To BARDA with Love

Yesterday we were confronted with the news that Rick Bright, the director, Biomedical Advanced Research Authority (BARDA) and Deputy Assistant Secretary in the Office of the Assistant Secretary for Preparedness and Response had been fired. He claims this was in retaliation for his insistence that all potential diagnostics, therapeutics and vaccines for coronavirus infection undergo rigorous scientific testing before they are widely used – including, especially, hydroxychloroquine. This stance is no different from mine, from any reasonable scientist’s, nor from Dr. Fauci’s. In fact, a recent, large (but retrospective) VA study showed that hydroxychloroquine is more dangerous to seriously ill coronavirus infected patients than placebo – vindicating our skeptical view of the drug. While several, large prospective trials of the drug are still underway, it is now more than reasonable to maintain a healthy scientific skepticism when thinking about using this and related compounds for prevention or therapy of covid-19. His firing, if based on his scientifically rigorous approach to testing, is nothing less than a national disgrace. 

BARDA, as an agency, has been a constant light in a dark cave of antibacterial research and development for almost the last decade. Without funding and support from BARDA, our meager pipeline of antibacterial drugs would be virtually non-existent today. BARDA evolved from being restricted to only funding those projects that could result in countermeasures for bioweapons and having to avoid funding phase 3 trials to being a key funder in the research and development of antibiotics for the treatment of resistant infection in all phases of discovery and development. And thank goodness for that. 

I don’t know Rick Bright well, although we have spoken on occasion. Based on his direction of BARDA, though, it is clear that he has a clear-eyed understanding of the issues facing us in terms of antibiotic resistance and our need for new therapies in the face of a broken marketplace. BARDA’s recent agreement with Paratek is proof of this. Rick has been an aggressive leader of BARDA’s involvement in the search for diagnostics, therapeutics and vaccines targeting covid-19. Once again, it’s hard to imagine how companies could have accelerated the testing of many of these various projects without support from BARDA. 

I want to now turn to those scientists, contract experts, lawyers and everyone else working at BARDA.  We need you. We need you to keep BARDA alive and well.  This administration will pass into the depths of history – hopefully sooner rather than later.  What you have done and are doing at BARDA will provide a living legacy of valuable products for decades to come. When I arrived at Wyeth as a naïve academic physician-scientist, one of the first things I learned was the importance of dealing with failure.  Since almost all projects initiated in the laboratories of the pharmaceutical industry are doomed to failure, it became important to show scientists how to deal with these constant blows. I counseled them to focus on the science. I told them to keep good records, write papers and put them aside until such time as they could be published. We all need everyone at BARDA to keep their focus.  This is too important a moment to allow what is happening to Dr. Bright to distract you from your goal of keeping the rest of us safe. We need you to provide us with the wherewithal to get through covid-19 – to say nothing about the importance of improving our antibiotic pipeline. 

Now I am going to ask all of you out there to write your representatives insisting that the treatment of Rick Bright get the investigation that is clearly warranted.  We cannot let this stand – at this time, in this moment – this cannot stand. 

 

What Happened to the CDC?

Last week, Tom Frieden, the former Director of the US Centers for Disease Control in the Obama administration, wrote an editorial in the New York Times. In his article, he praised the professional staff at the CDC emphasizing their scientific acumen, skill, experience and expertise. I have come to know many scientists at the CDC to one extent or another over the last 40 years and I agree with Dr. Frieden’s assessment.  At the same time, Dr. Frieden points out that the CDC has to do better in our current pandemic. That must be the understatement of the century. 

The botched CDC attempt at providing testing for public health labs around the US was clearly a major roadblock to establishing the kind of robust testing we would have needed early in the US outbreak.  As I noted in a previous blog, what we needed to do at the beginning was to identify infected individuals, get them quarantined and then identify all their contacts, test them and quarantine them as necessary. By the time we had any sort of access to widespread testing, limited as it has been, it was too late to carry out this basic outbreak control measure and we were stuck with our current situation – everyone and everything locked down.  This critical misstep may have led to the fact that the CDC has been shunted aside. 

