ulcer drug

>> good morning. i'm mark, the director of the nih office of technology transfer. it's a pleasure to have you all here today and especially in honor of phil chen and his distinguished contributions to tech transfer.

particularly in the early days at nih, and especially our distinguished speakers, cliff barry from niaid and carol nacy from sequela. just to make a personal note before i joined the office of tech transfer 12 years ago, i worked in the tech transfer

office for niaid. so i have found memories of working with cliff. and carol on their collaboration projects when cliff was at rocky mountain and carol is starting up locally. so it's great to see them and to honor their work.

so we look forward to your story. but i want to introduce my supervisor and the director, deputy director for intramural research among his many duties is oversees tech transfer. and that's dr. michael gottesman.

he's celebrating his 20th anniversary as ddir and we thank him for his many contributions and especially for his support it's a pleasure working with him and i thank him for all the support. so dr. gottesman. [applause]

>> one point i wanted to mention, in your brochure, there's a list of inventors. so to honor all of our inventors, we've given an institute of all the inventors so we want to honor them as well. >> thank you, mark.

this is a wonderful annual occasion for us, a chance to recognize phil chen who is, i'll tell you in a few moments, a very important part of our intramural program for many years. and a chance also to recognize the importance that technology

transfer plays in the mission of nih. that is to do research to improve the public health, improve the public health part requires technology transfer, and it's really important that we have stories like the ones you're going to hear today in

order to fulfill our mission. so this is the 8th annual philip s. chen distinguished lecture on innovation and technology this series i node honors phil chen, a collar, a science administrator, a trusted advisor to many directors and deputy directors and a friend to many

of us at nih, and many of his friends i can see are in the audience. phil was born in michigan and grew up in massachusetts. he was a graduate of clark university in physics, got his ph.d. in pharmacology from the university of rochester.

and at the time when he was a graduate student, he was also an atomic energy commission predoctoral fellow. and actually spent some time with the atomic energy project out in nevada. also, as a graduate student, he coauthored a paper entitled

micro determination of phosphorus. any of you in the audience vfer measured inorganic phosphorus have used the chen method to do that. it is one of the most highly cited papers in the history of biomedical research.

certainly in the top hundred. and that's an amazing achievement in its own right. he did a post doc in copenhagen, developed a relevant love for denmark and things danish and his wife lisa who is here, is a representative of that. and also here today are many of

his children and grandchildren who have been faithful attendees to this and kiley who has been here every year. and she's going directly to her post doctoral fellowship next year. philip came to nih in the late 1950's where he worked with fred

barredder, the legendary physiologist on binding of cortisol to plasma proteins. went back to a faculty position at rochester but the siren call of nih brought him back again where he served for 30 years basically in the office of the director, served eight different

nih directors. and most of his activities were in the office of intramural research. and during my time there, he was a trusted senior advisor and a wonderful source of very valued information. phil's special interests include

international affairs, particularly arctic research. and technology transfer. he as you heard established the office of technology transfer and he invented our most beloved document called the crada cooperative research and development agreement.

so a lot of technology that's been transferred wouldn't have been possible without phil. as a senior member of the office of intramural research, phil over the years became known as a caring, knowledgeable and creative administrator. people would come to him with

the most difficult and almost impossible problems and he would find solutions. it's quite amazing. phil, we need you now. the subject of today's lectures is tb. it takes more than a village to raise a remedy.

we don't have a village here although we have a nice community. but we do have two wonderful speakers. as you've heard, dr. cliff barry who is chief of the tuberculosis research section in the lab of clinical infectious diseases at

niaid. and carol nacy cofounder and chief executive officer and chairman of the board of directors of sequela. what i'm going to do because they're going to do a tag team. they are so well coordinated as a result of our tech transfer

process that they're going to be bouncing back and forth. so i'm going to introduce them both. dr. barry is an internationally recognized researcher on tb, particularly in identifying targets and developing new drugs to treat micro bacterium

tuberculosis. he has a ph.d. in organic and bioorganic chemistry from cornell. he was a post doc at hopkins. 20 years ago, he joined the rocky mountain lab out in hamilton as you heard. and 15 years ago when he was ten

-- tenured to nih he moved to twin brooks near bethesda. he has many connections and collaborators which i think you'll here about some of them. that has helped to move forward the drive to develop new drugs to treat tuberculosis. cliff, are you going to start

out today? he'll make the opening comments. our next speaker, our other speaker is carol nacy. she did her undergraduate degree in ph.d. from catholic university. spent most of her scientific career at walter reed army

institute of research where she studied various tropical infectious diseases. and has since moved to the private sector where she was chief scientific officer initially at contra med part time chief scientific officer at annergen before she found the

sequela. she's been recognized in many ways for both her scholarly work, academic work and for our entrepreneurship. she was elected to the american academy of microbiology and he was elected president of both the american society of

microbiology and the society for leukosite biology. her biotech has been recognized in many ways as well including being need the top 50 innovator of the u.s. and top entrepreneur of the year. she was award the humanitarian award for alliance against aids

for her work to create new drugs for tb. without further adieu, i think cliff will take the stage and then we're going to hear a wonderful talk today. thank you. >> is this on? yes.

