IDSA Update on Antibiotic Development - Hope or Stagnation?

In a recent publication in Clinical Infectious Diseases, the Infectious Diseases Society of America (IDSA) provides its view of the state of antibiotic development.  They report that there are seven new antibacterial agents that have reached phase II or later stages of development.  Of these, one is from Polymedix, which recently declared bankruptcy.  Their compound, brilacidin, had toxicity issues during clinical trials. So that takes us down to six.  Of these six, three are combinations of beta-lactams with a novel B-lactamase inhibitor, avibactam.  This compound was originally discovered in Roussel-Uclaf-Aventis then spun out with Novexel.  Novexel was purchased by Astra-Zeneca who has taken these combinations, with their partner Forest Laboratories, into phase II and III trials. Although this pipeline provides hope, the IDSA correctly notes that there are precious few compounds that provide coverage against highly resistant Acinetobacter and few deal with metallo-B-lactamases like NDM-1. 

Eravacycline, a new tetracycline, does provide improved activity against Acinetobacter compared to tigecycline, but whether this will translate in the clinic is as yet unclear.  A compound that has not yet reached late stage development and hence was not cited by the IDSA, aztreonam plus avibactam, should provide activity against metallo-B-lactamases assuming it can avoid toxicity during its ongoing (but currently on hold) phase I trials.

IDSA says that it was unable to identify phase II or III trials in community acquired pneumonia – but they must mean for drugs active against Gram negatives since Cempra’s solithromycin is currently being studied in phase III for this indication.

The IDSA states that much of antibiotic discovery and development is now centered in biotech.  This is clearly true. But, for the most part, they ignore the critical relationship between large pharma and academic researchers and biotech.  When I speak to investors (I do a great deal of this), they routinely tell me (confirmed at the last Brookings meeting) that the only exit they consider worthwhile is an acquisition.  So – the option of “going it alone” to the market and financing phase III by going to the public markets is not an option for investors at the beginning.  This becomes a poor second choice for them if they are unable to partner their company. When investors think of partners, they think of smaller companies like Cubist and Forest and the large pharma companies.  But even including these small companies, there are probably only six or so potential partners and this number remains unstable (just look at Astra-Zeneca).

Therefore, to keep investors interested in antibiotic start-ups, we need (desperately) deep-pocketed companies willing to invest.  I made this case at the last Brookings.  We MUST keep the current large pharma players in the game and we MUST attract new players if we are going to be successful. But we are not succeeding if the Astra-Zeneca situation is any sort of indicator. We also need a backup plan – in the likely case that we ultimately fail.

To keep the deep pockets in the game, push incentives and a clear pathway to an attractive (not just break even) economic return will be required. My own view of this is that tax credits are not nearly enough (except for small companies like Cubist or some publicly owned biotechs). But large R&D grants such as those provided by BARDA clearly work.  I remain a little skeptical about IMI – but if the EU taxpayers are willing to do this – who am I to argue?

In terms of the pull side, government market guarantees are also likely to be too risky a gamble for large pharma – just look at the mess our government is in to say nothing about a chronically dysfunctional Europe.  Value-based pricing seems like the way to go.  And even though payers seem willing to provide such prices, large companies like Astra-Zeneca simply don’t believe that this is true.  We must convince them.  It may be that no one will be convinced until it happens – I’m just not sure we will last that long. The first product to cross this finish line where a higher (but not the really high) price could be attained will, in fact, be Astra’s ceftazidime-avibactam.  They just need to persevere to get it across the finish line.

How about a backup plan?  We better figure out a way to train researchers in antibiotic research because this expertise is dwindling faster than a speeding bullet.  I believe that the best place to train new (or old) researchers is in industry – either large companies still active or in biotech who know what they are doing (there are only a few of those).  The NIH has said that they would help here (I have this on tape!).

Public-private partnerships have to be part of our back-up plan – but again, without adequately trained researchers we are going to waste a lot of money for a long time while these folks gear up.  I’m worried that investors will lose patience before we get where we need to be.

I applaud the IDSA’s efforts to keep us focused on this problem.  I would just ask that their own focus be a little more laser-like.

India, Novartis and Antibiotics

Disclaimer – I am certainly not a patent lawyer and can’t even play one on TV.  But this is an important story that we should all try and understand.

In a recent decision on Novartis’ patent for Gleevec, an anti-cancer drug, India’s Supreme Court ruled that its patent was invalid.  Gleevec, like some anti-viral drugs, is a miraculous controller of (but does not cure) chronic myelogenous leukemia, an otherwise fatal disease.  The drug must be taken chronically.  In the developed world, it sells for up to $70,000 per year while the generic version manufactured in India sells for $2500 per year according to the New York Times. The question is – is this ruling anomalous and specific for this particular situation or does it have serious repercussions for patients, physicians and the pharmaceutical industry beyond Gleevec itself?

The ruling is based on section 3 of India’s 1970 patent law, which states that a new form of a molecule that does not show increased efficacy cannot be patented. India passed a new patent law in 2005 to bring it more in line with those of World Trade Organization countries, but apparently limited this new law to drugs patented after 1995. Gleevec’s original patent was filed in 1993 (alpha crystal) followed by a separate patent for a different crystalline form (beta crystal) in 1998 in India (and elsewhere).  The beta form, it claimed, was superior for manufacture and made the alpha form obsolete. This argument is accepted for patentability by World Trade Organization member states. But since the new crystalline form apparently did not show or was not studied for increased efficacy compared to the original form, it was ruled that it was outside the 2005 and the 1970 patent laws in India and therefore not patentable.

The court in India was asked to provide a balance between India’s status as a trading partner in the world and its position as the pharmacy for the developing world. India is an important manufacturer of generic drugs for the developing world.  The New York Times noted that 80% of the active ingredients of all drugs are now manufactured in India and China.

At the same time, India, China and a number of emerging economies in Asia and elsewhere are rapidly growing markets for pharmaceuticals (at least until last year).  Bayer’s deal with Trius for sales of their antibiotic that just completed its phase III trials is an example of the industry recognition of this fact. This growth comes in large part from home-manufactured generics but also comes from multi-national branded products.  The reason for the latter is that there is a growing middle class population in these countries that can afford to pay for branded drugs and recognize that their home-grown generics are of variable quality.  An example of this is the fact that the FDA recently withdrew approval for 27 generic drugs in the US manufactured by Ranbaxy, an Indian generic manufacturer, for quality problems. Europe has done the same.

But for the industry to be able to have access to these growing markets, their patents will have to be recognized. If the markets of emerging economies are isolated from the rest of the world, they may have access to cheaper medicines, but those medicines may also be more dangerous and less well regulated than branded products. Lets also remember that generic companies do not develop new drugs.  Pharmaceutical companies that brand new products develop new drugs.  Without access to these emerging markets, the pharmaceutical industry will undergo even further consolidation and cost cutting.  This will of necessity lead to less research and fewer new drugs for all of us.  Is this the outcome that India wants?  Do any of us want this? 

We clearly need a pathway for those less fortunate in the world to have access to new medicines while at the same time preserving intellectual property.  The pharmaceutical industry has tried (perhaps not so successfully) to address with with various rebate and price reduction programs. They probably need to try harder. 

In the case of antibiotics per se – India is the epicenter of antibiotic resistance in the world.  NDM-1, one of the most resistant super-resistance elements around was born there and is endemic there.  It is spreading from India to the rest of the world. Does India want to risk being without needed new antibiotics to fight these infections?  Do any of us?

So lets hope that the Gleevec decision is an isolated one and that the industry will not see this as a retrenchment in India but rather as an anomaly.

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.