Dr. Frieden says that the CDC website is the best place to get information and guidance on the outbreak. I respectfully disagree. I look at the CDC coronavirus websites every day.  Compared to the John Hopkins site, worldometer, and others, I’m ashamed at the lack of utility of the CDC site for understanding the current covid-19 epidemiology in the US. 

Recently the CDC released guidance for allowing employees at essential businesses to work follow an exposure to a known covid-19-infected individual. This guidance suggests that as long as the individual is asymptomatic, it is OK for them to be at work. But this guidance flies in the face of clear evidence suggesting that pre-symptomatic or asymptomatic individuals are responsible for up to 25-30% of covid-19 transmission to others. I queried the CDC as to the scientific basis for this recommendation.  They responded without actually providing the kind of scientific data I requested. They do recommend that workers be screened for fever and that they maintain a distance of 6 feet from others . . . .

Currently, the CDC is relying on death certificates (with many caveats) to tabulate coronavirus mortality. But they know that this is entirely unreliable. We will probably have to resort to a statistical approach looking at excess deaths be geographic area, age and other variables to estimate covid-19 mortality rates. Where is the CDC leadership on approaches like that? (In fairness - they say they are working on it). 

Dr. Frieden is again correct when he says that the CDC has the expertise to validate the various tests we need to be using including the current ones used to identify infected patients and the antibody tests we need to determine who has already been infected and who might be immune to the virus. Where are these analyses – especially of the many antibody tests that are currently on the market in the US without having been formally validated by FDA? 

He notes that the CDC does have funds to distribute to public health facilities around the country. But this funding is woefully inadequate and has been decimated by successive administrations and congresses for years.  

To open the country up to anything resembling normal activity, we still have to be able to go back to our basic outbreak control measures of case finding and contact tracing. Even with access to testing way beyond what is currently available (based on lack of reagents and swabs), we will still need an army of contact tracers.  The requirement for tracers could be reduced by using smartphone technology as was done successfully by South Korea, Taiwan and Singapore to name a few. Those countries also enlisted police and army reserves to help with contact tracing. Massachussetts and California are gearing up for this task with or without smartphone technology. But, in my view, the CDC should be leading the charge here.  Where are they?

I have wracked my brains trying to understand what could have happened to the professionals at CDC. One example might be Dr. Nancy Messonnier who tried to warn Americans of the coming epidemic at the end of February. We have hardly heard from her since. I’m tempted to speculate that the CDC, similar to what happened at FDA a number of years ago, came under severe political pressure with the result that career scientists are keeping their heads down. If so, I find this to be incredibly unfortunate since the CDC is one place where we have the expertise we need to face this epidemic.  It just seems like the CDC experts have been missing in action.  

While I recognize CDC’s missteps in handling this epidemic, I also understand that the CDC could still provide critically important leadership in getting us out of this mess. I miss the CDC I used to know. 

In a future blog, I’ll discuss my thoughts on how we get back to some semblance of normality. 

 

 

Covid-19 - The US Debacle (Part 2)

In spite of study after study and the writings of expert after expert over the last 25 years, we, as a society, have failed to provide for our own security in the face of a potential public health threat.  We have failed to supply and maintain our strategic national stockpile, we have consistently underfunded our public health infrastructure and we have underfunded our hospitals' preparedness. 

Let’s first discuss the Strategic National Stockpile (SNS). The Department of Defense maintains its own stockpile and has done so since the 1930s. The thinking that led to DoD’s preparedness ultimately led to the formation of today’s SNS for the US population at large.  In 1998 Bill Clinton signed a law forming the National Pharmaceutical Stockpile.  In 2003, after 9/11 and the anthrax attacks, the role for the stockpile expanded considerably and became the Strategic National Stockpile managed primarily by CDC under the Secretary of Health and Human Services and the Department of Homeland Security. The stockpile is kept at various regional locations around the country. It stocks a wide variety of pharmaceuticals and vaccines as medical countermeasures against biological attack.  A summary of these holdings can be found here. Many of those countermeasures were purchased by the stockpile under BARDA. The NIAID and BARDA were responsible for a large fund called Project Bioshield established in 2003, under President George W. Bush, to support research into these medical countermeasures.  NIAID, with over $5 billion in funding for Project Bioshield, established a number of regional centers of excellence to study dangerous pathogens that could potentially be weaponized.  This funding established sites that were equipped to handle these pathogens under strict security – physical and biological. The research yielded important basic scientific understandings of these dangerous pathogens and toxins, but little in the way of actual vaccines and countermeasures.  The latter came mainly from small biotechs who believed that the SNS might serve as a business model for their R&D. (In my view, they were, in the main, disappointed).  

