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- Highlights from BCX9930 data (3/22/21):
- Significant and sustained increases in hemoglobin
- No transfusions needed in 100% of treatment naive and 83% of poor C5 responders
- Other key biomarker data hit
- Greatly improved patient quality of life
- Moving straight to pivotal trials for PNH
- Orladeyo approved in the U.S. and Japan, EU approval expected in Q2
- Year end cash of $303 million which provides runway into 2023
- R&D day March 22, 2021
- For our most recent research report, click here
For a link to slides from the R&D conference call, click here
R&D Day Transcript
John Bluth (CCO): Good morning, and thank you for joining us for biocryst first virtual r&d day. I’m john Bluth head of Investor Relations at biocryst. And over the next two hours, we’ll highlight for you how our unique approach and expertise in developing oral medicines for rare diseases has produced a full pipeline of molecules. Today, we’ll also focus on the exciting new data we’ve just announced with one of those molecules, our oral factor D inhibitor, BCX9930, which we are now advancing into pivotal trials as a monotherapy. For complement mediated diseases. I do want to remind you that we will be making forward looking statements, so please refer to the cautionary statement and the accompanying presentation slides and review the risk factors in our SEC filings, including in our most recent annual report on form 10k. these risk factors could cause actual results to be materially different from those experienced or implied in the forward looking statements.
Throughout the program today, we will introduce you to members of the biochars team, and a panel of physician and patient experts in complement mediated diseases. You can find Bios on all of our speakers on the Program website by clicking on the speaker bio button, which is the green right hand button at the bottom of your screen. The biocryst team and our panel of experts will be available for a q&a session with you at the end of the presentation. If you have a question, you can submit it to us at any time in the q&a box at the bottom left of your screen.
So let’s get started.
Video: JOHN Montgomery and I started collaborating developing this technology of structure based drug design. And we incorporated the company in 1985. So it took it took a number of years to accomplish but resulting in in what what was a company that was one of the leaders in this new field of structure based drug design. Jama gabri was a world renowned medicinal chemist. And although he died early in the history of bow, Chris, the group that he built lives on and is one of the top organic chemistry groups I think in any company.
Our very first employee about Chris was Dr. Babu. I met him first at Oxford University. When I was there as a visiting professor. He was one of their rising young stars at Oxford,
“I was a bit apprehensive about being the very first employee of the company. But looking back I can’t imagine life without BCRX”
Dr. Babu is a spectacular scientist works well with people and just was the perfect person to launch bow Cruz. Claude Bennett was very well known in the field of medicine at UAB. He was chairman of the Department of Medicine for years, and went on to become the pressed into the University of Alabama in Birmingham. So when he decided to retire from the presidency of the university, immediately recruited and move on full time with us. He was the editor of the textbook of medicine that used by medical students all around the world everywhere we went, everybody knew cloud Bennett and he was just a spectacular addition to the company.
“I’ve always wanted to do something in medicine that would really benefit everybody. And I thought this company offered the best possible route to do that.”
Jon Stonehouse (CEO): Why is it that Biocryst has been able to discover develop oral drugs for patients suffering from rare diseases when very few others have tried and even fewer have succeeded. Everybody has the same tools, the same software, the same equipment. Heck, even many of the patients crystals can be found on the internet. But not everybody is able to do what we do. Today, you’ll not only walk away with the why, but you will also get to experience the Why? And by answering the question, you will better understand what this means for the future and value of our company.
As you saw on the video, it all started with a small group of accomplished scientists coming together. Dr. Charlie bug, dr. john Montgomery, Dr. Bennett and Dr. Babu. The team and the scientific platform of structure based drug design were and are the foundation of our company. In fact, Biocryst founders and scientists were some of the early pioneers of this intersection of art and science and drug discovery.
Babu was the first employee at biocryst. He did his postdoc training at Oxford, which at that time was one of the leading crystallography research centers in the world, and included luminaries in the field like Nobel laureate Dorothy Hodgkin.
As Charlie said in the video, Babu quickly rose to one of the bright young stars at Oxford. And this was the start of him becoming a world expert in crystallography and structural biology.
