Tiny RNAs, Big Cures!!! Dr. Sanjay Shukla, President and CEO, ATyr (ah-tire) Pharma
Before the pandemic, just about everyone knew about DNA. But with the COVID vaccines, we learned about mRNA creating a decoy spike protein to alert our immune systems to the potential future arrival of an actual COVID virus. Doctor Sanjay Shukla, the president and CEO of ATyr Pharma, takes us one tiny step further to an unprecedented way to create new medicines. Attire's first drug candidate is looking to treat pulmonary sarcoidosis. Doctor Shukla, welcome to the program.
Dr. Sanjay Shukla:Nice to be here. Thank you for inviting me.
Dr. Moira Gunn:Now just a few years ago, we wouldn't have been able to find the words in everyday English to talk about what your company, ATyr Pharma, is doing today. But we live through a pandemic, and the newest vaccines are these mRNA vaccines. Now just to remind the listeners, our entire programming, each of our bodies, our DNA is that's all of our bodies. And as we live and breathe and go about our life, it's constantly the tiny parts of that total DNA programming, they're copied and those copies are called mRNA, messenger RNA. And when each of those mRNA programs are run, if you will, it produces a protein.
Dr. Moira Gunn:And we learn that with the COVID mRNA vaccines. We use technology to program the MNRA to create a spike protein, which appears on a whole COVID virus, but without the virus behind it. So when you got an MNRA vaccine, the MNRA produced the COVID spike protein, and our immune system saw this isolated spike protein and created a big immune response. So later, when a real COVID virus entered our bodies with a real spike protein, our immune system saw it and said, oh, seen you before and eliminated it. So now let's get back to our bodies.
Dr. Moira Gunn:We have DNA, the entire program for the body, then these short MNRA programs are picked up and copied and the MNRA produces a protein. And now we're ready to understand a little more. I know you just got used to DNA, MNRA, protein, but now we're ready for just a little more and that's where Atyr Pharma comes in. Now my first question to you, doctor Shukla, is relative to the little more to the DNA MNRA protein. And as I understand it, for the MNRA to build that protein, we need to know that a protein is a string of amino acids and the MNRA builds this string of amino acids one amino acid at a time.
Dr. Moira Gunn:So for each one, the MNRA needs 2 things, a tRNA, a transfer RNA, and a matching enzyme called a tRNA synthetase, which we won't say again, but it's a it's a it's a matching enzyme. So to our DNA, MNRA protein, to produce that protein, the MNRA needs a series of tRNA and matching enzyme pairs, each of which build in line a an amino acid. Now did I get that right at least in simple terms?
Dr. Sanjay Shukla:Yes. You you definitely essentially get got that correct. I'd give you a a b on on that test for sure.
Dr. Moira Gunn:Oh, passing.
Dr. Sanjay Shukla:Very good. Very well, Laura. Very complex here. We are trying to understand, things in, more simple terms. But essentially, yes.
Dr. Sanjay Shukla:In developing proteins, the part of translating our code from DNA into those proteins involves a number of players beyond mr mRNA. And tRNA plays a big role, but we also need a matching enzyme pair, and these are called tRNA synthetases. And that helps us build one amino acid at a time, the the the real protein that is coded, in our in our d n d DNA. So this this is, essentially correct, and, I think you've done a nice job there.
Dr. Moira Gunn:Okay. I'm going with my b so far. Unlike my students who all want a's, I'm real happy with a b. Now science knows this and it is well understood, but that wasn't understood and was subsequently proven by the scientific founder of your company, doctor Paul Schimmel. Tell us about doctor Paul Schimmel and and tell us about what he believed and then proved about this tRNA matching enzyme process.
Dr. Sanjay Shukla:So doctor Schimmel has been a pioneer in RNA and tRNA biology, first at the MIT, at MIT and then later at the Scripps Institute. He's founded, pioneering RNA companies like Alnylam. But what he really discovered, recently is this this interaction between these tRNA enzymes and how they basically do more than just, link this reaction with an amino acid. So this this matching enzyme has a specific job to, link a specific amino acid to help build proteins. And this was understood for some time.
Dr. Sanjay Shukla:What doctor Schimmel discovered is for some reason, these matching enzymes break apart into small fragments, and those fragments do something very, very different, and they seem to be a untapped area of immunology that we now can understand and we learn more at a tire about this. We are looking at the fragments of these key players within ourselves that help us make proteins and discovering they're doing some extraordinary things outside of the cell when they break apart into these small fragments.
Dr. Moira Gunn:Okay. So they go down into small fragments, and each of these small fragments do something different? These little guys?
Dr. Sanjay Shukla:Yes. These little these little guys of which there's we've mapped out about 400 of these seem to play a role in helping us basically live our lives and control our immune system, locally. What I mean by that is in a at at the level of your lungs or your liver or your heart or your kidneys. So they're working in the background there to keep thing, everything safe and organized, and also helping us deal with injury and infection and things like that. So they're working in the background, and these little guys are essential to our, our health.