The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) is the organization that decides what goes into the stockpile. They have expanded the stockpile over the years to cover needs for other situations such as hurricanes and earthquakes for example. They have also stocked key hospital supplies like masks, gowns and ventilators in preparation for a pandemic like Ebola, Zika or influenza. In their budget, maintenance of inventory is an essential item.

Funding for this overall effort began with an infusion for a 10 year period in 2003 ending in 2013. After that, congress moved Project Bioshield to BARDA and funded it on a reduced year over year basis. In spite of the reduced funding, BARDA has been a stalwart in our effort to find and stockpile medical countermeasures. Early on, BARDA was constrained to funding antibiotic R&D only for those products that clearly had an application as medical countermeasures. That expanded later to include antibiotics active against resistant infections. This was clearly appropriate given the public health threat of these infections. Initially, BARDA was also constrained to focus only on those products that were entering late stage clinical development. Now, BARDA has become a key funder of CARBX – focused on early stage research of antibiotics. They have also been able to support “portfolios” of antibiotic research within companies encompassing late stage as well as early stage R&D. In a recent move, perhaps to address the suffering antibiotic marketplace, BARDA has entered an agreement to fund Paratek’s omadacycline as an agent for the treatment of drug resistant anthrax with a commitment to ultimately purchase the drug for the national stockpile. It is clear that without BARDA, our antibiotic pipeline would be in even more disastrous shape than it is currently. It is also clear that with additional funding, BARDA could do so much more.

In addition to the SNS, there are funds distributed by the CDC to local public health authorities and to hospitals for preparedness. A history of funding for these various programs is shown in the figure below. If you focus on funding for hospitals, you will see a drastic decrease over time. Funding for these programs has decreased by 30-50% not counting inflation. The years cover both democratic and republican administrations and congressional majorities. Apparently, in spite of strident warnings by both experts and two of their own – Tom Daschle and Judd Greg – government was not willing to invest sufficiently for our future security. (Although the Trump administration proposed cuts to both the hospital preparedness program and to the emerging zoonotic diseases program, congress maintained or even slightly increased funding for these areas in 2018 according to Politifact. Obviously, this was still not sufficient.)

As we slowly emerge from this horrible pandemic, will we learn from our missteps?

 

Vaccines and Therapies for Coronavirus

I thought that this would be a good time to review the various vaccines and therapies being studied to combat the coronavirus pandemic. In such a short article, it will be impossible to review them all.  Additionally, the number under study grows substantially every day so this article might well be out of date when its published.

First, without trying to throw cold water on all your hopes, we should take a look at the odds. A vaccine or therapy that is found in a laboratory has only a tiny chance of making it all the way to approval by a regulatory agency. Once a vaccine enters the earliest stages of clinical trials (phase 1), usually in healthy volunteers to study safety and get an early read on possible immune response, the chances of ultimate approval are only around 15%.  For a therapeutic (like an antiviral drug), those odds are more like 10%. But, if a vaccine or drug makes it all the way to the last stage of clinical testing (phase 3), chances of ultimate approval go up to 75%. 

(Disclaimer – I don’t pretend to be a vaccine expert – and I’m not trying to play one on TV. Feel free to challenge my thoughts with your own research or, if you are an expert, respond to the blog). 

