A Path Forward for New Antibiotics. Astra Zeneca Responds.

By Guest bloggers 

-     Bahija Jallal, EVP Research and Development, MedImmune

-          Briggs W. Morrison, Head, Global Medicines Development and Chief Medical Officer, AstraZeneca

-          Menelas Pangalos, EVP Innovative Medicines and Early Development, AstraZeneca

-          Manos Perros, VP and Head of Infection Innovative Medicines, AstraZeneca

-          Steve Projan, Senior VP Infectious Disease and Vaccines Innovative Medicines Unit, MedImmun

-       John H. Rex, VP and Head of Infection Global Medicines Development, AstraZeneca

In March 2013, AstraZeneca announced significant changes to our strategy and global site footprint. Going forward, we will concentrate our research investment on three core therapy areas (respiratory, inflammation and autoimmunity; cardiovascular and metabolic; oncology). In addition, we will remain active in infection, vaccines and neuroscience, where we will progress a more focused portfolio in addition to supporting our marketed products.

AstraZeneca has a significant presence in infectious disease R&D. Last year we brought to market ZINFORO (a new cephalosporin for the treatment of serious bacterial infections) and Q-LAIV (the first quadrivalent vaccine for influenza). As David Shlaes notes, our pipeline includes one of the most promising molecules in late-stage development, avibactam. And there is much more to be excited about in our earlier-stage portfolio.

But, the path forward for these promising new drugs is not easy. The challenging regulatory environment is well known — the usual approach to drug approval requires enrollment of thousands of patients into Phase 3 trials. As a result of significant interventions, important steps have been made to facilitate the regulatory pathways for new antibiotics so that increasingly efficient and cost-effective R&D is possible (The Lancet ID 13:269-275, 2013).

This progress on regulatory pathways is exciting but it is not enough. To ensure a steady of supply of use new agents, we must now turn our attention to the other major challenge of R&D for new antibiotics: reward for the investment made by the innovators.

Decades of R&D have produced a range of antibacterial agents which treat once deadly infections caused by bacteria that are not yet resistant. As available agents are often generic and relatively inexpensive, the expectation until recently has been that future antibiotics should be similarly priced.

We believe society will not have a diverse, vibrant pipeline of novel agents unless this pricing model changes. Drug development is costly and we must ensure developers are motivated to work on this challenge. Given the dramatic, curative nature of antibiotics and their corresponding societal value of returning years of life, an appropriate analogy can be made to premium pricing models now accepted for cancer therapies.

Underpinned by steps we have taken towards enabling a “personalized” approach to bacterial infection treatment, such premium pricing models are now widely discussed. As an example, at a 31 Jan 2013 roundtable hosted by the Pew Charitable Trust, one participant noted that when a suitable antibiotic “... is given to the right population, I don’t think anybody’s going to have any issues about reimbursement.” (The Pink sheet 4 Feb 2013)

We are committed to continue work to prepare for this new treatment paradigm. Going forward, we must debate the following:

-          Right drug for the right patient: How will we diagnose the right patients for these new medicines, so that we apply effective stewardship?

-          Advanced diagnostic tools: What diagnostic tools do we need to facilitate effective stewardship, and who will bear the cost? How can we combine new diagnostic tools with new regulatory insights to further reduce the cost of development?

-          Valuing a new drug: How do we reward innovators so that return on R&D investment is attractive and competitive relative to other therapy areas? What data will payers consider as justification for reimbursement at premium pricing?

-          A global challenge: How will premium pricing models be adapted around the world? How can we ensure patient access to these therapies when needed? How will we work with prescribers and physicians to help evolve medical practice towards the new reality?

Antibiotics have an extraordinary ability to improve health: in many ways, modern medicine is made possible by antibiotics. We applaud the recent public comments by Dr. Margaret Chan (Director, WHO) and Professor Dame Sally Davies (Chief Medical Officer, United Kingdom) as these comments further raise public awareness in this matter and are now mobilizing key stakeholders to address the growing challenge.

As a community, we must ensure that suitable antibiotics are always available. Today's anti-infective environment is challenging and will require all stakeholders work together to make the business case so that R&D in infection is both attractive and competitive from a return on investment perspective. We are pleased to be part of that response.

Will Astra-Zeneca be Next?

The news this week is that Astra-Zeneca, as part of its downsizing effort, will cut its investment in antibiotic R&D. This has to be one of the most disappointing developments since Roche first left the field in 1999.  They will, however, continue to support their efforts in oncology.  This misguided misreading of the opportunities is yet another demonstration of the sclerotic thinking of large pharmaceutical companies.  These executives and their commercial leaders are stuck in a world that no longer exists.  What they fail to understand is that antibiotics IS the new oncology!

