Antibiotics - The Perfect Storm - The BOOK - NOW AVAILABLE

Friday, August 29, 2014

Labor-day and Antibiotics


Today is the beginning of the Labor Day weekend here in the US. I find my thoughts turning to all those who fought so long and worked so hard to bring new antibiotics to the patients and physicians who so desperately need them. At the same time, I find it depressing to see that the future of antibiotics is as threatened today as it was a decade ago. This seems true even though the FDA awoke from their Ketek-induced psychosis over two years ago; even though the world has never been so aware of the threat of antibiotic resistance; even though more new antibiotics have been approved over the last year or two than over the previous 10 years; even though there is greater understanding of the economic value of antibiotics today than ever before and with this, a greater willingness of private investors to fund antibiotic-focused biotech. Why are antibiotics still under the gun?

I hate trying to answer “why” questions. I think that the answer lies in a congruence of events. First, there is that big gorilla out there – Pfizer. Pfizer is once again looking for an acquisition – preferably one where the tax bite is less.  The two main candidates people are discussing are AstraZeneca and Actavis.  It just so happens that the entire avibactam B-lactamase inhibitor pipeline of three combinations – all with varying activity against highly resistant superbugs – are owned jointly by these two companies.  Yet Pfizer is the company that jettisoned their entire antibiotic research and development group several years ago.  AstraZeneca is the company that is still considering dumping its antibiotic research effort because they worry, in spite of all the evidence to the contrary, that they will not make a sufficient return on their antibiotic research investment. The loss of the antibiotics efforts of AstraZeneca would be a serious blow to antibiotic research.  The loss of Actavis as well – in spite of all their issues – would only make things even worse. The optimism that currently reigns over private investment in antibiotic research could evaporate overnight. 

Then there is the persistent worry  that nations and societies will be unwilling to make antibiotic research provide an appropriately valued return for the research investment.  So far, there has been much talk, many taskforces and no money.  Show me the money!

Finally, there remains a certain regulatory uncertainty since no one has yet successfully undertaken the kind of feasible trials outlined in both European and US FDA guidance focusing on resistant pathogens.  Until this occurs, or we somehow get more assurance from the regulators that they will, in fact, entertain such designs, this uncertainty will persist.


In spite of all this potential doom and gloom, I remain the optimistic pessimist.  I just can’t help believing that everything will somehow work out such that we do have a future with the antibiotics that we need.  In that light, at the start of this Labor-day weekend, I raise my glass (even though its still early today) to all those who have dedicated their lives to the search for these new antibiotics.  May you all have all the success that you and all the rest of us deserve!

Thursday, August 21, 2014

Ceftazidime-Avibactam - At Long Last?


This week AstraZeneca announced its top line results from two pooled clinical trials of ceftazidime-avibactam in complicated intraabdominal infection. The combination of ceftazidime with the novel B-lactamase inhibitor avibactam is an important piece of AZ’s antibiotic pipeline and is one of three avibactam-containing combinations being developed (we all hope) by the company. Avibactam was acquired by AZ when they purchased Novexel, a biotech that had been spun out of Sanofi-Aventis.  Avibactam (then called NXL-104) was part of the preclinical assets from Sanofi-Aventis upon which Novexel was based. 

When I was at Novexel, I was pleased and surprised that the early clinical and pre-clinical safety profile of the drug was so promising.  In addition, avibactam inhibits several  classes of B-lactamase beyond the single class (A) inhibited by the currently marketed inhibitors like clavulanate and tazobactam. One of these is the KPC carbapenemase responsible for so much carbapenem resistance among the Enterobacteriaceae. Thus, avibactam combinations hold out the possibility of effective therapy for these highly resistant infections.

According to the press release, the pivotal phase III trials, RECLAIM-1 and RECLAIM-2 demonstrated non-inferiority of ceftazidime-avibactam plus metronidazole to meropenem in complicated intraabdominal infection.  The statistical analysis demonstrated that the non-inferiority margins of 12.5% in Europe and 10% in the US had been achieved.   AZ and their partner Actavis (ex-Forest-Cerexa) are pursuing other indications for ceftazidime-avibactam including complicated urinary tract infection, hospital acquired pneumonia and efficacy in the treatment of ceftazidime-resistant infections.

