The Killer Combo

Bacteria are constantly evolving to be antibiotic resistant and are a real and present danger to our ability to treat common infections and carry out standard medical procedures, including organ transplantation, major surgery and cancer chemotherapy, among others. According to the O’Neill UK government AMR report (2016), global deaths from AMR may reach 10 million per year by 2050, which is more than cancer and diabetes combined (1).

Innovation in both the short and long term is essential if mankind is to keep pace with ever smarter and deadlier microbes. The fight to outsmart infection falls broadly into rapid diagnostics technology and targeted treatment strategies involving new and updated antibiotics.

But the pace of discovery and production of new chemical entities (NCEs) hasn’t been so promising and has failed to keep pace with the unpredictable rate of bacterial evolution. In fact, big pharma has mostly ruled itself out of the antibiotics game. The high cost of creating a new chemical entity and the low market price of new antibiotics deters large pharmaceutical companies, leaving the fight for antibiotic survival with the small biopharma companies, in what is the most urgent field of drug development. But small biopharma companies, even those which reach the market, struggle to sell NCEs. This is because, under present conditions, the market will not accept a price per course which will reimburse the high cost of developing an NCE. For example, if the cost of developing an NCE is say $200-500 million and the maximum unit price of a course of the NCE is $1-2000, it is difficult to make a reasonable profit. This conundrum is illustrated by Achaogen’s filing for bankruptcy, in spite of reaching the market with an FDA approved NCE. Other small companies have and will survive in the market with NCEs, but achieving the equivalent profitability to successful blockbusters in other medical fields looks to be remote at the moment.

An alternative to the traditional pharma model is to use combinations of antibiotics. This is a route used to reduce the emergence of resistance in diseases such as tuberculosis, malaria and AIDS. Curiously, combinations (excluding those with beta-lactamase inhibitors which do not prevent resistance unless the inhibitor also has potent antibacterial action) are not often approved by the regulators for common bacterial infections. However, combinations hold the potential for a longer lasting, lower development cost, and lower price per course market solution. This strategy is based upon employing synergistic combinations. Simply, an old drug already in the market (called an antibiotic resistance breaker (ARBs)) is combined with an old antibiotic also on the market. The ideal combination of drugs boost each other, which is known as synergism. This route re-uses old antibiotics by boosting them to overcome mutations developed by bacteria-conferring resistance. ARBs work in many different ways, including by facilitating the penetration of bacterial cell walls to allow existing antibiotics to work more effectively.

The ARB rejuvenation process can be performed repeatedly with different combinations of existing antibiotics. These new combinations can restore the original potency of existing antibiotics, against both Gram positive and Gram-negative bacteria. A small antibiotic biopharma called Helperby Therapeutics has been developing combinations for 15 years and has shown that some combinations have unique synergistic mechanisms of action that differ from other antibiotics in clinical use. Helperby Therapeutics has already completed a Phase I clinical trial and is Phase II ready with the first combination of azidothymidine (AZT) and the so-called last resort old antibiotic colistin against highly resistant carbapenem-resistant pathogens.

The World Health Organization has identified three multi-drug resistant species of bacteria which they classify as critical priority (2). These are all carbapenem resistant and require the immediate development of new treatments. The bacteria are called Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae.

Multi-drug resistant bacteria pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. But we also need longer-lasting strategies. In my view, rejuvenating existing antibiotics with synergistic combinations should be an integral part of the fight against drug resistance. These strategies, combined with progress in the areas of prevention and diagnostics, are crucial to preserve a world where simple infections do not routinely kill healthy people. The pharma industry is responsible for countless groundbreaking therapeutic innovations, but it will all be wasted if we ignore the growing issue of antibiotic resistance.