The regulatory world of antibiotics is changing quickly and radically.  It will now be possible to develop antibiotics more quickly and with less expense than ever before. And, developed correctly, payers are ready to pay oncology prices for new products (see this blog).  More opportunities for non-dilutive support for antibiotic R&D exist now than ever before and some of these large grants can pay for pivotal trials.  Astra-Zeneca has been the recipient of some of these grants. None of this existed 10 years ago – where the large pharma executives still seem to hiding in a time warp.

Antibiotics remain less risky and more likely to succeed once they enter development than products from almost any other therapeutic area.

And that the decision to cut antibiotics R&D is coming from Astra-Zeneca seems all the more incongruous.  Their infection development leader, John Rex, has been at the forefront of all of the discussions with regulators and with payers where these opportunities have become clear.  John has been a leader in devising the rapid development plans that could get us to oncology prices.

While one can understand the plight of large companies like Astra-Zeneca, whose big products are being rapidly eroded by generic competition, it remains hard to understand their decision making process. Although I can imagine exactly what happened.  AZ executives looked at the potential gains from oncology and cardiovascular drugs and even when adjusted for the risk of development they still dwarf gains (in the past) for antibiotics.  But of course I am sure that they did not factor in the kind of prices antibiotics will now command, they failed to account for the lower development costs they will incur and they probably underestimated the risks of their efforts in cardiovascular medicine and oncology.

At the same time, Dr. Margaret Chan and Dame Sally Davies of the WHO and England respectively, are warning about a post-antibiotic era where we will live in a world where mundane surgical care will no longer be possible without extraordinary risk in the absence of antibiotics active against resistant pathogens.  While I still believe that this is somewhat exaggerated, the loss of one of the stalwarts of antibiotic R&D over the last decade will be a tremendous blow to our efforts to avoid such a calamity.

The loss of company like Astra-Zeneca will reverberate throughout the pharmaceutical industry.  Private investment in antibiotics will plunge further in the absence of yet another potential large pharmaceutical partner for academia and biotech. Biotechs and academics with advanced projects will struggle even more to partner their late stage products that they cannot advance into pivotal trials.

It is possible that I am over-reading AZ’s statement to the press.  Perhaps spending less does not mean they are getting out of antibiotics R&D.  Maybe they will be able to continue robust discovery and development activity in spite of the cuts.  But long experience (Pfizer, J&J, Wyeth, etc, etc)  has shown that when a company says that a particular therapeutic area is no longer a high priority, it forshadows the complete amputation of that area.

I would like to remind Astra-Zeneca that if and when they consider their amputation of antibiotic R&D, that they remember that there are other good alternatives to simply cutting and burning.  There are spin offs and other out licensing opportunities that could be utilized.  Astra-Zeneca has one of the most important assets in the late stage antibiotic pipeline – avibactam. Their first priority must be to get this new product to the patients and physicians that need it. 

The View from Asia

I have just wrapped up three days at the ISAAR (International Symposium on Antimicrobial Agents and Resistance) where I delivered one of the plenary lectures.  But I am writing to tell you, dear readers, that no matter how much you read on resistance in Asia – there is nothing like being here and speaking to physicians and microbiologist about conditions on the ground.  NDM-1 is the most common mechanism of carbapenem resistance among E. coli and Klebsiella in Malaysia.  You remember NDM-1 – the superbug resistant to just about everything (with the occasional exception of tigecycline and colistin) that arrived in Europe from India a few years ago.  This is also the superbug that is found in the water in New Delhi and other parts of India and Pakistan. Well its here in other parts of Southeast Asia with a vengeance. In both Malaysia and Sri Lanka over 50% of community acquired urinary tract infection caused by E. coli is caused by strains carrying ESBLs and these are frequently so resistant that oral therapy for the infection is not possible.  So the patients have to be treated intramuscularly or intravenously either as outpatients or in the hospital (as opposed to staying home and taking pills).

(Parenthetically, I have a plea for all who do surveillance for resistance – including the CDC in the US.  Please provide actual patient based incidence rates – resistant infections per discharge from the hospital per unit time).

I learned that 5% of the global pharmaceutical market is made up of counterfeits.  80% of the copies are made in Asia and over 40% of their use occurs in Asia. Most of the counterfeits contain no active ingredient.  Some contain lower amounts of the active ingredient – great for selecting resistance.  Some contain another product altogether – at least they won’t select for resistance.  Some of these counterfeits are actually sold in Europe and the US.