I’ll limit myself to only a few vaccines either already being studied in the clinic or about to enter Phase 1 clinical trials. None are farther along, hence the long timeline of 12-18 months before anything could reach the marketplace. The vaccine by Moderna that has entered phase 1 is based on mRNA. Once we knew the nucleic acid sequence of SARS-Cov-2 (today’s pandemic virus), the scientists at Modena were able to choose a portion of that sequence that encodes a key viral protein without which the virus would be unable to attack our cells. If such a vaccine could stimulate our immune cells to target that protein, we might be protected from the virus. mRNA vaccine is a scientifically “cool” technology and has promise. Not only is this an early effort, but previous mRNA vaccines have never worked to prevent an infectious disease in humans. The risk of failure is high. The same is true of the vaccine from J&J.  It seems to be based on the use of a defective adenovirus (the technology used is not publicly available as far as I can see). Once again, this approach has never worked before in humans. Nevertheless, both Moderna and J&J (with the backing of BARDA) have high confidence in their candidate vaccines. Finally, there is the vaccine announced recently by the University of Pittsburgh. To me, this has the most promise of the three I’m reviewing for you. In this case, they have purified viral proteins and impregnated a Velcro-like device with micro-needles to deliver the proteins. The microneedles inject the viral proteins just under the skin – a target known to provide for a strong immune response. This kind of approach has a good precedent for success (micro-needles aside).  If they have chosen the right proteins in the right dosage and safety is not a problem, this might work. 

I am optimistic that we will have an effective viral therapy before we have a vaccine. The first and most promising drug being studied is remdesivir from Gilead Pharmaceuticals. This drug is an analogue of the building blocks of the viral nucleic acid and stops viral reproduction dead in vitro.  It has also worked in animal models of coronavirus infection including mice and monkeys. Because remdesivir was originally studied against Ebola in clinical trials, we already have a significant safety database suggesting that safety in humans will not be a problem. Unfortunately, the drug did not work for Ebola.  But it currently is in phase 3 trials for coronavirus looking at patients with both severe and mild to moderate disease.  There is also an expanded access program available through Gilead in various centers around the world. The drug can only be given intravenously. This will be a disadvantage since, based on our experience with other antiviral drugs, it is most likely to work when given early to those with mild to moderate disease.

Favipiravir, that is similar in concept and mechanism to remdesivir, is an orally bioavailable drug, and is approved for use in the treatment of influenza in Japan. Favipiravir is a rather broad- spectrum antiviral drug with activity in vitro against Ebola and SARS-cov-2.  Here, we have much less data.  But the drug is already in phase 3 trials for treatment of coronavirus infection based on it approved use for the treatment of influenza and a large safety database. 

A discussion of drugs against coronavirus would not be complete without talking about chloroquine, hyxroxychloroquine (plus or minus azithromycin). These are not direct-acting antiviral drugs.  All work by trying to improve the host response to viral infection. To say the least, the data here are incomplete and controversial. I have found four small studies using these drugs singly or in combination. Two suggest that there might be efficacy and two find no effect – especially in moderate to severe disease. Only one paper has been peer-reviewed so far. All studies are too small to allow for any sort of statistical comparison between treatment groups. Here I must agree with Dr. Fauci and others who suggest that these drugs should be reserved for those who can benefit from them – patients with lupus and rheumatoid arthritis. Panic buying will expose the public to counterfeit drugs and will deprive patients with legitimate needs of these drugs in order to live a normal life. 

All the other therapeutics are well behind the two drugs cited above. A number of companies are studying the use of monoclonal or polyclonal antibodies for the treatment of coronavirus disease. This is a promising approach that is generally well behind the antiviral drugs I noted above. Immunity will probably depend on antibodies and antibodies are probably mainly responsible for clearing the viral infection. Afflicted patients are currently being studied using convalescent plasma from patients who have survived infection.  If we can achieve sufficient antibody titers with this approach, it could save lives. It would be important, as always, to treat early. We should have an answer for these studies soon. 

I hope this brief and incomplete review puts some of the vaccine and therapeutic approaches to coronavirus infection in some perspective. For a recent, more complete (and more technical) review see this excellent article by Miguel Martinez.  Also see the analysis provided by Alan Carr of Needham.

