David's New Book

Friday, November 3, 2017

The Broken Antibiotics Market Claims Another Victim

What happens when the antibiotics market remains broken? Companies get out of the antibiotic business – that’s what happens.  The latest example is The Medicines Company. Their anti-infectives business in 2016 consisted of intravenous minocycline for Acinetobacter infections and oritavancin for Gram-positive infections.  In 2016 the sales for those two products were $8.6 and $16 million respectively according to their annual report.

The Medicines Company just saw the approval of meropenem-vaborbactam (Vabormere) for the treatment of serious antibiotic-resistant Gram-negative infections. In spite of this, they are getting out of the business. Obviously, the company no longer sees a future in the antibiotics business. This move, apparently, will help them trim their staff from its current 400 employees down to around 90.  The market greeted this news with enthusiasm. And who can blame them?

The anti-infectives core of The Medicines Company came from Rempex who discovered and developed Vabormere.  They have always landed on their feet in the past and I am hoping that this will be nothing more than a speed bump for them.  They have some interesting early stage compounds in their pockets that deserve, someday, to see the light of day. But in today’s environment – who knows?

What company will be next?  I have my eyes on Allergan.  Unlike The Medicines Company, Allergan has no antibiotic discovery effort. They have assets that they sell including Aycaz or ceftazidime-avibactam, dalbavancin and ceftaroline in their stable.  Their rights to Aycaz and ceftaroline are limited to the North American market.  In 2016 they sold around $36 million of Aycaz, $134 million of ceftaroline and $39 million of dalbavancin. This is not too bad given that two are sold only in North America and that they all fit in the hospital antibotics market. But none of these are blockbusters and all three together account for a tiny proportion of their $5 billion annual revenues. Will Allergan stick with the antibiotics they have and continue to fight it out? Or will they follow The Medicines Company, AstraZeneca and so many others?

The problem is obvious to everyone who knows anything about antibiotics today.  The market is broken. Compared to billion dollar sellers in the fields of diabetes, neurosciences and cardiovascular medicine, antibiotics just don’t stack up. If we don’t fix this broken market using a combination of push and pull incentives (like market entry rewards), we can expect to see a parade of companies, both large and small, exiting the field.  This could be the worst exodus from the area since the great departure during the first few years of this century. With such an abandonment by companies, investors will quickly follow.  The future of biotech, start-ups and even academic research will all be threatened. We cannot let this happen. And we know what to do to prevent it. Are we just going to sit on our hands and watch while Rome burns?

Sunday, October 22, 2017

We Deserve What We Get - But Do Our Children?

Emerging antibiotic resistance is not going away. MRSA is maybe less common today than it was 20 years ago – but MRSA infections occur in my small hospital population every week. Plasmid-mediated resistance (mcr) to colistin, our very last line and very toxic antibiotic that does not even work that well, continues to spread. The CDC is tracking mcr in the US and the picture is not encouraging. Carbapenem-resistant Enterobacteriaceae – those Gram-negative pathogens resistant to our last line safe and effective class of antibiotics – have now been reported from every state in the US except one, Maine. This is in spite of all of the work, all of the publications and all of the hand-wringing that has occurred over the last several decades.

We know what we have to do.

·      Preserve the utility of the antibiotics we have through appropriate use including in animal husbandry.
o   This also means regulating antibiotic use and antibiotic production in countries that do not currently do so.
o   But even appropriate use will, ultimately, select out resistant strains.
·      Provide for a robust pipeline of new antibiotics active against the continually emerging resistant pathogens.
o   Solve the scientific problem of getting antibiotics to permeate into Gram-negative bacteria.
o   Stop the continued loss of antibiotic discovery research through attrition of companies working in this domain.
o   Train a new generation of antibiotic hunters.
o   Fix the broken antibiotic market.

All of this has been the subject of numerous new articles, documentaries, and even, in the prior administration in the US, a part of the political debate. And yes, we have made and are making some progress on all these fronts EXCEPT the problem of the antibiotic market. If we don’t fix that, everything else is a house of cards that will collapse of its own weight.

The problem I have is that I know that I am already speaking to a population of interested parties.  Maybe some of you are the converted, the true believers. I now have to ask all of you who read this blog to become more involved.  I have in the past requested that you contact your representatives in government. I hope you did so. Now I must ask that you contact all of your family members, distant cousins, friends, acquaintances and anyone you can think of and ask them to do the same. 

Some of you are involved in training professionals.  Make this a learning topic.