Based on current guidelines in both Europe and the US, a single trial would not be sufficient to support approval for marketing the compound.  It seems like an additional trial, most likely cUTI or the ceftazidime-resistant infection study, will have to be submitted along with the RECLAIM data to garner approval.  When I queried John Rex (Vice President and Head of Infection, Global Medicines Development at AstraZeneca) on this, he provided little in the way of information beyond what is available in the press release. But the timeline for submission of the dossier for Europe is first quarter 2015.  I surmise, therefore, that at least one of the other studies will have to complete for submission to occur. I also presume the same would be true for the submission by Actavis to the US FDA.  (Actavis is responsible for the US filings and marketing according to the agreement between the two companies).

The two companies also are developing two other avibactam combinations. When I asked John for an update on ceftaroline-avibactam he just noted that it is in phase II development for complicated urinary tract infection. But it has been there forever.  Unlike ceftazidime-avibactam, the cefaroline combination would not have activity against most strains of Pseudomonas, but would be active against MRSA.  It could thus be positioned as more of a hospital workhorse type drug while ceftazidime-avibactam could be more of a Gram-negative ICU type antibiotic.  Is this too much overlap?  I suspect the partners are cogitating this and that his accounts for some of the delay.

The other combination in development is aztreonam-avibactam that John notes is in phase I where it has also been for slightly less than forever. This is a particularly important drug since it could offer activity against the metallo-beta-lactamase producing pathogens such as those expressing NDM-1.

While I rejoice at the prospect that AZ and Actavis will soon be submitting a dossier for ceftazidime-avibactam, I am at the same time led to question their dedication to the avibactam combinations and to antibacterial development in general.  Its generally a bad sign when your CEO says that he will reduce resources for your therapeutic area and then tries to sell you off or partner you with someone else.

Novexel was purchased at the end of 2009.  The phase II data for ceftazidime-avibactam were available by the end of first quarter 2010. The phase III dossier won’t even be filed until first quarter of 2015 and approval will not occur until the end of that year if all goes well. I count over five years here. What have they been doing for five plus years?  If this were a promising oncology drug, it would be approved and marketed by now.  If the drug were being developed by another company (which one???), it would already be approved and marketed.


AZ and Actavis are entrusted with these very important weapons against resistant pathogens. Now is not the time for them to drop the ball!

Sunday, August 17, 2014

8 More Ways

Matt Metz and I have just published an article in Antimicrobial Agents and Chemotherapy that I wanted to highlight for you here.  We provided eight strategies in addition to those previously proposed by Bartlett et. al.  Our list is a little more unexpected and subtle than the more obvious strategies you may have seen elsewhere, which is why I think its worth highlighting our list here.  For details, please see the link to the article above.

1.     Reduce Clinical Trial Risk and Uncertainty. Basically, we ask the FDA to make their data on previous antibiotic trials available such that external, historical controls can be constructed using pharmacometrics.  This would allow for the feasible conduct of rapid superiority trials for new antibiotics targeting resistance.
2.      Boost Market Value for Not Feeding Animals Antibiotics. Here we ask the USDA to develop a label certifying that growth-promoting antibiotics have not been used for the product so labeled.
3.      Strengthen Regulation of Farm-Feeding Antibiotics.  Here we suggest that the EPA require manufacturers of antibiotics for agricultural use to generate data on the environmental and public health consequences of such use.  The EPA would then set standards under which such use would be allowed (or not).  They already do this for fungicides, insecticides and rodenticides – why not for “bactericides”?
4.         Unify US Government Efforts.  We are just asking that the federal government do a better job of coordinating efforts of all its agencies in this regard and that this coordination be given enough teeth for enforcement that the agencies will be incentivized to actually work together on this as opposed to being in constant competition.
5.      Incentivize Early Sharing of Data. Although much is now published early online – there are still delays for reviews and revisions.  While these lead to higher quality publications, sometimes these delays may be deleterious to the public health.  We just ask that journal Editors be aware of when something like NDM-1 is being reported for the first time that speed of public notification might be more important than worries about prior publications and other editorial concerns.
6.      Assure the Quality of Generic Antibiotics. We just ask that the FDA be a little more strict in its requirements for generic manufacturers of antibiotics.  In this case, the generic must achieve a level of pharmacokinetic equivalence within a 90% confidence interval compared to the branded product. Given the complexities of the pharmacodynamic relationship between activity of the antibiotic against bacteria in vitro and its presence in human tissues in vivo, maybe we should be more demanding here.
7.         Level the Playing Field between New and Old Antibiotics. Here was ask that the FDA continue along its current trend of re-evaluating generic antibiotics to make sure that they will meet today’s FDA standards for branded products.  That is frequently not the case – especially as far as determining breakpoints is concerned. Re-review of breakpoints for generics is a key activity for the FDA in our view.  
8.         Assure value-based pricing of new antibiotics. You’ve heard this one from me before.


