As many regions face a rise in antibiotic resistance, new weapons against infections are needed. Bacteriophages have been used with some success in the old Eastern Bloc. Can the West now reduce the regulatory hurdles to enable their use elsewhere?
With concern about antimicrobial resistance growing increasingly acute, it is perhaps a surprise that the science behind new drugs that could bolster threatened antibiotics was developed in eastern Europe, including under communism. But such is the case with ‘bacteriophages’, a buzzword in many medical circles at present, usually shortened to ‘phages’. A number of international conferences have already been held this year on the subject, which has been widely dubbed ‘the Year of the Bacteriophage’.
Little known in Western medicine, at least until recently, bacteriophages are viruses that infect and replicate within a bacterium to attack it. They have been in regular use in Poland, Georgia and Russia since the 1920s as a substitute for antibiotics. But today, with the growing resistance of many bacteria to antibiotics in developed countries, more attention has been focused on bacteriophages, which could soon move from the fringes into mainstream medicine as a result.
One major obstacle, however, is that almost all the clinical studies into phages have taken place in countries that were once behind the Iron Curtain, and that is proving an obstacle to their acceptance elsewhere.
In most cases today, phage therapy is not regulated or permitted in EU member states, and there have been cases of patients travelling to Georgia for phage treatment
Notably, while a great deal of clinical information exists about bacteriophages, unfortunately much of it lies outside the present regulatory framework covering medicinal products in the European Union (EU). The therapy was intensively developed in the former Soviet Union (a response to Moscow being shut out of antibiotics advances in the West) and used in the treatment of Russian soldiers in World War 2. But the Cold War prevented the science being taken up globally in the post-war years.
In most cases today, phage therapy is not regulated or permitted in EU member states, and there have been cases of patients, for whom antibiotics have been ruled out, travelling to Georgia for phage treatment. Some in the EU medical profession believe it is high time that regulations were eased. But while possible, industry experts think it unlikely for some time yet.
That is not because of a lack of scientific papers, though. In a paper published in 2012 by the Phage Therapy Unit of the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy in Wrocław, Poland, the first phage therapy (PT) unit in the EU, PT was described as ‘a unique method of treatment of bacterial infections using bacteriophages (phages) – viruses that specifically kill bacteria, including their antibiotic-resistant strains’. The paper noted that over the past decade ‘a marked increase in interest in the therapeutic use of phages has been observed, which has resulted from a substantial rise in the prevalence of antibiotic resistance of bacteria, coupled with an inadequate number of new antibiotics’.
In general, data suggest that PT can provide good clinical results in a significant cohort of patients with otherwise untreatable chronic bacterial infections
Reporting on the results of PT between 2008 and 2010 for 153 patients with a wide range of infections resistant to antibiotic therapy, the Institute said: ‘In general, data suggest that PT can provide good clinical results in a significant cohort of patients with otherwise untreatable chronic bacterial infections and is essentially well tolerated.’ But, like the results of many other researchers and studies conducted in central and eastern Europe, the results and their tests do not meet the clinical trial standards of regulatory bodies in western Europe, North America and other rich jurisdictions, which would pave the way for market approvals.
The subject was considered in some detail at a workshop held by the European Medicines Agency (EMA) at its London HQ in June. Representatives of academia, industry, policymakers and patient organisations discussed possible issues related to development of phage therapies for the treatment of bacterial infections.
As an EMA note said, while PT was used in some parts of Europe, it was currently not authorised as a medicinal product and it was ‘important for the Agency to fully appreciate the level of scientific evidence available to support this therapy, and the potential therapeutic indications for which phage products could be further developed’.
It is important for the EMA to fully appreciate the level of scientific evidence available to support this therapy, and the potential therapeutic indications for which phage products could be further developed
Commenting on the present position in a report summing up the workshop, EMA said: ‘At one end of the spectrum, medical doctors are using phage therapy on a compassionate use basis to treat individual patients for difficult-to-treat bacterial infections. They advocate for possibilities to develop phages targeting specific pathogens on a single-patient basis. At the other end of the spectrum, pharmaceutical companies are concerned with formulating “fixed phage cocktails” to be used in clinical trials. These fixed phage cocktails are produced under good manufacturing practice (GMP) conditions, in line with current guidelines for biological medicinal products. The ultimate aim is to achieve a marketing authorisation in the EU.’
The EMA report said that the Agency was taking steps to facilitate the development of such products. It maintained a position of openness towards exploring all possibilities for using the current regulatory framework to allow the further development of this therapeutic approach. However, EMA emphasised that ‘a medicine cannot be recommended for approval before its efficacy and safety have been proven on the basis of appropriately designed clinical trials’. This was not currently the case for bacteriophage therapies for which very few randomised controlled clinical trials had been conducted to date, it said.
