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Sunday, January 25, 2015

Biotech Failings, Ear Infections and Generic Drugs from India.

Several news articles caught my attention this past week.  One dealt with the antibody cocktail for the treatment of Ebola (Andy Pollack was an important source of information here).  I note that I have managed to avoid the entire Ebola news cycle since I’m more of an antibiotics person than an epidemiologist or virologist.  But Andy’s article reminded me of something I wrote about in my book five years ago.  Biotechs, with a few notable exceptions, are notoriously bad at thinking about manufacturing their potential products during the early stages of their development.  This oversight can lead to severe problems and long delays later.  That is exactly what appeared to happen to ZMapp and its partners including BARDA (Biomedical Advanced Research and Development Authority – an agency of HHS). ZMapp, if you don’t remember, is a biotech company that had discovered a mixture of antibodies that could cure Ebola in a monkey model of infection.  Their product was actually used to treat a few patients. Whether it works in humans or not is anybody’s guess since no actual trials were ever carried out and patients do recover from Ebola spontaneously in 30-60% or so of cases. But the company’s idea of manufacturing was to use genetically engineered tobacco plants.  This idea is not new – we were talking about this in Wyeth in the 1990s. But so far, no marketed product has ever been manufactured this way since achieving the scale required for commercialization or even decent clinical trials has never yet been achieved.  But this is where ZMapp placed its future.  When BARDA partnered with ZMapp, one of the first things the BARDA scientists did was to explore other modes for manufacture.  All this takes time and it is not even clear that even if they were to use a more traditional method (like CHO cells for e.g.), the resulting antibodies would have the same activity.  Therefore, the new antibodies might have to be tested once again in the monkey model.  How many years of delay is this?  I don’t know, but to me this is another great example of the shortsightedness of biotech when it comes to manufacturing their products. 

On the ear infection front, another placebo-controlled trial was just published in the Journal of the American Medical Association. First, I need to remind you that two such trials were published several years ago looking at the clinical cure, relapse and complication rates of antibiotic vs. placebo treatment of acute middle ear infections.  Both trials definitively showed that antibiotics have a substantial treatment effect to the point where the FDA now allows non-inferiority trials of ear infections once again. The new data published in JAMA were obtained during trials that were carried out before and during the earlier trials.  This is important since it is becoming highly questionable whether it remains ethical to withhold therapy from children with well-documented acute middle ear infections. The trial was carried out in Finland – like one of the earlier trials.  These new data show that the antibiotic-treated children had an impressive rate of resolution of the middle ear fluid that builds up during the infection compared to those that received no antibiotic therapy.  This also may be associated with a lower rate of hearing loss in the treated children according to the authors. While I agree that these new data are of potential value to physicians considering whether to treat children with antibiotics or not, I think that it is long past time to stop initiating placebo-controlled trials of antibiotic treatment of such children.

Finally, Europe has banned a 120-page list of generic drugs manufactured in India by Abbott Laboratories, Actavis, Dr. Reddy's Laboratories, Mylan Pharmaceuticals, Sandoz, Takeda Pharmaceuticals and others.  The reason for this ban is that, according to French inspectors, a contractor called GVK biosciences manipulated the EKG data of subjects during studies to show that the generic drugs were equivalent to the branded products in question. While it is unlikely that this actually would affect the health of patients taking these drugs, it is more evidence that India, as the world’s largest and possibly least expensive manufacturer of drugs, is also the most perilous place to carry out such production.

Wednesday, January 14, 2015

Roche Does it Again!

Yesterday, Roche, Meiji and Fedora pharmaceuticals announced a deal that could be worth up to $750 million to develop OPO595, Fedora’s phase 1 DABCO B-lactamase inhibitor. Roche will develop the drug throughout the world with the exception of Japan where Meiji will obtain commercialization rights.  I was unable to find the details of the deal – but this is the broad outline according to a Fedora press release.

There are a number of fascinating aspects to this.  The President and CEO of Fedora is Christopher G. Micetich, the son of Ron Micetich.  Ron was the discoverer of tazobactam, one of the early inhibitors of B-lactamase and marketed by Wyeth as piperacillin-tazobactam – a billion dollar plus product. I was involved in the early days of tazobactam showing that piperacillin would be a good partner for the inhibitor.  Later, I helped develop the drug in the clinic and even later was involved with the marketing strategy for piperacillin-tzobactam for Wyeth. The world is so small . . .

