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CARB-X’s first round of grants goes to firms big and small in antimicrobial resistance fight


By Nuala Moran
Staff Writer

LONDON - The U.K./U.S. public-private partnership set up to rejuvenate early stage antibiotic research has awarded $24 million to 11 biotechs in its first round of grants.

The projects – to develop 10 new drugs and one diagnostic – will be eligible for a further $24 million in milestones over the next three years from the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), while the companies will themselves put in a further $27 million.

Coinciding with the announcement of the first grants, the U.K. charity Wellcome Trust said it will contribute $155.5 million over five years to the $450 million CARB-X program.

The grant winners, selected from 168 applications, are a declaration of CARB-X’s intent to address the biggest threats, with the 10 antibiotic programs all aimed at gram-negative bacteria that have been prioritized by the CDC and the World Health Organization.

The eight U.S. and three U.K. projects include three potential new classes of small-molecule antibiotics and four non-traditional products that represent innovative ways of killing bacteria.

While the grants will accelerate promising research, there is a high risk of failure, acknowledged Kevin Outterson, executive director of CARB-X. But he said, “If successful, these projects hold exciting potential in the fight against the deadliest antibiotic-resistant bacteria.”

Successful projects will be funded through to early stage clinical development and the point where they can attract backing from private investors.

The largest grant of $4.8 million, with a potential $4 million in milestones, was awarded to Forge Therapeutics Inc., of San Diego, to develop small-molecule inhibitors of LpxC, a zinc metalloproteinase found only in gram-negative bacteria and essential for the formation of their resistant outer membrane.

LpxC previously has attracted the attention of Pfizer Inc. and Merck & Co. Inc., amongst others, because it is conserved across gram-negative bacteria and not found in gram-positive bacteria or in humans. However, for several reasons it has proved hard to drug, though Achaogen Inc. of South San Francisco, has a late preclinical-stage LpxC inhibitor that is active against Pseudomonas aeruginosa.

Forge has used its chemistry platform, which focuses on binding to the metal ions in the enzyme’s active site, to discover novel and stable inhibitors, and those are now being optimized in a partnership with Evotec AG, of Hamburg, Germany.

Meanwhile, the winner of the smallest CARB-X grant, London-based Oppilotech Ltd., has been awarded $120,000 to screen for modulators of a new target it has discovered that also is involved in synthesis of the bacterial membrane.

The target was identified using a very detailed computer model of each biochemical step involved in the formation of the membrane that was created by Oppilotech’s scientific founder, John George, a microbiologist at Leeds Beckett University.

“No one has built such a detailed model. It is mainly based on E.coli, but can apply to other gram-negative bacteria,” Ajay Mistry, Oppilotech CEO, told BioWorld Today.

The aim of the CARB-X funded screen is to identify potentiator drugs that hit the target and disrupt the cell envelope, increasing its permeability. Oppilotech said those could be used in combination therapies to restore the clinical utility of antibiotics that have become obsolete due to resistance; to cut the required dose of antibiotics that remain effective, thus slowing the development of resistance and reducing toxicity; and to make gram-positive antibiotics active against gram-negative bacteria.

Potentiators would have the commercial advantage that they could be put to immediate use and would not have to be left on the shelf as last resort antibiotics.

Winning the CARB-X grant is a significant endorsement of Oppilotech’s approach, Mistry said. “Out of all the companies, we are the earliest – I’m the only employee. To be amongst those big guys is really good.”

CARB-X was formed in July 2016 in response to the U.S. national action plan to combat resistant bacteria and following publication of an independent U.K. review of antimicrobial resistance (AMR), which called for a concerted effort to confront the problem. (See BioWorld Today, July 29, 2016.)

The partnership received initial funding of $30 million from the Biomedical Advanced Research and Development Authority (BARDA) and $14 million from the U.K.’s AMR Center. Over the five-year program, BARDA will contribute up to $250 million and the AMR Center up to $100 million. That is expected to fund development of 20 new antibacterials, with at least two advancing into clinical trials during the five years of the program.

Years of insufficient investment mean the antibiotics pipeline is “all but dried up,” said Tim Jinks, head of drug-resistant infection at Wellcome Trust, announcing its contribution. “Through CARB-X we are filling the void in early discovery research.”

