes from the deadly pathogens that exist in uneasy cohabitation on planet Earth. Tensions mounted in 2015 after the mcr-1 gene was detected on plasmids in China and Europe and were heightened last year with the first U.S. case of a patient with an infection resistant to a last-resort antibiotic.
As BioWorld’s Superbug series pointed out last year, plenty of bugs that are not completely drug-resistant are nevertheless resistant enough to kill the individuals they infect. According to the CDC, 23,000 people in the U.S. die of drug-resistant infections each year. (See BioWorld Today, June 21, 2016.)
“The number of deaths [from AMR pathogens] in the U.S. each year is equivalent to a jumbo jet crashing each week, yet we haven’t done anything new in 40 years,” Ankit Mahadevia, president and CEO of Spero Therapeutics LLC, told BioWorld Insight. “I can’t find another societal issue where jumbo jets full of people are dying every week but we’re doing the same thing we were doing 40 years ago.”
Four-year-old Spero, of Cambridge, Mass., attracted an oversubscribed $51.7 million series C preferred financing in early March to advance its pipeline of antibacterial assets, including lead candidate SPR741, an outer membrane protein modulator thought to increase the spectrum and potency of more than two dozen classes of gram-positive antibiotics. That program is in the midst of a double-blind, placebo-controlled, ascending-dose, multicohort phase I trial to evaluate safety, tolerability and pharmacokinetics. (See BioWorld Today, March 9, 2017.)
In the Review on Antimicrobial Resistance, also known as the O’Neill report, commissioned by the U.K. Government and the Wellcome Trust and published in May 2016, the authors estimated that by 2050, antimicrobial resistance, which currently accounts for 700,000 deaths annually across the globe, could reach 10 million deaths a year. At that rate, AMR-related infections would easily outstrip heart disease, currently the leading cause of death, accounting for 7.4 million deaths in 2012, according to the World Health Organization. (See BioWorld Today, June 9, 2016.)
‘viable marketplace’ for differentiated antimicrobials
It’s no secret that government agencies and not-for-profits have been largely responsible over the past several decades for pushing antibiotics forward by underwriting the cost of early stage research and helping to fund pipeline development. A lack of commercial, or pull, incentives in antibiotics severely dampened the appetite of big pharma to nurture or acquire such candidates. Setbacks in the field, such as the FDA’s complete response letter on solithromycin (Cempra Inc.) late last year along with its request for a large pre-approval safety study, continue to spook the sector. (See BioWorld Today, Dec. 30, 2016.)
But the industry’s appetite for agents that address AMR infections may be changing. Academics are hard at work, and more small companies are moving into the space. Although innovation isn’t a term necessarily associated with antimicrobials, more than 70 assets targeting serious bacterial infections have moved into the clinic, according to Cortellis Clinical Intelligence, including nontraditional approaches such as monoclonal antibodies, lysins and vaccines. (See BioWorld Today, June 22, 2016.)
“There’s evidence in the commercial landscape that drugs that have a differentiated bacteriological spectrum and profile do have viable marketplaces,” Mahadevia said.
Antimicrobial peptides (AMPs) – cationic AMPs, in particular – are among the newest kids on the block. Molecules that are known to disrupt cellular membranes of living organisms, AMPs have shown the ability to kill gram-negative and gram-positive bacteria, enveloped viruses, fungi and even cancerous cells. AMPs also offer the prospect of enhancing immunity by functioning as immunomodulators.
The field of AMPs generally is traced to a pioneering report in Nature 35 years ago by Hans Boman and colleagues about the discovery of cecropins, according to academic organizers of the 2017 Antimicrobial Peptides Gordon Research Conference (GRC), held in March in Ventura, Calif. That simple study revealed that an insect challenged by a pathogen protects its inner workings by expounding high concentrations of AMPs. The first GRC on AMPs was held in 1997, with the gathering of scientists in the field held biannually ever since.
In the ensuing 20 years, AMPs have been shown to be widely expressed in plants and animals and have been studied in states of human health and disease. The five-day AMP GRC examined topics such as the design and characterization of cationic AMPs, their interaction with target and host cells, their development to address drug-resistant bacteria and biofilms, their synergism with antimicrobial lipids, their combination with conventional antibiotics to combat multi-drug resistant pathogens and their regulation in developing anti-infectious drugs.
