Davos and Merck

Its Davos time again – or at least it was last week. During the Davos meeting, the final DRIVE AB report was released where pull incentives were highlighted. A report from the AMR Industry Alliance was also published focusing on the fight against resistance by industry. But at the meeting itself, almost nothing was said regarding resistance and incentives as far as I can tell by looking at the publicly available highlights for the conference.  (Needless to say, I was not there).

The AMR Industry Alliance report was interpreted by some as saying that GSK and J&J are leading the effort in the fight against resistance.  I did not interpret it that way.  The report did say that both companies are opening some of their data to public collaborations – but that does not mean they are ahead in the fight against resistance. In my own view of the industry in this regard, there are companies like Entasis with both strong clinical and preclinical efforts that probably deserve better ratings than GSK and J&J.

One clear message from both Drive AB and from the AMR Industry Alliance was that pull incentives are desperately needed and that, there, no one has seen much progress.  Yes – there has been a lot of writing in many publications, position papers, white papers. Folks like us have been talking among ourselves. My friend John Rex keeps saying that ten years ago we never dreamed we would be having these conversations - and he is right.  But in terms of concrete action – no one is seeing anything.

This brings me to Merck and the recent announcement of the spinoff of many of its preclinical assets in the antibiotic space, Prokaryotics. Wow!  This looks like a good team.  Terry Roemer is leading the science and Keith Bostian is the CEO. I invite you all to look at their website.  BUT – what does this say about Merck? To me it says that with its acquisition of Cubist and its products in the marketplace like ceftolozane-tazobactam, tedizolid and its pipeline compound, imipenem-cilastatin-relebactam, they have had it with the antibiotics space. They do not want to dig themselves a deeper hole. And without clear pull incentives, the rest of the industry is going to follow in their footsteps and of those of the Medicines Company and so many others over the last 20 years.

The AMR Industry Alliance called on all stakeholders to “move beyond statements of intent and to take concrete action to address AMR.”  Amen. Of course, it has not been like there has been no action.  We have a good deal of money for push incentives – take CARB-X as an example. But when it comes to the strategy that will be the most costly and yet is the most desperately needed, pull incentives, we are nowhere.

The antibiotics market is broken. It requires financial intervention in the form of pull incentives to assure the continued availability of new antibiotics active against ever-emerging resistant pathogens. Without this intervention we will all be stuck talking to ourselves on the deck of a very large Titanic.

Antibiotic Price Perversion - The Data!

Many thanks to Alan Carr of Needham & Co. in New York for providing the IMS data I needed to look at the question of price perversion in the antibiotic marketplace that I discussed in my last blog.

The chart below is based entirely on IMS sales data for the US that has been converted into prescription data.  As such, it has its limitations. The data starts with the April 2015 US launch of Avycaz. Nevertheless, we can see that the overall treatment of carbapenem-resistant Gram negative infections has decreased since late 2016 – consistent with data showing a decrease in KPC Klebsiella infections during this time.

The graph shows that there are 7-9000 CRE infections treated each month in the US and that these numbers decreased starting in mid-2016. Colistin and polymyxin appear to be used for about half of the total patients even after the launch of Avycaz. Avycaz is used to treat about 2000 patients per month.  The rest are treated with tigecycline or other drugs or drug combinations not including colistin, polymyxin or Avycaz. The fact that Avycaz seemed to have little impact on use of colistin/polymyxin suggests that price perversion is real and is adversely affecting patient treatment. Even if some of the organisms treated were avycaz-resistant because of metallo-B-lactamase expression, most would still do better with Avycaz + aztreonam than they would with polymyxin/colistin (in all likelihood).

Even though these data are limited by the extrapolation from sales to prescriptions and from the weakness of hospital recording for these IMS data, they are still likely to show real trends in therapy.  And that, my friends and colleagues, is discouraging.  We should be doing all in our power to avoid treating sick patients with colistin/polymyxin regardless of antibiotic price!

