David's New Book

Friday, November 30, 2018

Melinta - Are We Getting the Message?

Along with Achaogen, Melinta has now announced a corporate restructuring where they will amputate virtually all of their R&D efforts and may close their New Haven facility.  This is occurring just after they received approval from Europe to market Vabomere (meropenem-vaborbactam) similar to how Achaogen’s reorganization rapidly followed the US approval of their plazomicin. This is becoming a repetitive pattern of success breeding failure in the antibiotic space. 

Expensive development programs followed by disappointing launches are chasing investors from antibiotics.  Over the last year, Melinta’s share price has dropped 85% and their current market capitalization is around $120 million. 

As I have noted previously, when companies and analysts overestimate the potential market for an antibiotic, disappointment when reality is finally confronted is inevitable. This, in my view, contributed to the situation now facing both Achaogen and Melinta.  But the greatest problem facing all antibiotic companies is the utterly broken antibiotic marketplace. 

I feel that 2019 will be a make or break moment for the antibiotic market. Either we will come together to provide solutions to the broken market, or we will see a continuing and catastrophic exit of companies, large and small, and a sharp erosion in investor confidence and therefore in funding for antibiotic commercialization. This situation may have a dramatic effect on the willingness of organizations such as CARB-X, the Wellcome Trust and others to continue investing in antibiotic R&D since there may be no chance for any resulting products to be successfully commercialized and delivered to the patients who need them. 

European data now clearly demonstrate that the burden of antibiotic resistant infection on the population equals the burdens of tuberculosis, influenza and HIV infection combined. 

We must obtain and then (appropriately) use new antibiotics active against resistant infections.  To continue to use ineffective and toxic polymyxins rather than spend the money on available, safe and effective new products is unforgivable (see this).

Once again, I implore everyone to continue the drumbeat on their political representatives to tackle the broken antibiotic market such that we can replenish our woefully inadequate pipeline of products. The US congress will clearly not act before January.  But they may never act unless we can do a better job than we have been doing to make them understand the severity of the problem and the seriousness of the threat we are now facing.  Europe must also act - either as national authorities one by one or, preferably, as Europe.  A little help from Japan, China, Korea and other Asian countries would also be extremely useful.  But we must get this done and 2019 is the year!

Monday, November 12, 2018

Antibiotic Awareness Week - Talk vs. Action?

This is antibiotic awareness week. To mark this week, there has been a great deal of talk and the publication of several important papers and workshops on antibiotics and resistance. At the same time, just after having achieved approval for their new antibiotic, plazomicin, Achaogen has downsized once again essentially jettisoning their R&D effort to focus on commercializing their new product. Why? Because they do not have enough money because investors do not believe their product will be very successful.  And why is that? Just look at the antibiotic marketplace. 

In the US, our National Academies of Sciences, Engineering and Medicine just published a report of their workshop, Understanding the Economics of Microbial Threats. The workshop was held by the Forum on Emerging Infections first established by Josh Lederberg and on which I was honored to serve for seven years. For those of you who have followed this topic or this blog, the workshop report offers little new in terms of the economics of antibiotics and antibiotic resistance.  It does provide an analysis by the workshop group of the National Academies, perhaps our most prestigious scientific body, which reports and supports what many have been saying for many years now.  The antibiotic market is broken and it will take government action on a global scale to fix it.  If we do not act, antibiotic resistance will continue to rise without a sufficient influx of new antibiotics to combat this threat. 

Specifically, the workshop report quotes a RAND study estimating the global cost of resistance by the year 2050 to be anywhere from $13-120 trillion dollars in reduced global GDP depending on various assumptions and discounting variables. This is similar to the $100 trillion dollar estimate from the O’Neill commission in the UK. 

The report acknowledges that pull incentives are essential to providing a means for companies to achieve a return on their R&D investment in new antibiotics. It notes that there is some debate as to which pull incentives would be best.  There seems to be an emerging consensus that pricing adjustments will not be successful (since they have not worked as yet). The preferred incentive may be a transferable exclusivity voucher – but the report does not provide details.  The report suggests that industry and government work together to better define what an appropriate pull incentive would be. My own view is that industry input is important, but must be taken at arm’s length. 


