PACCARB 11th Public Mtg, Day 1 Pt 4: PANEL 3: Antibiotics, Therapeutics, & Alternatives


>>Lonnie King: So, for our next panel, we’re
going to continue to focus on innovation and also antibiotics therapeutics and alternatives. So, we have four panelists, and thank you
for being with us. So, we’re going to start the discussion with
Discovery of Veterinary Spectrum Specific Agents and the Need for Innovation in Animal
Health. We’re very pleased to have Jeffrey Watts with
us from Zoetis. It’s up to — you’re on.>>Jeff Watts: Thank you so much, Dr. King,
for — and to the council — having me here today to talk about something that I’ve really
been passionate about for many years, and that’s antibacterial discovery. So, I’m going to talk specifically about the
need for veterinary spectrum-specific agents in animal health. Next slide, please. So, just as a matter of disclosure, I do work
for Zoetis. We’re the world’s largest animal health company,
and the key thing on this slide that — of all the different factoids up there is the
focus is around — we have a portfolio that’s 42 percent companion animal, 57 percent livestock,
and we also have a split of about 45/55 between vaccines and pharmaceuticals. So, next slide, please. So, when we start talking about One Health
— and we strongly support the One Health initiative — we look at this tripartite philosophy
here of healthy animals, healthy people, and healthy environment. And I want to bring out the fact that when
we talk about veterinarians many times, we’re talking about their role in animal welfare. However, we also need to think about their
role in food security through the food inspection service and also through those activities
in the protection of public health. Next slide. So, we start talking about the innovation
across the entire continuum of care in animal health, which is one of the things that we
talk about. We talk about predict, prevent, detect, and
treat. There certainly are opportunities for innovation
in all of these spaces, whether it’s genetic analysis, whether it’s vaccines, diagnostics. But what I’m going to really talk about today
and focus on is the medicine piece, and that’s the antibacterial discovery in pharmaceuticals. Next slide, please. So, as everyone is well aware, we’ve had the
emergence of therapy-limiting resistant organisms of both human health and veterinary medicine,
and this has caused a crisis in which one of the things that we need to be doing in
animal health is looking for novel, non-shared class agents for the treatment of animal diseases. And so, we talk about — the phrase we use
is veterinary spectrum-specific agents, where we’re going to tune a spectrum or look for
those compounds that have activity only against the specific animal diseases if possible. We’re going to try to skew activity toward
those animal disease pathogens; we’re going reduce activity against the ESKAPE pathogens;
we’re going to reduce activity against zoonotics; and we’re going to have — and we’re going
to be focused on our primary diseases, which are pneumonia in cattle and swine, mastitis
and skin and soft tissue infection in dogs. And those are the claim structures and the
routes of administration that we live under in a regulatory structure. Next slide please. So, now we’re going to talk a bit about substrate,
and when we start talking about substrate, I separate them out into two broad categories. The first is traditional small molecules,
and these are capable of effectively treating acute disease as standalone therapies. And so, we start talking about novel analogs,
which is where you’re going to take your medicinal chemistry efforts, and you’re going to focus
those on changing the spectrum of a compound within an existing class to have greater activity
against of a veterinary pathogen and away from the zoonotic pathogens. Or you may look at novel classes, where they
usually have some issue that precludes their use in human health — a toxicity issue, a
safety issue, something like that. Within the last category I think is really
an area that I find very exciting in that is it’s using the bacterial genomics capabilities
that we have today to try to find separate targets. These are targets that only exist in veterinary
pathogens; they were not existing in the pathogen. Therefore, we would have compounds that would
only have utility in veterinarian medicine but would be as effective as any other traditional
small molecule agent. And I provide an example for that — of that
for you in the pre-read information that I gave you. Next slide. So, the other type of substrate that we talk
about are the alternatives — what are commonly referred to as the alternatives to antibiotics,
or nontraditional antibacterial. And these are really envisioned as direct
swap-outs for traditionally antibacterials. So, when I talk about — when I think about
alternatives to antibiotics, I’m not thinking about vaccines; I’m not thinking about management
programs or disinfectants. I’m thinking about something that we swapped
out as a replacement for an antibiotic. For that reason, I use the term SMARS, which
is Small Molecule Antibiotic Replacements, and this encompasses multiple categories of
agents. So, we’re talking about peptides; we’re talking
about bacteriophages, including the — I lumped in the phage lysin constructs there; immunomodulators;
variance modifiers; monoclonal antibodies; the microbiome and microbiome modifiers. And one of the things that we’ve been involved
in exploring some of the substrate over the past 10 years, and one of the things we’ve
learned, is that every substrate category has a learning curve, and it takes a certain
amount of time for you to just understand “What the questions are I should be asking
when I’m working in this substrate category?” And so, that takes a significant — sometimes
significant investment in research dollars just to understand the questions you should
be asking. And typically, what I would say — it takes
a minimum of three years, and probably takes you five years, before you’re ready to really
play in that substrate category. And the other thing that we found in exploring
this space over the past 10 years is that it’s most likely many of these applications
are going to be limited in the prevention and control indications. They are not going to have the efficacy that
will allow them to treat acute disease. So, that’s where I think most of these agents
will end up — if they’re approved regulated products, that’s where they will end up sitting. The only exception to that — and I know the
speaker following me will talk about this — is in the bacteriophage space. So, we may have the ability to actually treat
acute disease using bacteriophages. However, in many cases that may be as an ultra-narrow
spectrum agent where you’re treating a specific strain of a pathogen. Next slide. So, this is one of the things I’d like to
talk about in terms of whether or not we should be prosecuting individual assets, or whether
or not we should be going after substrate-specific programs. And so, when we talk about individual asset
prosecution, that was traditionally the animal health model. That is, we’ve leveraged in substrate from
our human health counterpart, and we prosecuted that one asset, and if it failed, we moved
on, and that was the end of it. However, now, because of separation from parent
companies and because of inability to leverage and separation in the antibacterial space,
what we’re finding is that we can’t leverage from the parent company, so we’re looking
externally, to start-ups and academia, to provide some of those individual substrate
opportunities. Many of those opportunities are single asset
opportunities. They’re often declined at the — as being