COLISTIN

Antibiotic Price Perversion

I am hoping that readers with access to antibiotic usage data will be able to help here.

One of the legs upon which antimicrobial stewardship rests is to assure that the most efficacious and safe antibiotics are used in the appropriate dosage for the appropriate length of time in the context of any given infection. Based on numerous discussions with infectious diseases physicians, microbiologists and companies over the last 30 years, I believe that this approach to the use of antibiotics is undermined by the pricing within the antibiotics marketplace. 

One can only (with some exceptions) use antibiotics that are available within one’s institution or organization – that is – those that are on formulary. Formulary committees vary somewhat in how they make decisions as to which drugs to make available to physicians and patients, but most take into account clinical data, pharmacoeconomic data, microbiology and price.  They then try and make a value decision. Two factors work against new antibiotics. Generics like colistin are cheap. Most clinical data comes from non-inferiority trials. Pharmacoeconomics and microbiology may act to counter negative factors, but then there is the overall pharmacy budget.  In institutions, regions, and nations where the budget is tight, generics will be favored. Was linezolid favored by antimicrobial stewards for the treatment of MRSA pneumonia – even after it was shown to be superior to vancomycin? I don’t think so. (As I noted in a previous blog, there may have been a number of reasons for this).

One particular comment from a European expert sticks in my mind. We were discussing the issue of value-based pricing for antibiotics.  I was speculating on what the price for a new drug specific for Acinetobacter, for example, would have to be to provide a return on investment for its sponsor.  The discussion was based on a 2013 meeting held by Pew Charitable Trusts. When I mentioned prices ranging from $10,00 to $30,000 per course of therapy, this expert recoiled in disgust saying that in their country they would just continue to use colistin. This was in spite of the fact that at the Pew meeting, insurers had expressed a willingness to cover such costs depending on the data supporting the safety and efficacy of the antibiotic in question. I was shocked – but also naïve. This opinion was frequently stated by experts and pharmacists during market studies prior to the launch of Avycaz.

Recently, two antibiotics were shown to be superior to colistin both in terms of safety and efficacy – ceftazidime-avibactam and plazomicin. Of those, only Avycaz is currently marketed (plazo awaits regulatory approval).  A recent prospective observational study of caz-avi demonstrated a 9% mortality in the caz-avi group vs 32% in the colistin group – a 23% reduction in mortality when caz-avi was used as compared to colistin. Most infections treated were pneumonia or bloodstream infections. Renal failure was significantly more common the the colistin group and overall, there was a 64% chance that caz-avi treatment would lead to a better outcome compared to colistin.  A third new antibiotic, Vabomere (meropenem-vaborbactam),  has shown superiority to “best available therapy” (that often included colistin or polymyxin) in the treatment of infections caused by carbapenem-resistant pathogens.    It is now being marketed by Melinta.  

Given that cetazidime-avibactam has now been available globally for a period of time, and given good clinical practice and good stewardship, it should be replacing colistin/polymyxin in terms of prescription volume.  But sales data for 2016 do not yet bear this out.  Apparently, the cost of Avycaz in North America at around $8000 per course of therapy remains prohibitive. Vabomere is priced at about $5000-$10,000 or so per course of therapy as far as I can tell.  I have been unable to examine prescription volumes for these drugs to further substantiate my fear.  But I strongly suspect that the price perversion of the marketplace is leading to continuing use of inferior antibiotics when new but much more expensive antibiotics would be a better choice for patients.

I hope that one of you out there can help research this topic by examining prescription volumes (or by other methods) . . .

I think that all physicians and patients would agree that inferior therapy should not be used for potentially life-threatening infections. The question is – which price are we willing to pay – the price in dollars or the price in lives?

2017 in Review

Once again – Happy New Year to everyone!  2017 was an eventful year and I want to review briefly a few of the highlights (and low lights) for me.

