Why Allergan thinks an 'open science' approach can help it develop new antibiotics
Earlier this week, researchers reported evidence a second U.S. patient likely had been infected with a strain of E. coli genetically resistant to colistin, an antibiotic considered to be the last line of defense in fighting bacterial infections.
Scientists had previously found colistin-resistant E. coli bacteria in a urine sample of a Pennsylvania women being treated for a urinary tract infection. In both cases, the bacteria carried the mcr-1 gene, known to be a marker of resistance to colistin.
And on Thursday, the Centers for Disease Control and Prevention reported the bacteria which causes gonorrhea, Neisseria gonorrhoeae, appeared to be developing increased resistance to the only two antibiotics left which still reliably cure the sexually-transmitted disease.
As concerns over antibiotic resistance mount, new proposals are being mooted to improve stewardship over existing antibiotics and incentivize development of new agents.
BioPharma Dive spoke with David Nicholson, head of R&D at Allergan, about his company’s continued efforts to develop novel antibiotics, even as other companies have dropped out of R&D.
The following Q&A has been condensed and lightly edited for clarity.
Where do anti-infectives fit in Allergan's approach to R&D?
Nicholson: At Allergan, we practice this model that we call open science. That means that we have a relatively small internal discovery research effort. We fill our development pipeline through collaborations with academia, biotech, small and large pharmaceutical companies.
Anti-infectives are right up there - one of our seven therapeutic areas. Clearly there is a huge need for the development of novel antibiotics.
Do you think the priority on R&D in the anti-infective space has increased over the past 5 to 10 years as antibiotic resistance has become an increasing worry?
Nicholson: What we have seen is that many pharmaceutical companies have dropped out of R&D and in the antibiotic space. We haven't.
I think everyone is aware of the dangers associated with development of resistance to antibiotics.
Having said that, the commercial return on antibiotic R&D has been challenging because the prices that you can charge for antibiotics are challenging in terms of getting a decent return on your R&D investment.
That is partly because a lot of people have moved away - including ourselves - from developing broad-spectrum antibiotics that work against all bugs. People have done that because of the challenges in finding those novel antibiotics.
But also because if you develop resistance to them, you are causing a huge problem. Since they are used against all bugs, the likelihood that you are going to develop resistance is greater.
You run into the problem then of developing agents for particular groups of bacteria where the incidence of infections with those bacteria is less. Then the clinical trials become more difficult to perform, they take longer to perform, or sometimes are more expensive to perform. It is more difficult to get to the market.
What are your thoughts on rewiring the economic incentives for developing antibiotics?
Nicholson: This is an evolving area and we are seeing it play out over the next few years. I would make a couple of points.
One is that it is great that President Obama is taking the lead here with the initiative to encourage people to work on novel anti-infectives.
But also the FDA is living up to some promises that it has made and making it somewhat easier to get registration and conditional approval for antibiotics.
So, for instance, our own agent Avycaz was approved last year for the treatment of urinary tract infections and intra-abdominal infections on the back of Phase 2 data.
Had the FDA previously been more demanding on having Phase 3 data first for anti-infectives?
Nicholson: Oh, absolutely, yes. This was a big change for the FDA and I think they absolutely should be applauded for doing that.
So there is a lot going on in the antibiotic ecosystem to encourage people to continue working in the field.
I would say that once a company has stopped, it is very very difficult to restart. Groups get defunded, expertise gets lost. It takes years.
Some proposals have talked about a prize for a novel agent rather than relying on that new agent to pay for itself. Is that worth pursuing?
Nicholson: Some people have proposed prizes. The prizes probably are somewhat more important to smaller companies than companies like Allergan. But that's great. Because we have an open science model where we want the small company world to be actively engaged in antibiotic R&D.
You touched earlier on the idea of moving from a broad-spectrum antibiotic to more niche indications. Are there other ways the concern over antibiotic resistance feeds back into where you focus R&D?
Nicholson: [For example] Avycaz is a combination of ceftazidime and avibactam. Ceftazidime is a super antibiotic against certain gram-negative bacteria—it works really well. But over the last few years, resistance has developed to ceftazidime, so there are now ceftazidime-susceptible and ceftazidime non-susceptible bacteria.
Avibactam is an inhibitor of enzymes that break down ceftazidime bacteria. The reason why you now have non-susceptible bacteria to ceftazidime is they develop a lot of the enzymes that break down ceftazidime quickly. So it doesn't work anymore.
But by combining ceftazidime with avibactam, which inhibits these enzymes in the bacteria, the non-susceptible bacteria become susceptible again.
Do you think that is a model you can follow for other drugs?
Nicholson: I do, yes. In our pipeline we are also developing aztreonam together with avibactam. We are now using the same trick of combining avibactam with aztreonam. Aztreonam works against different groups of bacteria than ceftazidime. They are also developing resistance and we can use the same trick with avibactam.
Is there any concern over developing a new product which people might counsel to be held back or used as a last line of defense? How much does the idea of stewardship over antibiotics use weigh on the commercial potential of a novel agent?
Nicholson: There should be stewardship over antibiotic use because the development of resistance to antibiotics can be slow, hindered, or even reversed with appropriate stewardship.
Of course, to some extent, that does mean reserving some antibiotics for certain uses. There has to be a dialogue between payers and manufacturers regarding the price of those agents if we are going to develop them.
If we get widespread resistance to antibiotics, so that we don't have any new antibiotics and resistance to all the ones we have got, people are going to die again.
I'm not sure everybody understands that. Drug pricing is a huge issue today—and I don't want to start talking about drug pricing—but people need to think about all of this: resistance to development of antibiotics; how do we make certain people still develop them; and the commercial return.
What would you point to as key differentiator between Allergan's R&D approach in anti-infectives and what other pharma companies have tried?
Nicholson: For the Allergan R&D approach, the open science approach, we need to fill our pipeline from what is going on in the outside world. To me, one of the key features of that is we look with an open mind at everything that is going on in our therapeutic areas of interest in the external world - which is much more than any one company can ever do, no matter how big that company.
We are at one end of the spectrum; we only do a very small of internal research. A lot of other companies do much much more.
All pharmaceutical companies now in-license and collaborate. But we are at the extreme end of the spectrum where we only do it. We want to pull things in. There is no internal competition.
By following exclusively this open science model, we can look at the entire external R&D pond to fill our pipeline.
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