David's New Book

Monday, June 3, 2019

Antibiotics - Motivating Investors

I recently had a chat with Rick Bright.  Rick is the Director, Biomedical Advanced Research and Development Authority (BARDA), Deputy Assistant Secretary in the Office of the Assistant Secretary for Preparedness and Response (ASPR), U.S. Department of Health and Human Services. I am hopeful that he will provide a blog for us on his evolving views on incentives for antibiotic research and development. But our conversation emphasized an important concept for me that I wanted to share with you.

Why do we want pull incentives and whom are we incentivizing? In my view, we need to pull investors back into antibiotic research and they, therefore, are a key target of such incentives. What is the best way to lure investors back to this area? By getting large pharma back into the area.  Why do we need large pharma?  Because large pharma provides the preferred exit strategy for investors in biotech. And how do we do get large pharma back into antibiotic R&D? By providing a substantial pull incentive for the approval and marketing of new antibiotics.  

Which pull incentives will work?  Almost all of them will work either alone or in combination if they are of great enough value.  My own view of that value is ~$2 billion.  Apparently, large companies have not been willing to commit themselves to any specific valuation that would be motivating for them – so my number is, shall we say, an educated guess. This value could come from patent exclusivity vouchers, from a market entry reward, from a priority review voucher, from value-based pricing and reimbursement (but the latter would probably have to be part of a larger package of incentives), and others. 

The dangerous state of our pipeline has been underlined by two recent events.  The first is the bankruptcy of Achaogen shortly after having a new and useful antibiotic approved for the US market.  This event underscored the complete failure of the marketplace for antibiotics and engendered a significant disincentive for prospective investors in the area.  The second is the discontinuation of phase 3 trials for murepavadin, the anti-pseudomonal peptidomimetic from Polyphor after renal toxicity became apparent.  While it is true that antibiotics that succeed in phase 2 usually make it all the way to the market, “usually” means not always.  (In fact, in the case of Polyphor’s drug, the number of subjects exposed prior to phase 3 was on the low side).  This means that a number of drugs in our current pipeline are doomed to failure simply based on the risk that something unexpected will occur during further research. We need to significantly bolster our pipeline to be assured that we will actually have the antibiotics we need when resistance catches up to us. 

We are now in a situation where the US and the rest of the world are either ignoring the coming antibiotic resistance disaster or are simply unprepared to provide the kind of pull incentives we will need to rejuvenate our precarious antibiotic pipeline. Experts around the world are struggling to find ways forward. This has led to proposals for publicly funded efforts, public-private consortia, pull incentives and combinations of the above. What we need, though, is leadership.  We need a country, a national entity, to take the lead by providing a useful way forward. I believe that must include significant incentives for investors and I believe the only way that will work is via incentives for large pharma as abhorrent as that idea may be, either as part of a larger plan or as a stand-alone approach. 

Monday, May 27, 2019

Antibiotic Research and Development - Public vs. Private Funding

Over the past decade, pull incentives as a solution to the broken antibiotic market have been proposed to entice companies into antibiotic research and development.  These incentives would essentially provide a market, and therefore a return on investment for pharmaceutical companies. Almost all of today’s inadequate antibiotic pipeline is provided by biotech and small pharma.  All are threatened with loss of investor interest because of the failed marketplace and many are experiencing difficulty in raising funds either from public or private markets.  One alternative to providing money to the “evil” pharmaceutical industry via a substantial pull incentive is to create publicly funded non-profit organizations or public-private ventures that would essentially replace the industry in antibiotic research, development and commercialization. Two proponents of this approach are Lord Jim O’Neill (of the O’Neill Commission or Antimicrobial Resistance Review fame) and Ramanan Laxminarayan of the Center for Disease Dynamics, Economics and Policy and of GARDP. Both, clearly, are key thought leaders in the area. 