Around the same time the NAS report appeared, the European Centers for Disease Control published a report estimating the disease burden of antibiotic resistance in Europe.  They estimate that resistance is responsible for 33,000 deaths annually in Europe based on modeling.  This is not so different (given our population differences) with the 23,000 deaths in the US according to our CDC.  The ECDC paper also estimates the increase in disability-adjusted life years attributable to resistance showing very impressive increases associated with resistant infection. My own guess is that both US and European estimates are low. It is extremely difficult to gather reliable data in this regard simply because death certificates are rarely granular enough to provide insight into the importance of an antibiotic resistant infection in the demise of any given patient. So these estimates are all based on varying mathematical models. 

In the NAS workshop report, Ramanan Laxminarayan was quoted.  He “also pointed out that the way to think about AMR’s consequences on human health needs to go beyond only focusing on the death tolls from drug-resistant pathogens. He highlighted that AMR deeply affects care-seeking behaviors. He described a scenario in which an elderly patient might forgo a hip replacement surgery because of the higher associated risk of a postoperative infection and has to live with a bad hip for several more years. He reiterated that behavioral adaptations in response to not having access to effective antibiotics or any antibiotics at all are likely to be significant, and he urged the audience to think about these often overlooked ramifications.”

This provides much for us to consider during this antibiotic awareness week. My own takeaway from all this is – blah blah blah!! At this point, we need action. We need to invest in our future and that of our children now – not 10 years or 30 years from now. To those of you in responsible positions of government – you have no excuse to refrain from acting. This threat is too important for us to ignore. 

Wednesday, October 24, 2018

The UK and Antibiotic Resistance - What Happened?

 In 2016 I wrote a series of blogs on the many ways the United Kingdom was leading the fight against antibiotic resistance.  Tamar Ghosh blogged about the Longitude Prize for a new rapid diagnostic for resistant infections. I wrote two (1,2) blogs speculating on the effect of Brexit on the UK’s fight against resistance and comparing efforts in the UK to those in the US in this regard. A key personality in the UK’s approach to resistance was David Cameron.  He was supported by George Osborne, his Chancellor of the Exchequer, and Dame Sally Davies, his Chief Medical Officer. Cameron made antibiotics and resistance a top priority of his government. Antimicrobial Stewardship became a high priority within the National Health Service and used financial incentives and disincentives to achieve goals. 

So, what has happened under Teresa May? First, antibiotic resistance is no longer among the “top five” priorities in her government’s strategy – where it was in that list under Cameron. With Brexit looming, the European Medicines Agency (Europe’s pharmaceutical regulatory agency) decamped from London and opened up shop in Amsterdam. In the UK you hear very little these days about action and funding to deal with resistance. Brexit dominates the news cycle. (Of course, in the US, one might say that things are even worse than in the UK).

While there was progress in the area of stewardship, many of the other recommendations from the O’Neill Commission (as I call it), have not seen any progress.  Specifically, those recommendations dealing with the broken antibiotic marketplace have fallen by the wayside. A recent report from the UK parliament highlighted these shortcomings of the May government. According to CIDRAP, the report makes a number of key observations and recommendations.

·     In spite of lowering antibiotic usage by a relatively small percentage, there has been an increase in resistance among bloodstream infections in the UK.
·     40% of all antibiotic use in the UK remains in animals. The report recommends that this be further curtailed.
·     The report targets environmental discharge of antibiotics and other waste that might provoke or disseminate resistance.
·     Finally, and of greatest importance, the report notes that there has been a complete failure to follow the O’Neill Commission recommendations on fixing the broken antibiotics marketplace.  They parliament suggests a six month time period for government and industry to get together and provide specific recommendations for dealing with this problem. In other words, find a pull incentive that will work and then implement it! (Seeing is believing).

I don’t live in the UK and don’t spend enough time there to judge for myself whether there is any chance that this parliamentary report will result in concrete action.  (If this occurred in the US, I know exactly what would happen . . . ). But I do remember the days of the O’Neill Commission, the days when Dame Sally Davies was frequently covered by the world press as she spoke about the dangers of resistance and when antimicrobial stewardship policies in the UK grew teeth. Are those days gone?