Dr. Sanjay Shukla:We've been able to map approximately 400 of these little guys, with looking at healthy people. And I could, right now, take some of your blood and start to basically see your levels of of some of these fragments, And we have been able to then see where they are enriched. Some are enriched in the lungs, some are enriched in other, organs. But it's a it's a very exciting area of science that doctor Schimmel, discovered.
Dr. Moira Gunn:So he proved that this was happening and then a tire comes along and the first thing it has to do is map, well, where are they and at what levels? Now who are you looking at? Are you looking at people with illnesses or are you looking at at healthy people?
Dr. Sanjay Shukla:So the first thing was to look at healthy people to to really draw this map is and to say, where are these guys functioning? Are they functioning more in the lungs? Are they functioning more in the heart? And different ones of these, different fragments, migrate to different parts of of our our body. Some are involved in controlling things in the muscle.
Dr. Sanjay Shukla:Some are involved in controlling things in the liver. Others are involved in controlling things in the lung. And one of the things we learned early on is they seem to play a role in controlling inflammation and fibrosis. So this is something that, Atire was founded to really develop therapies and therapeutics from these small fragments, and how could we then help and assist patients who may have dysfunction with particular organs. So it's it's really learning from healthies and then applying that on where we can supplement and assist folks and patients who are having, maybe issues, with a with a specific organ.
Dr. Moira Gunn:So how do you get the right little guys into a person?
Dr. Sanjay Shukla:Well, we we have, tools, available to us in the biotech community to take these fragments and essentially bioengineer therapeutics out of it. So, we've come a long way to bioengineer and make more of these fragments, make them more potent and essentially make them, in a form that now you can essentially receive a infusion. Our our, lead therapy is infused through through through an IV bag, a 1 hour infusion once a month. And this helps some of the patients that we're testing, a lung disease. We are currently in a lung disease called pulmonary sarcoidosis after learning that a particular fragment could be really useful in controlling lung inflammation, and that is administered, now through, through an IV.
Dr. Moira Gunn:Now tell us about that condition, pulmonary sarcoidosis.
Dr. Sanjay Shukla:Pulmonary sarcoidosis is a chronic lung disease, characterized by a lot of inflammation. There's a lot of immune cells in the lungs of these patients. They have a cough, fatigue, shortness of breath, and they need to be put on, immunosuppressants, drugs that basically calm down the immune system sometimes for their whole life. The scary thing is your lungs can progress to become scarred or fibrotic And that's a scary thing for these patients because once that happens, really bad things can happen. You you need a lung transplant or you might even die.
Dr. Sanjay Shukla:Now sarcoidosis is a condition we, you may have heard of a little bit more recently in the last 20 years because many, a high proportion of the workers who cleaned up the debris at 9:11, unfortunately, came down with sarcoidosis. Probably had to do with a lot of the inhalation of all that toxic matter down there. So those, those folks that worked on the pile, if you will, they are the ones that unfortunately breathed in a lot of that toxic material and it triggered, sarcoidosis in in, a very, very high proportion of those patients. And many of those individuals then progressed quickly to develop a scarred lung. And unfortunately, we've seen a lot of of death and illness, in in that population.
Dr. Sanjay Shukla:So sarcoidosis is really a condition where probably inhaling, bad things triggers a reaction, and that reaction, is is something that, is unremitting and leads to a lot of bad things for patients down the road. And I should also mention when I talk about immunosuppressants, typically these patients are put on steroids and steroids are something that many of the listeners will know about for a variety of conditions and they're very potent drugs that basically can tamp down and control, your immune system. It could be they can be used for a variety of conditions that they've been around for a long time. Unfortunately, they do also come with serious side effects, but patients sometimes have to take steroids to live their lives. And it's a it's a it's a tough bargain for them to have to take this toxic therapy to basically, live their lives.
Dr. Moira Gunn:Ityer is well along with testing this treatment for pulmonary sarcoidosis. You're actually in phase 3, but tell us what you've done starting in phase 1. What did you do and what did you learn at each stage?
Dr. Sanjay Shukla:Yes. And this is very important because we are chartering charting new ground here. We are pioneering a new area of therapy. So we have to start very carefully. We understood again how to make these little guys into therapies, but then you had to test it.
Dr. Sanjay Shukla:And then as you mentioned, phase 1 is where you first start testing things. Phase 1 is where you test in healthy people. You want to make sure the new therapy you give to individuals does not cause any additional or new harm. So healthy volunteers were tested. We tested 6 doses of, our therapy and, basically incrementally worked our way up where the first all six doses were viewed to be safe, by the FDA.