The proposal sounds great. Who wants to give the pharmaceutical industry money, after all? But I find myself scratching my head about this. How, precisely, would this work? I presume we’re talking about government funding for an antibiotic R&D organization. In the US, would this be the National Institute for Allergy and Infectious Disease?  They have a strong track record in vaccine and in antiviral research – but antibiotics – not so much. Commercialization of products - not at all. In the UK would this be the Medical Research Council?  In Europe would it be the European Commission?  None of these august bodies have the experience required to establish a successful antibiotic R&D organization (in my humble view). The Innovate Medicines Initiative, an EU-funded public-private venture, has had mixed success tackling small pieces of antibiotic R&D but has not delivered a product to market and was not designed for that purpose. Then are we talking about establishing an independent organization with government funding? Who would decide who would lead the group? (On the positive side, there are lots of available antibiotic researchers available for hire.) To whom would the organization be accountable?

In addition to the questions posed above, we should all recognize the precedent this approach could set. Just think.  We could solve the entire pharmaceutical pricing problem with publicly funded R&D efforts – not just for antibiotics, but for all therapeutic areas. We could eliminate the evil pharmaceutical industry altogether.  Do we want to go there?

My experience suggests that it would take several (2-3) years just to get something established on paper and then bring it online.  Then we can count on about 5-10 more years to identify antibacterial lead compounds and then 10-15 more years to get something through clinical trials and to the market. So . . . maybe 20 years with some luck. During all these years, funding requirements would escalate enormously.  As more early leads are identified, it will take more scientists to move all of them to some go-no-go decision point. As more preclinical leads come online, the costs increase further. Finally, clinical development costs will become predominant – phase 3 trials are not cheap. The advantage of this program is that, at the beginning, the costs are relatively low - $10s of millions. But by the end, we’re in the $100s of millions per year assuming multiple clinical development projects. 

As an example, Achaogen, a small biotech in California, invested over $400 million in public and private funds to get plazomicin to the market and to carry out discovery and development programs for other lead compounds.  The company started in 2002 and plazomicin was approved in 2018. It earned about $1 million during its initial launch leading to its bankruptcy. A larger organization with multiple lead compounds, which is what we will need, will be much more expensive. 

While I’m not against establishing a publicly funded or public-private non-profit antibiotic R&D organization, I need to have a much better understanding as to how it would be established and what the funding needs would be. And I am very skeptical that government is willing, interested or even capable of carrying out this task. 

I believe that the two approaches, pull incentives for the existing industry and establishing a publicly funded non-profit, are not mutually exclusive. We could consider doing both – but we have to do it right! Pull incentives need to be substantial so that they actually work to replace the broken antibiotic market. A publicly funded entity must have the right leadership, the right accountability and adequate funding. Then, over time, perhaps the publicly funded entity could replace the industry in antibiotic R&D – if that’s what we really want. But again, color me skeptical in the extreme. 

(Email queries to the AMR Review and to CDDEP went unanswered).

Innovation - response to comment

Google blogger no longer allows me to respond to comments in my own blog.  I am obliged to respond, if needed, in a separate blog . . . .Progress!

I wanted to respond to the anonymous correspondent to my previous blog who suggested that the recently approved antibiotics were just incremental improvements over previous drugs and therefore that they deserved the market response they achieved. 

Incremental, apparently, is in the eye of the beholder. During my early years as an infectious diseases physician, a new B-lactam (but a B-lactam nevertheless) was undergoing phase 3 clinical trials.  My surgical intensive care unit was closed because of an outbreak of Gram-negative (Serratia) infection resistant to all marketed antibiotics except colistin. I was able to procure this new B-lactam (imipenem) under a compassionate use program at Merck.  It was miraculous and saved lives that would have otherwise been lost.  But it was just another B-lactam – or was it?  Is a new B-lactam-B-lactamase inhibitor combination active against KPC-bearing carbapenem-resistant Gram negative pathogens incremental?  Is a non-B-lactam B-lactamase inhibitor not innovative?  I would also note that the most innovative antibacterial compounds and strategies will be the most challenging to develop from both a regulatory and a commercial point of view (see this link). 

