With the specter of antimicrobial resistance (AMR) posing a serious threat to global health systems, discovery of new antibiotics has become paramount in order to replenish the sparse medicine chest caused by a slowing of research and development in the field that began in the 1970s and persisted for almost 30 years. As a consequence, it is recognized that we now have to play serious "catch-up" and accelerate innovation to not only discover new and effective antibiotics but ensure that the regulatory pathway to the patient is shortened considerably as we do not have the luxury of waiting the average product development cycle of 10 to 15 years for those much-needed antibiotics hit the market.

That was the backdrop for a workshop that focused on anti-infectives and innovation for AMR held at the BIO 2016 International Convention in San Francisco. The session examined ongoing initiatives designed to encourage the development of new antibiotic medicines and featured 10 emerging companies who briefly outlined their research strategies designed to overcome AMR and the candidate molecules that they are advancing toward the clinic.

The event was organized by the Innovative Medicines Initiative (IMI), The Wellcome Trust-funded Community for Open Antimicrobial Drug Discovery (CO-ADD) and the IMI-funded ENABLE (European Gram Negative AntiBacterial Engine) project.

The overarching message delivered by representatives from those three organizations to the more than 200 event attendees was that it will take a massive collaborative effort from researchers around the world to uncover new, diverse compounds to combat drug-resistant infections.

Pierre Meulien, executive director at IMI, the multibillion-euro public-private partnership involving the European Commission and the pharmaceutical industry, said the goal is to address the inefficiencies and challenges in current drug development by creating a neutral platform where all participants from patients, researchers, industry and regulators can engage in open collaboration on shared problems.

Meulien summarized the 10-year "New Drugs for Bad Bugs" effort established in 2012 and designed to address bottlenecks in the drug development process. (See BioWorld Today, May 30, 2012.)

The program is addressing several scientific and business challenges, including the Drive-AB initiative that is looking at new business models that need to be created to keep stakeholders engaged and willing to invest in antibiotics research.

There is no doubt that support for early stage programs from academia and SMEs is vital going forward, he noted.

Matt Cooper, of the Institute for Molecular Bioscience at the University of Queensland, described the university's not-for-profit CO-ADD program to screen compounds for antimicrobial activity for academic research groups at no cost against a key panel of susceptible and drug-resistant bacterial and fungal pathogens.

It is a global effort looking for new chemical diversity to solve the emerging AMR crisis, Cooper said.

Currently, there are 150 participating groups from 33 countries that have submitted approximately 106,000 compounds, with 48,000 screened so far.

In the primary screening, compounds are tested against key ESKAPE pathogens. Active compounds then go on to be tested in dose response antimicrobial assays to confirm their activity. The program makes no claims on results or IP and participants will have two years to publish or patent positive hits. The data will then be made available in an open access database for use by the community.

Early stage discovery

Major global initiatives such as those are also helping smaller companies in their early stage discovery efforts. There is no doubt that the early stage product development pipeline needs to be full in order to meet the expected future needs for treatments of serious infectious diseases. In addition to the approximately 46 antibiotic products currently in mid- to late-stage development, there is a growing body of research in that field being conducted by newly formed, small biopharmaceutical companies who are engaged in developing next-generation antibiotics and also uncovering potential nontraditional approaches, such as microbiome modulators, lysins and monoclonal antibodies. (See BioWorld Today, June 22, 2016.)

The goal of the participating companies at the session is to identify promising lead molecules and move them into preclinical testing over the next few years.

Labège, France-based Antabio SAS, for example, has developed a portfolio of first-in-class programs targeting high unmet needs in the antibacterial space. In 2013, it received a €4.7 million (US$5.2 million) Wellcome Trust Seeding Drug Discovery Award to fund the discovery of a safe and efficacious inhibitor of bacterial metallo beta-lactamases (MBLs) from leads to preclinical candidate nomination.

In March, the company reported that it had achieved two milestones in its collaborations with the Wellcome Trust. The MBLi program is targeting gram-negative bacteria, which account for most hospital infections worldwide. Current antibacterial chemotherapy, the company said, is increasingly inadequate due to the rise of clinical resistance, mainly related to the spread of genes encoding various carbapenemases, including the MBL enzymes of the NDM and VIM types, for which no inhibitors are currently available or under clinical development. Antabio said it has identified a highly active in vivo lead series with drug-like features and MBL coverage against clinical isolates including NDM variants. It is expected that a preclinical development candidate will be nominated by the first quarter of next year.