so i want to start by saying thank you michael and thanks for the opportunity because i don't think we really get the opportunity very often to say thank you to the tech transfer folks here at nih. mark can say with behind site we have found memories of it but i

don't think he remembers how much work it really was. i think i continue that trend today to really occupy a lot of time and energy from the office of technology development because of the field that i work this is inherently linked to intellectual property and to

develop many things. and i think it's great to have the opportunity to say thanks not only to phil but thanks to the entire tech transfer community here at nih for making that possible. and i think to start out, i want to sort of just refresh your

memory of what tech transfer was intended to do in this sense and why we developed relationships like this. so this is from the federal technology transfer act of 1986 which was an work that first tried toreverdaitnstosi3 rard ol tubls$of rprocn

i think the best at that was an editorial that appeared in the economist in 2002 that's credited that piece of legislation with reversing america's precipitous slide into the industrial relevance and called federal and academic labs, the golden goose of

innovation that turns the u.s. around competitively. i think that's been great in some fields and i think where we struggled with it over the years and what is the story that you're going to hear about today really speaks to more how do we translate that into global

health issues where perhaps the incentives and the risks and the benefits of the technology that you're talking about aren't as straightforward as monetary incentives or as benefits to u.s. industry directly. and i think one of the things to think about when you're entering

into relationships like that is you really have to understand the risk and the culture in both the place that you're at the government academic lab and in the company setting or the partner with which you're entering that. so every different kind of

organization has different perspectives on what is risky behavior and what's risk, what's the benefit of taking risk. we, governments and act demonstrate yeah all sort of lump together think that risky stuff is inherently a good find and should be doing it all the

time. in the caveat with government maybe you try to minimize that risk a little bit more. but in biotech and pharma which are the two sectors i interact with is more diverse than act demonstrate yeah is and pharma is the extreme case that nothing

essential is laboratory ready but products not ready is really of interest to them. and i think if you don't understand who you're partnering with through this process then you can't translate something from the brain to a product in the end.

and i think that's really what ott's and otd and niaid has been to really start to piece together those agreements and put together partnerships between prospective industry collaborators that can translate ideas into products with groups within nih or groups within

different institutes that can actually come up with the ideas that are things that are worth turning into products. and i think they are really good at finding the right balance of things. i can remember long conversations with mark about

the beautiful [indiscernible] negotiating it and trying to understand what went into it and all of the caveats and things that we tried to get right in this so we could take something that's an idea in the brain and turn it into something that is this is really the subject of

today's talk. this is a drug packaged for use in clinical trials that are going on now in phase three. and i think that translation doesn't happen without setting the partnerships up right and i think the real credit to phil and to the check transfer

community is they've learned how to do that. the subject today is going to revolve around global health. and global health really is from a satellite meeting that happens last week here in washington d.c. really is these days the same as america's health.

there's no wall you can erect to keep people with drug resistent tb or drug resistant anything from flying into the u.s. it's very difficult to cross the international borders with respect to infectious diseases and global health issues. and i think the more we

recognize that, the more we understand that part of nih's mix is not just worrying about health problems that are imminent and current epidemic that happen within the u.s. but thing that might emerge in the future or things that we can't block coming in through our

borders. and of course, i'm going to let carol talk about infectious diseases. >> is this all right? so, infectious diseases are the second leading cause of death worldwide. so tb is actually in the top 10

lethal infectious diseases and in this country i can't tell you i speak with venture capital firms and funders all over the country. the word tuberculosis has not been in the lexicon for 50 years and they don't actually realize how big the problem is outside

the u.s. but infectious diseases they're starting to get a picture of that, and now i can at least tell them that 40% of all the deaths and the countries where we would sell products if we were to be a successful company are doing the two infectious

diseases interestingly. we're now seeing that many of the autoimmune diseases have an infectious origin. i think that's going to help us all in understanding more about how microbes interact with our bodies both in the beneficial way and in a difficult way for

our immune system to understand. i think more than anything that's scaring the public health community around the world is the fact that multidrug resistent organisms are coming to the fore. and we don't have enough antibiotics and we've really

paid no attention to antibiotics for a number of years. the classes, the new classes of antibiotics are knew and far between, they are fairly specific for what you name the gram positive organisms these days. and where we're actually

experiencing a crises both in this country and in europe. and multidrug resistent infections and in particular multidrug resistance is now considered a national security threat both in the united states and in europe. so tb is a problem on every

continent. we're not without our tb. you can see by the color of the country how many cases per hundred thousand that exists clearly in areas that have the darkest number, we have the most number of tb patients. but we have them in the united

states as well. and i don't know how many of you remember the sars epidemic when we were completely panicked about sars. this came out basically talking about sars is a problem yes but that's sars. in terms of number of people

affected by sars number of people who died of sars there were at that time around 500 people who died of sars. at the same time 2 million people died of tb. so the scale of our panic over certain of the infections across our borders is unfortunate,

let's put it that way. tuberculosis which we have a wonderful tb elimination program in the united states, has moved tb down out of our line of sight. but outside the world it's burgeoning everywhere. part of the reason that it's so