Dr. Sanjay Shukla:And the top three doses were the ones that then moved into phase 2. And phase 2 is after you get through healthy volunteers and you've proven that the drug is safe and well tolerated in a healthy population. Phase 2 involves administering the therapy, giving the therapy to patients because now what you wanna see is, well, can you offer any benefit? Is this a therapy that will improve their lives in any kind any kind of way? And we did complete a phase 2 trial last year prior to moving into phase 3.
Dr. Sanjay Shukla:And there's a number of things we learned there. Again, the primary thing is to make sure the drug is still safe now in a patient population. And we were able to show that that the drug, again, these top three doses were safe and well tolerated. In addition, we wanna see that the drug actually starts to do something in these patients. So we looked at that multiple ways.
Dr. Sanjay Shukla:The most common way you look at things when you administer therapy in the lungs is to see if it's breathing, if lung the lungs got better. Things like pulmonary function testing is what the doctors wanna see improved. And we did see trends of improvement in our top two doses that we tested in that trial. We also saw, perhaps more importantly, a significant improvement in the quality of life patients. Patients coughed less.
Dr. Sanjay Shukla:They had better, less shortness of breath, and their fatigue was really, really improved. So now we're seeing that the lungs are feeling better and they're also their quality of life is better. The biggest take home, however, was we did all that while removing steroids, And this has not been seen before. It's a trifecta. You wanna be able to show at the local level, the lungs start start to feel better.
Dr. Sanjay Shukla:People start to feel better. And now you're also able to remove some of this toxic therapy because that therapy is causing other things. So very, very encouraging results that we published last year in a major medical journal before we went into phase 3.
Dr. Moira Gunn:So tell us about phase 3. This is a much bigger trial.
Dr. Sanjay Shukla:Phase 3 is a bigger trial. Phase 3 now is where you have to align with worldwide regulators. We are conducting this trial not only in the United States, but in 9 countries, Europe, also in Japan. And this is the first phase three trial ever in pulmonary sarcoidosis. So we're looking to, replicate some of the findings we saw in the previous trial, which was a small trial of 37 patients, this trial will be 264 patients.
Dr. Sanjay Shukla:You need to now look at a bigger patient population so that you can run statistics to prove what you saw as trends in phase 2 are really true in in a in a larger patient population. So we are testing the 2 doses from phase 2, the 2 highest doses that we saw the best results, and now running a placebo controlled trial in 264 patients. And instead of just following them for 6 months like we did in the previous trial, we're gonna follow them for a year. Our goal here is we think we can improve quality of life. We think we can improve lung function, but most importantly, we're going after steroids.
Dr. Sanjay Shukla:We hate steroids. I hate steroids in my career as a drug development physician. I've always tried to attack steroids in different conditions. Steroids are something that we think we know we can reduce based on the results from the last study. Could we even get an can could we even eliminate steroids in these patients?
Dr. Sanjay Shukla:That's what we're testing here. That would be a phenomenal result. That's something we're looking to, to test here in phase 3.
Dr. Moira Gunn:Now I know a tire is working on other conditions, and you've got your map. You've got your map there and you've got other conditions going on. What are you working on and what do you foresee working on?
Dr. Sanjay Shukla:Yeah. So I remember we talked about this map where we see all these little fragments from this area of biology with these matching enzymes. And looking at that map, we know there's other fragments that seem to be, a little bit more targeted to say the liver or even the kidneys. So what we're looking in those other organs is how do these fragments work there, and could they be useful in other forms of inflammation and fibrosis? What we're learning quickly is that this is a system in our bodies in healthy people that might be able to help people with patients who have, some sort of disability with certain organs.
Dr. Sanjay Shukla:So it's a way to supplement now, attacking maybe liver, inflammation or fibrosis or kidney inflammation or fibrosis. So it's really exciting times when you think about it of the of these 4 nearly 400 fragments. We didn't just get lucky picking the first one and putting it in just one disease. I I I think I think there's exciting times here to look at some of these other fragments and what could they do and how could they help patients with other kinds of diseases where those organs may be affected.
Dr. Moira Gunn:Well, doctor Shukla, I'm gonna give you an a. I hope you're happy, but you might not be totally happy. I'm giving doctor Schimmel an a plus. I think he deserves that. Don't you think?
Dr. Sanjay Shukla:I think my grade is still pending, but I certainly agree with that. Doctor doctor Schimmel, absolutely gets an a plus.
Dr. Moira Gunn:Oh, that's a great idea. I'm so I I watch out. My my students are allowed to listen to this and say, I'm sorry, doctor Gunn. My grade is still pending. Right.
Dr. Moira Gunn:That there's always something to learn here. Always something to learn. Doctor Shukla, thank you so much for joining us, and I hope you'll come back and see us again.
Dr. Sanjay Shukla:Thank you again, and I absolutely will be happy to come back.
Dr. Moira Gunn:My guest today is doctor Sanjay Shukla, president and CEO of Attire Pharma. More information is available at attirepharma.com. That's attire, atyr, attirepharma.com.