Thursday, May 2, 2019

Antibiotics, Investors, Where we Go from Here

What do investors think about antibiotics companies?  Not much. Paratek, at a price of just $5.42 has a 36% short ratio.  That is, 36% of is tradable shares are being shorted by skeptical investors. Market caps under $200 million do not bold well either. Melinta is selling four antibiotics – they made $96 million in total revenue in 2018. Anyone who doubts that the antibiotic market is broken need only ask the investors.

As I noted in my previous blog, it is unlikely that we will see a significant pull incentive this year. Investors, I’m told, prefer a direct reimbursement above the DRG for expensive new antibiotics as described in the DISARM act of 2018. But hospitals may well balk at being reimbursed for an expensive product they may not use. I’m not sure the investors have asked the hospitals what they think. In the UK, meanwhile, they are still considering the added value of antibiotics to their healthcare system. But, it seems, they have already decided on a value or on the price of a market entry reward, or whatever pull incentive they may or may not apply.  I first heard this number from folks at Wellcome last fall – £50 million. By strange coincidence, in the recent opinion piece by Jeremy Farrar of the Wellcome Trust, he notes that the fair share for the UK of a $1billion reward would be 5% or $50million (that’s even less than £50million).First – I believe a more workable number for a market entry reward is $2 billion, especially if we want to attract large pharma and investors back into the space. Secondly, I’m not sure that a $50 million contribution by the UK would be considered a good thing by investors – that small a number might even be a disincentive. The only way that approach will work is if 20-40 other countries join in – a scenario that seems hardly likely. This approach seems less like leadership and more like something else.

On a possibly brighter note, the WHO recently released a report on the antibiotic resistance crisis. One key conclusion was –

Additional effort, investments and incentives are needed to spur innovation in antimicrobial medicines, diagnostics, vaccines, waste management tools, safe and effective alternatives to antimicrobials and alternative practices, as well as operational and implementation research, in human, animal and plant health. 

In typical WHO fashion, this leaves much to be desired in terms of providing for a significant global pull incentive for antibiotic R&D. 

All of this gets me back to where I was in my last blog. What can we do while we wait for someone to lead with a significant pull incentive?  We lobby the Infectious Diseases Society of America (IDSA) do its job! I’m sorry – but the current situation is simply unacceptable to me as an infectious diseases physician. I just reviewed the IDSA/American Thoracic Society guidelines on treatment of ventilator-associated and hospital-acquired pneumonia. These are remarkably well thought out with a great deal of literature research for the year of their publication -2016.  But much has changed since then.  Would the IDSA/ATS still stand by their statement that “We did not identify any RCTs assessing colistin as empiric therapy for VAP, but a systematic review and meta-regression of observational studies comparing colistin to other antibiotics found no differences in clinical response rates, mortality, or nephrotoxicity [184]?”  (Personally, I have instructed my family to threaten any physician contemplating treating me with colistin/polymyxin with a malpractice suit!)

I worked on guidance from IDSA and the Society for Health Care Epidemiology in the 1990s. The guidance appeared three years after we started our work and was not updated for 10 years. Of course, I like to think our guidance document was so far-sighted that it did not need updating – but that’s just me.  The bureaucratic wheels grind slowly, especially when there are two different organizations trying to get things approved and published. I think the Societies need to find a way to respond to rapidly changing data to update physicians in a real-time way with updated guidance. This would go a long way to alter physician behavior and get our patients the right antibiotics when they need them most.  It would also spur hospitals to have the right antibiotics on their formularies and, in consequence, would provide one step towards improving the antibiotic marketplace. 

Monday, April 15, 2019

Pull Incentives - Don't Hold Your Breath!