A second PBi program with the Wellcome Trust is focused on small-molecule drugs for the treatment of chronic Pseudomonas infections in cystic fibrosis (CF) patients. The company has identified a potent and selective in vitro lead series and its goal is to have a preclinical candidate selected by 2018.

Bioversys AG, of Basel, Switzerland, is deploying its transcriptional regulator inhibitory compounds (TRIC) technology to screen, identify and develop molecules that switch off bacterial resistance mechanisms. A lead series has already exhibited excellent characteristics in rendering multi-resistant Mycobacterium tuberculosis sensitive again to the classical antibiotic prodrug ethionamide. The company said it is expanding its screening and compound portfolio to nosocomial bacterial strains (e.g. Pseudomonas aeruginosa, Enterococcus faecium or Acinetobacter baumannii).

Precision microbiome engineering company Epibiome Inc., of South San Francisco, has a bacteriophage-based therapy, which it believes represents a natural and effective alternative to stem the overuse of antibiotics in agriculture, which may be contributing to the rise in antibiotic-resistant bacterial infections in humans. Its mission is to develop effective and sustainable FDA-approved therapies to combat infectious disease in humans and in agriculture without the use of small-molecule antibiotics. The company recently completed a $6 million series A financing.

The first product will address bovine mastitis, an inflammation of the udder tissue in dairy cows, usually caused by bacterial infection.

Neem Biotech's lead candidate, NX-AS-401, is a potential new treatment for patients with cystic fibrosis designed to help eradicate the Pseudomonas bacteria. The compound is a quorum sensing inhibitor. It disrupts communication between bacteria, thereby preventing them from forming the film that is crucial in protecting them from current anti-Pseudomonal antibiotics. It is expected to commence human clinical trials in 2017.

Deborah O'Neil, CEO of Novabiotics Ltd., of Aberdeen, Scotland, told delegates at the BIO 2016 event that a multi-attack and multistrain approach to the development of new antibiotics is the only way to meet the rising challenge of AMR. The company also presented at the Microbe 2016 conference last week where it reported new data on how Nylexa, its parenteral formulation of cysteamine, in early stage development, improves the antimicrobial efficacy of antibiotics and reverses multidrug-resistant infections.

The active component of Nylexa is cysteamine, and results showed that it reverses resistance to clinically important antibiotic classes such as aminoglycosides, fluoroquinolones, macrolides, folate pathway inhibitors and beta-lactams. The company also presented data to show that cysteamine reverses MCR-1 and other forms of colistin resistance.

Redx Pharma plc, of Alderley Park, U.K., also presented data on its bacterial topoisomerase inhibitors (NBTIs) at the Microbe 2016 conference. It reported discovery of a series of NBTIs that demonstrate broad-spectrum antibacterial activity, a low potential for resistance development and a mechanism of action distinct from quinolones against ESKAPE pathogens.

Funding flows for antibiotics research

The renewed interest in the quest for new antibiotics and the supportive political climate for companies operating in the space has not escaped the attention of venture firms, who are beginning to add early stage companies to their investment portfolios.

For example, just this year, Spero Therapeutics LLC, of Cambridge, Mass., generated $30 million in preferred B funding to advance its therapeutic potentiator platform, designed to improve drug potency and enhance the utility of existing anti-infective medications. The company also plans to advance its dihydrofolate reductase (DHFR) program, which targets gram-positive and negative bacteria, fungi and protists. The DHFR program is seeking to expand an antifolate's antibacterial spectrum to treat trimethoprim-resistant isolates, including key gram-negative pathogens. (See BioWorld Today, Feb. 3, 2016.)

Spero said its potentiators interact with the outer membrane of gram-negative bacteria to enable access and, in combination, enable agents traditionally used only for gram-positive infections to treat multidrug-resistant gram-negative infections and to increase the potency of agents targeting gram-negatives.

Newcomer Iterum Therapeutics Ltd., which secured $40 million from a series A financing round, said it licensed global rights to an anti-infective compound from a top-tier multinational pharmaceutical company. The transaction is consistent with its focus on in-licensing and developing anti-infective candidates targeting multidrug-resistant pathogens. (See BioWorld Today, March 25, 2016.)

Appili Therapeutics Inc., of Halifax, Nova Scotia, said it raised about C$3.3 million (US$2.5 million) to advance research and development of its anti-infective candidates and to open a medicinal chemistry lab in Halifax. The firm's pipeline consists of ATI-1501, a taste-masked treatment for Clostridium difficile infection, and ATI-1503, an antibiotic with broad potential against gram-negative infections.

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