I remember doing my own diligence over 14 years ago, before joining Biocryst I spoke to two leading drug discoverers from large pharma companies who had done diligence on Biocryst for a large investor at the time. One of them told me Babu can do with 10 people what he wasn’t able to accomplish with 300 chemists. And the other said, Babu was one of the few people on the planet he’s met that can place atoms in three dimensional space in his head. These are not individuals that passed out praise easily. Babu’s brilliance and the team he built is one of the main reasons I joined Biocryst.
The team led by Dr. Babu at biocryst has been working for over 30 plus years, perfecting our ability to discover drugs using structure based drug design. Not surprisingly, how well the team works together as another key component to success. Having a group that’s worked together for decades helps how our computational chemistry, medicinal chemistry and biology teams work to solve problems together is key and quite unique. Instead of working in silos, we’re melding our expertise. Instead of just building a department, we built a capability. So remember this when you see the building of Orladeyo today, it is experience and these groups working together to solve complex problems. That allows us to build drugs one atom at a time.
But that’s not the end of the story. We all know great science doesn’t always translate in the clinic, many mice have been cured of cancer. But turning that science into drugs on the market is a whole lot harder and has significant risk. So choosing where to take the risk is another important piece to the story. This is where our strategy of focusing on oral drugs for patients suffering from rare diseases comes in. It starts with the enzyme target that causes the rare disease. We don’t go after disease targets unless there is clear and abundant scientific evidence that the target plays a key role in the disease. For example, plasma kallikrein is the critical enzyme in the pathway that leads to HAE. The same thing goes for factor D and PNH and l two and FOP. So if we’re able to block these targets, we should be able to affect disease and patients and thus have a better shot at success in the clinic.
Where we are willing to take risk is where you need potent binding and selectivity to the specific enzyme. Many of the rare disease enzymes are part of large families like serine proteases, for plasma kallikrein in factor D, and kinases without too.
The reason we could take this risk is because of our expertise and structure based drug design.
The capability allows us to build molecules that bind tightly to that one specific enzyme and not others in the family.
So when you combine it all together, the expertise the people working together and the focus strategy, you do see great science translate into the into the clinic. And that’s when you see the transformation and success follows
Biocryst is now undergoing a major transformation. We have shown that we can take great science and translate successful outcomes that lead to products patients want to need. The evidence is Orladeyo. In a matter of weeks, we expect approval in the EU. This will be our third of three of the largest territories in the world. And the beauty of this strategy is we will do it again. And again and again, applying the same approach and everything we learned in HAE to 9930 and complement mediated diseases, a pipeline and a molecule. We will continue to go fast with drugs in our pipeline, and continue on to the next discovery of a drug for another rare disease. This is no longer aspirational. This is happening right now. And today, we’ll show you the evidence. This is how we’re building our company. And this is how we will build greater value.
So today, we’re focusing on factor D and one of our most exciting molecules BCX9930. You’ll hear from thought leaders on what’s important to them the treatment of complement mediated diseases, you’ll hear from a patient directly and gain insight from our market research on what’s important to that.
And you will see the data from our clinical trial and PNH with BCX9930. And why we are so excited about this program.
But before we do that, we wanted to give you more of a feel and understanding of our drug discovery capability. Under normal circumstances, we could have invited you to join us at our facility in Birmingham. But nothing’s normal in COVID. And so we put together a video to bring to you take a look.
Video of Team: Hi, hello, hello, you’re putting me on the spot. namaskara Hello, there was no mistake.
There’s no such thing as a typical day if I agree with you know, we’re committed. But we also like to have fun doing it, we’d love to feel it. Yeah, we get excited about that.
This is a state of the art Research Center in the business park here in Birmingham, Alabama. It’s beautiful inside and out. And it’s bright and airy, and a sun comes through and it has bright, vibrant colors and the lab space, we’re so very proud of it, we love to show it off to everyone.
The goal of the Birmingham facilities to come up with new drugs. So every day, the chemistry group, the biology group and the structural biology group, we work together and try to come up with the brand new molecules that have an impact on the patients, it is a lot of fun, I get to wear 3d glasses, we take the target proteins for which we are going to design the drugs, we grow crystals of them and get the three dimensional structure and you feel really excited to work with to refill excite. crystallization is not purely a science, it’s something of an art, you have to have some good luck to grow some crystals. Of course, this is teamwork. And anybody can come into my graphics lab. And we can exchange ideas freely, which makes for a great environment to do science.
