Sunday, March 2, 2014
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
Wednesday, February 19, 2014
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.
Tuesday, February 11, 2014
I apologize for the time lapse – but we were down in Columbia visiting John Quinn’s family there and the research institute where he worked with his widow, Maria Virginia. She is still carrying on the battle against resistance. Keep your eyes on this blog for an update.
In the last few weeks, there has been some media attention to the problem of resistance. I am ignoring the constant discussion over the use of antibiotics in animals since I consider that what needs to be done is obvious and that the FDA just has to do it. But I did want to explore some of the press recently on antibiotics for humans.
First, there is a blog by Tim Fothergill, a microbiologist, in the Huffington. Basically he notes that we have a problem with superbugs and says he will talk about solutions in his next blog . . .
Then there was a report of a meeting at Harvard featuring some luminaries like Stuart Levy. They address the same question but stick to old tunes like stop using antibiotics (good idea but this won’t be enough) and prolonging exclusivity on sales of new antibiotics. The latter has been shown clearly to be insufficient to attract companies back to antibiotic R&D unless they happen to have a drug or drugs with a relatively short patent life.
Finally, with a breath of fresh air, Matt Herper wrote a piece in Forbes talking about the importance of premium pricing for antibiotics. Now we’re talking. For superbugs, he suggests a super price! Yes boys and girls, we will get what we pay for. If we want to be able to continue to have antibiotics that work then we will have to pay a price - as in money - ka-ching! Anyone who tells you different is living in Colorado and smoking something.
It seems that not only large pharma, but venture capitalists as well, have figured out that the new regulatory pathways and talk of super-pricing make antibiotic R&D an attractive investment again. The old Rib-X, now called Melinta, announced a new round of funding of $70 million to develop delafloxacin. Delafloxacin is a quinolone antibiotic that is orally available (you can take a pill) and active against some Gram negatives but also against MRSA. The problem is that, as a quinolone, you take a 40% chance that it will fail either during late stage development (phase III) or post-launch. My belief is that it is for this reason that no pharma company has jumped in to partner the drug – they are all waiting to see what happens. But the fact that Melinta continues to be able to raise money to support the development of delafloxacin says something important about the appetite of private investors for antibiotic R&D.
At Astra-Zeneca, it seems to be the head-in-the-sand approach to antibiotic R&D. In a piece of potentially bad news (at least sad news), Astra-Zeneca announced that it was closing its site in Bangalore, India where they carried out research to find antibiotics against TB and Malaria. On the one hand, since such products are unlikely to contribute to AZ’s bottom line, we can understand this decision. The question is – what does this augur for the rest of their antibiotic R&D in Waltham, MA and Wilmington, DE. In spite of the most promising antibiotic pipeline in the industry, they have already announced that they will focus on key areas like cardiovascular to the exclusion of non-key areas like antibiotics. We await further developments here – but I’m worried. It seems that the forces that are driving private investors and other large pharma companies towards antibiotic R&D are not influencing AZ’s management one iota.
Monday, January 27, 2014
In a recent business news article for the Wall Street Journal, Hester Plumridge noted that some large pharmaceutical companies are once again testing the antibiotic waters. Of course, she would have known all about this had she been reading this blog (Sanofi, Roche). I would like to add some granularity to her article. The first large pharmaceutical company to announce they were abandoning antibiotics research was, in fact, Roche in 1999. Roche was followed in rapid succession by Bristol Myers Squibb, Lilly, and Wyeth. Abbott and Bayer followed in 2003 and 2006. Sanofi spun out their antibiotics assets into Novexel in 2004 (Novexel and its products were acquired by Astra-Zeneca and Forest in 2009). J&J and Pfizer pulled out in 2011 or so. Novartis never formally pulled out of antibiotics research and maintains a research effort in their Emeryville site in California. But they are a schizophrenic company with a strong and enthusiastic research group and very unenthusiastic commercial and development organizations. So I count Novartis as de facto out. This left us with Astra-Zeneca, GSK and Merck. Even there, Merck’s program is small and is based on a single product (MK-7655 – B-lactamase inhibitor in phase II).