successful is that it's an airborne transmitted disease. you may not know this but no spitting laws in new york city aren't about the fact that spitting is gross it's about transmission of tb. so to be able to transmitted by the air easily you have to have

a certain particle size and that's where sars is. and that's where tb is. so it is the perfect size to be passed person to person by sitting next to one who is infected. and in the united states, whether we are comfortable

knowing that they're not, we have drug and multidrug resistent tb. there were a thousand, over a thousand cases of drug resistent tb in the u.s. last year. 10,000, that's 10%. and we had six cases of virtually untreatable extremely

drug resistent tb for which we have no drugs. and right now, in the world, we have poor drugs. with the drugs we have there are eight to nine million new cases of drug sensitive to tb every it takes six months of treatment with four drugs, each of which

have their own toxicities, some blindness, some liver toxicities, and there's about an 80% treating it global. there are now 500-650,000 cases by the health world organization. they're resistent to the first two best tb drugs out there

[indiscernible] you then have to choose from six of the hoe rendously bad drugs. one is -- which the patient calls that gives them a psychotic episode -- you have to take these drugs for up to 24 month in order to secure this disease.

there's only about a 48% cure rate. an extremely drug resistent tb which is now here in the united states and is now detected in every country in the world. we believe much more than 24 months to treat these patients and there are no drugs.

they are trying everything in the armament to find drugs and cliff is a leader to find drugs that will rescue these people from certain death. how teufl? kind of anxious now. the problem we have in tb is that this is a pathogen that can

live inside cells and can live outside cells. so we have to have drugs that only can get to the interstitial fluids in our tissues to kill those drugs that are outside but we need drugs that can penetrate the macrophage where it lives and replicates and kill the bug

there. it's pretty tricky to get a drug that can go through a macrophage membrane that can waddle through the macrophage cytoplasm, can get into the -- where the tb organism is and can survive there long enough to get inside the tb organism and then to it.

so finding the drugs for tb is a challenge. because we have another issue with tb, this is confounded the problem of finding drugs. and that is that tb used to be the number one tumor of u.s. citizens prior to 1950. those of you who are as old as i

am, all have a relative who died of tb. this organism was the impetus for pharmaceutical companies to get into the business of drugs, discovery and development. and only of the first drugs that came out were specifically directed to tb.

every time we introduced a drug, within six months the organism became resistent to that drug. now we know we have at least a minimum of three drugs that we have to treat people with to avoid resistance that occurs, to penetrate those appropriate tissues harboring the bacteria

and to cure both replicating bacteria. and a trick that micro bacteria does, it goes dormant. lies there unassumingly waiting for a chance to start replicating again and we don't even know where it is. so the goals of the tb drug

development include identification of drugs with novel mechanisms of action. we need to pair three novel drugs together for distribution and to kill bacterial forms. we need to reduce the regimen toxicity which is a problem in drug sensitive tb but which is a

terrific problem in ndr and xdr/tb. this is not a regulatory goal but it's certainly a public health compliance goal. so we're going to go in, cliff is going to take over here but i never actually told cliff why we started working together.

he probably has his own story as well but i thought i would just reveal to you what happened to cliff and carol together 15 years ago. so at that time tom kent was both a friend and a colleague and i had a problem and he had a problem and we agreed to try to

help each other. my problem was nearly trivial. my problem was i started sequela and someone wanted to make a documentary film the subject of which has long left my mind. and i needed an office that look the like an office. i was running the company out of

my home. not with children's books but with medical texts. and he offered, we moved his bookcase which was very beautiful as a background for that. his problem was more concerning. he had a very very bright young

scientist who was working in hamilton, montana. and who he had to bring back here to the nih campus. and this scientist was the exactly happy to be coming back here. he had a very nice life in i don't know how one does that

but nonetheless. [laughter] and so tom asked if i would introduce myself to cliff and see if i could generate a project when he got here that would keep him interested enough. he was very concerned cliff

would get here and then would leave, leave the nih and he thought that the government need the cliff. so i went to a conference on tb and i introduced myself to cliff and we talked and this whole process worked. because he's still here.

so anyway, so that's the story why we are together. now i'm going to let cliff tell you a little bit about his lab. >> that wasn't in the script, carol. >> i know, sorry. >> so we're going to take just a second to briefly introduce each

of our respective organizations and where this project fits and then we're going to wind the clock back 15 years and literally walk you through the project that happened. i think there's nobody in my laboratory and there's a few of you out there now was present in

the laboratory when this budget started or even when we stopped working on it for a long period of time. so what my group does these days and we've done different iterations of this and have different emphasis over time is we try to build a pipeline.

there's always talk at nih about bench to bedside stuff. well i'm a chemist so i don't have benches, i do hoods. we talk about hoods to bedside stuff. we tried to recreate from the entire process of doing drug discovery to the point that we

can do it at nih within the intramural research program. so a lot of the lab will work on things like throughput screenings, system biology, trying to understand what are vulnerable points in metabolism and how do we deal with this organism.

then we'll move in to animal model studies. that happens to be a very cute little monkey there so we do some things in monkeys, some things in mice. and using tools that we can apply in the clinic like imagining analysis.