Coronavirus - the US Debacle (Part 1)

 We have now locked ourselves down for the last two weeks.  Happily, we’re not in New York City. But we are unable to read the news every day and observe the lives of family and friends without anxiety bordering on depression. Personally, I am angry, and I want to share the source of my anger with you while emphasizing the things that we can do differently for the next emerging infection. None of what I will discuss has not been previously contemplated or foreseen. None of what is happening is a surprise, but it is so unnecessary. 

The US has failed on so many fronts

There was the lack of US intelligence during the early days of the epidemic in China and the lack of attention to the intelligence on the seriousness of the infection during January. 

There was a lack of preparedness for testing that directly led to our current situation of sheltering in place. 

We have a national stockpile that exists just for events like covid-19.  But it is woefully undersupplied and, clearly, our plans for re-supply are completely inadequate. 

We continue to underfund state and local public health facilities and workers.

Today, though, I want to briefly review the history of our approach to pandemic preparedness and the current testing debacle. 

Inspired, mainly I think, by Josh Lederberg’s report from the American Academy of Medicine in 1992 on the threat of emerging infections, experts began to seriously consider the possibility of a worldwide health crisis caused by a new (or even old) infectious agent. I was fortunate to have been asked to join Dr. Lederberg’s Forum on Emerging Infections of the National Academy in the late 1990s. We reviewed public health capabilities in the US, in other developed countries and in the developing world. We found that all were seriously underprepared to deal with anything like the kind of infectious disease we were considering. In all cases, including that of the US, we identified gaps in current infrastructure making observations on how these could be addressed.  (As a “Forum” we could not write reports or make specific “recommendations.”) After 9/11/2001 and the following anthrax attacks we reviewed preparedness for biological and chemical attacks against the US on a larger scale. These deliberations shared considerable overlap with our previous reviews of public health capacity.  We constructed models and projections of the effects of such attacks. Later, after having dealt with SARS, MERS, Ebola and Zika, the Academy released a report on pandemic planning in 2016 where improvements in global  public health infrastructure and preparedness were emphasized. All this as well as experience with an H1N1 pandemic and the emergence of avian flu led to the development of a pandemic playbook during the Obama administration. Please note that this history spanned the administrations of Clinton, Bush, Obama and now Trump – republican and democratic. 

One of the key components of preparedness is the availability of detection systems that provide early information on emerging infections that might become pandemic. In 2010 and again in 2016, reports examined progress in timeliness of identifying outbreaks and in communicating their existence.  The authors found that, overall, the world community had improved from 2000-2010 but very little since then.  Lagging regions included the Americas, Europe and South-East Asia.  (Hmmmmm).  In the 2016 Academy of Medicine report, it was recommended that the WHO take responsibility for detection and coordination of a global response. 

This brings us to covid-19 and its beginnings in China. We now know that the outbreak began in November 2019 in the Hubei region of China among customers of wild animal markets.  Local authorities were aware of clusters of pneumonia in the region but apparently were reluctant to report this. China did not acknowledge the outbreak until late December.  The WHO announced the outbreak on January 5. According to the Washington Post, US intelligence agencies had been warning about the potential of this infection since early January. (One might ask where US intelligence was during December). On January 18, Secretary Azar (of HHS) was trying to convince President Trump about the potential seriousness of this outbreak. By the third week in January, we were repatriating diplomats and others from Wuhan and the Hubei Province. On January 31 travel from China to the US was restricted to US citizens and permanent residents and their families. Somebody in the administration recognized the danger posed by this virus.  

Business Insider has published an informative timeline on testing. By January 10, the sequence of the virus was published. With the nucleic acid sequence in hand, diagnostic testing became possible. One week later, the first diagnostic testing kits were available.  By February 6, the WHO had shipped 250,000 test kits to 159 countries.  South Korea, as soon as the news of the virus from China was available, invested heavily in the manufacture of kits so that when the sequence was available, they could deploy testing to the population on a large scale. As used in South Korea, the test took about 10 minutes to complete and individuals had their results within one day. The US, for reasons that escape me, decided they would develop their own test and that it would be run at first at the CDC and later at state pubic health labs. 

