David's New Book

Thursday, June 30, 2011

Antibiotics - Half Full or Half Empty

Low-temperature electron micrograph of a clust...Image via Wikipedia
In my job as a consultant to companies trying to discover and develop new antibiotics, I keep my fingers on the pulse of the industry at least to a certain extent.  Today, I wanted to share my growing confusion with all of you.  For some reason, I have had a burst of new business both at the beginning of this year and again within the last several weeks.  This business is coming from everywhere - large pharma, biotech and investors - wanting everything from on the ground help with discovery and development tasks to evaluations of potential products at various stages of development.  But then when I look at the number of large pharmaceutical companies who have abandoned the area and the great difficulties that start-ups are encountering in obtaining funding, I wonder which end is up.  Of course, there are still a few (2-4) large companies still pursuing antibiotic discovery and development.  There are still a few antibiotic indications where clinical trials remain feasible at the FDA (urinary tract infection, skin infection, intraabdominal infection - although several of these are under review - hold on to your hats).

I think I understand the dynamic here.  There is hope.  Many very smart people and talented scientists recognize that we cannot go on with no antibiotic pipeline.  They realize that the FDA will, therefore, ultimately have to see reason.  They also believe that, somehow, a way forward for funding will be found.  Perhaps some of them believe that the GAIN act will be a major positive influence (I am not so sure) in terms of providing an incentive for both biotech and their potential partners or even for public markets to finally get back in the act. Maybe some see BARDA as a way forward (although without an ability to fund phase III, I remain skeptical).  Nevertheless, hope and optimism are good things.  Not only that, but they help keep me in business and, I hope, they will help keep the world supplied with new and needed antibiotics. So today, for me, the glass is half full.
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Sunday, June 19, 2011

Antibiotics in the US - Effecting Change

United States Capitol in daylightImage via Wikipedia

Once again I was privileged to be a participant in an ongoing conversation on antibiotic development and the FDA involving experts from large and small pharma, academia and the Infectious Diseases Society of America.  The conversation started with the ironies of FDA statements and their recent draft guidance documents, especially that focused on the development of antibiotics for skin infections.  I will leave that part of the discussion for a future blog.  But the conversation ultimately found its way to the topic of what can be done to ameliorate the situation.  This, after all, is the ultimate conundrum.  We, for various reasons, believe that people will, at the end of the day, be reasonable and rational.  We are always disappointed and surprised when that is not the case.  But anyone who has been living the nightmare of the FDA and antibiotic development over the last decade will understand what I am talking about.  We live in a world where reason and rationale have given way to survival in a hostile political environment.

So – what to do? I think it is too much to hope that the FDA will come back to some semblance of feasible trial designs with realistic and clinically relevant endpoints for antibiotics in the near future. I also think that legislation to provide real incentives for industry and real limits for the FDA is beyond reach this year.  I continue to believe, though, that the way forward lies overseas. 

Americans must be made to realize what the FDA and congress are doing to them as far as antibiotics are concerned.  First, the continued use of antibiotics in animal feed is only going to continue to increase the incidence of resistant infections in our citizens.  If Montana has its way that will be our fate.  Now that we will continue to assure ongoing resistance, we will also assure that we have no new antibiotics to fight these infections.  The FDA has constructed a series of guidances for industry that require either infeasible trials or use clinically irrelevant endpoints or both.  So even if industry wanted to develop new antibiotics, and most large companies have already voted with their feet and abandoned the area, they can’t – at least not in the US.  One of the few exceptions is in skin infections where the trial designs are at least feasible, but where the endpoint is at best of debatable clinical relevance.  The other issue for companies is that the trial designs for skin infections required in the US have nothing to do with those required in the rest of the world – this creates additional (but not insurmountable) challenges for industry.

Where is congress in all this?  They are busy trying to protect cattlemen in Montana by allowing continued and unnecessary use of antibiotics in animal feed.  They are unable to pass legislation to provide for real incentives for companies to develop antibiotics where the return on investment for companies is poor.  And, congress is unable to rein in an FDA gone mad.  Trying to speak to congress about this is a little like swimming upstream in jello.  While the basic concept of the problem we face is easily understandable, coming up with legislation to address the problem is not so easy.  The GAIN act, for example, is going to be too little to really incentivize companies and too weak to effect change at the FDA.  But even that bill is having trouble making it through congress.  A plan with real teeth has been proposed by the London School of Economics and has been proposed as law to the European Commission.  This plan would work – but has not even made it into any sort of bill in the US congress.  All we have is a US-EU Task Force that will make recommendations someday.

In addition to continuing to speak with congress and the FDA, I think the way forward is to actually develop new antibiotics active against resistant strains in the rest of the world.  Companies should negotiate reasonable trial designs in Europe and then present these to the FDA.  If the FDA makes it impossible to carry out the trials – so be it.  These new products will at least be available in other areas of the world where the medical need is great.  Companies can always re-approach the FDA at the time of submission for marketing approval in Europe or even post-approval. I know that this advice will be hard for large companies to swallow since the US market, even though stagnating or shrinking, is still large and therefore hard to give up. Nevertheless, for those truly committed to the development of antibiotics, providing them for the rest of the world is still a very good thing.   And putting pressure on FDA and congress to make approval of new antibiotics to fight resistant infections feasible in the US is also better than not developing antibiotics at all. 
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Monday, June 13, 2011

Dr. Margaret Hamburg on Biocentury TV

WASHINGTON - MAY 07:  Dr. Margaret Hamburg tes...Image by Getty Images via @daylife

Yesterday I watched an interview with Dr. Margaret Hamburg, Commissioner of FDA on Biocentury TV.  In general, the questions were softball.  I think the word antibiotic was used only once.  That was for a comment the interviewer heard from a venture capitalist.  The VC said that he had three no-go areas for investing in pharmaceutical start-ups – diabetes, obesity and antibiotics. At least antibiotics is in good company these days.  Dr.Hamburg responded by stating that she and the FDA are aware of this issue and that her interest remains in putting in place the regulatory science that will allow for trials that can show safety and efficacy such that Americans can have access to new therapies in these areas.  But I have to admit that I don’t know what the “new” regulatory science is. We have used Bayesian approaches to trial design in oncology for years.  We have used validated biomarkers in HIV and for oncology for years. 