We are mixing chemicals to come up with a new molecule and turning into a drug that is safe, efficacious and improve the quality of life. But we had to make sure we do it in a small amount of time. That’s the key smallest amount of time because they are waiting for us.
When we get a molecule from the discovery lab, it’s made in very small quantities, we improve the process and make large quantities for testing. I can relate to myself as a creator. I’m making molecules and everybody’s using that. That makes me feel good.
Microperfomance pharmacokinetic studies. And we also develop disease models for current projects that are in the pipeline. It’s so exciting. We get to go from theory to the bench and you actually see it all develop. And is the study when we see it works. You know, that’s the most important thing it’s got to work.
My role as a senior research biologist is to analyze clinical samples from patients who have been treated with our drug. So that’s exciting to see whether or not our drug is having a great effect. We recognize that there are patients who are struggling with rare disorders and to be able to see a positive result through our work. It gives us that satisfaction to know that what we’re doing makes the difference.
My role at Biocryst is the development of the drug from the discovery all the way to the commercial stages. It’s fun, it’s having challenges some day is good, some day is bad, a lot of gray hair, I take it from the milligram which you cannot see. And I make kilograms in kilogram and tons of the molecule. We receive sample from discovery we receive sample from the development and we try to understand how to make the drug more pure, more active, give it the purpose of life. Give it the
best chance to succeed in life. It was a baby. I took it all the way to making keto to become an adult. And that’s what when we transition between group between discovery and development or between development and supply chain, what we tell each other, we’re handing you our baby. It’s yours now. We’ll trust you. Go for it.
We love it. We love it. And because we know at the end of the day, we’re going to help somebody, we’re going to help these patients.
Jon Stonehouse (CEO): Babu is the leader of our team in Birmingham. He doesn’t venture out of the lab and onto Wall Street very often. But we thought today, it was important for you to see how we do what we do. So we’ve asked Babu to show you how we built Orladeyo. He will explain how the goal is not only potent binding, but it needs to be highly selective and bioavailable as well to become a viable drug candidate.
Yarlagadda Babu, PHD (CDO): My name is Babu alligator. I’m the head of the drug discovery at biocryst. I have been with the company from the beginning of the company. And this morning, I’ll be walking you through the discovery of holiday Oh, a potent small molecule plasma collecting inhibitor. As an example of the discovery capabilities and biocryst which could be applied to many other similar proteins. The goal of any drug discovery processes to identify novel molecules that have interactions with the with the therapeutic target, plus metallic prime is a slim protease, it belongs to a family of serine protease members of about two to 300 enzymes, some of them are very close to the plasma collect crying, the an ideal plasma character and inhibitors will be potent, highly select you to reduce the off target toxicity, and at the same time highly bioavailable.
The features that improve the improve the potency may or may not work for the other two. And vice versa. The way to overcome this challenge is to structure based drug discovery approach where we know in greater detail, the 3d structure of the protein, and the structural features help us to design a molecule that gives the potency selectivity and the bioavailability. And the first step in the structure structure based drug discovery approach is the identification of the target and the 3d structure of the protein. The 3d structure of the protein is given by the protein crystallization and an X ray crystallography. And in this representation, you’re seeing all the 3000 to three Toad and that protein atoms of the plus metallic line. Each one of them is represented by a point atom, and color coded by the type of atom. The red color represents the oxygen the blue represents the nitrogen and the gray represents the the carbon atoms, it may not show very well the finer, finer features of the protein, but it explains the function and the mechanism of the protein. Another representation could be a bare bones representation of the backbone of the protein, which source the secondary structure fault of the protein. Again, that doesn’t help us much in terms of the discovery, that kind of representation. The best representation is the space filling model, where each atom is represented by a sphere, that is the size of which is proportional to the radius of the atom. And you can see already start seeing the ridges and the cavities on the surface of the protein. And some of these fishes are very important for the for the enzymatic activity of the plasma colic crime. This the long stretch here that you’re seeing like a trench, going from the left side to the top of the top right hand corner is where the high molecule rate kind of then would bind. And the active site of the enzyme would cleave that into two parts, generating the Brady keinen, which is the bad actor in HAE. as we as we zoom into the active site, you can see in much greater detail the features of the active site.