Monday, August 4, 2014

Making Antibiotics Attractive - HELP!

For the last six months I have been diligently working to establish an international conference on antibiotic pricing and reimbursement strategies. And I obviously need help. The conference would be a meeting with payers – that is large insurers like Aetna, United Health Care and Kaiser in the US and with national authorities in Europe and in Asia.  The main goal of the conference would to provide payers with an understanding of what kind of data they would have from feasible antibiotic trials targeting resistant pathogens (LPAD-like drugs) and the kinds of data that might be available outside such trials.  The payers would then respond as to their needs for providing the kinds of reimbursements that would be required to provide a return on the investment of pharmaceutical companies in such products within the context of feasibility. Various payment models would be discussed (see my last blog).

To organize this conference, I have been in contact with the Pew, The Center for Disease Dynamics and Economic Policy, the IMI (indirectly), and with a number of pharmaceutical companies.  I have discussed the project with some South African authorities.  I have approached friends, colleagues and consultants.  While everyone has been helpful on their own individual level, the conference is going nowhere. Among my pharmaceutical company contacts, among the 250 things on their desks, this idea has a priority somewhere between 249 and 250. I have been unable to make contact with any insurers or national health authorities. And as yet I have no commitment for funding – understandably since I don’t have key participants lined up yet.

I think there are several factors working against this idea.  The main one being that no one with money (payers) wants to discuss spending it in a public forum. Making commitments publicly probably scares them. Antibiotic stewardship is OK.  Discussing antibiotics for growth promotion or prophylaxis in animals is OK (not that we in the US want to do that either). Discussing using anti-influenza drugs for flu rather than antibiotics is OK. But there is no getting around the fact that we will and do now need new antibiotics active against resistant pathogens. And there is no way for us to have those antibiotics other than investing.  

Another factor working against this concept is the multitude of task forces working around the idea – nibbling at its edges. There is the Transatlantic Task Force on Antibiotic Resistance (TATFAR), the President’s Council of Scientific Advisors whose report is imminent (PCAST) and the new task force put into place by David Cameron. Of these only the UK group established by Cameron is likely to broach payers – but they have a very EU focus. These efforts, in my view, distract us from the goal in many ways.  We need implementation of existing ideas or a discussion that leads to implementation of new ideas.  The key word here is implementation.


I don’t think we need new task forces or think tanks.  I think we need to get payers to understand what is at stake and to get them to become stakeholders in this struggle. If anyone can help get this done – either do it yourself or let me know what I can do.  But right now, I’m at a standstill. Just email me directly or through my LinkedIn account.

Wednesday, July 23, 2014

Antibiotics - Misguided and Paralyzed

Back when I wrote my book during 2009-10, I was disappointed and frustrated with the US efforts at antibiotic regulation compared to the rational and advanced view in Europe. Europe made the development of new antibiotics against resistant infections a top priority for their regulatory body – and the EMA (European Medicines Agency) came through. The US had no such stance and it took the frustration of a few leaders in the upper management of the FDA to finally realize that they were driving on the wrong side of the road and taking us into a head-on collision.  Although the results of their “reboot” are not perfect, and there are a number of things I would like to change (particularly their endpoints for trials), I think that as far as regulatory reform goes, we have come a long way since those dark days when I was hammering away at the keyboard.

