PANDEMICS: FINDING A NEW PURPOSE FOR OLD DRUGS

Helperby Therapeutics aims to produce affordable, rapid and effective combination solutions to treat infectious disease.

COVID-19 has drawn attention to how unprepared we are to find treatments quickly for pandemics. With the speed at which a crisis can unfold, developing an entirely new treatment from scratch is clearly too slow to be available for the first peak of the pandemic. There has been recognition that combining repurposed existing drugs could provide a quick and effective solution to this problem; the first solid progress on discovering a treatment for COVID-19 has come from an old drug, Dexamethasone, which was approved in 1961 and has now been intelligently repurposed. Further work developing new combinations of repurposed old drugs will build on this success and will be vital to our efforts to cope with the COVID-19 pandemic. This work is necessary for us to be better equipped to handle recurrent waves of this virus and any future pandemics that we may face in the years to come.

The recognition of using combinations of repurposed old drugs (like Dexamethasone) has sparked widespread interest in the topic. Combining old drugs started many decades ago and are the only effective treatments for infections such as tuberculosis and HIV, but using combinations for most other types of infections has not been well researched to date. Many old drugs can be repurposed outside of their primary designated use because they have other useful effects that can be identified. Well designed combinations take advantage of overlapping useful effects while minimising potentially harmful ones. Helperby has a long history in developing patented, new combinations of old drugs.

Helperby has been using this approach to tackle the crisis of failing antibiotics. Every class of antibiotics has met infections that they cannot treat and in these cases, doctors are unable to carry out routine procedures such as transplants, hip/knee implants and cancer treatments. There is a trend of new bugs emerging which can’t be treated by our existing inventory of antibiotics and that currently kill an estimated 1m people each year. This is progressively rendering the inventory of existing antibiotics ineffective and extrapolating this trend suggests that in 30 years, bugs that can’t be treated properly will kill more people than currently die of cancer today.

Doctors are demanding more effective drugs. Developing new drugs from scratch has shown to be prohibitively expensive given the sizeable development costs and unknown market size. Helperby’s approach is around 10x cheaper and develops optimally matched combinations of repurposed old drugs that are exceptionally effective against even the most challenging infections. This cost advantage has been key to its survival as most new antibiotic companies have gone bankrupt in the last few years trying to develop new drugs from scratch. Similarly, large pharmaceutical companies have generally left the field because developing a new drug from scratch is not commercially attractive for them. Interest in combinations has the potential to allow smaller companies like Helperby to develop cheaper and quicker permanent or interim solutions to manage the crisis of failing antibiotics.

Helperby’s lead product, Zidistin®, is in phase II clinical trials. As well as addressing the WHO’s Critical Priority pathogens that have few other treatments, Zidistin® is expected to be profitable independent of government incentives. Zidistin®’s initial authorisation is planned to be for treating complicated urinary tract infections of which there are 6.6m cases per year (projected revenue of $164m on a 25% market share) in the EU and USA markets.

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Helperby and COVID-19

Helperby’s commercial model is to develop combinations of repurposed old drugs to fight common resistant bacterial infections. Currently, this combination model is universally utilised for the treatment of diseases such as tuberculosis and AIDS, but not for common bacterial diseases. In the case of COVID-19, this model has resulted in other groups identifying with randomised clinical trials, two old drugs, each in separate trials which significantly reduce the death rate. The names of these drugs are dexamethasone and interferon-beta which were used in combination with other old drugs.

In the peak of the European COVID-19 epidemic, Helperby designed a randomised clinical trial with a combination of repurposed old drugs for the treatment of Coronavirus-positive cases. This trial was to be run in Poland in parallel to the Company’s complicated urinary tract infection randomised clinical trial. Recruitment of patients was to be fast because the availability of the patients would become very limited when the peak disappeared. The necessary paperwork for the trial was completed. A detailed, high quality grant application was submitted to a British government funded organisation. The application was short listed by the British Government and attracted significant interest from prospective investors. However, the Company decided to withdraw the application when a separate (unrelated) trial led by Oxford University indicated that the proposed combination may not be as efficacious as the Company had hoped.

Meanwhile, the Company entered into an agreement with another company with the aim of bringing a new automated hand disinfectant system for the coronavirus. This program aims to bring this system to the market before Christmas (see HAND in “Pipeline)

Two infectious disease crises: both need combinations


TWO INFECTIOUS DISEASE CRISES

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.

SECOND CRISIS: SARS-CoV-2
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.

TWO CRISES: BOTH NEED COMBINATIONS
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.

Are New Antibiotic Combinations The Solution To The AMR Crisis?

Combinations of old antimicrobials such as Helperby’s colistin and azidothymidine are a possible alternative to developing new chemical entities, because they cost one tenth of the price.