I accept that I am getting older and that sooner rather than later I will end up in hospital risking that highly resistant infection that may take my life. But I have a hard time accepting that my children and grandchildren will have to deal with antibiotic resistant pathogens for which we have no or only very limited therapeutic options.

I hope that all of you feel the same way I do and that you will act!

Wednesday, October 4, 2017

Antibiotic Approvals - Is the Glass Half Full?

Since the reboot of antibiotic development that the US Food and Drug Administration undertook in mid-2012, there has been a clear acceleration in the rate of approvals of new antibiotics.  The graph below shows FDA approvals of New Molecular Entities of antibiotics over time – and it speaks for itself. Clearly, even after the reboot, we are not reaching the rates of approval we saw during the 80s and 90s – the heyday of antibiotic discovery and development. But there seems to be a clear improvement.

A close look at those approvals shows that two of the antibiotics approved in 2014 (dalbavancin and oritavancin) were holdovers discovered in the 90s that had previously been discontinued from development related to changing FDA regulations, to market considerations and to technical issues. Both are administered intravenously and target only Gram-positive pathogens. Nevertheless, the post-2012 approval rate remains encouraging. Will this continue?

I “borrowed” the analysis below from a public presentation by John Rex describing the DRIVE-AB recommendations for pull incentives. Here he analyzes the current pipeline focusing on resistant pathogens in terms of WHO priorities and the likelihood of approval of products currently in clinical trials. It looks like it is conceivable that today’s rate will continue over the next five years but that new antibiotics active against resistant strains of the gonococcus, Acinetobacter and Pseudomonas will remain rare for the foreseeable future. The forecast is much more favorable for antibiotics active against Enterobacteriaceae including those possessing extended spectrum B-lactamases and those active against Gram-positive pathogens.

The WHO has concluded that this pipeline is insufficient to meet our needs over the next decade and it is difficult to argue with that.  Clearly, we need to stimulate additional research – hence the need for both push and pull incentives.

Tuesday, September 26, 2017

Pull Incentives for Antibiotics - Update

There have been at least two recent developments on proposals for pull incentives.  One comes from the DRIVE-AB meeting this month and the other from the Office of Health Economics in the UK.  Both recommend “partial de-linkage” models. As I have said consistently, de-linkage is a non-starter and I think the prevailing opinion is now in agreement with that view.  De-linkage means that there would be no “marketing” spend by companies in the sense that they would not need any “sales” to support income.  Revenues would come entirely through a market entry reward of some sort. But this approach divorces the company from needed physician educational efforts and provides no incentives for generics to enter the market after the expiration of exclusivity for the product.

The recommendation from DRIVE-AB is illustrated below. It shows a market entry reward starting payments at the time of drug approval and continuing for five years. At the same time, the company is allowed to charge some price for the drug that is sold during those years.  The company can earn sales revenue both during the five years of the reward payments and thereafter. The reward remains contingent on various milestones that the company must meet including manufacturing, physician education, microbiological surveillance and other activities essential to introducing a new antibiotic to the market. DRIVE-AB predicts that this approach would stimulate antibiotic R&D to the extent that antibiotic approvals would quadruple over the next thirty years.  Personally, I think that probably does not take into account sufficiently the scientific risk inherent in antibiotic discovery and therefore that this is an optimistic prediction based on historic rates of approval. Nevertheless, I agree that this would clearly stimulate antibiotic R&D and would motivate investors and companies to continue in antibiotic R&D or to get back in that business.

The new publication from the Office of Health Economics promotes an insurance model as a market entry reward. In this model, with the approval of a new, needed antibiotic, company would receive sufficient reimbursement to provide for a net present value (NPV) of $100 million. This would cost the health system something like $262 million per year over ten years or $2.6 billion.  The question for me is, is $100 million in NPV enough? The answer from the marketing folks at Wyeth in the year 2000 was “no!”

Both of these models and a number of others, including and especially the exclusivity voucher model, could work. The insurance model is a better fit in Europe where most countries provide some sort of national health insurance already.  It is probably not a good fit in the US. I guess I don’t see anything wrong with different countries using different approaches as long as there is a clear and predictable return on investment for the companies such that they are motivated to continue or to re-enter the antibiotic research field.

I see a number of questions that are still extant. First -  how much do we really dislike and distrust the pharmaceutical industry that will be the source (in all likelihood) of these new products? During a recent lecture one of the audience members posed an interesting question. “If we are going to have to spend this amount of money, why wouldn’t we spend it on research in a government antibiotic R&D effort that would not require profits?” I’m sure this question comes, in part from a basic distrust of and anger towards a pharmaceutical industry that many see as consistently gouging consumers. And who can argue with that?  My answer was that the expertise exists today within industry.  But I suppose that could change, even though I remain extremely skeptical.