too early, and the reason for that is many times they come to us, they have in vitro
data, they maybe have some rodent data, but they have no target animal efficacy. And so, that’s really the piece of information
that would convince us that this is an asset that we should be spending millions of dollars
on to advance. That POC study is usually a cost barrier to
me and the company. So, for example, if you’re working in mastitis,
and you need to do a POC study in dairy cows, dairy cows are $5,000 each. That’s a cost barrier that many small startup
companies cannot bear, and so that’s where some of these assets fall by the wayside. And the other thing is that the sponsors themselves
have to have the ability to scout for that expertise, identify the opportunity, and to
get into a substrate area, and then we have to be able to rapidly evaluate those assets. And so, that’s the other thing, is the expertise
within the company sometimes is lacking in these specific alternative spaces. When we start talking about substrate-specific
programs, now we’re talking about something that looks more like the large pharma type
of programs where you actually have a medicinal chemistry program. You have a target you’re going after; you
screen against it; you create analogs; and then you create the stream of lead candidates
that you’re going to be evaluating. If one dies, then you just pull up your backup,
and you start working on it. But you stay in that program for years. That requires a longer-term investment; it
requires a lot more expertise to be sitting internally, for the most part, in terms of
medicinal chemistry resources, in terms of screening capabilities, those sorts of things. Many of the animal health companies lack the
resources to run more than one or two of these programs in a space, so that’s one of the
other limiting factors that we have. So, one of the things we may start to do,
and they need to do, is look externally to externalize some of those screening and medicinal
chemistry opportunities. Again, that’s a matter of money and resources
to allow you to do that sort of thing. So — next slide. So, as I thought about this and put it together,
what I wanted to do is give you some recommendations, and I wanted to do it within the context of
the National Action Plan. And so, all of the things that I’m — all
of my recommendations actually fit under goal four of that plan. And so, in Section 4.3, under “intensify R&D
for new therapeutics,” it would require adding the requirement for the need for novel animal
health agents to address MDR animal pathogens, and one of the things that I would ask is
that all the human health antibacterial screening programs include a few strains of some of
the MDR veterinary pathogens. That way, if they find compounds that have
activity against veterinary pathogens but not against human pathogens, we would be able
to see them; we would be able to identify them. Right now, they’re going in the waste bin,
and they’re getting thrown away. We’re not talking about screening large numbers;
we’re just talking about screening a few. Under 4.4, “develop nontraditional therapeutics,”
we need clear separation of the SMARS products in that section from vaccines and disinfectants
and other types of alternative approaches. And then, under 4.6 and 4.7, where we talk
about enhancing public-private partnerships, the animal health components need to be included,
and I think we need to enhance some of the resources available to the veterinary startups
so that they would have additional funding and expertise to help them get those compounds
through their early POC studies and across what’s been termed the valley of death in
the pharmaceutical space. So, with that — next slide — I believe that’s
it. Okay. So, thank you very much.>>Lonnie King: Great. Dr. Watts, thank you very much. We appreciate that. Again, we’ll just hold our questions and our
discussions till after all of our panelists. So, now we’ll turn our attention to Phages
as Antibiotic Alternatives and their use in Humans, Agriculture, and Aquaculture, and
we’re glad to welcome Nancy Tawil from Phagelux Incorporated.>>Nancy Tawil: Thank you so much for having
me. I am very honored to be part of the discussion
today. I want to talk to you about what we are doing
in the field with bacteriophages as the antibiotic alternatives in humans, agriculture, and aquaculture. Next slide, please. So, I think that we can all agree that we
need to find novel or alternative ways to antibiotics, and, ironically, we believe that
this novel way might just be the prehistorical predator of bacteria, bacteriophages. Bacteriophages are viruses that are very specific
against bacteria, and they’re found everywhere in the environment and in the human body. They recognize their bacterial strain by specific
receptors; they then inject their DNA inside of that bacterium and use the replication
machinery in order to replicate its DNA, assemble its components, and then afterwards they lyse
the bacteria from within, dispersing hundreds of phages within the environment. And then, in turn, each one of these bacteriophages
will go and infect another bacterium. And so, this is called the lytic cycle, and
for the purpose of this talk, I’m sticking to lytic bacteriophages. What’s really interesting about bacteriophages
is that they have the ability of dispersing biofilms, and if you don’t want to use the
whole bacteriophage, the whole virus, then you can use the bacteriophage and the lysins,
which are the phage enzymes, to actually lyse the bacteria from without. You can also engineer bacteriophages in order
to re-sensitize resistant bacteria to antibiotics. Next slide. And so, at Phagelux we use bacteriophages,
lysins, and other biological solutions as an alternative or an adjunct to antibiotics,
and we are targeting, of course, antibiotic-resistant bacteria. Our human health division is currently specializing
in topicals for burn care and ulcers, but we also have lysins for acne and eczema, and
we work on the prevention of peripatetic joint infections as well as the treatment of PGIs. The AgriHealth Division has four franchises. We have our crop sciences, our food safety,
animal health, and feed additives. In the AgriHealth Division, we have currently
13 products under development, with eight products that are currently on the market. Next slide, please. And so, if we take a look at what we’re doing
for diabetics, also, as we know, the market value will reach $10 billion by 2020 and that
invasive infections are responsible for 51 percent of deaths after burn injuries. And so, we believe that, for human applications,
what we need to do is to find the proper delivery system, because, of course, we — if we are
making products not only for the U.S. but for the developing countries, we need to make
sure that these products are stable. And, also, we need to make sure that they
can be stored at room temperature, which is very hard to do with liquid solutions of bacteriophages. Also, when we use those amino acid biodegradable
polymers, we also protect the bacteriophages against Ph enzymes, that in the human body
might not be — might reduce the efficacy of bacteriophages. And so, we take those amino acid biopolymers,
and we make patches. The patch that you see here is the third generation
of its kind. The first and second generations were sold
in the Republic of Georgia, and although there has never been any clinical — formal clinical
trial, it has been used on hundreds of patients. And so, in order to bring it to the U.S. market,
we have improved on the copolymer, the phages, the way that we are producing them, et cetera. We also make other spray bandages for burn
and ulcers. Next slide. Our AgriHealth Division — we have a sister