A Global Antibiotic Research and Development Partnership (GARDP) Blog on this topic, first published on revive.garpd.org on 15 October 2019 is available below.

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The New England Journal of Medicine

The New England Journal of Medicine announces that Azidothymidine produces synergistic activity in combination with Colistin against antibiotic-resistant Enterobacteriaceae. Antimicrobial Agents Chemother. doi:10.1128/AAC.01630-18. The NEJM review entitled Colistin-Azidothymidine synergy against Enterobacteriaceae suggests that azidothymidine may have a future role against Enterobacteriaceae, particularly for urinary tract infections.

click here to subscribe & read the full article. https://www.jwatch.org/na48250/2019/01/09/colistin-azidothymidine-synergy-against-enterobacteriaceae

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The drugs don’t work: what happens after antibiotics?

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WHO Recognises Antimicrobial Resistance As One Of The Most Pressing Global Threats To Medicine

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Antibiotic Resistance Plan To Fight Urgent Global Threat

The World Health Organization recognises antimicrobial resistance (AMR) as one of the most pressing global threats to medicine.

Without effective antibiotics, much of the success of modern medicine, such as the levels of unprecedented survival rates from major surgery or super effective, chemotherapy treatment, would be totally compromised. With our defences running out, where is the innovation and investment in the next generation of antibiotics? Who is stepping up to take on the challenge? ​

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Helperby to collaborate with UCLA on new fast track antibiotic therapies

Helperby has announced a collaboration with Dr. Pamela Yeh and her team at the Department of Ecology and Evolutionary Biology, University of California, Los Angeles (UCLA).

Dr Yeh recently published on the phenomenon of emergent synergy of combining two or more existing antibiotics and their efficacy against pathogenic Escherichia coli1(E-coli).

It was previously held that the risks of combining antibiotic drugs often outweighed the benefit because of adverse interactions. But Dr Yeh’s team found the direct opposite, and reported that as more drugs were combined, an elevated frequency of synergy was observed1.

“In my opinion Dr Yeh’s team’s recent observations could be the most important breakthrough in the fight against antibiotic resistance,” said Professor Coates, founder and Chief Scientific Officer, Helperby.

Helperby and Dr Yeh’s team will work closely to explore the commercial opportunity of additional, new, combination therapies. The collaboration will include the sharing of data, expertise and research methodology.

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Helperby Therapeutics announces study results active against the WHO Critical Priority Carbapenem resistant bacterial pathogens

Helperby Therapeutics announces study results demonstrating promise of its unique combination antibiotic therapy - active against the WHO Critical Priority Carbapenem resistant bacterial pathogens

The combination of azidothymidine (AZT) and low-dose colistin shows synergistic antibiotic activity against carbapenem and colistin-resistant Enterobacteriaceae (CRE) infections.

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ECCMID Published Papers - Safety & Pharmacokinetics of i.v azidothymidine alone & combined with Colistin

P2195 Safety and pharmacokinetics of i.v. azidothymidine alone and combined with colistin being developed for the treatment of carbapenem - and colistin- resistant Enterobacteriaceae (phase-1-study)

Azidothymidine (AZT) in combination with colistin (COL) has in vitro synergistic activity against COL-susceptible and -resistant and carbapenem-resistant Enterobacteriaceae(CRE), including mcr-1-producing Escherichia coli strains. In this phase-1 study the safety, tolerability and pharmacokinetics of IV-administration of AZT and colistimethate sodium(CMS) alone and co-administered were assessed in healthy male and female volunteers.

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ECCMID 2018 Published Papers- Azidothymidine

O0574 Azidothymidine is bactericidal against carbapenem-resistant Enterobacteriaceae and produces synergistic activity in combination with colistin against multidrug-resistant Enterobacteriaceae

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Gram-negative bacteria are prevalent and are extremely difficult to treat. Reusing of existing drugs and rejuvenating the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an anti-retroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here we investigated the efficacy of AZT against a variety of antibiotic resistant Enterobacteriaceae. We also tested the ability of AZT to enhance the potency of currently used antibiotics particularly colistin against antibiotic-resistant including NDM-1 Enterobacteriaceae.

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Helperby Therapeutics announces phase 1 results demonstrating multiple benefits of its unique combination antibiotic therapy

  • The combination is azidothymidine (AZT), which is a new class antibacterial, and low dose colistin.
  • The combination is active against all three WHO Critical Priority Carbapenem Resistant Pathogens.
  • In addition, AZT and colistin act synergistically against carbapenem and colistin-resistant Enterobacteriaceae (CRE) infections.

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Helperby Announces Market Advantages

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New Thinking IS Required To Create Desperately Needed New Antibiotics.  We Must Act Now

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Rise of Superbugs Puts Everyday Surgical Operations In Jeopardy

Tens of thousands of patients in Britain are struck down by superbugs because antibiotics to protect them during surgery have failed, a global study says.