pet ct scans, bio markers. you try to pilot into clinical trial designs. then we actually do clinical trials starting pretty much with phase two where we try to take those things we learn from the animal studies and translate them directly into people.

and i'm not going to talk about anything in the last two phases of this, i just want to point out that we're engaged in that sort of activities these days. back in 1998 or so we really focused much more on the early part of the pipeline because we didn't have very much to go with

the pipe line at that point. i wanted to show you this because i think it's important for two reasons. one, because this is my current group. i love to make people in the group angry by pointing they are ordered by importance of

disciplines, the scientists are in front and the animal people languish in the back. all of the clinical work we do is offshore. mostly in south korea and china. this is a part of my clinical team and other visitors. that's actually put these things

into humans and get information that feeds back all the way back to the beginning of the pipeline to develop better and better tools and better and better approaches introducing new chemotherapies. i also just wanted to acknowledge up front the people

who really did this work. and the principal driver of a lot of this particular project was a post talk trouble fellow who joined me after finishing up at oxford who was a very talented chemist and now runs his own very successful group that still works in tp drug

discovery at st. jude's down in tennessee. i'm absolutely sure i left people off this slide because literally this was 15 years ago but a lot of this was really starting and people were jumping in and out of it. it also included the people in

tech transfer that made fundamental contributions to setting this up right at the beginning so at the end we had a product to show for and we didn't get lost along the way. i'm equally certain i left people off that list but those are the ones i can remember that

dealt with the kind of day-to-day basis in establishing this project up front. >> i would like to introduce you to sequela [indiscernible] started sequela with two other founders by the way, in 1997 as a way to focus energy of a biotechnology company on a

global health issue which was we've gotten a lot different in the last 15 years for a variety of different reasons, and now we have actually compounds that work on all of these different infections. we do drug discovery in house, we played off of cliff, cliff

taught us how to do chemistry and we brought it in house so now we have a compound library of about 250,000 molecules on various different classes. and i have two fabulous russian women chemists who are beyond belief, good at what they do. so we're currently focused

specifically on three micro bacterium tuberculosis, one third of the world infected. lots of people get it annually. [indiscernible] -- have better statistics one in two, awesome isn't that it. there are two million cases, two million deaths every year and

there's a lot of antibiotic resistent. i won't talk about clostridium dificile but we do have a program on that. what i will talk about today is the compound we ended up with cliff and he'll tell you how we got here.

there's an consideration that's currently tb. it's now in a russian registration trial multidrug resistent tb and the phase two trials are drug sensitive tb. it's an awesome drug. this shows you how many colonies come out of the standard of

care. tb drugs at the end of a four month treatment, and this is sq109. it's a good drug. i also wanted to mention that it's a multifunctional drug. it has a very limited number of bacteria that it can work on but

it does work on [indiscernible] and we've done actually a phase two proof of principle trial for vectors of the stomach. in fact we can pull the biomarker on to undetectable levels. we're having of having another indication as well of this drug

because it's a really good drug and so far i notate the issue. >> so let's wind back the clock. so the project started with ethambutol -- it's in that regimen so at least two million patients receive about 360 million doses of this drug every single year.

and because it's the least active, we thought long and hard about what, if we could improve ethambutol. it came from a program then at the laboratories of american -- before they became american home product, etcetera, etcetera. when tb was still a big deal in

this country in a program in the 1950's, they identified in a whole cell screen this compound [indiscernible] as an inhibitor of tuberculosis drug. through a very laborious process they went through and made 2000 analogs which was a big program at the lab in those days.

it would be a big program these days in any indication area. what they end up with was what they knew in 1961 when they disclosed this to the world, ethambutol was really active against lung infections in mice with human tb, with oral administration.

and it was active in vitro and it looked safe and it's really blocked the development of resistance when you did co-therapy in mice. and so clinical trials being what they were in the 1960's in mid 1961, they disclosed this by the end of 1961 it was in

clinical trials in humans. and so less than six months. discovery to actual first dose in humans which is pretty incredible and pretty heart to replicate these days. >> impossible. but it also comes with some risks right and this is a good

example of the risk because in that first clinical study which involved 150, 18 patients developed an ocular toxicity as a result of that. you can see the example of the toxicity and we understand the mechanisms of them but in those days they had new no clue what

the mechanism was. this was a dose limiting toxicity for the drug. so the next round of clinical trials we sequentially lower and lower doses. by the time they dropped the dose the efficacy was pretty questionable at that point which

is how we ended up with the weakest drug in that for-drug regimen. and so in 1998, carol and i asked the question can we do better. perhaps irrationally exhill rated by the fact that the lunar prospects had successfully

crashed in a crater on the moon and found water i thought we could make something better an i was really trying to recreate my frame of mind back in 1998. we, like much of the world that did medicinal chemistry those days were totally infatuated with combintorial chemistry.

the only analogy i can draw to that i think has had a similar impact on a popular culture was beanie babies, right. everybody had to have beanie babies. the more you had the better and it is like this combintorial chemistry.