company here in the U.S. in Salt Lake City called OmniLytics, and OmniLytics have been
spraying our crops since 2005 with a product called AgriPhage. They treated Xanthomonas and Pseudomonas species
for tomatoes and peppers as well as Clavibacter for tomatoes, Erwinia for pear and apple disease,
and Xanthomonas species for the citrus canker trees. So, we are producing approximately 70,000
liters of the phage products every year for the AgriPhage, and we are spraying this on
large areas in the United States. It’s safe, it’s organic, it’s eco-friendly,
and we are EPA-registered. Next slide, please. OmniLytics is also working on two products
for E. coli. The first product they are producing is called
Finalize [phonetic sp], and they spray around 3,500 heads of cattle every year before slaughter. The second product has not received the GRAS
notification yet, but our results are very positive. We are targeting shigella toxin-producing
E. coli, and we will be starting trials in vivo as soon as we get that GRAS notification. Our other product targets salmonella, and
it’s called SalmoPro. Basically, what we do is we spray SalmoPro
on eggs, poultry, and beef, and we control salmonella in foods. Next slide. In China, we produce — well, 688 million
pigs are slaughtered every year in China, and because our company is based — its headquarters
are in Shanghai, and we have many manufacturing facilities and research laboratories in China,
we are actually looking at how to reduce antibiotic use in pigs. So, China is responsible for half of the world’s
pork production, and they inject pigs with around 170 million tons of antibiotics a year. As with the U.S., the Chinese government is
trying to lower the use of antibiotics, and so in many provinces they have a big problem
with exudative epidermidis. Basically, the piglets are infected with Staph
aureus, Staph hyicus, and Staph sciuri, and what they usually do in order to help with
this is they inject penicillin inside of these piglets, and then they flush their skin with
0.1 percent of purple salt. And so, what we did is, instead of doing this,
we just spray those piglets with a phage cocktail once a day for five days, and the results
are pretty dramatic. Next slide. We also have launched bacteriophage product
for shrimps this year, and so what we are aiming to do is treat hepatopancreatic necrosis
syndrome in those shrimp that is caused by Vibrio parahaemolyticus. And so, this results in $1 billion of economic
losses per year in China and 80 percent of output losses. I know that we have the same problem in Mexico
right now. So, in Southeast Asia this is a huge problem
— next slide — again, what we do is we create cocktails of bacteriophages, and we go inside
of the field. Here you can see that when we do treat our
ponds with bacteriophages, we see an increase in shrimp length in those treated ponds when
we compare them to controls, and in the larvae ponds we see a 14 percent increase in yields. What’s interesting is that we see a complete
clearance of Vibrio parahaemolyticus inhibition within 24 hours of putting those bacteriophages
in the water, and the bacteriophages — what we’ve seen — stay there in the water for
about five days, and then there is — they’re not there anymore. Next slide. So, in conclusion, I want to stress that phages
are naturally occurring, they’re safe, and they’re effective in treating or preventing
bacterial infections. We have a lot of data on this. There might not have been controlled studies
in humans here, but we do have data from the European countries, and we also have data
in the U.S. since 2005 for crops. Phages also can re-sensitize resistant bacteria
to antibiotics. So, yes, bacteria can become resistant to
phages, but it comes at a cost, and so most bacteria that become resistant to phages become
sensitive to antibiotics. We’ve seen that in humans. We haven’t seen any resistance in the fields
in the U.S. I can come back to that after. I just want to say that there is synergy between
phages and antibiotics, and it can be used in human health, agriculture, aquaculture,
and food safety quite effectively. Thank you.>>Lonnie King: Great, thank you very much. So, now we’re going to invite Dr. Steve Brooks
to talk about internal biosecurity — oh, no, that was another — Antibiotic Manufacturers’
Commitments: Supporting Measures to Reduce Concentrations of Antibiotics in Manufacturing
Waste Discharge. Dr. Brooks, thank you.>>Steve Brooks: Thank you, and it’s a pleasure
to be here this afternoon. What I’m going to talk about is in part commitment
and in part progress that has been made in the industry to address the issue of manufacturing
wastes from antibiotic production plants, so I’ll hopefully be able to show you some
progress has been made. Just — if you could put me on the first slide,
please. I work for Pfizer, a leading global biopharmaceutical
company and with a very significant presence and investments here in the United States,
as the slide will illustrate. We are a leading supplier of anti-infective
medicines, and we work closely with the anti-infective community to — together to address commitments
to addressing the challenge of antimicrobial resistance across many aspects. And we’ve been talking about several of them
here today, but what I’m going to talk about is responsible manufacturing practices. So, if you could take me to the to the next
slide, please, you’ll see the logo sort of change to the AMR Industry Alliance because
I’m also the chair of the manufacturing group of the AMR Industry Alliance, so I’m really
going to talk about the progress that’s been made through the Alliance. I’m happy to, you know, add color commentary
based on my Pfizer experience as necessary. I’d like to start by saying that affordable,
accessible antibiotics are essential to public health, and they bring huge societal benefits. And our supply chain as an industry is global;
we have a significant footprint of manufacturing operations in emerging markets as well as
developed markets, and there have been reports that you’ve probably seen concerned about
pollution from manufacturing plants, particularly in some of those emerging markets like India
and China. Key reports such as O’Neill have asserted
that there’s a link between drug production, pollution associated with drug production,
and development of antimicrobial resistance, and of course there’s been plenty of academic,
media, and even investor interest in this issue, all highlighting concerns related to
our manufacturing processes and antimicrobial resistance. This is recognized as a concern by many stakeholders,
including the industry, and there are many calls for action, including action by governments. I’m going to go on in a moment to show you
that there are several sources of antibiotics in the environment — manufacturing is one
of those potential sources — and the AMR Alliance that I’m here representing today
is the life science industry’s response to the call to action on AMR, including on manufacturing
matters. Next slide, please. So, this diagram is really a simple illustration
that antibiotics can find their way into the environment through many sources. I’m here to talk about the manufacturing elements
of that, but most of what we manufacture, of course, ends up as medicines that patients,
be they human or animal, take. I think we’ve already heard this morning 80
percent of what we take is excreted through normal uses, not metabolized very well, and
it’s excreted out into the wastewater systems wherever we live and wherever we are. Equally, antibiotics are used in treating
livestock and can enter the environment through that route and other agricultural uses that