Another remaining question revolves around the numbers. How much NPV should society provide?  This, in turn, depends on how we value new antibiotics active against key resistant pathogens. It also depends on how we value the existence of a robust pipeline that is, in a way, our insurance against emerging resistance to the new agents that we are using sparingly hoping to avoid the rapid emergence of resistance.

No matter which model we prefer for pull incentives, and no matter whether we are angry at the pharmaceutical industry, we still need a robust pipeline of new antibiotics for the future.  And the only way we will get there is by assuring companies, at least for the foreseeable future, that they will have a sufficient enough return on their investment that they should, in fact, invest in antibiotic research and development.

Friday, September 15, 2017

Antibiotics and Climate Change

What do antibiotics and climate change have in common? We have our heads in sand for both.  If we can’t see it, it won’t hurt us. I was inspired by an article in the New York Times today on climate change contending that even some Republican congressmen and senators are reconsidering their hardline positions on climate change in the wake of hurricanes Harvey and Irma. I asked myself , “Is this what it takes? Do we have to suffer through death and destruction to recognize the accuracy of climate science?”  If the answers to these questions are “yes,” then I guess we also have to wait for the antibiotic apocalypse before we get a substantial change in policy.

On the antibiotic-resistance front, we seem to be able to insist on antibiotic stewardship.  Initiatives from the Centers for Disease Control with enforcement through the Center for Medicare and Medicaid Services assure that hospitals and now outpatient and even long term care facilities will establish antibiotic stewardship programs in the US. But these regulatory moves (mandated by the 21st Century Cures Act) don’t cost much in terms of real government funding and, ultimately, will probably save healthcare dollars. The same thing is true for regulatory moves that will establish feasible and rapid clinical development pathways for antibiotics that target very specific, small populations of patients such as those that are only active against a single species of bacterial pathogens (Limited Population Antimicrobial Development [LPAD] in the 21st Century Cures Act) (LPAD Guidance is expected soon from FDA).  All of this and more in the 21st Century Cures Act is good and we should all be thankful that Congress was able to get its act together and pass this important legislation.
But all of this, including the critically important regulatory innovations will be for naught if we don’t fix the broken antibiotics market. Without a clear path for a return on their research and development dollars, private industry will simply not invest.  Companies that are currently investing in the area may finally give up the ghost and, like many before them, abandon the area altogether.

In thinking about the climate change article in the Times, I am reminded of the global pandemic of methicillin-resistant staphylococcal (MRSA) infections that began in the early 1980s. By the 1990s, MRSA became part of common language.  I gave a lecture at a retirement community yesterday and everybody recognized the term, MRSA. These resistant isolates grew to 30-50% of all staphylococcal infections, and in emergency rooms, up to 70% by the turn of the century.  Until 1999 there was only a single reliable antibiotic to treat serious MRSA infections – vancomycin.  By 1989 vancomycin resistant enterococcal (VRE) infections had emerged and were causing havoc in US intensive care units.  In 1999 linezolid (Pfizer) was approved and in 2003 daptomycin (Cubist) was approved.  Both these drugs became over $1B per year sellers because they offered an alternative to the only other drug available for MRSA, and they offered possible therapy for enterococcal infections as well.  But look what we had to endure before these drugs came out.

Today, we are dealing with KPC, NDM-1, Acinetobacter and other highly resistant infections.  Yes, we have drugs available today that we didn’t have just a few years ago and we have more to come in our thin but existing pipeline. The question is, will we have to wait until emerging resistance in Gram-negatives becomes like the MRSA and VRE of this century. To be assured of a robust antibiotic pipeline, we must take this last step and provide an assured return on investment for those companies that deliver such needed new therapies. If we wait for the apocalypse, it will take us a decade or more to rebuild lost abilities to discover and develop antibiotics.

There have been a number of well-considered proposals on how to fix this broken market (stay tuned for more details). All involve spending real money.  I’m talking about a total of $2 billion per year for 10 years globally.  The US share would depend on which other countries would partner with us (I assume Europe would do so. China?). And here we run into the problem.  Just like climate change, we would have to spend real money.  Of course, compared to jet fighters, nuclear arsenal maintenance, and other priorities, $20 billion over ten years is peanuts. But to our administration and to congress, this seems to be an insurmountable obstacle.

Please – lets not wait for the apocalypse. Lets do something now before we lose more companies and more expertise to denial of the inevitable.