One in five infections picked up during common operations worldwide is resistant to standard antibiotics, suggests research that reveals how far resistance to drugs has advanced towards a so-called doomsday scenario.

The research also raises fears that performing everyday surgery will become impossible.

Scientists say infections that are resistant to antibiotics are more widespread in the developing world and will make routine operations difficult without urgent global action.

The rise of bacteria that are resistant to antibiotics is a threat to medicine as common infections could lead to deaths if the bacteria become impervious to such drugs.

Surgery is a concern because routine procedures could become too dangerous to attempt if antibiotics given to prevent infection no longer work.

Dame Sally Davies, the chief medical officer, has warned of a “post-antibiotic apocalypse” where cancer is untreatable and hip replacements or caesareans become impossible because of the threat of superbugs. The World Health Organisation has warned that this will mean the end of modern medicine as we know it.

For the first time an international team has sought to assess the global state of infection during surgery, looking at 13,000 patients in 66 countries undergoing operations such as appendix removal, gallstone surgery, complex hernia repair and treatment for abdominal injuries. Overall 12 per cent contracted infections within a month of surgery, including 9 per cent of 7,339 patients in rich countries, mainly Britain.

Tests showed that 22 per cent of infections were resistant to standard antibiotics given to prevent infection. This figure varied from 17 per cent in the West to 36 per cent in poorer African countries, according to results published in The Lancet Infectious Diseases.

“The level of antibiotic resistance is higher than we would have expected. It’s something we should be concerned about and we need to come up with a strategy to deal with it,” said Ewan Harrison, of the University of Edinburgh, who led the project. “The bugs don’t recognise geographical borders. So even though there are higher levels of antibiotic resistance in other countries that does mean something for the UK as well.”

Dr Harrison said the findings highlighted fears that some operations might become too risky to attempt. “It does underline that concern. It is a concern for the future if antibiotic resistance continues to increase. It may be that we get to a point where we can’t give antibiotics that are effective in preventing infection.”

The study looked specifically at gastro-intestinal surgery, which is carried out a million times a year in British hospitals and where infection is likely to be more common. However, Dr Harrison said the results could apply to many more of the five million surgical procedures carried out in Britain each year. “It is reasonable to generalise beyond the patients we looked at. The same conclusions that we’ve drawn from this could be applied tentatively to other parts of surgery,” he said.

Almost 5 per cent of patients with an infection died after surgery, compared to 1.5 per cent without. They also stayed in hospital for a week on average, more than three times as long as those people who avoided infection.

Nicholas Brown, a consultant medical microbiologist at Addenbrooke’s hospital in Cambridge and director of the campaign group Antibiotic Action, said the findings were a sign that standard preventative antibiotics were failing. He said: “The doomsday scenario, the end of the antibiotic era, is in some countries only a theoretical possibility but in other countries it is beginning to have a very significant impact.”

Chris Smyth, Health Editor, The Times. February 14 2018

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number of new antibiotics has fallen sharply since 2000

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Overuse of antibiotics in farming is a major new threat to human health, says UN

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Life expectancy has dropped because of antibiotic resistance, says ONS

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Latest European Data Shows Increasing Antibiotic Resistance

The European Centre for Disease Prevention and Control (ECDC) released the latest annual data on antimicrobial resistance trends in 30 European Union (EU) and European Economic Area (EEA) countries today, in anticipation of the European Antibiotic Awareness Day, which takes place on Nov 18.

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New Treatments To Solve Antibiotic Crisis Have Potential To Reach The Market As Early As 2020

Doctors increasingly rely on last resort antibiotics such as carbapenems and colistin, but as harmful bacteria continue to mutate, this final line of resistance will eventually fail.

The World Health Organisation (WHO) has dedicated World Antibiotic Awareness Week (13-17 November 2017) to ‘Handle Antibiotics With Care’.

Helperby’s solution to this critical problem, and ground-breaking innovation, is Antibiotic Resistance Breakers - novel technology that rejuvenates existing antibiotics into resistance-proof long-term effective combination therapies.

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Helperby Therapeutics - Phase I results

Helperby Phase I Press Release - FINAL 16 Mar 2017

Breaking Resistance One Antibiotic At A Time

Helperby’s antibiotic-resistance breakers are a powerful tool serving to prolong and boost antibiotic efficacy and should help counter the growing global crisis of antibiotic resistance.

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Helperby Therapeutics held a pre-IND meeting with the FDA

On March 9th 2016 Helperby Therapeutics held a pre-IND meeting with the FDA division of Anti-Infective products. The outcome is a road map for the clinical development of a drug product for the treatment of complicated urinary tract infections.

This is an important area of research due to the rapidly emerging multi drug resistance of gram negative infections.