we’ve also heard about today as well. So, there are many ways in which antibiotics
can find their way into the environment. So, we recognize with manufacturing, although
we are not the main source of the presence of antibiotics through our manufacturing processes
in the environment, that it is a concern, particularly in the local cows around manufacturing
locations. So, next slide please. So, the industry in 2016 agreed to a number
of commitments to reduce environmental impact from the production of antibiotics. The four commitments — and I’ll just briefly
summarize them — the first basically says that we will review our own manufacturing
processes, our own plants and supply chains, to ensure we’ve got good practice in place,
and that’s really an individual company commitment as members of the Alliance. The next three commitments are what I call
commitments in kind. Together we committed to do the following:
to develop a framework for antibiotic manufacturing, kind of a sound practices for environmental
management, and we said we’d do that by 2018. We also said that we’d work with stakeholders
to develop a practical mechanism to transparently demonstrate that we’re meeting our commitments
in terms of the supply chain, and we also said we’d work with other experts as well
as our own to develop science-driven, risk-based discharge targets so that we could kind of
establish a basis of safety for discharge from manufacturing plants. We said we’d do that by 2020. So, these are the commitments of the Alliance,
and just to ground you, there’s about 100 companies — biotech, research pharmaceutical
companies, generic pharmaceutical companies — diagnostics in the Alliance and the associated
trade associations as well. If you take me to the next slide, of those
companies, 15 are really in commercial manufacture of antibiotics. So, those 15 companies are really now the
companies I’m going to talk about in terms of what we’ve actually done. So, in January of last year we published a
common antibiotic manufacturing framework. It’s published; it’s on the website that’s
at the bottom of the page. And what this does really is codifies what
I believe is to be good sound environmental practice. It’s not rocket science, but it is good practice,
and it’s there for not only our guidance but for anybody that wants to use it. It lays out what we expect at our sites, but
also, really importantly, in our supply chains, so obviously it talks about auditing of our
supply chains so that we ensure suppliers that we use in our supply chains are manufacturing
responsibly. I believe adherence to the framework will
drive the selection and use of appropriate suppliers, and there is some room for improvement
in that space, just to be candid. If you take me to the next slide, please. We’ve also developed ahead of time the discharge
targets that I spoke about, so we published in September of last year a list of discharge
targets for over a hundred antibiotics. We shared our industry data on eco-toxicity
of the antibiotics that — between the companies we make, and we’ve published those data. So, those are typically what we call the environmental
discharge targets, the predicted no-effect concentrations based on traditional eco-toxicity,
and then we’ve reviewed the state of the literature, the current literature, and we have opted
to use the minimum inhibitory concentration that is published by Larson et al. based on
clinical data. So, this is really an indicator of resistance. It’s not a true measure of resistance. So, we have side by side now a list of antibiotics,
the predicted no-effect concentration, environmental predicted no-effect concentration — MIC — and
we — our position is that companies should use the lower the two numbers so that we can
be protective of both the environment and of any risk of development of resistance. So, these are available to anybody, again,
on the website. We are also publishing a peer-reviewed paper
which should come out later this quarter, actually, which will talk to more of the science
behind the methods that we chose to use. I should just add that these limits are, you
know, typically in the parts per billion range. These are exceedingly low concentrations,
and it will take industry time and money to meet these targets over time, but our commitment
is to get there. If you could just take me to the next slide,
please. So, what I want to stress is that the industry
Alliance is part of the solution. We’ve made commitments, and we’re delivering
on those commitments individually as companies but collectively as an organization. So, we’ve published the framework; we’ve published
limits — discharge targets, we call them — and we will publish our progress reports
in January of 2020. So, those of you that may be familiar with
the Alliance may remember we published a report in January of 2018 sort of outlining where
we were at then across the range of areas that the Alliance addresses, not just manufacturing. We will — intend to produce a report in January
2020 which will show you progress against the various commitments that the Alliance
has made, including meeting our manufacturing framework and our discharge target commitments. I do believe strongly that widespread adoption
of the framework in particular beyond the current Alliance members will be a significant
step in minimizing the presence of antibiotics in the environment — in the local environment
to manufacturing facilities, and it will minimize the risk of the selective pressure on resistant
organisms which net — should help reduce the risk of antimicrobial resistance developing
and spreading. So, if you just move into my final slides. So, in terms of considerations, I did look
at the latest version of the National Action Plan. I didn’t really see anything addressed the
manufacturing issue here in the United States. It’s definitely prevalent in other national
action plans. I do think, though, that here in the United
States that we could stimulate and fund more research to better understand the nature of
any linkage between the presence of antibiotics in the environment and clinically relevant
antimicrobial resistance, because there is nothing that really proves that yet. There are plenty of hypotheses. And I also think that we should examine the
relative contribution between agriculture, hospital discharges, manufacturing wastes,
et cetera, and armed with that knowledge, we could target our resources to most appropriately
address the issue. I do also think that in the public arena we
should look at technologies that may take antibiotics out of waste streams, even in
publicly owned treatment plants, because, as I’ve already said, the majority of antibiotics
in the environment, particularly in the United States, would not be coming from manufacturing
itself. So, my final ask is that we work with the
other governments, and it’s already been said today, to make sure that other governments
implement their national action plans, because effective implementation of their national
action plans will greatly help the United States address the risks here at home. And I’ll just finish with the final slide. Industry is part of the solution, so please
continue to engage us. We have a lot of knowledge and expertise which
we’re willing to share. You know, there is a challenge between balancing
access, because many more people die from lack of access to antibiotics than from antimicrobial
resistance, so we need to be able to have access to affordable antibiotics, and then
increasing the manufacturing expectations and likely the costs of antibiotics. And we need to engage governments and international
organizations, and we stand ready to help. Thank you.>>Lonnie King: Dr. Brooks, thank you very
much. So, our final panelist this afternoon, Dr.