Once again, this deal clearly shows that Roche is serious about getting into antibiotics.  This will be their second major clinical stage deal after their deal with Polyphor late in 2013. It also leads me once again to question exactly what they are doing.

As far as I can tell from published data from ICAAC in 2013, OPO595 is a DABCO type non-beta-lactam beta-lactamase inhibitor – that is – it is similar to both avibactam and Merck’s MK-7655. Avibactam (partnered with ceftazidime) has completed one phase 3 trial and will complete another soon.  The FDA’s advisory committee has already voted to approve avibactam (combined with ceftazidime) mainly based on its phase 2 data.  Merck’s MK-7655 is partnered with imipenem and is still in phase 2 trials as far as I can tell. But both of these DABCO inhibitors are years ahead of OPO595 which is only in phase 1. Why would Roche leap into a third DABCO inhibitor.  Perhaps they are thinking about its “enhanced” anti-bacterial activity beyond its ability to inhibit beta-lactamases.  But my experience (and I have a lot of it) with this class is that some antibacterial activity is typical.  Avibactam can have activity against E. coli at as low as 4 ug/ml.  Novexel had a DABCO compound, NXL-105, with activity against Pseudomonas aeruginosa that was thought to be partly related to its ability to bind PBPs of Pseudomonas.  In fact, the entire DABCO series started at Roussel-Uclaf  targeting antibacterial activity through PBP binding and was only later discovered to have potent B-lactamase inhibition activity. So I’m not convinced that OPO595 will have much of an advantage over the other DABCOs based on data published so far.

One potential strategy for Roche/Meiji would be to try and quickly develop a combination with a monobactam similar to the aztreonam-avibactam combo that is in phase 1 trails at AstraZeneca. This combo has the advantage of being active not only against Gram negatives bearing extended spectrum beta-lactmases, but also against those harboring metallo-beta-lactamase like the NDM-1 superbugs.  Many of us have been screaming at AZ to develop their version of this quickly for years – but so far – no dice. Here Roche/Meiji might try and beat their competition to market with this combination targeting NDM-1 like superbugs - and go on from there. But will this pay off? We await further developments . . .

Monday, January 12, 2015

A New Way to Find New Antibiotics!

Last week (during my vacation), Losee Ling, Kim Lewis and their collaborators published a paper in Nature that was picked up by the world’s press – and deservedly so.  But most of the news articles missed the key point – at least to me.

What the press focused on was the new antibiotic discovered and described in the paper, called teixobactin.  It turns out that teixobactin represents a new class of antibiotics that binds to the bacterial cell wall and thus inhibits further synthesis of the cell wall.  This mechanism is similar to that of vancomycin, teicoplanin, dalbavancin and other glycopeptides, but teixobactin has a completely novel structure. Teixobactin was even active in a mouse model of infection.  If it ever gets developed, it will be only available by intravenous (maybe intramuscular) injection and will only be active against Gram-positive pathogens including superbugs like MRSA.

Teixobactin itself, in spite of all the hype, is not so exciting to me.  First, Gram-positive pathogens, even the MRSA superbug, are not the area of major medical need right now.  We have lots of old and new antibiotics active against these organisms.  We need new drugs active against Gram-negative pathogens like the carbapenem-resistant superbugs now plaguing patients and physicians around the world. 

Also – antibiotics like teixobactin are a little like old news. We at Wyeth, and many pharmaceutical companies during the 1990s, carried out programs where we re-examined our collections of natural products going back to the 1940s when soil was being collected from around the world and screens based on microorganisms from soil were used to identify new antibiotics. We discovered an old natural product sitting around on our shelves since the 1960s called mannopeptimycin.  The extract from the culture of the producing strain was active in vivo in a mouse model just like teixobactin.  And mannopeptimycin bound the cell wall in a way that resembles teixobactin.  Alas, mannopeptimycin caused severe inflammation of blood vessels in animals both at the site of injection and at distant sites and could never progress into clinical trials. The fate of teixobactin remains to be seen as further studies of the safety of the new product are carried out.