The active site is the business end of the enzyme that is where the reaction takes place. That is where the hyperactive the hyper activity of the enzyme is contributed by the active site. The best analogy to describe the active site and the enzyme goes back to about 100 years. The lock and key approach the lock and key analogy. Here the lock is the plasma kallikrein enzyme, the key the substrate or the drug molecule that fits into the key and the key hole is the active site. So if you know how the keyhole looks like, we can design a key that perfectly matches the keyhole in the same fashion. If you know how the active site looks like you can design them molecule that fits the active site and binds to it very tightly.
The active site is represented in four different sub sites here, the s one, s two and s three and s four.
Each one of these societies is critical to the binding the binding of the inhibitor. The already Orladeyo molecule has been built one small fragment at a time by optimizing each fragment to bind in that particular sub in that particular sub site. As you can see, the first sub site what we have gone after in terms of the fragment design is the ES one sub site. It has well defined features and it has a deep cavity. And we we have substituted we have designed a fragment that binds very well in that sub site s one with a six member King, anything smaller than this one would be very loose, anything bigger than this six membered ring would be aesthetically clashing with the protein. And a six membered ring is the perfect size to fit into that fun, we are still in the cavity of the of the s one site to get out of the cavity, we have identified another smaller fragment that attaches to the six membered ring, that brings us out of the cavity. And with that thought with that, with those two fragments joined together, we have ideally filled the space with the shape and the space with this fragment here. To access the rest of the active site, we have used this atom here as a point of attachment and access the rest of the active site. We design this flattering to lie on top of the relatively flat surface here and attach that fun create peptide bond. And awarding that it’s here. As you can see here, we can still have the S four site and the s two site. And by attaching a different link structure, we were able to position that link between this crevice between these two walls and at the same time going deep into the into the cavity. Finally, the the the molecule is finalized with the final fragment that goes and binds into the S four site of the active site. The combination of all those five fragments, joining them together is what gives rise to the Orladeyo molecule filling the active site completely not only not only the shape, complementarity, but also the charge complementarity. So if we replace this point atoms by the appropriate size spheres, again, you would see very clearly the tightness of the fit between the enzyme active site and the drug molecule, the golden ello what you’re seeing here is the is the drug molecule bound and designed to fit in the active site and the contents of the protein active site and the contents of the drug molecule they perfectly match each other not only at this position, but also this position. The shape complementarity and the charge complementarity is very good between the two. And that gives rise to a potent and selective molecule. And and that resulted in the Orladeyo, the credit goes to the drug discovery team at at Biocryst. The medicine chemistry group, the structural biology group and the research biology group. They have been working together on many similar products for the last 20 years using the same approach. And they were able to come up with a potent molecule like this one in under two years, 12 months to 18 months. And this molecule has been advanced into the IND enabling studies in 2014. And at the end of 2020 we got the approval by the FDA in US. That’s a remarkable achievement to all the teams in biocryst. And we’re all very proud of that one. Thank you.
Jon Stonehouse (CEO): Thanks Babu. What you just saw ababu do with Orladeyo. It’s also how we approach 9930 and how we approach every molecule we build at biocryst. This amazing team will keep going after more targets because we know patients suffering from rare diseases are waiting for more oral therapies.
Now I’m going to ask Dr. Bill Sharedan our chief medical officer to join us and as he does let me say that bill was the principal architect in getting us to focus our strategy on oral drug rare diseases. Bill came to us from Amgen almost 13 years ago, and after we had a chance to really take a look at what we had. Bill got feedback from our
Side experts that lead us to the target plasma callate crime and the rest is history.
So Bill, my first question, is it one thing to discover a molecule like Orladeyo, in less than two years, but to go from phase one to file for approval in less than five is also amazing. Tell us what what you learned from that program and what capability you and your team have built, and how it’ll help us with programs like PNH nephritis with
Dr. Bill Sheridan (CMO): John, I think we learned three key things. From the HAE program for Orladeyo for all of them, we can apply those to every Rare Disease program, every project at the company. So number one, the importance of active listening to regulators to topics but to patient advocates, do clinical sites. And the reason is to get the strategy and the execution right. Number two, the importance of establishing and maintaining great relationships. We had pipped boutique CRO, we have their clinical and medical stuff partnered with the CRO to maintain direct site interactions and be as responsive as possible to what’s going on with the clinical sites.