Elaine Hamm from Ascend BioVentures, will address the topic of Realities and Challenges
of Pharmaceutical Development. Dr. Hamm?>>Elaine Hamm: Thank you and thank you for
having me here. Unlike my colleagues here, who are here for
their successes, I am here because of my failures. Also, that was the one joke of my talk, so
I hope you enjoyed it. [laughter] Next slide. When they first approached me, they thought
I had two companies in developing infectious disease products, but in the time that they
heard about me and the time that they called me, those two companies had failed, and I
asked if I could talk about the realities of drug development. And we have all heard the statistics — startups
are hard; developing drugs is hard; infectious disease drugs are particularly hard to develop
— but I wanted to give you an idea of the reality of what it’s like to be a startup
in this particular area. Next slide. Okay, so hunker down. This is the important slide, but my husband
informed me this is the most boring slide, so bear with me. There’s a lot of really great things about
being in a startup company. I have spent most of my career in a startup
company either as a scientist, I’ve been on the investment side, and now I serve as the
head of a pharmaceutical accelerator company where we serve as the management team for
a portfolio of early-stage companies. It’s a great environment to be in because
we’re head of R&D, and I’m also the legal department, and we can move contracts through
very quickly. So, we, unlike other organizations where it
might take months — we’re the speedboat where some are the cruise ship, so there’s a lot
of advantages. In addition, I am the little guy in the sense
that I am not in Boston, and I’m not in San Francisco or Silicon Valley. I’m in Oklahoma, the Midwest. There’s a lot of really great reasons to do
drug development where I’m at. We have a number of state incentives and state
organizations such as OCAS and i2E that are particularly invested in helping pharmaceutical
startup companies, and that has helped us even get federal funding. So, SBIR grants, CDMRP grants. They have been incredibly helpful. It’s actually easy for me to raise a $2 million
Series A round, whereas my colleagues in Boston and San Francisco have problems, so much so
that they actually have me license their technology to Oklahoma so I can raise that series A.
It’s cheaper in Oklahoma; our land and our labs are cheap, but quite frankly, we can
do science anywhere. Most of our companies are virtual, so we can
do science at contract research organizations, very easily enabling me to run a microbiology
lab in North Carolina from the comfort of my home in Oklahoma. But there’s a bad side of being in the center
of the U.S. in that we’re isolated. Where we can do science anywhere, it is challenging
to do business development. You have to go pound on doors, you have to
be where the companies are at, and that takes time, and it takes money. And the amount of money that it takes to go
to JPMorgan that was here a few weeks ago could pay for one or two technicians’ monthly
salary, and so we have to make the decision of whether we want to do business development
or if we want to do science and have to make those choices. And then there’s the ugly. Funding — I mean, we all have this problem
— lack thereof, or just plain slow — and I’ll get into that in the next few slides
— and experienced management. Unfortunately, in the startup world we have
a lot of hungry, excited scientists and young entrepreneurs, but they are young and don’t
often have the experience to run a business or do drug development. And finally, there’s also some discrimination
issues. I have learned — I’m a pretty decent grant
writer, and I have learned that if I want to get a grant funded that I have to find
the oldest guy in the company and put him as the principal investigator, and that way
I can get the grant funded. I mean it’s sad but true, and that’s a problem. The NIH funds a lot of scientists, but less
than 1.6 percent are under the age of 36, and that is an issue. That’s not just the NIH; that’s a lot of other
funding organizations. The equity funding of last year — 76 percent
went to all-male founding teams and not female-founding teams, so it’s a problem across the board. I don’t have a solution for it; I’m just stating
these are some of the issues that we’ve experienced personally. Next slide. But as I thought about this issue of why we
failed time and time again, the issue was time of funding, of experimental, and of deal
timelines. Next slide. This is a very busy slide, but for a reason. This is a snapshot of one of our companies,
Synereca, and what we went through in the past year of trying to get grants. Those of you in academia, this is not unfamiliar. You know the issues of when you want to get
funding — if you want to get — if you run out of money in June, you better start planning
in October. The same thing for us in the startup area. Equity is no different. If you want to start a deal — if you get
investment, which is also a big challenge of getting a venture capitalist to even listen
to you about your infectious disease product, it can still take quite a bit of time just
to get the funding. And as I mentioned, it can be expensive just
to do the business development aspect of this. Next slide. Overlay the issue of experimental timing. We had — one of our companies had in-house
chemistry and an in-house animal facility. This gives you an idea of what it takes to
do one experiment. Obviously, we’re doing a lot of experiments
at the same time, not just one at a time. If we wanted to outsource, we have to add
time. And I have to say the NIH has a lot of really
great free resources that we have utilized to do our experiments, but again, it just
takes time. When you work with large company CROs, we
had one that took — it was supposed to take three months; it took us seven months. By then, I was the only one working at the
company, so kind of a sad day to receive data. Next slide, please. These are two examples of the company’s infectious
disease that were in our portfolio. We had Synereca and Pamlico, and both had
really great early-stage data. One of them was actually a finalist for CARB-X,
which, by the way, is an amazing program. I highly hope that everyone continues to support
that program. We have great investment from local investors. With Synereca, it was a little bit too early-stage,
I think, for a startup company, but we ended up in this weird funding purgatory where we
were either too early or too late, leaving us in this gray zone. We also had differing feedback from different
large pharma companies of “if you just did this, then we’ll be interested,” and then
someone has a completely different list, and so that kind of left us struggling to prioritize
what we needed to spend our time on. With Pamlico, it more suffered from a business
development issue. It was highly specific, but that meant a very
limited patient population. It was an antibody therapeutic, which made
some — the manufacturing costs go up in terms of cost, and so pitching that business case
was actually very challenging for us. So, two examples of two companies that could
have almost made it but did not. With Pamlico, we had great in vivo data, but
the next round for us was $5 million to $8 million, and it didn’t make sense for us to
carry on with that, because we didn’t have any partners to help us, and no venture capitalists
to help fund us. So, next slide. Are these challenges that we all have? Yes. This is not just for infectious disease startups. Money, resources, management — all of those
are challenges across the board in startups in general. But I have found in our portfolio infectious
disease was particularly challenging. We have diabetes, hearing loss –we’re currently
working on a fatty liver disease technology that has no proof of efficacy, and people
are clamoring to work with us, and that’s a problem. We have a lot of people that are interested