Once the CDC had their test approved by the FDA, they shipped it out to the state labs – but it was faulty in spite of having passed an FDA approval process. Then, instead of immediately approving other tests for use in this emergency situation, the FDA continued to rely on its usual stodgy protocols for approving diagnostic tests. While I agree that we need the FDA to assure us that the tests are going to be accurate and useful, we also need them to have a way of accelerating their process in response to a public health emergency. They can do this but chose not to for another month. Then again, their initial approval of the CDC test was not such a good precedent either. 

The problem with this US response is that it flies in the face of basic epidemiologic principles (unless things have changed in the last 25-30 years).  The ideal way to deal with an outbreak is to identify cases and then their contacts and quarantine them for the incubation period. The first US case was reported January 22. Without widespread testing, we were unable to identify cases and therefore unable to quarantine contacts. This allowed the disease to spread throughout the US. 

South Korea instituted very wide testing of the population testing 3500 people per million population.  Even today, we are testing a measly 240 or so per million. South Korea’s test results were available within minutes to 24 hours.  Our test results still come in about 5 days later. South Korea also used cell phone localization data to track movement of identified cases and to warn those whose phones had been in the vicinity of the confirmed case. They used police to supplement health care workers in testing and searching for contacts. They were able shut down the epidemic without having to shut down the country. Of course, their epidemic started and was centered around specific church in a specific geographic area of the country so perhaps their task was a little easier than it is in our vast country. 

Like South Korea, Hong Kong, Taiwan and Singapore were all able to test widely and keep the epidemic controlled without shutting down their economies. 

One of the major problems with the covid-19 virus is that about 30% of all transmissions are from asymptomatic or minimally symptomatic people. This means that very widespread testing would be required to identify all the cases.  But other countries have succeeded anyway.

This delay in widespread testing, case -finding and contact isolation has left us with only one solution – social distancing. Our only way out of this current state of affairs involves widespread testing, case identification and contact isolation. We are nowhere near where we need to be.

In my next blog – to follow soon – I want to discuss the role that the strategic national stockpile could have played in helping to control the outbreak in the US.  And I want to explore our support for the local public health facilities and workers on the frontlines in the US and how that could have been so much better than it has been. 

Coronavirus - My Secret Hope

Coronaviruses are a large family of viruses that cause disease in animals and humans. They were discovered as a cause of the common cold more than 50 years ago.  In some studies, up to 30% of colds in children and adults were caused by these viruses. Coronavirus colds, in temperate climes, have a clear seasonality with a preference for the winter months (Figure below). They occur more sporadically in tropical climates, but there they seem to prefer spring and fall. 

CF = complement-fixing antibody

SARS or severe acute respiratory syndrome was another pandemic that started in China.  Like the current covid-19 pandemic, it originated in bats.  The intermediate host for SARS was thought to be civet cats sold in China’s ubiquitous wild animal markets. As with today’s covid-19 outbreak, the epidemic was initially hidden by Chinese officials. SARS was a more transmissible virus, where each infected person transmitted the virus to 3.5 other people compared to covid’s 2.5 others. And SARS was more deadly with a mortality rate approaching 10%.  Covid-19 looks like it will end up with a mortality rate of well under 1% globally when all the testing is finally done. This figure will depend on many factors including the capacity and quality of the healthcare systems where the epidemic is occurring. SARS ultimately infected 8000 people globally with the vast majority of cases in Asia and caused over 700 deaths.  But the most hopeful observation about SARS is its epidemic curve (see below).  The pandemic started in November of 2002 but was over by July of 2003. Why? It’s hard to believe that suddenly our ability to carry out case-finding and isolation of contacts had improved to the point where we could stop the virus in its tracks. I’m voting for seasonality.  Why didn’t it come back the next year?  Certainly not because the world was immune. I don’t know – perhaps some of you have the answer. 

Another deadly coronavirus to cause epidemic disease was MERS – for Middle East Respiratory Syndrome. Again, the origin of the virus was bats but the intermediate host appears to have been camels. The disease appeared in epidemic form in Saudi Arabia in 2012 and still causes sporadic small clusters of disease mainly in that area. Overall, there have been 2442 confirmed cases globally and 843 deaths according to the WHO. MERS is also seasonal with a peak in Saudi Arabia during the winter months and spring and fall in outside the Middle East (mainly Asia).  

