Community Antibiotics - Juice vs. Squeeze?

Here it is Sunday, and I have been obsessing on the following conundrum.  (I need therapy)! 

I have been railing against the current regulatory policies in the US and Europe requiring placebo-controlled trials for approval of antibiotics to treat otitis media, acute bacterial sinusitis and acute bacterial exacerbations of chronic obstructive lung disease.  A quick search of the clintrials.gov website reveals that there are currently no new antibiotics being studied in either phase II or phase III trials for any of these indications.  Otitis media is a key entry indication for pediatrics – but it remains off the table. Of course, this is no surprise since the placebo-controlled design required by the regulatory authorities is probably infeasible.  An example of a current dilemma for clinicians is – the severely penicillin and cephalosporin allergic pediatric patient where macrolide resistant pneumococcus is a likely pathogen. The only choice left is a fluroquinolone, that many pediatricians use in spite of the safety warnings against use in pediatric patients. A new ketolide or other alternative would be a welcome product for these patients – but it is not to be.

But here is the sudden thought that got me thinking.  Does the pharmaceutical industry care?  I admit that I don’t have the precise numbers at my fingertips, but I daresay that these three indications still account for some huge percentage of all antibiotic prescriptions worldwide.  These indications at one time accounted for a large bulk of the total dollar volume of the antibiotics business. Most of the antibiotics used for these indications are generic and cheap, and physicians and patients still believe, regulatory authorities aside, that antibiotics are beneficial in shortening the duration of illness even for these “mild and self-resolving” infections.

Twenty years later – the world has changed.  When these indications drove the antibiotics business, each prescription had to be sold to each physician and each patient.  It was a marketing war out there. But now, payers are as much the target audience as physicians and their patients.  If one can justify a new antibiotic to the payer, half the battle is already won. Nevertheless, to get to that point with an antibiotic for otitis, sinusitis or bronchitis, what will it take?  Will it take placebo-controlled trials to prove value?  Will it actually take a superiority study to show an advantage over an existing regimen? If so, we are lost since those trials will probably never take place. And even if a more feasible non-inferiority design would work for payers and physicians, does the industry have the stomach for the marketing spend that will still be required to sell in the community market?  I’m not so sure.

So I wonder if we are not finding ourselves at a curious coalescence of views between the regulators and the markets.  The regulators insist on infeasible designs and at the same time, these same designs might be what the payers will require.  Yet the market spend required, even if the trials were feasible, might also work to dissuade companies from thinking about these indications at least for now.

This means that for physicians and patients, we had better be able to live with the antibiotics we have now because nothing new is going to be approved for these indications for a very long time!  This seems unfortunate because a number of drugs are in late stage development that could address future medical needs (presumably driven by resistance) in these infections.  The list includes, CEM-101, a ketolide from Cempra, BC-3781, a pleuromutilin from Nabriva, PTK-0796 and TP-434, tetracyclines from Paratek and Tetraphase, and perhaps others. As it stands now, none of these are being developed for use in otitis, sinusitis or bronchitis. 

Antibiotics, Big Pharma and Deals

There is a good deal of speculation in the trade press that large pharmaceutical companies are looking for deals – especially ex-US.   The pressures that drive them to deals are manifold and include; failed late stage trials, failure of internal R&D to deliver, generic intrusion, rapidly growing markets in emerging economy countries and a large cache of cash in spite of stock buyback programs to keep shareholders happy.

At the same time, these same pressures are conspiring to make antibiotics attractive once again.  Generic intrusion into the statins and anti-depressant markets combined with the failure to deliver new drugs for these indications are decreasing the potential for multi-billion dollar blockbusters in these indications.  While many companies still dream of big breakthroughs for Alzheimer’s disease they remain elusive. So the average NPV of antibiotics is starting to look competitive once again in the context of a hospital portfolio. 

From my view on the ground, though, I must say that I am not impressed with the number of large pharma companies banging on my door or the doors of my clients searching for antibiotic biotech deals. It remains a buyers’ market out there. 

One interesting speculation though revolves around Astellas and Basilea.  Astellas, as reported in a recent blog, recently returned the rights to telavancin to Theravance.  At the same time, they have a deal with Basilea for their antifungal drug, isavuconazole.  Basilea is now trying to re-apply for marketing approval via the EMA at least and the FDA if possible for ceftibiprole, their anti-MRSA cephalosporin that would then compete with ceftaroline from Forest.  Given that these two products probably account for the vast majority of the value of Basilea, an acquisition by Astellas is certainly not out of the question.

Even if this all comes to pass, Astellas would have to outperform Forest considerably given the slow uptake of ceftaroline in the US. Forest’s net sales of ceftaroline (Teflaro) were $6.5 million in the 3^rd Q last year. Forest, though, remains very optimistic on the potential for Teflaro given the early patient numbers, the ex-US market is still to come and the fact that the respiratory season had not started until after the 3^rd Q.

As always, I await further developments with great interest.  But if the situation for antibiotic biotechs does not improve soon, even this source of new antibiotics will be an endangered species.

Antibiotic Development - EU vs. US.

Image via Wikipedia

Image via Wikipedia

The European Medicines Agency has now released its new guidance on the development of antibacterial drugs.  This document demonstrates how advanced they are in their thinking compared to the US FDA.  I will highlight a few key points that differentiate their approach from that of the FDA below.

The EMA notes that a number of patient types will not have elevated temperatures or white blood cell counts at the time of enrollment.  They therefore do not require these as inclusion criteria. 

In Europe, it is clear that clinical outcome at test of cure is the preferred primary endpoint for studies of antibacterial agents.  This is completely in line with the desires of most physicians and in complete disagreement with the FDA. The EMA would treat the test of cure in the all treated and the clinically evaluable populations as co-primary – again in distinction to the FDA.