in other markets other than infectious disease, not just from pharma, but also in the venture
capital world. They want to invest in things that are going
to make them a 10X return, not a 2X return, and that makes it challenging. Next slide. So, not to beat a dead horse with a dead horse,
but these are the things that, if I could have a wish list, this would be it. Having large pharma. I know large pharma is sort of — can be a
negative term, but, frankly, we need them. It’s not going to be a company of me and another
guy getting a drug approved; it’s going to require a collaboration with large partners
including pharma as well as venture capitalists to be incentivized to actually invest in companies
and invest in antibiotic drug development. We need innovative new business models to
help address this issue. Oklahoma — we’re very invested in drug development,
and that’s why many — multiple partners have invested in the pharmaceutical accelerator
concept to help address some of the issues of early-stage drug development, particularly
in infectious disease. And more importantly, also, support for us
little guys, not just from a startup but in the rest of the country, too. So, thank you.>>Lonnie King: Very good. Thanks very much. So, we can now open up for questions, so,
Marty, did you want to start? And we’ll go from there.>>Martin Blaser: All right. I have a couple of questions, but I’ll just
ask one for starters. Dr. Hamm, thank you for coming here and telling
us your story, or stories. And you told us a lot of daunting things;
you said one thing that caught my attention, which was that CARB-X was very good for you.>>Elaine Hamm: It was.>>Martin Blaser: Can you tell us why? What was it about CARB-X that was helpful
to you? So that maybe we can learn from that model.>>Elaine Hamm: Yeah, absolutely. So, it was multi-stage so that you didn’t
have to spend time writing a 100-page application. You could, you know, stage it out. So, that was helpful just from a logistics
standpoint. But they were willing to take risks, and risk
is where the innovation happens. They didn’t want same old, same old; they
didn’t want “me too’s.” They were interested in looking at things
that probably sounded a little crazy, and that’s great for us that are trying to help
create new innovative drugs. They were very helpful throughout the process
and guiding us through the application process as well. That was really helpful. And frankly, from an investment standpoint,
and from a partnering standpoint, it was incredibly helpful for me to say to a potential partner
or investors that we were CARB-X finalists. Just those words alone were the validation
we needed to get our foot in the door.>>Lonnie King: Kent?>>Kent Kester: So, once again, great presentations. Thanks very much. For Dr. Tawil — so I think we all see the
value, and the need, in fact, of different approaches to the treatment of bacterial infections,
antibiotic-resistant or not. We know that bacteriophages were used in the
U.S. until the antibiotic era, and unfortunately much of the experimental data is in Russian,
or perhaps now more recently in Georgian. But, you know, it seems to me that the punitive
value in bacteriophages are sort of this idea of cocktails that can sort of treat a lot
of different things, especially in mixed infections, and the idea that you may be able to customize
the components of these cocktails, you know, for specific infections. But that really raises a regulatory challenge,
and so I’m just curious, as, you know, we’re — you know, part of our — well, really,
our goal here, our mission, is to help advise the government, you know, in terms of strategies
going forward. You know, given what I see as pretty significant
regulatory challenges to getting a bacteriophage cocktail, you know, or, you know, admix cocktail
that occurred — that’s done based on particular infections, how do you see the regulatory
environment specifically for use in humans?>>Nancy Tawil: Absolutely. So, I think that a few years ago you could
say that we weren’t really too sure what regulatory looked like for a bacteriophage product, but
in recent years I think that the FDA, especially CBER, has really given us guidance for all
of the companies that work in the phage environment. And so, pertaining to cocktails, we have the
option of making those cocktails and then swapping out bacteriophages from cocktails
— taking out one bacteriophage, replacing it with another — just by submitting very
strong CMC data, genomics data, to the FDA. So, I think that the FDA is extremely open
to the idea of bacteriophages, and they have been helping us a lot throughout the regulatory
pathway.>>Lonnie King: Helen?>>Helen Boucher: Thanks so much and thanks
for great talks. I wanted to just comment on a couple of things. So, Dr. Hamm, I really appreciated your comments
and just wanted to pick up on a couple of things. Your comment about early-stage companies having
less experience in development — that has been heard, and I think we’ve heard from colleagues
there’s been a number of FDA workshops, and both BARDA and GARDP in Europe have collaborated
to have a number of these workshops to help with the basics, from the early discovery
to first in humans and those kind of things, which I think is a great step, and we hope
to see more of. And we heard about CARB-X being a great push
incentive, which is terrific. The challenge now is on the pull side, and
we have a paper in press looking at the IDSA’s 10 by 20 initiative, and the good news is
there are 10 new systemically available anti-infective antibiotics before the year 2020. The bad news is that we might not have them
because the companies are doing so poorly. They’re at risk of going bankrupt, and as
of yesterday for the five companies, the stock price — Melinta, $0.88; Tetraphase, $1.15;
Achaogen, $1.76; Nabriva, $1.94. So, that’s four under $2.00, and one, Nabriva,
$6.50. Compare that to Big Pharma that are on the
orders of $40 to $60 to $80. And we know that large pharma has largely
left the space, so the need for pull is huge. And I just wanted to circle that back to the
stuff about antibiotic discharges that Dr. Brooks talked about, because it’s really great
that Pfizer and others are leading the way in this, but when we look at what the — where
the antibiotics are being developed, it’s by little, tiny companies who are struggling. And so, I really worry, and I just want to
raise for the committee about how we’re going to manage things like discharge and residues
in really struggling companies going forward.>>Steve Brooks: So, maybe just, if I could,
I’ll put the record straight. First of all, I appreciate the honorary doctorate,
but it’s Mr. Brooks, just for the record [laughs]. No, thank you. So, the Alliance includes BIO, which is the
trade association for the, you know, biologics companies, and we have been talking with BIO
about the need to consider the manufacturing aspects as, when, and if companies get to
that stage. So, you know, they’re aware, and there’s receptivity. Obviously, they’ve got to get to that stage
first. And again, we’re available to share our knowledge
and expertise with those companies as, when, and if they get to that to that stage. So — but I hear your concern, because at
the end of the day all of this takes expertise and money.>>Lonnie King: Sir?>>Locke Karriker: I’d like to say thanks
to the panel for the information and direct this question to Dr. Watts. You mentioned public-private collaboration. Could you expand on exactly what those are
as two broad groups there? Is that pharma and universities, or what groups
do you think have the most potential for synergy, and what are the characteristics of those
groups that will make more of those synergies happen?>>Jeff Watts: Well, I think there’s a couple
of different synergies there, but maybe mainly it is a lot of early research is coming out