Months ago, long before the 2018 election, I was led to believe that Senate candidate Jackie Rosen of Nevada was seriously interested in working to solve the broken antibiotics market.  In the months before the election and since then I have been speaking to the now Senator’s staff about this issue.  I have sent them articles, documents, studies, and links to information on the internet. This week I learned that while the Senator is interested in learning about the problem, she is not ready to lead on the issue.  She has not even seriously approached her colleagues in the Senate or the House on the subject. She is interested in making sure that the NIH has enough funding for antibiotic research. But as we all know, we can fund all the research we want, but without a market, it could be like flushing the money away. 

My own congressional representative, Joe Courtney, has never said he would support pull incentives for antibiotic R&D. He is most interested in reducing drug prices. 

I had planned on a visit to Washington, DC this week to speak to staffers on this issue. But I now realize that this would be a waste of my time and theirs. 

In both these cases, reading between the lines, I feel that the prospect of providing financial support to the greedy pharmaceutical industry is anathematic. It seems like no one in Washington is willing to look beyond an upfront investment in such an incentive in order to realize future cost savings.  This is like supporting prices for vaccines that have shown that they provide a ten-fold return on such an investment. We already accomplish that by reimbursing for many vaccines especially for children – see this National Academies Report. Many studies show that inappropriate antibiotic therapy given usually because of unsuspected resistance costs lives. Having the right antibiotics available to physicians and patients would clearly be a life-saving, and therefore, a cost-saving benefit. Why can’t we make this investment in our future and that of generations to come?

There is a new DISARM bill in the Senate. This bill would provide for reimbursement to hospitals for the use of expensive antibiotics active against resistant infection above and beyond the medicare diagnostic related grouping payment. While this is a step forward, its just a baby step. The problem is that it is reimbursement. Hospitals would still have to actually stock the new and expensive antibiotics in case they should see such a resistant infection, even if their usual incidence of such infections is low. That means they have to pay an upfront cost and may not be reimbursed if they do not use the drug. We also must remember that 70% of US hospitals are under 200 beds and 55% are under 100 beds.  That is, most hospitals in the US are small community hospitals. They will be reluctant to take on these upfront costs. Most people I have spoken with only give this bill a 50/50 chance of passage – and its really a baby step.

If we are not likely to see a significant pull incentive in the US (or anywhere else) this year, a likely outcome, where can we go next? There are two actions we can take that will help. 

The first step is for the Infectious Diseases Society of America and perhaps the American Thoracic Society to provide clear clinical guidance that makes the use of colistin and polymyxin a practice of the past except in cases where there really is absolutely no other choice.  The availability of new antibiotics like ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam and plazomicin should all be prioritized over colistin/polymyxin for the treatment of Gram-negative infections where resistance is suspected or documented. Recent US data from Alan Carr on the use of Dificid for C. difficile diarrhea shows that guidance can make a huge difference in use (above). Compare that to the use of newer antibiotics for the treatment of carbapenem-resistant Gram-negative infections from the same report (below). 

The second action item for us is to be sure that we can begin testing the susceptibility of pathogens to new antibiotics when the drugs come to market.  Currently there is a one to several year delay that results in a delay in these new agents being used for treatment when they should be the drugs of first choice. This delay is mostly because of the way commercial susceptibility testing device companies run their business. This will be the subject of an entire blog in the near future. 

If you were hoping for a significant pull incentive for antibiotic R&D this year, my advice is – don’t hold your breath. We need to turn our attention to insisting on new clinical guidance from the clinical organizations and thought leaders that relegates colisitin/polymyxin to the past.  And we must hold the feet of the susceptibility testing device manufacturers to the fire and eliminate long delays between the launch of new antibiotics onto the marketplace and our ability to test pathogens to see if they are susceptible to treatment with these new agents. (This does not mean you should stop cajoling your representatives to pass pull incentive legislation). 

