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Questions from the audience and answers from the panellists
Many thanks to all those who asked great questions and to the panellists who have provided answers.
Time of the question.
17:33:51 From Bob Hancock to All panellists: I’m a bit concerned that combinations, while very promising, are essentially a stop gap measure. Resistance still occurs with combinations usually
picking off one compound at a time. I feel we really need to start thinking out of the box to a time where combinations will start to lose effectiveness. My own enthusiasm lies around alternatives to antibiotics as an area to pursue.
Anthony Coates. There is no doubt that alternatives to antibiotic/antimicrobials are going to be very important. Peter Beyer mentioned the use of the old drug dexamethasone which reduces mortality in COVID-19 patients. Currently this drug is often used in combination with other drugs. You suggest that combinations may be a stop gap measure and that resistance picks off one compound at time.
Yes, this is a possibility. Combinations have significantly reduced the emergence of resistance in tuberculosis(TB) patients for the past 70 years, but resistance is slowly emerging to TB. Could we do the same for the treatment of common bacterial infections? Hollow fibre data from many different laboratories suggests that we can. Also, if we used larger combinations, the number of possibilities is almost limitless. Mother Nature uses combinations to fight bacterial infections, and some bacterial species encode the genes for many different antimicrobials. We have much to learn from Her because the life-forms which surround us today, have found effective ways to survive attack from bacterial invasion. No doubt they use combinations of antimicrobials and alternatives.
Seamus O’Brien. There are many “alternatives” including membrane disruptors, pathoblockers and antibodies which will be used in combination with antibiotics.
Dennis Molnar. Combinations have been a stop-gap measure in Tuberculosis, HIV and Hepatitis. Single combinations may provide only incremental benefit, but in Tuberculosis and HIV we may achieve decades of benefits with combinations of 3, 4 or even 5 drugs. As Professor Coates notes, resistance is re-emerging in TB, suggesting that no matter how long the stop-gap is, we need to continue ALL other efforts to find new synergists, NCEs, new classes, antibodies, vaccines and every
other out-of-the box approach that we can. Combinations are not THE answer, but they have proven to be a very important PART of the answer in other infectious diseases. One other point of clarification is that not all combinations are created equal. Some combinations provide potentiation, other amplification, other additive benefit, others synergy and others antagonism. Beta-lactams plus beta-lactamase inhibitor combinations are the most common combination approach today.
Peter Beyer: You may want to have a look at the database of pre-clinical candidates which includes many non-traditional approaches. Many (but not all) will come on top/in combination of traditional antibiotics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386594/
17:34:35 From Prabha to All panellists: Question for Anthony: Could you address the use of combinations to delay the occurrence of resistance to existing antibiotics (as in TB, GC).
Anthony Coates. If it were possible to reduce or remove the emergence of resistance to antimicrobials, the Anti-Microbial Resistance pandemic would fade away. This is the most important issue we face today. In 1948 streptomycin alone was used by the British Medical Research Council to treat tuberculosis (TB) patients. Streptomycin resistance emerged and most of the patients, after an initial improvement, then deteriorated and died. The next cohort of TB patients was treated with a combination of streptomycin and para-amino salicylic acid. No resistance arose, and all the patients survived. Now, monotherapy is never used for the treatment of TB. The standard regimen, which was developed over 40-50 years is a combination of four drugs. Combinations have significantly reduced the emergence of resistance in TB patients for the past 70 years, but resistance is slowly emerging. In the longer term, say hundreds of years, could we make new combinations
which could last for say, a further 70 years? I think we could, and there are new drugs in combinations with old drugs which look promising in the treatment of resistant TB. This approach of using larger combinations has not been done for common bacterial infections such as Staph aureus, Streptococcus spp and Escherichia coli. It has potential in the long term. The standard of care for common bacterial diseases is monotherapy. Resistance has arisen to all antibiotics. A case in point is
gonococcal infections. Monotherapy has resulted in widespread resistance. Seamus O’Brien. Now, for gonococcal infections, combinations of existing antibiotics, new drugs and alternative therapies are being developed using PK-PD models to demonstrate synergy and reduction in the emergence of resistance. There is an argument for gonococcal infections that all antibiotics old or new should be used in combinations in order to reduce the emergence of resistance and to provide the broad pathogen coverage required to treat the syndrome of sexually transmitted infections.
17:35:03 From Andre de Fusco to All panellists: Accepting the repurposing and combination of older drugs (increasingly frequent in oncology), what solutions have been discussed to address the commercial/business problem? Is it all government financial support?
Anthony Coates. This is another key question. What is the problem? The commercial/business problems have arisen because the cost of development of a New Chemical Entity(NCE) is high, $250-750 million, the cost of sales is $30-100 million per year and the sales price is about $1000 per day. Unfortunately, sales of, for example plazomicin, were too low, so its parent company filed for bankruptcy and all its assets were sold for $16 million. Of the six companies which have entered the market in the past 3 years, four have failed, like Achaogen. Private investors lost their money and have left the field.