of universities, and many of the university scientists really lack the experience. We see the same thing in the startups. They’re very enthusiastic, but they lack the
experience in order to understand what they need to be doing. And they also don’t realize that they may
work on something for five or 10 years to finally have a lead candidate to deliver to
us, and it takes us another eight to 10 years to get to market. So, they’re 20 years — we have 15- to 20-year
cycle times, end of discussion. I mean, that’s the thing we need to think
about. And so, it’s being able to put those two groups
together, where you draw upon the experience of people who’ve actually taken products to
market and connect them with those early lead compounds. And I’ll give you a good example; it goes
to a question that was — the previous question, is you need to think about your differentiators
first. You know, everybody’s focused in human health
on activity against escape pathogens; in animal health, it’s all alternatives. I had a conversation with a person in a startup
one time that — and I said, “So, what your market differentiator?” and they said, “We’re
not a traditional antibiotic.” And I said, “Okay, let’s fast-forward eight
years. You come to market. There are five other compounds on the market;
they’re all alternative antibiotics. What’s your differentiator?” Dead silence for 30 seconds, then, “We never
thought of that.” You’d better build in your market differentiation
upfront; you better understand how you’re going to be separated from everyone else. And that’s part of that experiential piece
that comes from the companies that can be delivered into universities. It can also be used in teaching and mentoring
around some of the startups. I like the CARB-X model and the fact that
you have a resident expert who can actually interact with the companies early on to help
them troubleshoot some of their issues. So.>>Lonnie King: All right, Sara, now.>>Sara Cosgrove: Thanks to all the speakers
for great talks. I have a question for Mr. Brooks [laughs]. There are a lot of different antibiotics. What classes are you most worried about in
terms of affecting the environment? And then, in light of Helen’s comments, what
kind of studies do you think would be effective in figuring out, you know, which classes are
the worst and whether they are also impacting human and animal health?>>Steve Brooks: So, I think I need to be
Dr. Brooks to answer the second question, so I’m probably not best-placed to answer
the question. I mean, at the moment, we have applied our
approach and our philosophy to all the antibiotics that we make across the board. The discharge targets that we’ve published
obviously have — you know, they’re specific to a compound, so they’re all numerically
different based on the criteria that I explained before. So, I don’t know that I could tell you that
there’s a particular class of antibiotic that we’re most concerned about. I mean, what we’re concerned about, to be
candid, is the — first of all, we don’t want to cause environmental harm, and secondarily,
you know, we really don’t wish to be in the spotlight for this issue when what we’re trying
to do is provide antibiotics to alleviate pain and suffering. And you know, some of the reports that you
may have seen, you know, don’t present very nice pictures of, you know, the manufacturing
process, particularly in some of the emerging markets. So, there’s a big kind of optics issue around. It doesn’t look great, and we want to address
that. It doesn’t really matter, to me at least,
which antibiotic is being made. It needs to be made in a responsible manner,
and we need to make sure that any discharges are properly managed and at levels that we
believe would not cause environmental harm or resistance. So, we don’t — somebody can probably tell
you more scientifically whether certain classes might be of more concern than others, but,
you know, we’re basing it on our environmental management principles, which apply across
the board, and then the specific targets that we will sort of chase down to.>>Lonnie King: Marty?>>Martin Blaser: I wanted to ask a question,
and I forgot to congratulate everyone on their nice talks, too. So, thank you. I wanted to ask Nancy Tawil a question about
— really, two questions. One is you mentioned that you have the capacity
to make 70,000 liters of phage. That sounds like a lot, but on a national
scale it’s probably not that much at five MLs per dose per day. So, I guess one question is about scale-up. And the second question is, with your AgriPhage,
you’ve — it’s been — you’ve been using it already. What can you tell us about your actual experience
on the emergence of resistance?>>Nancy Tawil: Sure, two great questions. So, we are producing in Salt Lake City very
large quantities of bacteriophages for agriculture. When we think about scaling up CMC for humans,
that becomes challenging, and I think there are not too many companies out there that
have the resources in order to be able to produce bacteriophages on a large scale or
have a GMP manufacturing facility in order to produce bacteriophage products for humans. And so, what we did for the products that
are going into Phase I clinical trials — we have partnered with the Canadian research
National Research Council in Montreal, so we have human health facilities in Montreal,
and we’ve partnered with the Canadian government in order to have a GMP-like production of
those bacteriophages for Phase I. Now, when we’re looking at Phase II, we either
need to build our own GMP manufacturing facility or partner with another group, but there are
— they only have very small-scale fermenters, and so scaling up is a little bit difficult
for humans. We do not have any problems with the scale-up
for agriculture or the scale-up in China. So, that’s for the scale-up. And I think, for the AgriPhage, you are talking
about resistance, and so we have not seen since 2005 resistance in the field for the
AgriPhage product. I know from my colleagues who work on that
that what they do is they take — they have samples from greenhouses, from fields all
over the United States, and they know exactly what strain is resistant in each one of these
places, and they build very large libraries of bacteria, but also of bacteriophages. And if ever they feel that one of the bacteriophages
in the cocktail needs to be replaced by another bacteriophage that is effective, they can
also switch that bacteriophage, update their formulation, and make sure that the phage
cocktail is effective. A strategy that we are using in order to prevent
the emergence of resistance is to make sure that whatever bacteriophages that we are putting
in the cocktail have a sort of synergy, so each bacteriophage must have some different
properties from the other bacteriophage. And so, when you have this big cocktail that
target the bacteria in very different places, then you reduce the incidence of resistance. And although we are seeing resistance in the
lab in vitro, we have not seen it a lot in the fields. We haven’t seen it in the fields in our hands.>>Martin Blaser: I wonder if I could just
ask for a clarification. So, you said that you haven’t seen resistance
in the field. Or is it that you haven’t seen resistance
that you can’t overcome by substitution of a new phage?>>Nancy Tawil: We have not seen resistance
to our bacteriophages in the field.>>Martin Blaser: Good. Thank you very much.>>Lonnie King: Okay, I have a quick question
for Dr. Watts, and then we have three more to kind of finish. So, Dr. Watts, I can appreciate your emphasis
on innovation and discovery. I’m concerned about the number of companies
that are kind of deciding not to stay in this space at all. That can’t be a good thing over time. So, what do you see over the next five or
10 years in terms of discovery, innovation? More consolidation? Or what’s going to happen in this space, and
how do we actually improve it?>>Jeff Watts: So, I think you’re exactly
right. We’re seeing fewer companies playing in this