the more compounds you had, the surely if we had enough beanie babies that demand would get so large we could retire with everything we had in beanie every pharmaceutical company in the world went down this path. ten years ago we started to burn out on that and these days

nobody banks on that. but that was the mind set at that time we needed bigger and bigger libraries. so what is combintorial it is often called split and pool chemistry it's the process of building things on a solid suppose i had a green marble and

i take three different reactions with green mar bledz, one reacted with yellow one red and one blue. at the end i've got one molecule which is green and red, green and blue or green and yellow. if i pool those all together, i have a mixture of all three of

those and i split them out again in three different pots and we have a yellow blue and red doubt. in each pot i end up with discreet mixtures that i can pull back together and split again and act with another one. you can in a way not only make

these things combintorial by split and pull synthesis but you can also track them. there's an infinite variety of fancy ways of tracking an individual bead. so in this way it becomes possible to make libraries of millions of permutations and how

you code and decode them. we did a variety of different iterations. some use radio frequency transmitters inside of an some use dna bar codes. there's an unlimited number of ways of keeping track on any individual bead but i'm not

going to talk about that today. what i am going to talk about is how we reduce that practice trying to look for a better this is the chemistry so that means there's a solid involved. this little ball is the best representation a chemist can come up for a piece of plastic.

we'll just leave it as a piece of plastic at this point. in this case this is called a rink linker that just links the plastic to whatever you're going to put specifically on the position of the molecule. then you can activate that and then down here is the ethambutol

in case you don't remember the structures in the previous slide. i can take half of this and patch it on to that linker so it looks like this. so half of the ethambutol. can i take a linker and i've created this two carbon unit.

i can put on the other half so now the entire ethambutol molecule made on a specific bead. i can reduce that and cleave it off the bead and i've created the most expensive ethambutol. that's all i've done. but one where i can control

what's in each of those positions because i have a solid supported synthesis and i can -- that bead is actually made of. it doesn't take a huge leap of imagination then to erase the am by tall i put in and put r as a generic r and a generic link he were substitution.

you realize you can create a library of things. so the structures here aren't important. it just looks like a plate of spaghetti anyways. this just gives you an illustration of how fast and rapid this is and how quickly

you can get to astronomical numbers that are almost uncontrollable. so if i just take 58 different r 1's. and mix them up with themselves in the two different positions. i'm going to link them with 12 different positions.

there are 40,000 unique combinations. we can create lots and lots of we can do orders of magnitude better than labs did surveying what the chemical space is. when you couple numbers like that with the need to do assays of the organism you realize it

becomes difficult to screen that number of compounds against the organism itself. this is held nicely with a project held on at the lab at the same time. we've looking at the transcriptional responses and this is in the dark days of

micro rays. we were doing spotted arrays. the story is the same. we discovered things in those days we just had an incredible amount of noise. basically we took all the known inhibitors of tb, we looked at micro array patterns and matched

genes that went up and down. we looked at things that were common. what we could tell that we could lump things based on their big impacts on the cell based on their transcription. with the [indiscernible] in particular there was a unique

set of genes that was very sensitive to inhibition of that particular step we could then pull out from that u.s.a. and -- from that analysis. we took the genes that was no, sir sensitive with treatment of the ethambutol and transform

that into tb and now we have a train that when you hit it with ethambutol produces light. that's the kind of tool you need to do things in high throughput format so you can screen lots and lots of compounds against that particular kind of organ. this just shows you a dice

titration with different inhibitors and then the light production and the light production with ethambutol. you get a nice production of light when you hit it with we have a nice assay that could be reduced to plates so we could screen lots and lots of

compounds. we have a nice way of synthesizing lots and lots of compounds so we do it. that's richard up in the corner who went after this first. it's hard for us to recreate these and say how many actual analogs.

that's where we ended up publishing where we had an lit cul data that was actually supported. we made a library of that and different iterations. those are the ones that were characterized to go into it. then we screamed them using a

variety of relatively at that time sophisticated robotics of which seemed rather primitive now that i look at the pictures compared to what we did but that was the robotics of being able to do it. and you have a few technicians who kind of load plates into

these and continue to stack compounds, paracompounds with organizisms and light production. so after screening 100,000 compounds now, 50 times the number that was screened at the laboratories, what we came up with was 65 of them that were

reliably as good as or better as am by tall. these are compounds where we measure the best of those had an mic with a nanomolar. now of course the best ones always got some other problems, right. so this is just the first assay

and we go through a variety of different things selected for what the best one was that appeared safe and didn't kill all of these cells and had some pharmacology etcetera etcetera. i'm not really going to talk about that in any great amount of detail.

instead, what i'll tell you is this is what we ended up with there's many papers about this at this point so i'm not going to go through a lot of depth in the pharmacology. carol will give you more on what we had to do. this was our candidate that came

out of it, and what we considered to be the minimum pharmacophore. in the process of getting rid of this -- that's because as i mentioned before there's a lot of toxicity with the parent compound due to its ability to form a stable -- with the

amines. so we wanted to get rid of that and tried to destabilize any potential metals to avoid that toxicity. we got rid of the hydroxy groups so we don't expect to see the -- that we saw with the ethambutol in the beginning.