Other recipients of CARB-X grants include:

• Cidara Therapeutics Inc., of San Diego, which was awarded $3.9 million over 13 months and potentially up to $3 million in the following 11 months to support work on its Cloudbreak immunotherapy platform, which is designed to create compounds that direct a patient’s immune cells to attack and eliminate bacterial, fungal or viral pathogens. Cidara’s first Cloudbreak candidate, CD201, a bispecific antibiotic immunotherapy, is in development for treating multidrug-resistant gram-negative bacterial infections.

• Contrafect Corp., of Yonkers, N.Y., which will get $1.1 million over 15 months and potentially up to $1 million in the following nine months for its antimicrobial lysins targeting drug-resistant Pseudomonas aeruginosa infections. Lysins are bacteriophage-derived enzymes with potent antibacterial activity against antibiotic-resistant pathogens, robust antibiofilm activity, a low propensity for resistance development and pronounced synergy when used in combination with conventional antibiotics in preclinical studies.

• Entasis Therapeutics Inc., of Waltham, Mass., which is receiving $2.1 million over nine months and potentially up to $4.2 million in the following 12 months to advance its oral antibiotic for serious drug-resistant bacterial infections. Entasis is addressing the lack of an oral therapy to treat multidrug-resistant gram-negative bacterial infections, including those caused by carbapenem-resistant Enterobacteriaceae.

• Microbiotix Inc., of Worcester, Mass., which is getting $1.6 million over 12 months and potentially up to another $1.6 million in the following 12 months to support work on type III secretion inhibitors aimed at boosting the body’s ability to fight bacteria and potentiate host defenses against resistant P. aeruginosa in pneumonia patients. Microbiotix’s approach focuses on bacterial virulence and lead program MBX-400 is a nucleoside dual DNA polymerase/kinase inhibitor ready for phase II development for the management of cytomegalovirus disease in transplant patients.

• Proteus IRC, of Edinburgh, Scotland, which is receiving $640,000 over 21 months and potentially up to $480,000 more in the following 12 months to advance its optical imaging technology for rapid and accurate diagnosis of bacterial infection in the lungs. Proteus is developing technology to visualize bacteria and the host response in the deepest parts of human lungs in just 60 seconds, using bacteria-specific Smartprobes and fiber-based imaging.

• Redx Pharma plc, of Alderley Park, U.K., which was awarded $1 million over 18 months to focus on bacterial inhibitors targeting multidrug-resistant bacteria, with the potential for treating serious hospital-acquired infections. Redx has developed bacterial topoisomerase inhibitors, which have demonstrated activity against a range of resistant bacterial species and have shown efficacy against a multidrug-resistant strain of A. baumannii in an animal model.

• Spero Therapeutics LLC, of Cambridge, Mass., which is getting $1.6 million over 12 months and potentially up to $5.4 million in the following 24 months for its combination drugs aimed at disrupting the gram-negative bacterial membrane and allowing antibiotics to reach their targets. Spero’s lead program, SPR741, also called Potentiator, is a platform approach to combination therapy to treat multidrug-resistant gram-negative infections, such as Enterobacteriaceae and Acinetobacter baumannii, including carbapenem-resistant strains. SPR741 increases the spectrum and potency of more than two dozen classes of gram-positive antibiotics to include activity against multidrug-resistant gram-negative infections when used in combination.

• Tetraphase Pharmaceuticals Inc., of Watertown, Mass., which is getting $4 million over 18 months to advance its clinical candidate, TP-6076, a synthetic fluorocycline antibiotic against multidrug-resistant gram-negative bacteria. The phase I-stage drug candidate has demonstrated potential against clinically important gram-negative pathogens, including carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae.

• Visterra Inc., of Cambridge, Mass., which was awarded $3 million over 12 months and potentially up to $4.2 million in the following 12 months, to develop its antibody-drug conjugate as a single-dose curative therapy that is engineered to kill strains of Pseudomonas bacteria. The company emerged from the firm’s Hierotope platform and is designed to attach to the Pseudomonas bacteria to deliver its antimicrobial peptide.