Academics ‘working at the very front end’ of AMPs
The use of cationic, or positively charged, AMPs to tackle AMRs remains in its infancy, but interest is growing quickly.
“A lot of academic groups are working at the very front end of this,” said Deborah O’Neil, CEO and scientific officer of Novabiotics Ltd. “It’s probably a little bit of shutting the stable door after the horse has bolted, but interest now in antimicrobial resistance has led groups to refresh their interest in AMPs as a potential new solution to this issue. There’s been interest in key meetings in the space, and a lot of companies are working on antimicrobial peptides.”
Writing last year in Frontiers in Cellular and Infection Microbiology, Margit Mahlapuu, chief scientific officer at Promore Pharma AB, and academic collaborators explained that, in nature, AMPs are produced either by ribosomal translation of mRNA or by nonribosomal peptide synthesis. While nonribosomally synthesized peptides are mainly produced by bacteria, ribosomally synthesized AMPs are genetically encoded and produced by all species of life, including bacteria. Compared to peptides of nonribosomal origin that have been known for several decades, with many – such as polymyxins and gramicidin – used as antibiotics, ribosomally synthesized AMPs were more recently recognized for their role in innate immunity and for their therapeutic potential.
Nearly 30 AMPs, most at the preclinical or discovery stage, are in the pipeline, according to Cortellis Competitive Intelligence, targeting a variety of infections, wound healing and inflammatory disease. Many remain in the confines of academic institutions but a few have moved into companies.
One of those is LL37, a cathelicidin antimicrobial peptide stimulator that was advanced by Lipopeptide AB prior to its merger with Pergamum AB to form Promore, located in the Karolinska Institutet Science Park in Solna, Sweden. LL37, in development to treat venous leg ulcers, completed a phase I/II trial.
Promore’s lead program, PLX01, is a lactoferrin peptide with anti-inflammatory and antimicrobial properties that is being advanced to treat post-surgical adhesion and prevent scar formation. The company also has PXL181, a discovery-stage AMP candidate to treat uncomplicated skin and skin structure infections that has shown low potential to induce resistance while suggesting effectiveness in targeting methicillin-resistant Staphylococcus aureus (MRSA) infections. Those attributes also offer potential use for long-term treatment in additional indications such as secondary eczema infections.
‘What has nature taught us?’
Many AMPs display direct and rapid antimicrobial activity by causing disruption of the physical integrity of the microbial membrane and/or by translocating across the membrane into the cytoplasm of bacteria to act on intracellular targets, according to Mahlapuu and colleagues in their Frontiers paper. Membrane interaction, in fact, is a key factor for the direct antimicrobial activity of AMPs, both when the membrane itself is the target and when an intracellular target must be reached by means of translocation. Moreover, electrostatic forces between the positively charged cationic AMPs and the negatively charged bacterial surface are critical determinants for that interaction.
Novabiotics is seeking to exploit that relationship. The company is advancing a handful of antimicrobial agents that use new mechanisms of action to address AMR. Among those are cationic AMPs generated from the company’s in-house platform technology and in-licensed small molecules and compounds with proven safety profiles.
“My background and approach to tackling infection is very much as an immunologist from the host side,” O’Neil explained. “Rather than develop synthetic antimicrobials as a microbiologist, the Novabiotics approach is to look at what the host is doing. What has nature taught us?”
The best solutions to treating infection are mechanisms that mitigate the development of resistance, she maintained, and that perspective underpins the company’s approach.
Following an academic career, O’Neil founded Novabiotics in 2004 and had a ringside seat when scientists began to explore the regulation and mechanism of AMPs.
“From there, we thought if you were going to look at a blueprint for a new type of rapidly acting microbial killer – not just inhibiting molecules – this would be a great place to start,” she told BioWorld Insight.
Academics and other newcos in the field were equally excited about AMPs, but development threatened to outpace invention when some tried to “run before we could walk,” O’Neil recalled, “without realizing how complex the natural forms of these things were and understanding that they had other jobs in the body, not just as antimicrobials.”
Novabiotics reengineered the natural peptides and identified the core components of their essential antimicrobial activity to produce simpler versions – O’Neil called them “fourth cousins” – of the natural forms.
“They’re close enough to have the common mechanism of action but far enough removed to be new chemical entities in their own way,” she said.
