Thursday, January 24, 2013
Here we go again. Pfizer and Geno Germano hit the news again with the announcement that they were combining their four business units, oncology, primary care, specialty products and established products into two business units. The precise organization of this was not clear from the report, but what seems clear is that the analysts think that this presages a split of the pharmaceuticals business from the generics business. According to their thinking, this could even presage further spin outs from Pfizer. This follows the line of thought that Pfizer would be more valuable as multiple companies rather than as a single behemoth. I (as a financially naïve observer) am in complete agreement with this logic.
Apparently, the generics business will generate about $17B and the pharma business about $36 B in sales in 2013. The split could occur in 2015 via a spin off or sale of the generics business.
My interest in this is that this represents an important opportunity for Pfizer to reconsider their hasty and ill-advised exit from antibiotic R&D. They still have the possibility to spin out their existing antibiotics business (seems less and less likely). But as they consider their new structure and their future bottom line, the antibiotics business would seem a perfect fit.
On the regulatory and pricing front for antibiotics, things are changing faster than many expected. On the regulatory front, the Pew Charitable Trust will be reviewing the concept of an accelerated development pathway for needed new antibiotics as proposed by IDSA- called LPAD (Limited Population Antibacterial Development) the end of this month. The FDA is holding public hearings on this concept on February 4-5. This approach will provide a pathway for approval of antibiotics active against highly resistant pathogens via small, focused trials with a rapid approval process, but a restrictive label. This, by definition, will mean a high price (See Lew Barret’s blog on this). But wait!!! Is this oncology or antibiotics?
Europe has already embraced such an approach. Even the FDA signaled that a limited label is OK after the telavancin advisory committee last month. Questions remain around what kind of trials would provide the appropriate value to payers to support an oncology-like pricing strategy. But antibiotics actually cure disease. If we can take patients with highly resistant infections from the brink of despair to reasonable hope with new, effective antibiotics – what is that worth?
When you combine this with the power of sales growth of antibiotics (including branded products) in emerging markets, antibiotics start to look like the next oncology. If you put all this on top of a smaller, leaner company with less than half its prior revenues (as the new Pfizer might be), antibiotics should be looking pretty good. Of course, in the case of Pfizer, they would have to rebuild after getting rid of most of their internal expertise – but Sanofi is doing that. Why not Pfizer? And if not Pfizer – what about Roche, Lilly, Abbott (also splitting), BMS and the rest of you? Lets get going! Lets try and get ahead of the curve instead of staying forever behind it.
I have written a note to Geno Germano of Pfizer (whom I remember from my Wyeth days) – but I haven’t heard back yet . . . .
Thursday, January 17, 2013
Continuing in our series on grant writing for the discovery, optimization and development of anti-bacterials (much of this holds for antivirals and antifungals as well), I would like to focus on the transition from screening to optimization especially thinking forward to preclinical and clinical development.
First – before you even start your program, as we have discussed earlier, develop a target product profile. For the sake of today’s discussion, I am going to assume that you want to have both IV and oral bioavailability so that step down therapy is an option.
During your optimization program, starting from one or more lead chemical series, you are going to want to follow these general parameters.
ClogP or logD
Protein binding - this should probably initially be just an MIC shift in the presence of 50% pooled human serum.
You want to prioritize compounds with high potency, reasonable solubility and a less than an 8 fold shift in MIC in the presence of serum. But you also should be able to balance these characteristics such that you can give up a little on potency in order to optimize solubility and protein binding. You want to have a solubility of around 10 milligrams (not micrograms) per ml of water or saline. Obviously you can start with a lower solubility but this should be your goal.
At some point, you need to think about early in vivo studies. There are two schools of thought here. Some prefer early PK to assure bioavailability while others just want to see early efficacy. I am more in the latter category. The first in vivo model I prefer is an ED50 in treatment (at least 1 hour post challenge) in a lethal sepsis (peritonitis) murine model using a single bacterial pathogen. I prefer administering the drug subcutaneously. The PK for this is similar to IV – but the Cmax is frequently a little lower and this avoids some of the tox you can see with bolus IV administration of large doses of a novel compound. If your drug is aimed primarily at Gram negatives – start with E. coli for your first model. These days, you should allow for early sacrifice of moribund animals. I am biased to this model just because of my own experience and I understand how to translate from this to more precise efficacy models. Some would recommend starting with a model where you can show decreased bacterial burden such as thigh or pneumonia models. I shy away from those for a first try in vivo because the numbers of animals tend to be higher and the workload is also higher. But this is certainly a feasible approach and I have a number of collaborators and clients who go that way.