The EMA said it was ‘looking forward to gathering more robust evidence on the value of bacteriophage treatments and further discussing the scientific and regulatory aspects relating to the biological characterisation of the phages with stakeholders’. The current EU regulatory frameworks were considered a suitable starting point for discussing fixed phage cocktails and companies are encouraged to engage in early dialogue with the Agency by applying for scientific advice through which they can receive further guidance on how to develop their products.
Bacteriophages attacking a bacterium
In an interview with Manufacturing Chemist, Dr Marco Cavaleri, Head of Anti-infectives and Vaccines at EMA and chair of the bacteriophage workshop, said that the meeting had ‘opened the doors to a dialogue on bacteriophage therapy’. This was an important step, he said, because there had been a lot of misunderstanding. ‘We really hope this has been an opportunity to clarify what is our current position and the fact that we are very much willing to engage in further dialogue with the development of bacteriophages,’ he explained.
Dr Cavaleri said he expects individual developers of phage therapy ‘will come to talk to us and tell us what they intend to do and will put questions on the regulatory side to us. This would be a way of progressing our mutual understanding and figuring a potential pathway to allow this therapeutic approach to progress further.’ Dr Cavaleri looked forward to meetings with developers that would go beyond the context of a workshop, such as the one in June, where a number of aspects had to be kept commercially confidential.
‘Now we are progressing to a kind of more capillary interaction with the developers and after that, we’ll see if there’s an opportunity to re-convene, maybe with an important milestone reached about where we are with bacteriophage therapy and whether there is a need for a larger discussion with stakeholders.’ he said.
There are centres in Europe that are looking forward to using bacteriophage therapy as a potential tool to treat difficult infections with multi-resistant bacteria
Dr Cavaleri added: ‘I think there are clearly attempts in other regions of the world to look into the potential of bacteriophages to see if they could be a valuable therapy or option, particularly for certain kinds of infections. There are centres in Europe that are looking forward to using bacteriophage therapy as a potential tool to treat difficult infections with multi-resistant bacteria. So interest is growing.
‘Also in the US, it’s my understanding that there are companies entering into development of bacteriophages so I’m pretty sure there will be a growth in the coming months of this activity in different parts of the world. But we are far from the large experience that has been gained in the former Soviet Union – not only in Russia but particularly in Georgia, which has had a lot of experience with bacteriophages over the years.’
Dr Cavaleri said that in Poland, the development was still in the hands of the public health institute Narodowym Instytut Zdrowia Publicznego and was handled mainly in the context of a compassionate use approach. ‘It is our understanding that no industry partners for the timebeing are involved in that,’ he stated.
He said a similar situation exists with Georgia: ‘They have knowhow and can produce cocktails of bacteriophages to some extent, but our interaction with Georgia at present is rather limited.’
If it can be demonstrated robustly that bacteriophages work in terms of efficacy and safety, then clearly the EMA executive will find a regulatory path that will allow these products to be further developed and commercialised
On the question of regulation, Dr Cavaleri thought the EMA was ‘ready to prepare to look at this in the future.' However, at the moment, it is difficult to have a good understanding of what the Agency might be facing in a few years, in terms of bacteriophage products as medicinal products reaching the markets. He said that if it can be demonstrated robustly that bacteriophages work in terms of efficacy and safety, then clearly the EMA executive will find a regulatory path that will allow these products to be further developed and commercialised.
At present, there is plenty of uncertainty about the real potential of this therapeutic approach, but Dr Cavaleri is optimistic: ‘I believe that if in four or five years from now the clinical trials are on-going and will show that bacteriophages indeed have a value and that they work, then bacteriophage therapy could have a bright future…[with] products on the market.’
Bacteriophages are still little used and little understood in the US, although in 1998 the privately-owned biotech company Intralytix won approval from the US FDA for two ‘cocktail’ phage products. As a visiting researcher from Georgia, company cofounder and Chief Scientific Officer Alexander Sulakvelidze was astonished to find that phages were unknown in the US. In 1998 he formed Intralytix with an American colleague in Baltimore. ‘People die because Western medicine is no longer aware of phage therapy,’ Sulakvelidze said at the time.
One further potential problem stressed by medical patent experts is that there could be problems in securing patents for natural viruses such as phages in the long term, because they occur in nature. But some experts believe this could possibly be overcome by engineering the natural phage virus to create a patentable variation – but this could be a long way into the future.