You know, a really important piece of the story is that patients are enthusiastic about access to an oral drug. You know, the patient advocacy organizations help us immensely and encouraging enrollment.
So, throughout the whole thing, we keep our external experts fully engaged and informed and you know, that’s can only be to our benefit. The third thing is that, you know, applying these concepts with an attractive opportunity to change medical practice of like, or do or like BCX9930 in rare disease programs of more than no more than a few 100 patients really enables us to compete effectively. So I think all of that there, the lessons of golf are the 9930 programs to do it all over again, one indication after another and strive to be the sponsor of choice for everybody involved in those diseases.
Jon Stonehouse (CEO): Thanks, Bill. As I mentioned, Babu was our first employee. But now I’d like to introduce our newest employee, Dr. Helen thackray, whose first day is today at biocryst. Helen has been a member of our board of directors since 2019. And we are so excited that she’s chosen to join us as our chief Research and Development Officer. As a board member serving on the science and commercial committees, she’s seen firsthand the progress we’ve made in building our company. To give you a little bit of background on Helen. She’s a pediatrician, who served for over a decade on the research ethics Review Board of the National Center for Healthcare statistics, which is part of CDC. And she serves on the faculty of the Children’s National Medical Center, and George Washington University School of Medicine and Health Sciences. Helens combined experience as a leader, scientist and clinician will be a great addition to our company. So Helen, welcome to day one. What a way to start. Maybe you could say a few words about what you’ve seen regarding our approach to r&d from the board perspective and why you chose you chose to join our company.
Helen Thackray (C R&D O): Morning, john, thank you.
And I am delighted to join biocryst I’d be happy to share a few points as to why. First, I’ve seen what Biocryst can do. I’ve had the advantage of sitting on the board interacting with the company’s management team and hearing how the company conceptualizes plans and executes on the programs. As a member of the board’s Science Committee, I’ve come to know the extent of the scientific program and pipeline on the commercial committee. I’ve had a front row seat to observe and appreciate the carefully planned and orchestrated commercial strategy which has led to the launch now proceeding globally. Second, with the benefit of this perspective, I have great respect for the biocryst management team. And for the company. I’ll speak about discovery and development in discovery. The creative thinking and expert application of a structure based approach to novel drug design at biocryst is unparalleled. Understanding the key molecular relationships, leveraging these to design a better drug and achieving that with oral bioavailability is not easy. And yet the molecules Dr. Babu and his team are delivering have excellent potential to be transformative drugs for their intended patient populations. The recent launch of Orladeyo I was just the beginning. Oral delivery is hard to achieve. And biocryst has done it and is doing so repeatedly, repeatedly, with best in class qualities for potency selectivity and bioavailability. This is precision drug discovery. The existing pipeline and the future potential for continuing the advancement of new best in class molecules is just tremendous in my view,
In development, strategic planning and execution for drug development and rare disease is a specialty unto itself. And Dr. Sheridan bill, and the Biocryst team are expert and accomplished at this. They are thoughtful, and they put patients first in their planning, which is critical. biocryst understands what it takes to approach drug development for small populations, complex diseases, and in areas of unmet need, both medical need and need for improving quality of life for patients. And the company builds this into the programs with great impact. biocryst is nimble and execution and highly effective. The company is not only achieved registration for all at Orladeyo, as you said, but has simultaneously proceeded across the globe with global launch accordingly.
Third, on a personal level, this is a natural fit for me as I’m a pediatrician, as you noted, and a hospitalist with medical genetics training, working with rare, complicated, serious disorders is my own medical specialty. So to me, this is a natural, obvious fit Biocryst. So for all these reasons, I’m inspired by the opportunity to join biocryst I think the company holds great promise for continued success that will transform available therapies for the rare disease patient community and I’m honored had a chance to be part of that.
Jon Stonehouse (CEO): Thanks, Hellen.
So Babu, have a question for you. I know it’s not fair to ask who your favorite child is. But I’ve seen you talk about 9930 in a way that’s different from the way you talk about others. Can you tell us what it is about 9930? That’s special?