space in both animal health and human health. I think we’re going to see more and more innovation
coming from the startups. I think we need to assist the startups and
academics in terms of getting past those early innovation phases. You know, get them across the valley of death,
get them into development, but we also need to have that partnership where we’re mentoring
those companies. Then there has to be a partnership with the
bigger companies that have the infrastructure to actually do the development work and actually
have the know-how of how to take a compound from a lead candidate out to an approval. And so, I think that’s going to be the model
that we’re going to see more and more of, is more and more things coming in through
the startups. There will be more mentoring early on in that
public-private relationship type of opportunity, and then, once that happens, they’ll transition
into a traditional pharma process. I think in terms of the regulatory process,
you know, the Big Pharma companies certainly know how to bring something into a regulated
status, and they have the experience there with people in regulatory groups to do that. I think right now the thing that I see is
FDA has given us the flexibility and has provided innovation groups to allow us to develop these
novel products, so I think that’s to our advantage, and I think we’ll see more interactions with
the regulatory agencies early on in order to have those discussions around what those
regulated products and regulatory pathways need to look like in order to bring those
compounds to market.>>Lonnie King: Thanks very much. Kathy?>>Kathryn Talkington: Thanks. Thanks, all of you, for great presentations. I wanted to ask Elaine — a little bit, sort
of, building off of Ellen’s [sic] comment — or Helen’s comment — on incentives for
development of antibiotics. As was talked about, as you’re well aware,
and as many in the room are aware, there are lots of conversations going on about what
a pull incentive could be, what’s going to be meaningful to help keep companies — small
companies; large companies — in the business of making antibiotics. Do you have any particular thoughts on what
a pull incentive — a meaningful one — would look like, or, in your conversations with
VCs, what sort of indication would be helpful on that front? Thanks.>>Elaine Hamm: Yeah, of course. It’s — I wish I had the all-encompassing
answer for that. It’s going to be a challenge for a while. I mean, you talked about Achaogen, and their
stock prices fell, and that happened after they got a drug approved. That is bonkers. I mean — and then you have Alzheimer’s, where
people hit the same target again and again and have failure, and people are still claiming
to get in. In infectious disease, it’s the opposite problem. I hate to say it: drug pricing might be something
to consider, but that’s a very sticky subject these days. But as we — that’s one way to have some pull
incentives. Venture capitalists, maybe out of the good
of their heart [laughs] — a venture capitalist with a heart? Okay, that’s a bit of a [laughs] — sorry
if there’s anyone in the room — sorry, sorry [laughs]. But it’s — yeah, they have to be convinced
to make less of a return versus the larger return, but you have companies that invest
in — there’s a C. diff vaccine that’s in Phase II that can’t get into Phase III, not
because they’re not successful in their Phase II; it’s because they can’t raise that kind
of cash. I wish I had an answer, but, yeah, we’re kind
of stuck.>>Lonnie King: Paula?>>Paula Fedorka-Cray: Thanks for the nice
talks. Mr. Brooks, you talked about a hundred companies
in the AMR Alliance. I assume that this includes generic — manufacturers
of generic drugs, too?>>Steve Brooks: It does, yeah.>>Paula Fedorka-Cray: And is there a difference
between what we might see as far as compliance or problems with generic manufacturers versus
those of brand quality?>>Steve Brooks: Well, I’ll answer the question
first based on membership of the Alliance, because I think there’s a broader question
in there. But in terms of membership of the Alliance,
our generic manufacturers have made the same commitments as, for example, Pfizer has made
great. So — and I work every month with the EHS
leaders from those companies as we’ve, you know, developed these materials I’ve shared
today. So, there should be no difference in terms
of the commitments that we’ve made, and we’ll be reporting our progress. I do think that the broader question is — you
know, it’s challenging when antibiotics are, you know, a large part of the generic — and
Pfizer makes generic medicines as well –>>Paula Fedorka-Cray: Sure.>>Steve Brooks: — so this commonly applies
to generic manufacturers generally. I think we need to all look at, you know,
what the expectation is for what we’ll pay for antibiotics. So, the industry is largely — not completely,
but largely — outsourced to generic manufacturers in emerging markets. Again, not completely. And of course, those markets don’t have — and
we already heard about in other conversations — they don’t have the infrastructure that
you might expect for sanitation, for waste management. They don’t have the norms around some of the
industrial practices that we have learned through experience in the United States and
in Europe are important to protect in our society. So, there are some challenges there for sure,
and there’s 15 manufacturers in the Alliance, and even if we all met our commitments completely,
the problem would not go away. So, part of my mission is to encourage further
promulgation of the work that we’re doing, whether it’s through the Alliance, which would
be great, but we’ve published our materials. We encourage other groups, other trade associations,
to adopt the materials that, you know, we’ve developed.>>Paula Fedorka-Cray: That was one of the
most tactful answers I’ve ever heard [laughs].>>Steve Brooks: There you go.>>Paula Fedorka-Cray: Thank you.>>Lonnie King: David?>>David White: Thanks, Lonnie, and thank
you all for your presentations as well. I’d like to make a comment and a question
to Jeff. My comment is, moving from FDA to the university,
I’ve seen a culture of entrepreneurship among many of our faculty, and I’m very interested
in this space, and I think it is across this country, but there is no guidebook to help
them right now. It’s like being a parent. You know, “Here you go. How are you going to raise a kid?” I wish someone had given me a book. But these guys are lost a little bit, and
they have no idea what they should be doing for experimentation or even to start down
the road of the exploration of a new therapeutic, a new diagnostic, and so forth. So, that would — I’ve heard that, and I see
that now. My other question — Jeff, in particular,
for you — have you seen synthetic biology applications coming into this innovation space
yet, or do you think it’s a couple of years away?>>Jeff Watts: So, thanks for the comment. I really think that what you’ll find is that
there are companies out there — you know, first of all, there are individuals that have
left the pharmaceutical industry and now have set themselves up to be able to provide some
of that consulting and mentorship. But I think there are also companies out there
that are willing to mentor the right opportunities into their system, and that’s one of the things
I’ve been an advocate for in my company, is that we should be willing to mentor some of
the startups so that we can bring some of these leads forward. Synthetic biology. I’ve — we’ve looked at it a bit. There is a little bit of activity in the space,
but I think we’re still a couple of years off before we really see those sorts of applications.>>Lonnie King: Okay. So, I think there are no more questions right
now, so join me in thanking this excellent panel. [applause]>>Female Speaker: Produced by the U.S. Department
of Health and Human Services at taxpayer expense.

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