But the trend is now going in the opposite direction. Sanofi rapidly changed its mind and re-entered antibiotic R&D recently. They just don’t know where they’re going yet. They had hired Rodger Novak from Nabriva in Vienna in 2011 to run their antibacterial effort, but he left after less than two years in place. Roche has completed two deals in the antibiotics space – one for drug discovery and one with Polyphor for its phase II ready anti-Pseudomonas drug. Whether they know exactly where they are gong yet or not is yet to be determined. But it is not surprising that companies trying to re-enter the antibiotics arena would have problems. Since these companies lost most or all of their expertise years ago, they will need time to build this back up and re-establish themselves. How much time required depends on their corporate will and resources. In this regard, those companies that got out most recently like Pfizer and J&J might expect to have the least difficulty getting back in. In the case of J&J I believe this might be true since I know that a number of their old antibiotics R&D folks are still in place but working elsewhere in the company. Pfizer has pretty much dismantled their team and has left so much ill will behind them, that I predict that their climb back to antibiotics, if they so decide, will be a steep one.
The resurgence of interest in antibiotics has clear origins. There has been a complete turn around at the US FDA in terms of antibiotic development. They are no longer hostile – in fact – I think it has become just the opposite. They still need a few tweaks (big ones on hospital acquired pneumonia), but you can get things done at the FDA again. The EMA in Europe has been the stalwart regulatory agency throughout and remains so. The other main contributing factor is the increasing medical need caused by resistance and the possibility that this will drive higher prices in the marketplace. The convergence of rapid and efficient regulatory pathways to the market and higher prices combine to suggest that companies may once again be able to make a return on their investment in this area.
On a more pessimistic note, we are all still awaiting further developments at Astra-Zeneca who, under pressure from generic intrusions, announced that they would slow their investment in antibiotics research. Apparently, although they believe that the regulatory piece is in place (just talk to John Rex), they are not sure that the pricing piece is ready for prime time yet (just talk to their CEO). But if they were to back out entirely, it would be catastrophic for antibiotics R&D given their pipeline and their expertise in the area.
Monday, January 20, 2014
Or maybe this should be titled, “The FTC goes where the FDA cannot.” This month the Federal Trade Commission announced penalties and refunds levied against several companies selling diet aids for false advertising. They claimed that there was insufficient scientific proof that these products, including Sensa, L’Occitane skin cream and HCG Diet Direct actually benefited consumers in terms of weight loss. The implication is that in order to advertise health benefits for “supplements” or any other commodity, the sponsor would have to demonstrate “scientific proof” of efficacy. The question is, what constitutes scientific proof? Does it have to be randomized double blind trials as the FDA requires. The answer may be a resounding “yes!”
If all of this is true, then how come these products are not regulated by the FDA who actually have the expertise to evaluate whether or not they have achieved proof of efficacy or not? Well, because these products are not considered drugs and therefore, according to congress and the laws of the land, do not fall under the aegis of the FDA even if they claim drug like properties or effects from such products. Personally, I think any product making a health claim should fall under the FDA for approval to market based on such claims. Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, the sponsor is responsible for ensuring that the product is safe prior to marketing. Apparently, there is no requirement that the product actually provide any benefit whatsoever. The FDA can only intervene if there is reason to believe that the product is unsafe after it has been placed on the market. Does anyone (besides supplement manufacturers) believe that this makes any sense at all? It is clear that the majority of the time being spent by the FDA office of investigation is focused on bogus and unsafe supplements with undeclared additives, unlabeled ingredients and other problems all putting the health of Americans at risk.
Why do I, an infectious diseases physician, care about this topic? Just do a Google search on the term antibacterial supplements and you will see. There are myriad products out there from garlic to grape seeds to St. John’s Wort that are claimed to provide beneficial effects for infections sometimes when applied topically – but more importantly, when ingested. The data to support these claims, for the most part, do not come up to any standard of proof recognized by any sophisticated physician or scientist. For bacterial infections in particular, the ingestion of these so called cures could delay appropriate antibiotic therapy and lead to more severe illness and even death. But these claims are being allowed to stand as is on the internet, in newspapers and in health food stores.
It is time for congress either to give the FDA the power to protect us from these patently false claims of effectiveness or for the FTC to come to our rescue and prevent these manufacturers from continuing to bamboozle the American public. This is a potentially dangerous practice that should be stopped immediately.
What is wrong with us?