But lets talk about the most exciting aspect of the discovery – the new method for finding new antibiotics. The way Ling et al found teixobactin is novel, simple and may pave the way to a whole new generation of new antibiotics from soil microorganisms. If you think about it, microorganisms from soil were and are the source of most of today’s antibiotics starting with penicillin, cephalosporins, strepotomycin all the way through tetracyclines, erythromycin, vancomycin, daptomycin etc. But its been estimated that you can only grow less than 1% of microbes that live in soil using normal culture media.  And to extract antibiotics from the soil, you have to be able to grow them. What Ling et al did was to take soil samples and dilute them such that they would introduce about one bacterial cell in a test tube with a membrane bottom.  This membrane would allow nutrients to flow into the test tube.  The test tube (in this case actually a small plastic well) was then placed back on the soil from which the original dilutions had been made.  This would allow about 50% of the organisms to grow – presumably getting key nutrients from the soil that are not present in normal culture media. Ling et al could then extract the growth media from these test tubes to identify those containing products that would inhibit the growth of other bacteria – that is – antibiotics. They came up with teixobactin. By carrying out such a screening campaign using large automated systems and many soil samples, someday, we might even be able to find new antibiotics active against the Gram-negative pathogens where our medical need is the greatest.  To me, this is the key finding of the paper, not so much teixobactin.

My hearty congratulations to Drs. Ling, Lewis and their entire team!

Wednesday, December 31, 2014

Antibiotics in 2014 - A Banner Year!

This year was a big year for antibiotics. The FDA approved four new antibiotics this year including dalbavancin and oritavancin, two long-acting glycopeptide antibiotics that can provide for one or two dose therapy for serious skin infections. They approved tedizolid, a new and improved oxazolidinone active against some linezolid-resistant strains of staphylococci and available in both oral and intravenous formulations. Cubist's Ceftolozane-tazobactam was the only antibiotic targeting resistant Gram negative infections to be approved this year. As covered in this blog several weeks ago, the FDA advisory committee recommended that Actavis' ceftazidime-avibactam be approved for urinary tract and intra-abdominal infections when there are few or no alternative therapies available.  This latter was based primarily on phase 2 clinical data – a historical precedent for the FDA in its antibiotic approval history. Four new antibiotics in a single year breaks a record for the FDA going back to the 1980s or perhaps the early 1990s and it certainly provides a respite in the drought of approvals over the last 20 years.

In addition, looking ahead to 2015, we can expect at least one important approval.  Eravacycline from Tetraphase has already completed a trial in intra-abdominal infection and will soon complete its trial in urinary tract infection.  They should file in the first half of 2015 and, with any luck will receive approval later in the year. This is an important product because it is active against resistant Gram-negative pathogens AND IT WILL BE ORALLY BIOAVAILABLE.  This offers the potential to prevent hospital admission for large numbers of patients who today are admitted to hospital to receive intravenous therapy simply because none of the oral drugs will work because of bacterial resistance.

Unfortunately, 2015 is not going to be a banner year for antibiotics.  2014 represents what happens when the pipeline has lain dormant for five or six years and suddenly wakes up to the light of day (thanks mainly to FDA dithering).  In 2015 we will be back to the reality of a pipeline that still desperately needs new entrants.

Cempra’s solithromycin, a new ketolide antibiotic for the treatment of pneumonia and highly resistant gonorrhea has completed its phase 3 trials for the oral formulation of the drug in community acquired pneumonia.  Cempra has not provided a timeline for its NDA submission as yet – but it seems unlikely that it will be in 2015.

For resistant Gram-negative pathogens, looking farther into the future, we have Merck’s Relebactam (imipenem-cilastatin-MK7655) languishing in phase 2.  MK7655 is a beta-lactamase inhibitor closely resembling avibactam. There is Rempex-Medicine Company and Carbavance in an interesting phase 3 trial targeting highly resistant pathogens. Carbavance is a combination of a novel beta-lactamase inhibitor with meropenem. Finally, there is the aminoglycoside, plazomicin, from Achaogen that is active against many resistant Gram-negatives as well.

One drug to keep an eye on is the combination of aztreonam-avibactam by Astra-Zeneca, which would be one of the very few antibiotics active against NDM-1 like superbugs.  While it is still only in phase I, I think that it could be ready for submission in the next couple of years.  This would be a real breakthrough product for those most highly resistant organisms that only eravacycline can now approach.