The most worrisome issue that we still face is that of pull incentives for antibiotic R&D. DRIVE-AB has published a summary (this is a link to my blog on this topic) of their recommendations, but their final report originally planned for November is still not available.  Among other options, they highlighted the hybrid model where a market entry award would partially “de-link” revenues from sales volume.  In this model, a company would receive a sum of money on a contractual basis over the first several years after market entry.  At the same time, sales would be allowed to occur and revenues could increase over time. Another model discussed by several experts (see the same blog) was the patent exclusivity voucher approach.  I favor both of these.  The bad news is that NO ONE is making clear progress bringing one of these to reality.   There are more and more papers, reviews and yes, blogs, on the topic but as far as I can tell, there is no concrete action like legislation either here in the US or I Europe that is likely to actually become law in 2018.  But we can always hope.  We should also ACT and keep up pressure on our representatives in government to make this happen.  As I’ve said many times, this is the last frontier!

 

Linked to the failure to fix the broken antibiotics market, in my view, is the sale of the Medicines Company antibiotics assets to Melinta occurring just after the approval of MedCo's anti-KPC drug Vabormere.  Melinta’s delafloxacin was also just approved in 2017. It remains to be seen what will happen to the outstanding antibiotic research group that was housed within the Medicines Company and that discovered the B-lactamase inhibitor that is part of Vabormere, vaborbactam. I strongly believe that if there had been a market entry reward for which Vabormer would have qualified, the Medicines Company would not have been so quick to jettison their antibiotics assets and their researchers (see my blog on this).

There were a number of developments on the regulatory front in 2017.  I did not blog on all of them – but John Rex is keeping careful track of all these developments. I believe that we will see a guidance in 2018 on the development of antibiotics specific for pathogens like Acinetobacter baumanii and Pseudomonas aeruginosa. John covered the FDA workshop on animal models for pathogen specific antibiotics in March of 2017 for this blog.

The European Medicines Agency is moving from London to Amsterdam.  I am not sure what, if any impact this will have on the way Europe views antibiotic R&D. I worry about this move since I think that the EMA in London has been a shining light for all of us even in the face of the darkness that surrounded the FDA for a number of years. I also worry somewhat about the efforts at harmonization currently gong on between FDA, EMA and other regulatory agencies.  On the one hand, this could be a very good thing and will simplify trial designs for antibiotics.  On the other hand, I am hoping that we can forgo some of the early endpoints that the FDA uses for antibiotic trials in pneumonia and skin infections.  I still favor cure at test of cure as required by EMA as an endpoint here.

 

The numbers of antibiotic approvals has risen in the last five years.  Whether this will be a sustainable trend or not and whether the drugs in development will truly address the new WHO priority pathogens or not remains to be seen.

A potentially important highlight for 2017 was the paper by Richter et al on how antibiotics enter Gram-negative bacteria and avoid efflux. This was the topic of the blog in May. Richter and coworkers showed that a primary amine was good, rigid was better than flexible and flat was better than globular. Whether these rules will turn out to be universally applicable is not clear – but to me, this was a major milestone.  At the same time, a proposal that I helped formulate to establish a Manhattan Project to attack this very problem, we called it OMEGA, never succeeded in getting the necessary funding to get it off the ground.

In 2017 I saw how physicians face difficult decisions on how to treat highly resistant Gram negative infections every day on hospital wards. The case described in the blog I linked was one where ceftazidime-avibactam was a key component of the therapy that was required for this complicated polymicrobic infection. I am gratified that avibactam plays this role and I only hope that other B-lactamase inhibitor combinations that can be useful, such as aztreonam-avibactam, eventually see the light of day in the marketplace.

I hope that 2017 will mark the beginning of the end for colistin and polymyxin. At least two antibiotics have now been shown to be superior to these drugs that are highly toxic and not very efficacious.  I worry that antibiotic pricing will continue to apply pressure on hospitals and physicians to use these inferior therapies and I will have more to say about that in an upcoming blog.  Stay tuned.

In the meantime, I wish all of you a healthy and happy year to come and I fervently hope that some form of market entry reward becomes a reality in 2018!