Two infectious disease crises: both need combinations


Helperby Therapeutics develops rapid, effective and affordable combination solutions to treat infectious diseases and solve crises. Our immediate concern is how do we exit lockdown safely? There is currently no clear answer. We propose a solution: repurpose old drugs as a cure for COVID-19.

FIRST CRISIS: Highly resistant bacteria
The crisis of bacteria becoming highly resistant to antibiotics has taken longer to unfold but is projected to kill 10 million people per year by 2050. Increasingly, companies have attempted to tackle this crisis by developing expensive new chemical entities (NCE) which equated to correspondingly high sales prices. Uptake by clinicians of expensive and unfamiliar new drugs has been poor and subsequently this proved to not be a viable business model for these companies.

In contrast, Helperby Therapeutics has made it into Phase II clinical trials with its lead product, Zidistin®, (which is an improved dosing regimen of Colistin combined with Azidothymidine) at approximately one tenth of the cost of developing a NCE. Furthermore, Zidistin®’s in vitro and Phase I data shows it is more effective against WHO Critical Priority pathogens than any of the 9 most recent NCE antibiotics.

The exceptionally high efficacy is achieved by screening for and then quantifying the synergy between different combinations of old drugs to identify optimal matches. Synergistic interactions allow us to achieve this effect with lower doses of the constituent drugs which is safer. This also fosters antibiotic stewardship by avoiding using drugs that don’t work well (which therefore leads to antibiotic resistance). Our approach of using synergistic combinations is novel and we believe that there is untapped potential in the existing inventory of approved drugs in that there may well be further combinations yet to be discovered.

The new coronavirus pandemic has unfolded at an extremely rapid pace with no specific treatment in place. Estimates are that a vaccine is unlikely to appear before 12-18 months and similarly it would take too long to develop a targeted and safe NCE to treat the disease.

With no formally recognised best practice in place, doctors and hospitals around the world are trying a variety of drugs off-label alone and in combinations suggesting that they believe there may be merit in using combinations of old drugs. They are doing this at pace, but without the design platform for systematically combining old antimicrobials into new combinations nor the experience of having completed clinical trials with such combinations. Nonetheless, there is growing evidence that some antimicrobial drugs, particularly in combinations, have some effects against COVID-19.

One of our baskets of patented IP, HY-008B6 (now called Triviraz®), we believe is the basis for first effective treatment for COVID-19. Like our other programmes, Triviraz® is based on combinations of existing drugs making the trialling and testing of this product faster and more robust. This combination is empirically designed to have a wide spectrum of action against viral infection (targeting virus and host cells) which has the added advantage of potentially being useful against further mutations of the virus or recurrent waves. This is critical in order for us to achieve a successful exit strategy from the current lockdown situation.

Helperby plans to undertake a Phase 2 randomised clinical trial with patients who are suffering from early COVID-19 who are particularly at risk from developing serious disease. For example older people, and those with conditions such as diabetes who are predisposed to poor outcomes from the infection.

Many safe antimicrobials have a range of actions far broader than just their first labelled indication and can cross taxonomic boundaries; the antibiotic Doxycycline is also used to treat parasitic infections (Malaria); the antiviral Azidothymidine is now being harnessed by Helperby against highly resistant bacteria. We are agnostic as to the originally intended purpose of a drug and so we have discovered combinations with exceptional efficacy where no-one else was looking.

The speed, economics and exceptional efficacy of reusing old antimicrobials in new combinations made it the optimal approach for adapting pre-existing resources to affordably overcome the failed market of NCE antibiotics. Correspondingly, those same characteristics are precisely those required to manage rapidly occurring pandemics with only the tools we started with.