Last year I predicted that at least one additional large pharmaceutical company would re-enter the antibiotic R&D space.  That has not happened.  Not only that – but I took a more optimistic stand on Astra-Zeneca suggesting that maybe the CEO would see the error of his ways.  That has also apparently not occurred and AZ seems to be about to divest itself in one way or another of its antibiotic R&D. On the other hand, Merck clearly expanded their effort with their purchase of Cubist. I still believe that other large pharma companies will take the plunge – hopefully in 2015.  The medical need is clearly there. The economic climate for new antibiotics is going to improve. And the regulatory pathways have already vastly improved especially in the US (because they had much farther to go) but also in Europe.

Speaking about regulatory pathways – we have yet to see companies truly take advantage of the rapid paths now available in Europe. I’m not sure I see that happening until after 2015.  I do believe, though, that at least one company will establish a pathway forward for a pathogen specific indication either in Europe or in the US in 2015.  (I have been predicting this for two years now – but I still think its coming).

To keep you up to date on the activity of the blog – we broke the 200,000-view mark this year.  In order, the most popular blogs have been; (1) John  Quinn – In Memoriam (5415 views) (Don’t forget the John Quinn Memorial Fund); (2) Antibiotic Markets and SPLU (the old LAPD) (5244 views); (3) Rebooting Hospital Acquired Pneumonia from 2012 (3809 views). Other popular blogs included Astra-Zeneca is Cutting and Running, and, for some reason, Antibiotics in 2012 – an old end of year summary.
With that, I can only wish all of you the best in 2015.  For myself, for the first time in a long time, I am seeing bright lights at the end of an ever-shrinking tunnel.

Wednesday, December 10, 2014

Antibiotics go Wild and Crazy!

This week Merck announced that it will acquire Cubist for $9.5 billion at a 35% premium over the stock price. Cubist is a mid-size pharmaceutical company with a recently diversified portfolio of products all acquired through acquisition. They currently market Cubicin and Dificid for Gram positive infections and C. difficile respectively.  Cubicin is already a $1 billion seller. They will soon market tedizolid and ceftolozane-tazobactam through their acquisitions of Trius and Calixa. Merck is clearly targeting the specialty hospital marketplace with this acquisition and may hope to complement the Cubist products with their own imipenem-cilastatin-MK-7655.  7655 is currently in Phase II trials for urinary tract infections where it has been for two years now.

This announcement is bittersweet for me. This clearly continues a string of good news for antibiotics and antibiotic R&D.  It is further proof that large pharmaceutical companies now agree that antibiotics can provide a return on investment and that they are willing to put there money where there mouths are. The acquisition of Cubist will also bolster the appetite of investors beyond the excitement provided by Cubists own acquisitions of Optimer and Trius last year.

On the negative side, there are always the “synergies” that go along with these mergers.  The Merck investment in their antibiotic R&D portfolio has been exceedingly modest over the last decade or so.  Will this change or will Merck now go about ridding itself of the Cubist R&D organization to achieve its promised cost-savings?  On the risk side, essentially all of Cubist’s late stage antibiotics have come from external sources.  Their own discovery organization has contributed little to the late stage pipeline.  Merck’s own discovery organization has provided only MK-7655 – a knock off or avibactam – and little else for many years.  How Merck will deal with the two discovery groups is a matter of concern and remains a complete unknown at least to me.

Speaking about the commercial side, Merck is selling ertapenem, launched in 2002 where it is doing reasonably well. Cubist has done a yeoman’s job with Cubicin bringing in $1 billion in revenues almost exclusively from the US since its launch in 2003. Cubist has never had a real European marketing organization and has depended on unreliable partners like Novartis for their meager European sales. Will Merck be able to do better? One would hope so.

Recently, Cubist lost the first round in a battle over their more recent patents for Cubicin.  The patents that were denied by the court included methods for purification of Cubicin and for the current dosing regime that was discovered in preclinical and later in clinical studies to reduce muscle toxicity and at the same time maintain antibiotic efficacy. While these patents are subject to appeal, it is not clear the Cubist will prevail.  That said, Merck has clearly determined that the future revenues to be gained by Cubist’s new products, tedizolid and ceftolozane-tazobactam are worth the price they have offered even without the additional 4-5 years of exclusivity for Cubicin that may be wiped off the map by the courts.

 With the re-entry or expansion of large pharma’s efforts in antibiotics, the deep pockets of pharma have opened once again.  That means that venture capital and perhaps even private equity will now also loosen their purse strings to support new antibiotic research and development.  A new golden age for antibiotics is knocking at our door.  Lets be sure to welcome it with our ongoing efforts to improve the regulatory and financial climate for new antibiotics.