One bright light in this story in the UK has been and continues to be the Wellcome Trust. The Trust clearly understands the importance of the resistance threat and it reacts by providing funding for a large variety of efforts to combat this threat. They do this alone and through collaborations here in the US, in China and throughout the world. But without key government action (think pull incentives), the Wellcome, even with all its collaborations, will not be able to finally deal with the threat of antibiotic resistance that is knocking at our door. 



Tuesday, October 2, 2018

Musings on the Introduction of New Antibacterials to the Marketplace


I know its been a few weeks since my last blog. A great deal of discussion around antibiotic development and pull incentives is still occurring even though the topic has disappeared underneath the continuing stream of news out of Washington. Scott Gottlieb, our FDA Commissioner, recently gave a speech where he emphasized the importance of pull incentives in revitalizing the antibiotic pipeline. The FDA and the Duke Margolis Center just held a conference on the use of real world data and evidence in regulatory considerations. 

Since our webinar a few weeks ago, I keep circling back to the differences between what we need to accomplish for regulatory approval and what is needed to convince clinicians, patients, hospitals, pharmacists, payers and other stakeholders that our new antibiotic is a valuable and important addition to our therapeutic inventory. To be successful, we must address all of these parties above and beyond any regulatory requirements. While I still believe that in spite of all our best efforts, the antibiotics marketplace is still broken, I also think we could be doing a better job addressing the needs and concerns of our most important partners in health care. We clearly need to do better to convince these stakeholders that polymyxins are never the drug of choice when drugs like ceftazidime-avibactam, meropenem-vaborbactam or ceftolozane-tazobactam are also appropriate options. What steps can we take to ease the cost considerations that make our clinical stakeholders hesitant to stock these drugs for the relatively rare cases that they may encounter where these drugs could replace the polymyxins? Should we be going to multiple local depots where such drugs can be stored such that a hospital can obtain a non-formulary item within hours instead of days?  Is that practical? Should we simply not charge for orders but only for use such that hospitals can return unused product? 
 
What more can we do during our pivotal trials or in post-approval studies to convince stakeholders that our new drug should actually be used instead of the older, less efficacious and more toxic options that are readily available? Will sub-population analyses really help?  Will small, unpowered superiority trials help?  Will real world data gathering such as in prospective observations studies help? I can’t help feeling that we are not doing enough talking with the right stakeholders on these and related topics.  

Are we doing enough to convince stakeholders that our new drug, in spite of its cost, is actually cost effective? Have we learned from the approach of the antiviral community in this regard? What are we getting wrong here?

Finally, what can be done to speed the availability of automated susceptibility tests when our drug is launched? Delays of one year and more are unacceptable.  It is not clear that recent FDA guidance will help in this regard (more on this in a future blog). This problem can probably best be resolved at the level of the test manufacturers. 

I know that all companies attempt to explore all of these questions with a number of stakeholders prior to the launch of their new product.  But I also know that either they are not hearing what they are being told or that they are not being told what they need to hear. 

I think that its time once again to gather all stakeholders beyond the regulators together in an objective setting to explore these and other questions on the introduction of new antibacterials to the marketplace. 

Thursday, September 13, 2018

Pathogen Specific Antibacterial Development - Webinar Summary

On Tuesday, GARDP sponsored a live webinar on the development of antibacterial drugs for specific pathogens highlighting drugs targeting Pseudomonasand Acinetobacter. You can find the webinar and all the presentations here. We all recognize that such compounds could be valuable additions to our antibiotic armamentarium, especially in these days where good stewardship is becoming more and more important. My goal in presenting the webinar was to inform folks working in antibacterial drug discovery or those contemplating such work about the risks of pursuing these projects from the point of view of clinical development.  I here provide a brief summary of our discussion during the webinar – but I strongly encourage those of you who were unable to attend to watch and listen yourselves. 