You will need to look at oral efficacy or PK (see below) if you are planning for oral bioavailability.
If you see no efficacy and need to understand why – you might want to check PK (which means you have to have an assay) to confirm that you are getting exposure to the compound. You also might want to check protein binding with mouse serum since that is occasionally very different than what is seen with human serum. If this is an issue – do equilibrium dialysis both with mouse and human sera.
If you see low plasma exposure, plasma instability and metabolism are common problems – and you need to look at this early on anyway. Plasma stability is easy to assess and can sometimes be the first indication of chemical instability in an aqueous environment. Stability in gastric fluid can also be problematic.
Ultimately you will need an estimate of oral bioavailability. This is easily done with a simultaneous IV and oral PK study. Most people would accept a minimum of 10-15% oral bioavailability in a rodent as a reasonable starting point.
A chemist can frequently identify potential sites of metabolism and sometimes you can pick metabolites up early during your assay development anyway. Metabolism tends to be a greater problem for oral than parenteral administration. Early assays on CYP inhibition are also helpful. If metabolism, plasma stability or CYP inhibition are problematic – bring these assays forward in your optimization program.
This then becomes the optimization program for your series. Again, you can balance potency with favorable physicochemical properties, protein binding, plasma stability, metabolic stability, oral efficacy (bioavailability) etc. There may be other specific assays related to your specific lead series or your target product profile that I have not mentioned.
I know this is a short summary – but I’m not writing your grants for you.
The next installment will deal with preclinical development leading up to first in man studies.
Thursday, January 10, 2013
It has come to my attention that many of you think that since I am accepting no new clients and I am shutting down my website, this blog will also disappear. Nothing could be further from the truth. Just because I am trying to cut down on my workload does not mean that I intend to shut up!
In this beginning of 2013, I thought I would take time out from more serious matters to express my thanks. First, I am surprised and honored by the number of you who actually read this blog. Since its inception in May, 2008, the blog has received over 80,000 views half of which come from outside the US. I am staggered at this level of interest in antibiotics and what I have to say about the subject.
I want to express my special thanks to a number of individuals who have contributed to the blog over the years including Brad Spellberg, Paul Ambrose, George Drusano, David Livermore, Lynn Silver, Lew Barrett and others. Without your help, this effort would be much less interesting and, apparently, effective.
I also have to thank many of you with whom I have argued, debated, whom I have cajoled, pushed and to whom I have otherwise been unpleasant. I am grateful for the opportunity to speak with you, exchange ideas and even have you listen to my point of view.
Included in this group are those of you at the FDA who answer my questions on policy and guidance, patiently listen to my dissenting (sometimes sharply) viewpoints and yet are always respectful, polite and seemingly interested nevertheless. I am also grateful for the opportunity you have given me to interact with you at the Gordon Research Conference, the Brookings Institution and the Pew Charitable Trust. I know that you know how much I fervently support the concept of an effective FDA and I know that you take what I say in the spirit of “tough love” in which it is meant. I am grateful that you still speak with me.
Now – a little feedback for you. The most popular blogs of all time –
The FDA and Community Acquired Pneumonia from October, 2011 – 3463 views.
This is a little unfortunate since there have been several updates (even though there is still the problem of prior antibiotic use).
Rebooting Hospital Acquired Pneumonia from August, 2012 – 2850 views.
This blog contains my proposal for a feasible and scientifically justified non-inferiority design for HAP/VAP trials.
Antibiotics in 2012 from December, 2011 – 2830 views.
This was my set of predictions for 2012 – recently revisited at
Antibiotic Markets and SPLU (Guest blogger Lew Barrett) – 2141 views
Here Lew tried to make market predictions for an imaginary drug specifically targeting resistant strains of Acinetobacter.
Telavancin, Astellas and Theravance – January, 2012 – 1291 views.
This blog was about the effect of FDA waffling coupled with antibiotics of limited spectrum and manufacturing issues on the business prospects of biotech using the Theravance-Astellas deal on telavancin as the example.
Other highly popular blogs included the report on Pfizer abandoning antibiotic R&D in November 2011, my review of the avibactam posters at ECCMID in 2011, my piece on antibiotic breakpoints, the FDA, CLSI and EUCAST (followed later by a more authoritative piece by David Livermore), and finally my report of Janet Woodcock’s announcement of the FDA reboot in May, 2012.
Coming soon – the next installment in the continuing series of antimicrobial discovery grant writing.
Have a great year!