Yarlagadda Babu, PHD (CDO): Yeah, sure. First of all, thank you. If you have collected away, both water day or night meant that your special molecules to all of us both are serine protease inhibitors, and both have promised to be paid medicines. So it is really difficult to pick one or the other. Coming back to 9930. Factor D inhibitor is the most recent molecule from the discovery team. As you know, we have long interest in compliment and along with our colleagues at UAB. We were the very first one to describe the 3d structure of faculty. And it is active site in in atomic detail.
Factor D is an interesting molecule it normally circulates in the blood in the inactive form. And it becomes fully active only when it binds to factor B and C three B complex it’s matched to substrate. But what we have done is after careful consideration, we have decided to go to the inactive form for the duck discovery approach. This approach has both advantages and disadvantages to go up to the inactive form. First, On the plus side, the inactive form has a unique active site structurally very different from most of the other three proteins this so that gave us an opportunity to minimize the risk of off target toxicity by going up to the inactive form.
On the other hand, the same unique active site in the inactive form is not very well defined. So it presents some challenges to come up with a potent molecule to the active site. But our discovery team with experience from the plasma collected program was able to display at 9930 in a relatively short period of time. In fact, it was less than one year. That was a commendable achievement by the team. Definitely. That that is the structural point a few the other the other aspect of 9930. As you will see from the rest of the program today, both factor D and the alternative pathway play an important role in many complement mediated diseases. And we have a chance here with 9930 to have a real impact on the patient’s lives. So both from a structural point of view, and also its impact on the patient’s nightmare. That is definitely turning out to be an interesting molecule for us.
Jon Stonehouse (CEO): Thanks Babu. Bill. I’ve interviewed candidates after they’ve spoken to you and one of them said to me, he never saw a CMO’s to be so abusive about a program before when you were talking about 9930. Now I’m pretty sure most investors who know you pretty well would never accuse you of being abusive. So what is it about 9930 that get too excited.
Dr. Bill Sheridan (CMO): So john, it’s a combination of the inherent quality of the compound coming out of the discovery group. Combined with his track record in early development, and add to that the number of indications we can go after a while. So here we have a steering protease inhibitor that targets an absolutely unique conformation of the active site of an enzyme business case, factor D, that really helps trust specificity and lowers the risk of unwanted off target effects. So that’s, that’s really important. On top of that, all of the rich in vivo biomarker in vitro and target potency results that we gained during its preclinical development, told us we should have a drug that could perform in the clinic. And that is exactly what we saw from the first evidence and merging from the PNH study. So, you know, there are just so many serious and life threatening rare diseases driven by the alternative pathway, and it’s a fabulous opportunity to help patients and revolutionize medical practice. So that’s why I’m excited.
Jon Stonehouse (CEO): Great, thank you. Well, that wraps up this section of our program. I’ll turn it over to Bill and he’s going to do a deeper dive on our faculty program. Thanks.
Dr. Bill Sheridan (CMO): Thanks, john.
Now, it’s my pleasure to introduce our panelists for today before we get into the rest of the program.
First off Dr. Austin Kula Saqqara Roche MD practices as a consultant haematologist at King’s College Hospital in London, and Austin’s a leading expert and active researcher in PNH.
Mr. Barry Katz off is the founder and president of the P nh patients association of Canada and the founder of the PNH Global Alliance and in fact has PNH
Dr. Brad Rovin is Professor of Medicine and pathology in the Division of nephrology, The Ohio State University Wexner Medical Center.
So first off, we thought it would be helpful to ask asked him to explain what this disease PNH is all about, and what matters to physicians in its treatment. So, Austin, please join and with mark up, you have to say that this disease
Austin Kulasekararaj (MD Consultant Hematologist): Okay, thanks, Bill. Whoa, puppy Can you guys can hear me.
So what I will, what I will do in the next five minutes is take you take you through some basics of this disease, which I’m obviously passionate about this disease of paroxysmal nocturnal hemoglobinuria, as you as you obviously know, it’s an old trough and it’s an old trough and or a rat disease, where patients get a triad of significant complications, including chronic hemolytic anemias with paroxysmal attacks, and also have a propensity to get thrombo embolisms and also have an underlying bone marrow failure.