Anthony Coates and Dennis Molnar. What are the solutions?
1. Government or not-for-profit or big pharma funds. Jim O’Neill’s report suggested large funds should be made available. In this Webinar he has mentioned the Pasteur Act in USA which has not yet been approved by Senate. We all hope this will succeed because it may provide the much needed market incentives to rescue the antibiotics market. Support through the most expensive part of development (Phase 3 trials) can certainly help replace big pharma and investor loss of financial support. With a reduced cost, there may be flexibility to target narrower indications or charge a lower/more market favorable price to produce profits for earlier-stage and commercial stage investors.
2. Create a new commercially viable way of bringing antibiotics to the market-namely combinations of old drugs. Each of such combinations cost about one tenth of that needed for an NCE to get to the market, and once in the market, these new combinations should be able to compete in a marketplace dominated by generic antibiotics. Until investors return to the antibiotic field, government funding will be needed to get this approach into the market. But, for much smaller sums than NCEs. No antibiotics company has produced “profits” (defined as sustained positive Earnings Per Share) since Cubist more than a decade ago. Success breeds success. Just two decades ago, there were 6 antibiotics that sold more than $1 billion in annual global sales. We must find a way to also sell new antibiotics broadly. Such products would need to address common resistances in broad indications, be safe for broad use, and affordably enough priced to not break budgets. If we can do this with NCEs or new approaches, that would be wonderful. However, synergistic combinations of generic antibiotics are well positioned to achieve all these requirements.
Peter Beyer: Countries need to rethink the way they pay and procure new antibiotics that are significantly superior than current standard of care or overcome resistance in a sustainable manner. Germany has carved out reserve antibiotics from the current price setting system, UK are running a pilot moving away from paying for volume but rather paying for availability.
17:37:55 From Andreas Harris to All panellists: Hello, thank you for your insightful introductions. How does the panel see the potential future and spread of pull incentives in the discovery and production of antibiotics? The US, UK and Sweden have early pilot programmes. Are there other movers in the pipeline, who are the key players that need to come onboard to make pull incentives a success?
Jim O’Neill. As I mentioned on the call, there is currently an important initiative mixed up in the covid-19 stimulus bill, with the name “ Pasteur” Act, which if, enacted, would be effectively some version of the market entry rewards my review recommended, and I still believe in. While Senate control for the Republicans probably complicates it, there is a reasonable chance this could happen. I regard it as the most important pull incentive policy idea since my review finished in 2016. Dennis Molnar. I agree that Pull incentives would be an incredible step forward for supporting more research. However, I would caution that Pull Incentives must also target “commercializable” projects, otherwise we will also need Pull Incentives for commercialization, or spectacular failures will taint these efforts (as Achaeogen nearly did for BARDA).
17:44:31 From Roger Vickery to All panellists: Euronews reported this morning on the progressive loss of availability of antibiotics and other medication as pharma companies phase them out in order to focus on new more expensive drugs. Is it not going to be a very steep climb to get big pharma to take an interest. Is there not room for an entirely new industry and business model? Its happening in new energies.
Jim O’Neill. If the Pasteur Act happens, this would be significant for big pharma, and especially good for true R&D at the biotech level and attract VC interest. Anthony Coates. As Jim says, Pasteur might be a game-changer. But there will always be a need for more affordable antibiotics, and even with Pasteur, it is unlikely that the world will catch up with the relentless rise in bacterial resistance. This is where combinations of old/repurposed drugs(CODs) can fill the gaps. Yes, there is room for an entirely new industry and a new business model. As has been shown in other business fields, when the traditional high cost business model runs into some turbulence, a low cost business model emerges. That is the model that CODs represents. Low cost, fast into the market to address new strains of resistant bacteria, reduce the emergence of resistance and capable of massive expansion over of long period of time. The high cost(NCEs) and the low cost models(CODs) can co-exist in my opinion.
Dennis Molnar. For every big pharma who leaves the antibiotics market, a generics company takes its place. Manufacturing capacity exists for current antibiotics, but it has shifted from branded to generic antibiotics companies.
17:52:48 From Prabha to All panellists: We are developing narrow and more narrow antibiotics – do you see developing diagnostics side by side with an antibiotic?
Seamus O’Brien. This may be required for regulatory approval especially if they are critical for selection of patients in the pivotal regulatory studies. The economic model for diagnostics for small volume drug resistant or single pathogens also needs to be addressed with incentives for development.
17:52:56 From Rithika S to All panellists: Germany’s initiative to set up the Global AMR R&D Hub was lauded. What can multilateral institutions (including G7 and G20) do to effectively tackle the issue of AMR?
Jim O’Neill. I pray that under Biden, G7 and G20 start to ramp up their interest in AMR again, and I do believe under the UK G7 chairing next year in 2021, there is a chance. Seamus O’Brien. There is an opportunity to raise the focus of AMR as the silent pandemic and also for access to antibiotics to be central to pandemic preparedness.
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