Moving down regulatory, development pathways
Novabiotics is unusual in another respect: the Aberdeen, U.K.-based company is applying the use of broad-spectrum cationic AMPs both as antimicrobials and antifungals. The company’s most advanced asset, Novexatin (NP213), is a cationic antifungal AMP formulated as a brush-on-treatment for onychomycosis, commonly known as fungal nail infection. The company completed phase I and IIa studies showing that NP213 was safe, well-tolerated and clinically effective in resolving toenail infections following one month of daily application, compared to currently available topical treatments that require up to one year of treatment.
In 2013, the company inked an exclusive global licensing agreement with Taro Pharmaceuticals North America Inc., a unit of Taro Pharmaceutical Industries Ltd., of Haifa, Israel, for Novexatin’s co-development, manufacturing and marketing. (See BioWorld Today, Sept. 9, 2013.)
Novexatin is in a U.S. multicenter phase IIb study for mild to moderate onychomycosis that is expected to enroll approximately 180 participants, with data due to report this year, according to Cortellis Clinical Trials Intelligence.
Next in line is Lynovex (mercaptamine, NM001), a candidate to treat cystic fibrosis (CF)-associated lung disease through breakdown of excessive mucus produced by the lining of the airways in patients, killing of the bacteria responsible for the recurrent respiratory infections and disrupting the biofilms in which they colonize. Lynovex, designed to kill both gram-negative and gram-positive respiratory bacteria associated with CF infections and colonization, also enhances the activity of standard of care antibiotics used by CF patients, with its initial use intended alongside existing therapies to treat all disease genotypes.
Novabiotics is developing an oral formulation of Lynovex for CF exacerbations and an inhaled version for chronic CF therapy. The first phase of the global, pre-registration phase IIa CARE-CF program for oral Lynovex in acute infectious CF exacerbations is underway, with plans to recruit 100 patients at centers in the U.S., U.K. and Italy, according to Cortellis. The company plans to initiate a proof-of-concept study for inhaled Lynovex later this year or in 2018.
“We have gone a long way down the regulatory and development pathway with these molecules,” O’Neil said.
The company also is advancing the preclinical assets Nylexa (mercaptamine, NM002), an antibiotic potentiator derived from the same aminothiol platform as Lynovex, as a parenteral adjunct to extend the therapeutic activity of existing antibiotic classes; Novamycin (NP339), a poly-arginine-based cationic antifungal AMP for front-line treatment of deep-tissue yeast and mold infections, particularly those caused by Aspergillus and Candida; and Novarifyn (NP432), an antibacterial AMP active against a broad swath of resistant pathogens, including MRSA, Pseudomonas aeruginosa, Clostridium difficile, Acinetobacter baumannii and Escherichia coli.
‘We need multiple shots on goal’
Naturally, AMPs come with their own set of challenges.
“The struggle that folks have had with AMPs generally is how to separate the microbiological effect from the toxicological effect,” Spero’s Mahadevia pointed out, noting that selectivity is a key element of his company’s Potentiator platform. “If you are able to destroy bacteria, it’s really important that you don’t destroy human cells. The way that AMPs have traditionally worked, they can’t really make that distinction.”
O’Neil is keenly aware of potential issues.
“The challenge is to get your clinical development path right, get your [chemistry, manufacturing and control] absolutely error-free and, in terms of systemic use, get the formulation right – for cationic peptides, in particular,” she said. “These are highly charged molecules, with lots of lovely sticky components, so it’s essential to get the relevant drug concentrations right.”
The cationic AMPs developed by Novabiotics have “placebo-like safety profiles,” she said, in part because the time to kill is significantly faster than with traditional small-molecule antimicrobials, limiting systemic uptake. Some cationic AMPs also work effectively to kill static, non-metabolically active cells, which makes them attractive candidates to address biofilms, which O’Neil cited as factors in roughly 60 percent of infections.
The regulatory pathway for AMPs also is becoming clearer and more standardized in the U.S., Europe and elsewhere, she said, opening clear opportunities for additional innovation.
“I think there will be more spinouts, and it’s essential to encourage the academic field to continue, as well,” O’Neil said. “We need multiple shots on goal.”
With a global focus on the AMR threat, “it feels as if the time has come for antimicrobial peptides,” she added. “A lot more interest is certainly there. The commercial sector is waking up to this, and big pharma is now looking this way, as well, desperate to refill their pipelines with truly novel solutions.”
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