Billionaires are NOT Privatizing Antibiotic Research

A lengthy article appeared today in the New York Times entitled, “Billionaires With Big Ideas Are Privatizing American Science.” The author, William Broad, is a science reporter for the Times.  He notes how government funding for research has declined in real dollar terms for years. The chart below shows that in terms of constant 1995 dollars, the overall NIH budget has been falling for the last decade. (Click on the figures to enlarge). This has been paralleled by an ever-decreasing success rate in funding grants from investigators (second chart).  During the years I was reviewing for the National Institutes for Allergy and Infectious Diseases (NIAID), their payline was never over 10%.  That means that less than 10% of the grants we would review would get funded.  At the worst, the payline was around 6%.  One meeting, maybe 30 reviewers met in the basement of a hotel somewhere for two days and scored about 110 grants.  Seven were actually funded. Don’t get me wrong.  In the study section where I was reviewing, there were only a small number of truly deserving applications – but that number was certainly more than 6%. Reviewers typically spend a minimum of two hours reviewing each grant and writing up a report of their review. Of course, someone has to do this work – but it’s no longer me. The point of this is, as Mr. Broad has pointed out, government funding for research is going down the toilet in this great world power of a country. (Caveat – BARDA has been a wonderful exception here).

What appears to be happening is that, increasingly, billionaires are funding research.  According to Mr. Broad, what are the areas most likely to get money? Cancer – especially prostate cancer (most of the billionaires are men and some have had prostate cancer) - surprise. Other subjects popular among the philanthropists include the environment, exploration, aging and genetic diseases. Gee – what is missing from this list?  Oh – antibiotics and antibiotic resistance! The closest thing we get to support for that comes from the Gates Foundation and their work on malaria and TB.  This is wonderful and sorely needed – but what about resistance among Gram negative bacilli?  What about new antibiotics to treat resistant infections?  If we leave this totally up the pharma, we could be in trouble.  Don’t we need to hedge our bet here? Apparently, all the talk of the second coming of the pre-antibiotic era has not been enough to get the attention of the billionaire research patrons.  Why not?

I think it’s all about whom you know and who knows you.  I just don’t hang out with billionaires.  Does anyone out there have a line into a billionaire who might be interested in establishing an antibiotics research institute?  Lets make it non-profit and evergreen. Lets make it competent and staff it with academics who have spent time in industry and with ex-industry scientists with expertise on antibiotics.  There must be a ton of them out there looking for jobs given what’s been happening in pharma over the last 15 years. We could even make the institute, at least partly, geographically dispersed and connected virtually.

In the meantime, we have to hope that more pharma companies will get back into the antibiotic game and that they will do so competently.  I don’t think that there is any hope for a strong presence of government funding here.

Roche; Antibiotics - a Perfect Storm Twofer

This blog is a twofer.

First, I want to talk about Roche’s recent antibiotics deal and what this says about companies who get back into the antibiotic R&D game after having been out for many years. Roche recently reported a deal with a company called Discuva. According to their website, Discuva has a technology (SATI) using transposon mutants of bacteria and bioinformatics to help figure out why compounds that might have antibacterial activity work and potential mechanisms of resistance for compounds that don’t work.  First – a small disclaimer.  I have no knowledge of the specific technology Discuva is using and everything I say after this sentence could be entirely wrong (but I doubt it). To those of us who went through the genomics era of antibacterial research during the 1990s, and that includes people like Wolfgang Keck who was at Roche at the time, this is déjà vu all over again. Unfortunately, most of the compounds pulled out of chemical libraries that have activity, especially those with activity against Gram negative pathogens, are non-specific toxins.  So a target or targets will never really be discovered.  There are those that might be bona fide antibacterials with more than one target.  Many researchers believe that this is a good thing since it limits the possibility for mutational resistance.  But this also means that is harder for Discuva’s technology to identify the targets.

I am not convinced that this sort of approach is any better than the kinds of things one can do in one’s own laboratories with people who know what they are doing. And this brings me to the apparent problem at Roche.  Maybe they don’t. Who would be surprised if, after having pulled out of antibiotic R&D 15 years earlier, Roche no longer has the expertise it did during Wolfgang Keck’s time there? And this is the conundrum faced by companies who want to re-enter this area.  They have lost all their internal expertise.  So hire it, you say.  Right.  But who decides who to hire? Use consultants – like me for example.  Well, I’ve retired, although they never called anyway. But again – who chooses these consultants and who will be considering their advice?  Getting back in is not impossible, in my view, but it will take time and the learning curve will be steep.  I think Roche is in the first phases of this learning curve and I anxiously await further developments.  I just hope Roche of today has more patience than it did in 1999.