The EMA does not specify the non-inferiority margin to be used.  They indicate that one must have reason to believe that the treatment effect of the comparator drug would be superior to placebo and that the non-inferiority margin would conserve at least some of that effect.  But no specific margins are specified and it seems like the determination of the margin for any given study of any given indication could be discussed on a case-by-case basis. 

In this regard, Europe suggests that the historical database of so-called placebo-controlled trials is inadequate for the justification of treatment effect in modern trials.  They therefore encourage the use of pharmacometric analysis of modern trials for this purpose. The FDA is about to makes its first exploration of the value of pharmacometrics (hopefully) this year.  

Europe also provides a discussion of alternative trial designs in their guidance document that clearly shows they are thinking about difficult clinical development issues that could impede our ability to bring new therapeutic options to the sickest patients with the greatest medical need.  This is an area the FDA is just beginning to consider.  The EMA devotes an entire section of their guidance to this.  They discuss the study of rare infections such as endocarditis and meningitis.  They discuss adaptive designs implying they would be willing to discuss a Bayesian approach.  In this case the EMA clearly wants to be part of a detailed and careful discussion before agreeing – but at least they are open to the discussion. Although they clearly state that a randomized active control trial is always preferable, they clearly recognize that in some circumstances, an active control may not be feasible and a historical control might be necessary.  Again, such an approach would require considerable discussion with the EMA.

The EMA clearly states their preferences, but recognizes that it must be open to innovative approaches if we are ever to deliver the kind of targeted therapy we want to those patients with the greatest medical need. This openness, this willingness to discuss new approaches provides a breath of fresh air when compared to similar discussions at FDA who do not even seem to be sure where to start.  I suggest they start by looking at the EMA guidance and actually embarking on a serious harmonization process with the EMA.

When comparing guidance documents for antibacterial drugs, there is no comparison. For those of you with antibacterial products in development where you are struggling with innovative design options – go to Europe. At least you will get an open and considered hearing. 

Telavancin, Astellas and Theravance - Implications?

According to recent press reports and a regulatory filing by Theravance, the commercialization and manufacturing agreement between Astellas and Theravance has been terminated.  Theravance developed Vibativ or telavancin through phase III for two indications – complicated skin infections and hospital-acquired pneumonia.  Telavancin is an intravenous drug for the treatment of severe infections caused by Gram-positive bacteria like staph. Both sets of trials indicated that telavancin was non-inferior to vancomycin in these indications. But telavancin was associated with increased toxicity risk and, for the treatment of skin infections, a risk management strategy was required in the US and in Europe because of the risk to pregnant women and to those with pre-existing renal insufficiency.  

In the middle of the development of telavancin, the FDA changed its mind about what an appropriate endpoint should be for hospital-acquired pneumonia (HAP).  Until that point it had been clinical outcome – cure or failure.  But suddenly it was to be mortality.  Theravance’s trials were well under way if not completely enrolled at that point and were not designed (no trial can be designed like that anyway) to assess mortality.  The FDA rejected telavancin for HAP on this basis. Europe, where clinical outcome is still considered a valid endpoint, accepted the telavancin marketing application and approved the drug for HAP, but only for those cases where another alternative was not suitable. 

Telavancin’s sales have been dismal at about $4.5 million for the 3^rd quarter 2011. One could argue that this is not surprising since it is really, just another IV only Gram-positive only antibiotic that failed to study or prove superiority to any of the other drugs out there.  The EU approval for HAP also just arrived in mid-2011. Further, the trials compared telavancin to vancomycin whereas many feel that, certainly for HAP, linezolid is a superior drug. Given the risks of telavancin, it is obviously hard to make the argument that physicians should adopt this new therapy. One wonders what Astellas was thinking when they made the deal to begin with.  Although, Astellas clearly left themselves an out.  They apparently were not responsible for any of the development costs, and only paid $65 million upfront in 2005.  Additional milestone payments were also part of the agreement going up to an additional $156 million. Astellas was responsible for ex-US regulatory filings and for all commercialization with Theravance getting a 20% royalty.

Apparently the relationship between the two companies was not always smooth.  Recent manufacturing problems have led to drug supply shortages and this has also slowed sales. If they will have to change manufacturers, this could lead to a very significant delay of 1-2 years in drug supply and sales.

Theravance says it will now pursue other options including identifying another partner or partners.   But it is difficult to see another partner signing on under these conditions.

At the same time, Theravance has a much more interesting product in its pipeline (if one is interested in IV only, Gram positive only compounds), TD-1792.  Like telavancin, it is related to vancomycin.  But it is much more potent than either telavancin or vancomycin.  It now seems unlikely that this product will ever be developed either.

One might almost think that Theravance’s effort in antibiotics was cursed. First, there was the increased toxicity risk of its lead candidate where superior efficacy was not and could not be proven.  Then, the FDA changes course in mid-stream, putting a key indication out of reach for Theravance.  Then a severe manufacturing problem arises.  Finally, a key commercialization partner caves under all the pressure.

Are there implications from the Theravance debacle for other antibiotic developers?  I think there are several.  IV only Gram-postive only drug candidates should be approached with caution since the market is already crowded and superiority will be impossible (probably) to show. If one embarks on such a project, comparison to a drug that has shown superiority to vancomycin, like linezolid, is advisable. Manufacturing these large, natural-product-based molecules is not trivial – although in the case of Theravance, this appears to be a problem of a particular manufacturer and not necessarily an indictment of their manufacturing process. Finally, cautious partners remain cautious. 

Related articles

• Astellas Scraps Antibiotic Partnership With Theravance (xconomy.com)