so we succeeded right. well, kind of. the reason i say kind of because we did actually end up creating something that looks lik ethambutol and worked with a similar mechanism but we slipped obvious a little bit. instead of hitting the target

with ethambutol it's a very complicated schematic envelope looks like. it's a very complicated heteropolymer that consisted of three different units -- covalently linked. with ethambutol we know blocks production -- and what we found

in the end, and again this is all published work so i'll show you just a typo bit of it that's more contemporary in the lab. what we found in the end is actually we pushed the target up stream a little bit and we were blocking this transporter that push these acids from inside the

cell to outside the cell where they're attached to the cell envelope. the evidence to that is again complicated i think too much detail for this topic. i do want to point out that we discovered this, we settled on the molecule in about 2001,

20002 but it wasn't until 2012 that we actually firmly established which depth in the bio synthesis we are inhibiting. we did that through a combination of both biochemical studies where we identified these molecules we were accumulating within the cell.

and genetic evidence where we raise mutants that were resistent to the drug and we resequenced them and i d the targets and showed the protein was actually the target. and we flipped off the ethambutol slightly. it's important because when you

look at the in vitro data for sq109, carol will say this in a positive light. from my purest academic hat it's annoying because we didn't hit the target i wanted to hit. from the positive spin on this it still has activity against thate am by call organism.

we moved the target protein bio synthetic. so in vitro, this is a good drug. it has an mic that is less than micromolar against many different clinical -- extensively drug resistent different physician always that

were intracellular and non-replicating bugs and inhibits growth. as long as the cell has to be making a cell envelope it seems to kill them pretty effectively. in contrast this is inactive against a number of other cell lines so it doesn't carry --

micro bacteria of the genus. it's difficult for the organism to carry resistance because the surface we're blocking actually needs a very specific mutation to get resistance to it. so it's actually better in terms of resistent frequencies. there's some in vitro evidence,

there's energy between risks and inh indicating that this might really be something that could shorten therapy in tb patients. in vivo, we knew this sort of standardized way could protect mice from tb-induced weight loss. this is a high throughput

screening we do. we know it could reduce -- the activity in vivo that made it ten times better than ethambutol so we achieved that much in terms of potency. when you combine it and carol just showed you some of this, i'm going to show you the actual

numbers for it in just a second when you combine it in a four drug standard of care regimen in placement of ethambutol you clear mice much quicker. mice don't mean anything when you talk about human disease. i'll show a mouse data with a shamed look on my face because i

don't really believe this tells you anything about what we should expect in people. we don't know what's going to happen in people until we do the experiments in people. if you do what we hope to do in people you took the ethambutol and replaced it with sq109.

what the mice do is clear the bacteria much more quickly. this is about three months of treatment and if that translated into people, that would suggest that we had achieved something that would shorten the duration of therapy and people from six months as it is presently down

to about four months. so that's what we knew from the in vivo mouse stuff. frankly speaking if we had only been working in the intramural program that's where we run into the first huge road block which is how do we get enough stuff to be able to go into human trials.

>> yes. that's why it's nice to have a company that has a chief medical officer who knows exactly how to doal of this stuff. what you need to do is get a drug from a mouse to a human. what i basically want to tell you is that we wouldn't have

been able to do this without the help of a variety of institutes at the nih. this truly was an niaid initiated project but it flowed to other institutes at the nih and other organizations both here in the united states and also in europe.

this is a very expensive process. the estimates for taking the drug all the way through from beginning to end is now is upward of $7 billion. it doesn't take that much because they're amortizing everything that doesn't work.

but it does take hundreds of millions of dollars. and so it's difficult to, it's difficult to accomplish all the resources that you need to accomplish to move from point a to point b to point c in a systematic way in the clinic because the cost is so high.

so there was a program called the inner institute program between the national cancer institute which at that time had a number of contractors that were doing work for the cancer institute itself and for people who were working with the cancer institute and academic

institutions. and niaid. so it was a joint program. and it enabled niaid to select one drug that they would work with at the cancer institute with their contractors to help move it in order and move on to contest when we were very

excited. so we ended up working with the inner institute program and a variety of awesome people at the nci itself and also in the contracting group. and these are just some of the studies that had to go on before we moved this drug into first

studies in humans. i guess the one that's not on here that we did that was the most expensive was one that sequela actually did. this drug likes to be inside of cells. it likes to be inside of exactly the cells where tb hides.

and when it gets in there, the cells wrap it up in a vesicle that's called phospholipidosis. so there are about 35, 40, 50 compounds out there that cause the same kind of thing. and for a while we thought phospholipidosis was a toxic effect.