As I noted in the previous blog, our panel of presenters was outstanding and included -  

Sumathi Nambiar, Director, Division of Anti-Infective Products, Office of Antimicrobial Products, CDER, FDA
Mair Powell, Senior Clinical Assessor, Licensing Division, Medicines and Healthcare products Regulatory Agency (UK)
Ian Friedland, Clinical consultant, Friedland Strategic Consulting, LLC
Drs. Nambiar and Powell are key regulatory leaders and have directed and been involved in interactions with sponsors around the design of such trials, have participated in or led advisory committee meetings on this subject and have helped provide guidance documents on trial design and product labeling. Dr. Friedland has extensive antibiotic development experience, has led clinical trials targeting specific pathogens (I-CARE for plazomicin) and has been intimately involved in discussions with regulatory authorities on this topic. 

As noted by Dr. Friedland, the challenges associated with the clinical development of such a targeted product include –
·     small numbers of patients available for study;
o  to augment numbers, one may need to study the new agent in infections at multiple different body sites further complicating interpretation of the data;
o  study of infections at multiple body sites also complicates the choice of comparator;
·     multiple confounding factors;
o  concomitant therapy;
o  delay in initiating study therapy leading to prolonged empiric therapy that might confound study interpretation;
·     studies in very seriously ill patients are extremely challenging. 

Dr. Nambiar presented a summary of many of the meetings and workshops the FDA has held on this topic in recent years complete with links to presentation materials. One key message from FDA is that any trial must still meet the FDA statutory requirements for approval. While FDA can be somewhat flexible here, there are clearly limits. For example, the FDA would be willing to use a non-inferiority margin of 20% for such a product meeting an unmet need in studies of nosocomial pneumonia for example. This would clearly reduce the required trial size. Would this be sufficient to make such a trial feasible? That remains unclear. The FDA noted that the requirements of superiority trials have generally discouraged sponsors from choosing that route. A safety database of 300 subjects will be required – but these numbers can include normal volunteers as well as patients. 

Dr. Powell noted that previous guidance from EMA that can be found primarily in two previous guidance documents will be combined into a single document and be publicly available sometime in November. But she shared key concepts from the new guidance in her presentation. For this alone, a careful reading of the webinar presentation is highly recommended. One key requirement is that a randomized clinical trial be carried out with the statistical requirements limited by what is considered to be feasible. 

Both FDA and EMA agree that in vitro data must be strong and convincing. Animal model (or occasionally hollow fiber) data with clear PK/PD targets will be required. 

I tried to push the idea both of superiority trials and of the use of external or historical controls to help limit the enrollment requirements of trials.  Both regulatory agencies are highly skeptical of external controls, even if they are validated by a small randomized population in the context of a trial. Both note that sponsors are generally not interested in superiority trials. 

During the question session and panel discussion, there was clearly a great deal of confusion over the difference between an LPAD agent and one meeting an unmet need.  Dr. Nambiar carefully defined the difference in her response. 

During the webinar, I tried to point out that the regulatory requirements for trials are not the only consideration here.  What kind and how much data are required to convince physicians, patients, pharmacists and hospitals that your product is valuable and should be used? How will you convince payers? These questions go well beyond any regulatory requirements for approval. As Dr. Rex continually reminds us – to be first, you first must finish. Approval is not the end here. 

To summarize in just a few words –

  • These products may be valuable.
  • The development pathway has not yet been established. 
  • They face a high clinical development risk.







Tuesday, September 4, 2018

Webinar - Development of Pathogen-Specific Antibacterials

I am writing to invite you to our webinar on September 11, 2018. These webinars are part of a series – Clinical Development of Antibacterial Drugs for Non-Developers. They are designed with the discovery scientist, pharmacologist, microbiologist and others not directly involved in clinical trial design for new antibiotics. The goal is to provide a framework for those involved in antibiotic research to evaluate the potential development risk for various types of antibacterial products. Our first webinar was held in June, covered traditional (Tiers A and B) development and can be found here

Our next webinar will cover the development of antibacterial drugs for specific pathogens like Acinetobacter and Pseudomonas. The development of antibiotics for species that commonly cause infections at specific sites like Staphylococcus aureus in skin and skin structure infections and Neisseria gonhorroea in sexually transmitted urethritis is relatively straightforward.  But for much less common infections that occur at multiple body sites such as those caused by Pseudomonas and Acinetobacter, there remains considerable doubt around our ability to carry out and gain regulatory approval for products that target one of these pathogens specifically. Beyond regulatory approval, what data do we need to convince physicians, patients, payers, pharmacists and other stakeholders that such a product is valuable? 