Dame Sally Davies in the UK and Dr.Chan at WHO talk about the impending post-antibiotic era where medical procedures are no longer possible – well its happening and quickly here in Asia. Colistin seems to be running like water in the hospitals here even though we don’t know how well it works, we don’t know exactly how to dose it and we don’t know exactly how toxic it is.  For resistance – this is truly ground zero.

Apparently in some Asian countries you can get carbapenems, our last line against resistant Gram negatives, over the counter without a prescription. Here in Asia they are talking about actually requiring prescriptions for antibiotics.  They are thinking about requiring pharmacies to comply with this policy.  They are considering new labeling laws for antibiotics to prevent pharmacies from selling them over the counter.  But will these new laws and policies actually be enforced?  By whom?  Will corruption undermine these efforts?

So, while antibiotic resistance is a clear public health threat in Europe and the US, it looks like it is already a crisis here in Asia.  Our pipeline, such as it is, can’t mature too quickly for these Asian countries.  But unless we do something about how antibiotics are manufactured, branded and dispensed here, our pipeline will go up in smoke as soon as it hits the streets.

Resistance is Increasing!

Surprise!  The big news this week is that antibiotic resistance is getting worse here in the US.  The CDC has been following carbapenem-resistance in Enterobacteriaeceae over the last decade.  Do they do this in a systematic and prospective way covering all of the US?  Is this a reportable infection?  No and no.  The data they show is still disturbing.  Among Klebsiella, carbapenem resistance has gone from 1.6 to 10.4% in the National Nosocomial Infection Surveillance data and from 0 to 5.3% in the Eurofins TSN microbiology surveillance network over the last decade.  The data only go up to 2011 – so expect 2012 to be even worse. The CDC data does not address carbapenem resistance in other important Gram negative pathogens like Pseudomonas and Acinetobacter. 

It is time for the CDC to start easing off on MRSA surveillance and to start working on Gram negative resistance – especially resistance to our last line of antibiotics for Gram negatives, the carbapenems.  Many of these strains are either completely untreatable or are only susceptible to antibiotics that have not demonstrated efficacy in very serious infections like hospital acquired pneumonia caused by these strains (tigecycline and colistin).  Based on data from 2007, about 63,000 Americans suffered such highly resistant infections in hospitals every year.  That number has certainly increased and may have even doubled since then.

One might cynically ask why the CDC is publicizing these data at this moment in time.  Is it related to funding concerns with the sequester looming?  If so – more power to them – but they need to focus on the emerging resistance issues and public health threats of today.  And – we need prospective active and ongoing surveillance to get accurate population-based incidence rates for these resistant infections.

At the same time, the FDA seems to be trying to reboot.  This reboot is absolutely required for us to have the robust pipeline of new antibiotics we need to combat these resistant infections.  As noted in the last blog, the FDA has been involved in a number of fora recently including a public hearing on the LPAD pathway for rapidly getting new antibiotics active against these highly resistant pathogens to patients who desperately need them.   But they have also stopped following their own guidance on more traditional antibiotic development pathways.  In this regard, I pointed out at the last Brookings meeting that the FDA MUST go public.  Either the guidance documents must be revised to reflect the actual guidance they are currently providing to sponsors (this will take a long time) or they need to publicly note which areas of guidance they are no longer following.  They are allergic to “guidance by pulpit” – but they have to do something to get their current thinking out to the public.

As you faithful readers would have seen from my blog Calling All Large PhRMA back in December of last year, I invited a number of companies who had abandoned antibiotic R&D to get back in.  I believe that Roche-Genentech is dipping their toes in the water with a new deal with RQx to discover new antibiotics active against bacterial signal peptidase.  Whether this can be called a victory for the pro-antibiotics effort or not is hard to tell.  Lots of companies have already broken their teeth at least once on this target – but maybe RQx-Genentech have something special going on.  

In addition to the blog, I wrote several companies.  I had a response from one – who said no thanks.  I know that that particular company is well versed in what is going on in terms of the new regulatory environment and potential for new pricing models for antibiotics – so their decision seems to have been deliberate and strategic for them.  But for the rest – no response. Is this because they have given this possibility careful and informed consideration and decided not to go forward or is it because they no longer have the internal expertise to even think about getting back into antibiotic R&D?  Is it because they couldn’t care less?  I have no idea. 

But the FDA going public might help encourage companies to get back in.  So – FDA – back to you!