now we know it's a protective effect and what it actually does is it causes the drug to get into cells and then to be released how the into the circulation slowly over time. so but at the time that we submitted our ind, we had 90 day rats, 90 day dogs -- from a big

pharma company that had just gone through the fda and they actually demonstrated that there is no toxic effect of phospholipidosis [indiscernible] and in fairness to the pharma company, and they demonstrated this in monkeys. we were then asked because they

didn't want to ask one company to do this and not ask another to do a monkey study which ended up costing $3 million and delayed the onset of the human clinical trials by about a year. so we also found no toxic effects of phospholipidosis. and the panel including the --

people and the fda does now, they're interested in watching it but they're not rejecting drugs on the basis of phospholipidosis. and with that $3 million i think helps do that. so we did start some studies and the first set of studies sequela

did. this is in 19 -- in 2006. and we were completed this study close to the end of, middle of 2007. and as you may recall in 2007, the economy collapsed. and so we talked to the nih and they agreed that we could

conserve our money so we could stay alive as others and nih actually ended up doing the rest of the studies. we had no toxicity in patients up to 300 milligrams. it was really lovely to see the 14-day studies. we then went on to do a phase 2a

study in tb patient. this is funded by the european union by a program called -- and the african sites were called panaceas. so we now have more people involved in development of this this is the data. the data would tell you that all

these are -- by itself. this is sq109 in the presence of [indiscernible]. so in fact in the first 14 days of the patient treatment there's not a lot of activity of sq109 for tb but we had already done the mouse studies and we already knew that.

so we consider are this is a safety study in human patients. and in fact, we don't is a any activity of sq109 for the first three weeks. then we start seeing activity and then it goes on from there. so we are now, well again, safe. the only thing is it doesn't

taste very good but if you feed people while you give them the drug they're fine. and we know a lot about the drug now in tb patients. so now we have some ongoing clinical trials. the licensed the rights to sell this drug in russia and

affiliated states with russia to a company that was actually created around sq109 in russia. and they had an ongoing trial for registration of this drug for marketing and sales there. and if you can funded a phase 2b study looking for a longer duration of treatment to drug

sensitive tb done with panacea and with the [indiscernible] got lots of partners mostly in southern africa and in tanzania doing these studies and there are lots to do left before we can do a definitive trial for registration of this drug. we got them all planned.

we're just out raising money at the moafnlt. this is the time line for getting the time line. if you have millions you don't know what to do with see me after. by 2017 we're hoping this drug will have gone through its paces

and will actually be out in russia in marketing and sales. >> i think this was carol's tb flaring up again. >> yes, it is, don't worry. i have a drug that can cure you. >> anybody like to taste it so sq109 it's a long process. this is not atypical for tb

drugs but it takes years, it takes decades often to come up with how a particular drug i think the drug's got a lot of good things going for it. it might still bomb. there's no guarantees in this game. we take it and try to make the

best guesses we can and make the best animal studies we can. but these things can fail for any number of reasons. nonetheless we never would have gotten to the point of having the ability to test this in humans and put this idea together without the team of

people that really gathered around the initial idea and to translate this into a product. once again i want to take the opportunity to thank that whole team and to thank carol and i guess tom for making this possible. it's quite gratifying i have to

say. it's more of a bench basic scientist vibe to be able to put your hand on a pill and say i made this. we actually did do that and we made it and carol made it possible and sequela made it possible, and behind all of

that, ott and phil chen made this possible. again, i think both i and carol want to thank ott and phil and mark and the whole gang for sort of putting this together right from the beginning so we got the chance to take this big gamble and put this into people.

we hope in the future tb patients will fledge you with letters to thank you for that too. >> exactly. >> i think we'll end there and say thanks for your attention and thanks for the honor of doing the phil chen lectures.

>> i think we could have a couple questions. it's a little late but let me start. so you gave us some indication that the target was not the same as the [indiscernible] can you give us more what the target is and how it is toxic to tb.

>> sure. it's just literally two steps removed from the target we do think it's related in the way it work but these macro molecular complexes that make the cell envelopes sort of talk to the cytoplasm. it's at the point where the

precursor is pulled in from the cytoplasm and inverted before it's attached to the envelope. that's where the drug actually blocks that efflux. >> it's a cell wall, cell wall active drug. >> [indiscernible]. >> while, yes.

>> right up your alley. >> while cliff is, i just want to answer -- i want to make a statement. while cliff was disturbed we started out to make a second generation ofate am ball and we ended up with -- that actually created the opportunity for a

patent. because ethambutol was already patented and was off patent and it would have been an obvious thing if we had created a new so while i am delighted that we have a new mechanism of action and it's good because we can now not worry about ethambutol

resistance in multidrug resistent tb when we do our treatment. that's all. >> thank you for sharing this wonderful story. i have a question. we're seeing an emergence of a new requirement that the

preclinical work will have to be authenticated by an independent entity before going into patients. i would love to hear your comments to your reaction to how that would impact the pace of this translational process in your opinion.

>> you're talking about done at a clinical center or done here. >> it doesn't matter where it's done. there's a question of the validity of the preclinical work. people have done surveys broadly across products that have been

evaluated for clinical work and there's been some question of the authenticity of the product that was actually brought to translational, into the and so there's discussion about authenticating the preclinical product to make sure all the work is indeed what it's thought

to be. >> well, by preclinical you mean non-clinical but the discovery part of it, i can understand that completely. on the preclinical side it's all done glp and it's all checked and the fda is very rigorous about looking at it as well.

so you don't get into humans unless -- >> [indiscernible] >> on the discovery side quite honestly if i had any advice for universities i would ask them to begin teaching people how to do research under glp light, good laboratory practice light

because that's the biggest problem. if you don't have someone checking your lab book, if you don't have validated assays. by the time it comes to me, it takes me several years to reengineer it and to figure out whether you were right or not.

so it's a process. there is not, i have never seen a technology come out of an academic center-right into a small company and be ready to go. there's always lots of things we have to do to validate the so the more you can use good

laboratory practice and it's a painful thing and the more you can teach people to do that, the easier it will be to translate it but the faster we'll get to it. >> let me take a stab at that. carol has a different perspective.