Our next challenge is to do the best we can to contain resistance and at the same time to be prepared for its inevitable emergence. In facing this challenge, no one, not the US, not Europe, not Asia, no one is anywhere near ready. We have task force after task force working on the problem and mostly coming up with the same old same old. The GAIN act in the US is a great example.  Politicians crow about how they are helping in the fight against resistance while not spending precious taxpayer dollars.  But the GAIN act has not been sufficient to entice large pharmaceutical companies to get back in to the antibiotic R&D effort. And that result was predictable and predicted by yours truly among many others. The best thing about the GAIN act was that it required the FDA to get its act together. But on the business side, it offered only a patent exclusivity extension that was modest at best for antibiotics active against resistant strains.  This benefited only a small number of small companies that had products facing the end of their patent lives when they were introduced to the market.
 
If we want to restrict the use of antibiotics to avoid the emergence of resistance for as long as possible, the first thing to do is to restrict their use in agriculture.  In spite of statements by the PCAST – I believe this is a no-brainer.  Next - we have to provide a business model that makes sense.  The GAIN act is not going to cut it and the industry has demonstrated that by, for the most part, voting with its feet. Although two companies have re-entered the antibiotics game in recent years (Sanofi and Roche), many more have left. Now we have AstraZeneca threatening to depart as well.

In an article that appeared in the New York Times today, the industry decries the increasing cost of bringing new therapies to market and notes that antibiotics are on the bottom of their priority list because their return on investment is so low.  But it doesn’t have to be that way.  In the same article, the ex-head of R&D at Pfizer, John LaMantina says that firms are pursuing niche diseases and orphan indications where the return is lower but where the costs are much lower. Antibiotics of the future are going to fit in exactly that scenario – they will be niche products that will cost less to develop and will bring in less total dollars, but where the value will be attractive.  If, that is, we can get our societal act together and make sure that happens.

What business models would work and how would this effect taxpayers and governments?  First – we all must realize that there is no free lunch.  Either we spend money on antibiotics that can cure resistant infection, or we pay the price in longer hospital stays, more time on ventilators and in lives lost. My choice is the former- I don’t know about you. 

1.  The traditional pricing model.  This is what Gilead is doing with Solvadi – its new drug for Hepatitis C infection. In this scenario, small numbers of patients with demonstrated infection with a resistant pathogen or with a high risk for such would receive an antibiotic active against the resistant strain and pay up to $30,000 for a course of therapy.  The cost would be covered by health insurance, medicare, Medicaid, government and other payers in the US and by the national health authorities in Europe (good luck there).

2.  Guaranteed government purchases.  Here, governments would guarantee a certain upfront purchase of the antibiotic at the time of approval by the regulatory agencies. The price charged per course of therapy in each country would depend partly on the amount of its advance purchase. This serves to de-link the drug to some extent from the need for the company to spend money on marketing.  Marketing costs about 25-30% of total sales of any antibiotic. Also, the guaranteed purchase, coming right after approval, not only saves marketing spend that is normally especially intense at launch, but also increases the overall value of the antibiotic by decreasing its associated costs.

3.  The wild card patent exclusivity.  This is something I pushed with the Infectious Diseases Society during the preparation of their Bad Bugs No Drugs white paper. In this formulation, a drug company that brought forward a new antibiotic would be allowed to have 6 months to two years of additional patent exclusivity on another drug of their choice.  For example, Pfizer might have been able to have additional time to sell its branded Lipitor that was selling $15 billion per year. When the IDSA tried to lobby this in congress, they met a brick wall.  The generic manufacturers, insurers, and almost everyone else was against it. 


But look – we have to pay somehow.  I offer a few choices for how we might pay – but I am sure there are lots of other choices that I have not considered.