During the entire interview, I think I heard the word feasibility once. It seems clear that, at least in some areas, FDA understands that trials must be feasible, but is struggling to find a “correct” scientifically based way forward. The idea of conditional approvals was discussed – but only superficially and nothing new seemed in the offing.

 Its as if the fact that somehow “new” approaches exist means that our old ones are no longer valid. You hear that often at meetings – at least as a subtext.  During the last 60 years, it seems to be assumed that FDA approved ineffective antibiotics and that because so called biocreep towards inefficacy is a theoretic possibility, it must have occurred.  But, to my knowledge, this has never been shown scientifically.  So where and what is the “new” science after all?

If Dr. Hamburg and the FDA want to lay the foundations for new trial designs for antibiotics – more power to them.  But what is the problem with continuing with our “old” trial designs while the new templates with feasible designs are put in place?  Why can’t we grandfather such designs until such time as new and feasible designs are ready for prime time?  If we could do something like that, maybe cethromycin from Advanced Life Sciences would already be approved, maybe doripenem and telavancin would be approved for hospital acquired pneumonia is the US as well as in the rest of the world. In fact, it is clear that if we don’t do something like grandfathering the more traditional designs, Americans will be deprived of new and needed antibiotics for years to come.  The current FDA approach is certain to have a negative effect on the global supply of new antibiotics as well as on public health of Americans. 

It is long past time to rethink.
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Monday, June 6, 2011

Sanofi - Breaking the Mold?

Sanofi-Aventis, BerlinImage by sunxez via Flickr

In 1999 Roche announced that they would abandon their effort to discover and market new antibiotics.  This ultimately led to the formation of Basilea and Arpida – two biotechs of which Basilea is still standing. The antibiotic discovery group at Actelion is also made up in large part of ex-Roche scientists.  Of interest, with rare and small exceptions, none of these particular biotechs have yet managed to get anything all the way to a significant market. Since 1999, in terms of today’s mega-merged companies, eight others have followed Roche down the path away from antibiotics.  None, as yet, have reversed course and re-established a serious antibacterial discovery and development effort.  None have even licensed in an antibacterial for development and marketing.

But, as I learned several months ago, this may change.  One brave company may be the first of the large pharmas to go back.  In 2004, not long after Sanofi purchased Aventis, the company made what was, for them at the time, a very difficult decision to spin off their anti-infectives discovery group. They not only released their talent, but they also gave up any rights and they put in a large number of preclinical stage compounds – some more advanced than others. This spin-off was Novexel.  At the time of their purchase of Aventis, negotiations for the spin-off were already underway within that Aventis.  Sanofi hesitated – I think over a year – before finally giving the go ahead for the formation of Novexel. Sanofi hesitated because they were not sure they really wanted to divest themselves of their anti-infectives group.  In spite of the calamity of Ketek (an Aventis product that Sanofi had to bear on their shoulders), Sanofi was not sure that anti-infectives would not be an important area for them.  But, for whatever reason at the end, Novexel was born.  With its birth, Sanofi lost most if not all of its internal expertise in anti-infectives as well as any key anti-infective compounds that might have been in the company.  Novexel was a startling success selling itself to Astra-Zeneca and Forest for $505MM in “biodollars” by the end of 2009.  At the time, they had generated two promising phase II antibiotics and had their own discovery program with interesting preclinical compounds.  Sanofi could have had the same but did not.

After all this, several months ago, I received a call from a headhunter, as I do from time to time.  But when this recruiter told me what they were looking for, I practically passed out.  They were looking for a head of anti-infectives for Sanofi-Aventis.  At the time I knew that Sanofi had initiated a small effort at their facility in Toulouse, France to discover compounds useful for the treatment of neglected diseases such as TB and malaria.  But their current plan was much bigger. They shared the job profile with me.  It called for a person with experience mainly in small molecule discovery either from academia, biotech or pharma. They wanted expertise in microbiology or immunology – vaccine expertise would be a plus.  The person would direct research in neglected diseases, but also for new antibacterials, antifungals or antivirals for MDR pathogens.  Personnel reporting to the new unit as proposed would be located both in France and the US.  There could ultimately be 120 scientists and others in the various groups reporting to this person. Of course, to find a single person with all the required expertise to lead such a diverse effort seemed an unlikely possibility – but to find someone who could start from a strong base and learn all this seemed possible.  Of course, now that Sanofi has purchased Genzyme, the integration may complicate this entire plan. I have been in contact with the headhunter who tells me that they have made an offer to someone – but that was back in April.  I have had no further follow-up.

But I was still flabbergasted.  If this happens, Sanofi-Aventis will be the first company in over 10 years to get back into the field.  Even though I may be critical of the specifics of their plan, the idea itself is, to say the least, admirable and courageous.  They will have to rebuild almost everything from almost zero. I expect this will take years to come to some sort of fruition.  Nevertheless – assuming this comes to pass – cudos to Sanofi-Aventis!
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