Friday, March 29, 2019

Non-Traditional Antibacterials

We had our webinar-Clinical development for non-developers Part 3: Non-traditional Approaches yesterday.  I encourage everyone interested in this topic to listen.  I moderated, but the front line participants were 

Sumathi Nambiar
Director, Division of Anti-Infective Products
Office of Antimicrobial Products, CDER, FDA
Mair Powell
Senior Clinical Assessor
Health Products Regulatory Authority (Ireland) 
Ian Friedland
Clinical consultant
Friedland Strategic Consulting, LLC.

You couldn’t have a more authoritative and experienced set of presenters. 

What are “non-traditional” antibacterials? Based on our discussion yesterday, I think its better to think about what the products will do and how they will be developed.  Any protein, antibody, peptide, bacteriophage cocktail or other that can be developed and used as a stand-alone therapy can be studied clinically in a traditional indication such as ventilator-associated pneumonia, urinary tract infection, etc., using a non-inferiority trial design. This is by far the lowest risk way to proceed to demonstrate efficacy.  For these products, CMC and safety studies that will be required are quite different than those required for small molecules. 

For those products that cannot be studied as stand-alone antibacterials, such as inhibitors of virulence, critical but non-essential bacterial functions such as RecA for example, immunomodulators that might target host functions, therapies directed at the microbiome and others are more challenging to develop. One main problem will be coming up with a rationale to justify dose selection. Will you be able to use standard animal models of infection to carry out PK/PD studies to justify dose or not?  If not, you may need to carry out dose ranging trials in the clinic before proceeding to pivotal trials. A second major decision will be to determine whether the drug will be developed as part of a fixed-dose combination with a known antibiotic or whether it will be adjunctive therapy to standard of care. If it will be developed as a fixed-dose combination, you will need a strong rationale showing a dramatic effect of the new drug on its partner’s activity to justify this approach. If it will be developed as adjunctive therapy to standard-of-care, you will ultimately need to carry out superiority trials. In the latter case, the challenge to show superiority will be a significant one and not one to be undertaken lightly. 

In thinking about this, I have come to understand that there is also another issue – one that John Rex has mentioned frequently. That is, the value proposition. Regulatory requirements to achieve market approval are one set of challenges. But a plan to show the value of the new product to patients, physicians, payers and investors is another.  I think of this as a Venn diagram.  Demonstrating the value of the product to this important group of stakeholders is as important as obtaining market approval from the regulators. While non-inferiority trials for these products (when developed as fixed dose combinations) may allow for regulatory approval, they may not be sufficient to fulfil a value proposition.  Positive data from superiority trials are more likely to fulfil a value proposition, but the chance of success in these trials as currently envisioned is low.

Everyone participating in the webinar agreed that this is new territory. We do not have any real experience in developing or using non-stand-alone products like these. From the regulatory point of view, much will have to be decided on a case-by-case basis until we get a better understanding of how to develop these products. The regulators on both sides of the Atlantic are willing and even eager to hear from sponsors delving into this area.  They are open to listening to project proposals and providing advice even at the earliest stages of scientific investigation. I would encourage those of you working in this area to take advantage of this possibility before investing significant resources in product development. 

Dr. Nambiar has provided a number of links in her presentation materials to prior FDA workshops and advisory committee meetings that have examined this and related areas.

A few bottom line items from the webinar, at least for me, are:

Non-traditional products that cannot be stand-alone therapy remain a very high-risk endeavour. 
Any company working in this area should have a portfolio of projects that spread risk across more than one approach.
Have a Target Product Profile that is developed based on medical need and on a value proposition. Use experienced clinicians and scientists here. 
Speak to regulators early on about CMC, safety and efficacy.

Tuesday, March 12, 2019

Regulatory Conundrums

In the absence of any real news on the pull incentive front, I want to turn my attention to the regulatory side of antibiotic development. Before we get started, I want to express my thanks to John Rex who provided useful contributions to this blog.

 As I have been saying for years, for most new antibiotics, regulatory requirements are not a limiting factor. If a new antibiotic has a relatively broad spectrum or is specifically active against a very common pathogen such as Staphylococcus aureus or Neisseria gonorrhea, there are clear and feasible regulatory pathways allowing for development and approval on both sides of the Atlantic and globally. 