>> really. >> that's the time line of discovery which we showed at the beginning. we can call that an innovation gap. there are no new antibiotics that were introduced into the clinical practice between 1970

and the year 2000. no new class. we had lots of knock offs. what really changed the culture at fda. someone discovered streptomycin. we had become so drug reverse [indiscernible] and all the logic getting into phase one

that we killed antibiotics. there are almost no major programs currently [indiscernible] the reason it's too hard. it's too hard to get something, it's too expensive to take that shot to get into humans to fail and we've elected all these

barriers. so i take the opposite view. we shouldn't learn how to do glp we should learn how to reinhaven't clinical trials so we can get into humans faster and reduce the regulation in the clinical trial so we can get to humans faster.

>> i think risk is the biggest issue. the fda goes back and forth. we're sort in the middle now. it's a lot easier. our discussions with them, they're a lot more open for discussions. i have no problem with the fda

right now. in what they're asking us to do. there was a point at which they got very cranky about any safety issues. what they're now looking at is risk and benefit. and i think that's really there's nothing that you put in

your mouth that doesn't have risk including water. but we've gotten to the point in our communities where we don't, we don't allow, we don't want risk. and that's why there are parents all over the place not vaccinating their children

because one out of every 500,000 babies had the problem of vaccination. it's no. there is risk with everything that we do. and i don't want to go back to four months before we get to humans.

i already know that that's not good. but from the perspective of actually taking the risk, actually having the risk once you put the product out there. but i don't want to have a 15-20 year development cycle either. it has to be a balance.

>> i want to ask about the regulatory challenges of developing a drug that's going to be used in a multidrug combination therapy. so i noticed in your phase one that you tested just the sq109. were there discussions with fda, did they want to try it in

combination with the other drugs that you might be using in phase one? and then along with that, in your clinical trials, it's, in this case you can kind of slip it in for emb because it's a similar kind of pathway. but so how do you work it in

with combination? do you add it on or do you substitute? >> sometimes you add it on, sometimes you replace something. it's, when you, the first study you have to demonstrate that your drug is safe that it's not going to kill people and it's

not going to cause an irreparable damage. the phase 2a study that i think of as a tb patient safety study we did at it to in -- because we were interested to see whether in a short period of time we could make it look better as it does in mice.

14 days is too short. and now we're doing drug drug interaction studies in healthy humans and tb patients because tb patients are sick. they're going to respond differently. so it's a step process and at each step you try to reduce the

risk for the people that you're using as your guinea pigs. they are not guinea pigs, they are human beings. and so it's a process of trying to figure out risk benefit for each of them and moving along carefully so that you always know safety.

this is a principal issue for fda. efficacy is important but safe and efficacious. safe and efficacious. >> that was a great lecture thank you very much. i wanted to ask a question about whether there is any role for

consideration when you're developing drugs for -- wide spread in developing countries taken for a long time and so forth. i know cliff mentioned he made the most expensive [indiscernible] approach but for the final product how did that

come out? and you need the drug first i understand but is that a consideration at all. >> of course. antibiotics are not biologics and you can't call them add $300 [indiscernible] that's a program we've now done solution-based

chemistry and manufactured all of our batches that we need for the fda and the price will go down even further. it's way down now but it will go down even further once we scale up for commercial productions if we get to do that. and any venture cant in here?

are there any funders of high net worth investors here? all right. so from my perspective it depends. the price of my drug depends on who i'm talking to. if i'm raising money, i'm going to tell them that the market is

x because something is sold at that price. so it is sold at $100 a pill. i will say it's a hundred dollars a pill. i know in my heart of hearts we probably won't be selling it for a hundred dollars a pill but i might.

there is that chance. for funders the market opportunity is big means that they'll give me the money to get it to the point where i'll know what the price will be. so thank you for not having any venture capitalists and don't publicize this to any venture

capital people. >> you're being televised. >> i know. >> let's take one final question and then we'll have a rezippion in the back, you can meet with phil. >> phil talk very much for the lecture.

my question has to do with the slide before this showing that the technology transfer in drug development is concerned you need lots of partnerships and i notice you worked in tanzania -- bringing all these different people together. what would you recommend or

suggest is the most important thing to consider when you're trying to do something like this in a place like tanzania. >> i think the most important place for any relationship is to understand the role each group plays and to have respect for the work they do.

including the patients by the way. it's open and transparent and you talk about it i the things i need to do is different from the people in tans knee yeah wants to do for a patient. we have to talk, communicate, we have t

o u n derstand the agendas for everybody. we had great success with the panacea group and the investigator for our particular study is michael who had a site

in tanzania. >> all right. so first of all let me thank the speakers for a wonderful coordinated presentation. and thank phil and ott for making this all possible. and there is a reception in the rear.

you can talk to the speakers. and share thoughts about drugdevelopment

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