 

Next, I want to talk about antibiotic toxicity. 

In an article that appeared recently, Rao and coworkers examined the incidence of all cause mortality and serious cardiac arrhythmias occurring after 5 or 10 days of antibiotic therapy in a group of veterans treated with 1.6 million courses of drug.  This group differs from those in previous studies in that the cohort has more serious comorbidities than most other studies.  The most common problems include chronic lung disease, cardiovascular disease and diabetes – pretty much what you would expect in an aging veteran population. The rates of these events were 15 per 100,000 courses of therapy for amoxicillin given for 5 days up to 71 for levofloxacin given over a 10-day course. The baseline numbers are higher than I would have expected given previous FDA and other data – but this may be related to the higher risk groups studied here. To give you some other examples:  Chloramphenicol, which is virtually never used anymore, caused an irreversible, fatal anemia in about 1 in 50,000 to 1 in 100,000 course of therapy. This could and did occur in young, otherwise healthy patients. Telithromycin (Ketek) caused serious liver toxicity (not leading to death) in 1 in 100,000 to 1 in 200,000 courses of therapy and was withdrawn from use for bronchitis and sinusitis for this reason.  Augmentin – a combination of amoxicillin and clavulanic acid, causes serious liver toxicity at roughly the same rate as telithromycin – but is still widely used. When amoxicillin resistance ranges from 10 to 35% among respiratory pathogens and with azithromycin resistance at about the same level, what should the physician do?  Levofloxacin resistance remains at about 1% in those same respiratory pathogens.

The study by Rao and colleagues is a welcome and needed addition to the database on antibiotic toxicities.  It does not look at other toxicities like serious liver damage. And, it does not consider the necessity or appropriateness of the therapy used.  Until we have a good understanding of risk benefit for all these drugs, generic and branded products, physicians will not have all the information they need to make treatment decisions.  On the other hand, even with the new information, other than pausing before using antibiotics when they are not truly needed, I’m not sure the data provided by Rao will allow physicians to make different antibiotic choices for those patients who need antibiotic treatment.

Bob Moellering - Another Terrible Loss

It is both ironic and tragic that in this year, after we have come so far in paving the way for the discovery and development of new and needed antibiotics, we have lost so many of those who have fought this battle for so many years.  In the last 12 months, we have lost Don Low, John  Quinn and now, I am deeply saddened to announce, Bob Moellering passed away last Monday at the age of 78. 

I first met Bob in the mid-1980s.  A number of researchers working the area of antibiotic resistance met in Boston to discuss our impression that the NIH was not funding this research.  Bob was one of those present as were Stuart Levy, Gordon Archer, George Jacoby, myself and a few others. In meeting, we realized that we were probably correct in our suspicion and we engaged the NIH (Bob Quackenbush if I remember correctly) to provide us with their data on grants funded over the previous 25-30 years where antibiotic resistance was the subject of the research.  They provided us with a rather long list – but only a few had anything to do with the epidemiology or mechanism of bacterial resistance to antibiotics. The NIH apparently realized we might have a point and they scheduled several workshops to explore the question.  Science magazine thought we were “disgruntled.” All of this came to naught until one of Bob’s students, Lou Rice, along with Steve Projan and a few others, finally were able to convince the NIH to establish a new study section to review grants on resistance.  This occurred 20 years after our little group first met in Boston and suggested that a new study section was one of the key remedies to the problem.

After that time, I came to know Bob well as a colleague even though we never became close friends.  We kept trying to schedule time together either at our place in France or his place in Italy – but our calendars never meshed. I regret that we could never get closer to each other.