The remaining regulatory difficulty comes if you are trying to develop a product that is specific for a relatively uncommon or rare pathogen such as Pseudomonas aeruginosa or Acinetobacter baumannii. I have written about this previously and there have been many FDA meetings and workshops where this issue has been discussed. The conundrum as noted by Dr. Rex, is that patients, clinicians, payers and yes, regulators all want a statistically powered trial. But for these rare infections, it remains unclear that such a trial is feasible. 

Another workshop, this time to discuss the development of products for non-tuberculous mycobacterial infections, will occur on April 8.  The issue for this entire area revolves around the design of clinical trials where the enrollable population is small.  In these instances, enrolling a large, non-inferiority trial may simply be impossible or may take many years. Both FDA and EMA have struggled to provide guidance dealing with this problem. Both continue to reject the use of external or historical controls. These controls have their problems but could significantly cut the number of patients one would have to study in an active trial. 

There are at least two pathogen-specific antibiotics currently in Phase 3 trials. Murepavadin is an anti-pseudomonal drug being developed by Polyphor.  They are carrying out trails in hospital-acquired and ventilator-associated pneumonia. About 15-20% of these infections are caused by Pseudomonas. They plan to enroll about 250 patients in each of two non-inferiority trials. The feasibility of this approach remains to be seen. Entasis is studying a combination of a B-lactamase inhibitor with sulbactam for the treatment of urinary tract infection caused by Acinetobacter. In the latter case, in a phase 2 trial, patients received ExtSul plus imipenem.  Of 80 patients, 8 had imipenem-resistant isolates.  Will they be able to recruit enough of these patients and show enough of a difference in efficacy to gain approval? 

John Rex notes that, on the one hand, we do not want to have so many resistant infections that the Entasis trial enrolls easily.  On the other hand, we want to be able to approve and market drugs such as the one under study by Entasis. This topic is full of paradoxes. 

Many of the more innovative approaches currently being pursued are non-traditional in nature. These include anti-virulence, lysins, immunomodulators, bacteriophage and other targets.  Many of the resulting products will also be specific for certain uncommon pathogens. As John Rex often points out, all these approaches, traditional or not, must show to patients, clinicians and to regulators that the product under study has value to patients with unmet medical needs. Designing acceptable clinical trials that will accomplish this, especially for those products that will provide adjunctive therapy is, to say the least, challenging. 

Further, the FDA and EMA have rather divergent approaches to this topic. EMA, for example, has just published a new addendum for the development of antibacterials. They make it clear that they expect randomized clinical trial data.  Helpfully, EMA notes that the size of the data package will be based on trial feasibility including the required length of time for enrollment.  But this may conflict with criteria that FDA is using to determine trial size and makes one question the kind of statistical information EMA is willing to accept. EMA also notes that it does not consider bacteremia outside of well-documented secondary bacteremia, a clinical indication or even a disease. FDA, however, has accepted bacteremia in recent submissions. 

These apparent conflicting approaches simply signify that neither we as developers nor the regulators have come to any consensus on how to deal with antibacterial drugs targeting infections where the patient population is small.  But in order to move forward with the innovative products that are now being researched, this is a problem we must all work harder to solve. 

I am going to suggest that, as part of any legislation providing for a significant pull incentive, we insist on the inclusion of a mandate for FDA to identify feasible development pathways for products targeting small populations. Many of us thought this was already accomplished with the LPAD guidance from FDA – but in fact the guidance specifically states that there must be “substantial evidence of effectiveness.” This seems to virtually preclude small trial designs that might be feasible.

Obviously, we all have a great deal more work to do to make the global development of antibacterial drugs specific for uncommon or rare infections feasible. 

NOTE - To clarify - both FDA and EMA allow the study of bloodstream infections for products meeting an unmet medical need.  But, the label indication will not include "bacteremia" as I currently understand how this works.