To discuss the clinical and regulatory approaches to these trials, we have convened a panel of true experts and regulatory authorities.  In fact, I don’t think we could have a more authoritative group than this one. Yours truly will be moderating the discussion.  Questions from participants are welcome and encouraged.

Sumathi Nambiar, Director, Division of Anti-Infective Products, Office of Antimicrobial Products, CDER, FDA
Mair Powell, Senior Clinical Assessor, Licensing Division, Medicines and Healthcare products Regulatory Agency (UK)
Ian Friedland, Clinical consultant, Friedland Strategic Consulting, LLC
Drs. Nambiar and Powell have directed and been involved in interactions with sponsors around the design of such trials, have participated in or lead advisory committee meetings on this subject and have helped provide guidance documents on trial design and product labeling. Dr. Friedland has extensive antibiotic development experience and has lead clinical trials targeting specific pathogens (I-CARE for plazomicin) and has been intimately involved in discussions with regulatory authorities on this topic. 

Our webinar will take place at 11 am Eastern Time.  You can register here.


Thursday, August 16, 2018

Investors Hate Antibiotics - With Good Reason!


Back in the mid-1990s and even beyond the tech crash of the early 2000s, an antibiotic biotech could frequently raise $50-100 million in their first investment round. This was often in the setting of only one or two preclinical assets. Well folks, those days are long gone. 

Private investors are afraid of antibiotics.  In April of this year, I had a chance to speak to several private investors - angels and venture capitalists.  These were folks who strongly believed in the necessity to pursue antibiotic research and development. But they were unanimous in noting that it was becoming more and more difficult to invest in the space.  Among their colleagues there was a clear disdain for the area.  And as I investigated further, I found that this disdain is well founded in data. 

Recent antibiotic launches have been disastrous. Avycaz, tedizolid, dalbavancin, oritavancin all had launches well under $50 million.  Melinta now sells four approved antibiotics and their total sales revenue was under $15 million. Partly as a result of these figures, the market capitalizations of publicly held antibiotic biotech companies remain in the doldrums in spite of recently approved and launched antibiotics in many cases. 

Market Caps –

Achaogen - $252MM
Tetraphase - $163MM
Nabriva - $169MM
Paratek - $319MM
Spero - $191MM
Melinta - $234MM

The dynamic leading to these market cap numbers is an interesting one. When a company goes public, it shares its own data and market projections with investors. The analysts then carry out their own market survey research to one extent or another and come to their own conclusions.  But, in fact, they generally rely heavily on the company’s own projections.  Some CEOs believe that the analysts do not have a good understanding of the antibiotic marketplace and that this leads them to go along with what the company is projecting. But the company has a vested interest in promulgating, shall we say, optimistic forecast numbers. 

An interesting dynamic can be seen with Achaogen. I have no specific information on what sales revenues Achaogen projected.  But analysts generally thought that peak year sales of plazomicin would be around $300 million including both cUTI and CRE bacteremia indications. Their stock price (figure) plummeted from $12 to $5 when they did not achieve approval for the CRE bacteremia indication even though the analysts’ own projections indicated that cUTI would account for 80% of sales revenues. Why? Was this an emotional response to disappointment? Was this a true reflection of what they considered to be an important effect on plazomicin sales? Or was this a return to reality given another impending launch of an antibiotic into a broken marketplace? Or was it all of the above? I don’t know and I haven’t inquired. 

One biotech CEO I have spoken to over the years is praying for one good, strong antibiotic launch to rejuvenate investment in the antibiotics space. I don’t think that even that will be enough at this point. Investors will consider that to be a blip in an otherwise dismal environment. Two good launches might help.  But I honestly don’t see that happening.  

In my view, our only hope for preventing a complete collapse of the antibiotic R&D space is government intervention.  (Wow!! Did I really say that?) Government will have to step in beyond their important and considerable push incentives supporting antibiotic R&D.  They will need to provide substantial pull incentives to fix the broken market. I don’t see any other solution.