Bob never changed his focus.  He knew that antibiotic resistance was going to be an ever-present problem.  He remained a practicing clinician and saw patients suffering from infections caused by highly resistant pathogens all the time. He understood what this meant to his patients and for himself. Over the years, we served on many pharmaceutical company advisory boards and consulting sessions together.  Many were formed or held at my own behest during my years at Wyeth or later when I was consulting. Bob always thought that having more choice in antibiotic therapy was much better than no choice or even limited choice. He also realized, as does anyone with experience in pharmaceuticals that any compound that has not yet made it to the marketplace and some that have can always fail. Competition should be dissuasive, but only up to a point. Having seen so many compounds come and go he developed a wealth of experience, knowledge and, most importantly, perception and vision.

One of Bob’s great attributes was his ability to criticize politely.  I remember several sessions where he would ask a probing question – like, what if, or – can you explain your basis for saying that . . . Sometimes, even I, and I thought I understood Bob pretty well, would have to think about his questions in retrospect after the meeting was over before I could nail down the critique he offered. 

Bob was a big picture sort of guy.  Bob’s viewpoint, though, was always that of someone at the bedside – but in a big picture sort of way. Sometimes it was hard for those of us in the middle of the ocean to rise and see where the land was. Bob was an important guide in that respect.

I offer my most sincere condolences to his family and friends. I miss him already. 

The family has suggested that for those interested, contributions could be made to a yet to be established fund in Bob’s name at Beth Israel Deaconess Medical Center. Send checks to Beth Israel Deaconess Medical Center, Attn: Development, 330 Brookline Ave., Boston, MA 02215. Please make checks payable to BIDMC and include Robert C. Moellering, Jr. M.D. in the memo line.

Forest - Actavis?

I knew that something was going on at Forest. 

For those of you that don’t know, Forest Labs is a US-based medium sized pharmaceutical company that was most well known for selling Lexapro – an antidepressant.  But a number of years ago, it acquired the rights to a drug now called Teflaro (ceftaroline) – an intravenous antibiotic that works against some Gram-negative bacteria but also against the MRSA superbug.  To do this, they acquired Cerexa – the company spun off from Peninsula to hold Teflaro. They kept Cerexa, a company run pretty virtually, somewhat intact because Cerexa had all the antibiotic expertise – Forest had none.

Teflaro should have been a big seller.  But Forest, like many pharmaceutical companies in my experience, thought that they knew how to do things better than anyone else.  I’m not sure if they ignored Cerexa – the group they kept for their expertise, or if Cerexa was also naïve in the ways of new antibiotic sales. But the launch of Teflaro has to be one of the worst in the history of antibiotics.  Things are looking up for Teflaro, though.  In the third quarter of 2103 it brought in $22 million in sales. I wonder how much of that comes through their European partner, AstraZeneca (they call the drug Zinforo), and how much comes through Forest’s sales in the US.

Forest was part of the deal when AstraZeneca purchased Novexel back at the end of 2009. This deal was centered mainly around avibactam, Novexel’s broad spectrum B-lactamase inhibitor.  The combinations being pursued by both companies now include ceftazidime-avibactam, ceftaroline (Teflaro/Zinforo)-avibactam and aztreonam-avibactam.  All will have somewhat different antibacterial spectra (with some overlap), and all target different ranges of Gram-negative and Gram-positive superbugs. These constitute some of the most important potential additions to our antibacterial armamentarium in the last three decades. AstraZeneca has rights outside the US while Forest keeps the US rights.  This means that Forest deals with the FDA and AZ deals with EU and other global regulatory agencies. The two companies are tied at the ankles for key antibiotics important to the future care of patients.  They are also tied together therefore in the clinical development of all of these products. If one stumbles, they both stumble. To me, this has always seemed like a recipe for disaster in any case.

But Forest has just been acquired by Actavis for $25 billion.   If you had never heard of Actavis – you’re not alone.  From what I gather, Actavis is a Dublin (as in Ireland) – based company that mainly is involved in selling generics.  Actavis is the old generics company, Watson.  They acquired Warner-Chillcot a number of years ago. What do they know about selling branded products?  What do they know about antibiotics?  What are the implications of this purchase on the future of these key antibiotics in development? I can’t even begin to guess.  But this, coupled with recent statements by AZ management on the future of their own antibiotics franchise, leaves me trembling. We seem to by multiplying potential antibiotic disasters in an exponential way here.

So – a challenge to Actavis (Forest)/AstraZeneca – Show us how you will persevere to get these important antibiotics to the physicians and patients who so desperately need them.  Show us your way forward. Show us that this will happen.