The seasonality of coronavirus infections is the basis of my hope. If covid-19 goes on until July, as it well may, it will be disastrous for world health and for the global economy. But, if it is like SARS, it may then die out and not come back. Is this wishful thinking?  Yes – but based on scientific fact.  Should we hope for the best but prepare for the worst?  Absolutely. 

Practice Social Distancing – I’m talking to you, kids!

Stay Safe!  Keep your loved ones safe!

Coronavirus and Tetraphase

Obvious from the title, today’s blog is going to ramble a bit. I don’t apologize. 

Everyone is very excited about the start of coronavirus vaccine trials. Take a cold shower. These vaccines are mRNA based.  Once you know a gene sequence, mRNA is fairly easy to construct.  This approach to vaccine discovery is technologically “cool,” and scientifically attractive.  It has, however, never breached the species barrier in humans.  Side effects have been prominent in some trials. And then there is the problem of vaccine enhancement of disease that has been shown for a naturally occurring coronavirus infection of cats. (This has been a problem in the development of a vaccine for Respiratory Syncytial Virus in humans for decades). I would consider these approaches to be scientifically exciting, but more likely to fail than to succeed.

A recent paper from China explored risk factors for mortality among patients admitted to hospital with covid-19. Of 813 patients, 191 were included in the study (many of the rest were still hospitalized and hence had no outcome to measure). Of 191, 32 required mechanical ventilation and 31 (97%) died. Ten of the 32 developed ventilator associated bacterial pneumonia. No details on these secondary bacterial infections were provided, but bacterial resistance is rampant in China. One can only hope that, at least, they had effective antibiotics for these incredibly unfortunate patients. 

In other news, Tetraphase was sold to AcelRx for $14 million – less that cash on hand in an all stock deal. For those of you who don’t know (I didn’t), AcelRx is a company focused on sublingual formulations of drugs for pain control. Why they would be interested in a limited antibiotic like eravacycline I don’t know. This is essentially a bankruptcy without the bankruptcy filing. 

I consulted for Tetraphase for a number of years starting as eravacycline was entering its phase I trials. I even helped design their failed phase 3 trial in complicated UTI.  But the basis of that trial, and of my belief in the potential for eravacycline, was its oral bioavailability. I said from the beginning of my interactions with the company that I felt that without an oral drug, they did not have a path to commercial success. I retired just before the cUTI trial began but followed the data closely. The trial was an adaptive design with an interim evaluation to choose between two oral doses used to follow-up intravenous therapy. The interim data suggested that both oral doses were equally effective, and the higher dose was chosen for the continuation of the phase 3 trial.  As is so often the case, the interim results were misleading, and the data failed to show non-inferiority to the levofloxacin IV/oral comparator. Most of the failures in the eravacycline arm were those who received early oral therapy. To me, that signaled a failure for the drug as a whole.  Tetraphase decided to continue by carrying out a second phase 3 trial in intraabdominal infection hoping that eravacycline’s advantage of low side effects compared to Pfizer’s tigecycline would provide sufficient market for them in this single indication. That proved to be more hope that real. Eravacycline achieved $8 million in sales as of November last year. 

I’m sure I will get anonymous on my site again saying that Tetraphase got what it deserved. Maybe so.  I certainly never thought that the single indication of intraabdominal infection for an IV only drug would work commercially and I’m not sure that the analysts did either. But this is yet another nail in the coffin of investor confidence in antibiotic R&D.  And, there is more of this to come. So far, the efforts in Sweden, the UK and here in the US to take baby steps to support the antibiotic market have been (and I believe will continue to be) inadequate to bolster investor confidence. We need a bolder approach from a country or region willing to lead.

And this takes me back to the coronavirus pandemic. How important will secondary bacterial infections be in the ultimate mortality rate? Will we have effective antibiotics to combat these secondary bacterial infections.  What about the next pandemic?