So it’s it is a very extremely rare disease. We think the incidence of this disease is around point five to one per year with the prevalence being higher because of the improvements in the therapy with complement inhibitors. Since the since the first clinical trials of distal complimentary inhibitors C five inhibitors. So people always used to say if you understand PNHyou understand a lot about hematology and medicine because it’s a it’s a disease, although it’s rare, and most patients could be stable. It can be associated with the number of life threatening complications, which lead on to mortality and morbidity. And one of the key things is this thromboembolic manifestation or having complications with clots in different parts of the body, including cerebral hepatic and other parts. And historically, prior to the advent of compliment therapy, the mortality for patients with PNH was close to at five years, nearly 1/3 of patients were had life threatening complications predominantly related to thrombosis. And this intriguing relationship with an underlying underlying bone marrow failure was also was also seen in this.
So if we move on to the next slide, so this is, if you look at if you look at the lifespan of Fred cells, we all know that the bone marrow is the factory which produces but we’re probably not, most of us are not aware that 84% of the cells in the human human body are red cells, which are 20 to 30 trillion. And if you have a human adult healthy human adult producing around 2.4 million new erythrocytes per second, think of it in the context of PNH.
And I know this is bit of a technical slide, but I just wanted to take you Through this slide where normal red cell lifespan is around 90 to 120 days, it circulates in the system for three to four months. If you have a patient who’s 100% of the cells or composed of peonage, ie they are affected with PNH, you can see that each of these individual trillions of cells, instead of living for 120 days, will one day live for 10 days, which again, means that these patients get significant hemodialysis due to the lifespan of these cells not being sufficient or not living. And not only that, once the cells lice and die off, which live after eight to 10 days, your bone marrow produces more and more of the same red cells and they have the same pH defect and they continues to have hemolysis or destruction of their of their red cells.
So, essentially, what is involved in the pathophysiology of hemolysis in the context of PNH, so, red cells, white cells and platelets or any cellular population which comes out of the bone marrow, ie stem cells will have complement regulators which are protecting the red cells or IE all I call them as shields around the red cells. And we know complement is one system which is part of the innate immune system, which is always active in everybody’s body as we are all sitting here in different places you have a background complement activation at all time. So, what happens is this complement activation does not do anything to the anything to the interact red cells. But if you imagine a patient who’s got PNH these red cells will be naked without compliment activating molecules on the surface of the cell. And when you have complement activation, this leads on to hemolysis of the PNH red cells leading on to all the complications symptoms associated PNH patients, which significantly impact the quality of life seen in this group of patients. So, so, it is important that this complement activation because we know that we a unless a patient undergoes a stem cell transplant, we are not able to stop the production of these big a mutant cells or compliment sensitive cells. So, the one possibility of treating this patient is to stop the complement activation pathway thereby allowing these red cells to live for a longer duration of time and thereby stopping the hemolysis.
And another way of to pictorially depict this is using this cartoon, where the complement pathway is lined up horizontally rather than vertically with alternate classical and lectin pathway indicating a domino effect of activating the downstream pathways with cfib by activation and a terminal complement activation of membrane attack complex inducing red cell red cell lisis.
So, what happens is it this is what normally happens, but if you if you inhibited the terminal complement pathway at C five, this hemolysis intravascular hemolysis is abolished, but what continues to happen is the and there are patients who have mutated sci fi, which stops binding effect lose map, but for patients who are on terminal complement pathway inhibitors, the proximal pathway is still active with the alternate pathway and the takeover hemolysis with amplification loop or continuously going on that it leads on deposition of say 3d fragments on the surface of the red cells. And, and, and these, these cells, the cells need to be cleared in the reticular endothelial system, ie in the liver and in the spleen, and thereby inducing what is the concept of called SSC 3d mediated extravascular hemolysis, which happens in the liver and the spleen leading on to hemolysis of the cell.
So, we’ve changed the disease with significant intravascular hemolysis due to the proximal complement pathway, activation with C 3d deposition into a component of C 3d mediated hemolysis. And that is where compounds which broke the proximal pathways, more particularly targeted compounds rather than broad c three inhibitor, ie blocking factor B factor D and other molecules is specifically in the proximal pathways could be significantly interesting and more important from a patient perspective. If these compounds are oral, and they induce better quality of life with the improvement of hemoglobin and transfusion independence.
So I think I’ll stop there. Just trying to go over the landscape of PNH treatment and hand it over to Bill. Thank you.
Dr. Bill Sheridan (CMO): Thanks, Austin. So, you know, clearly the C five inhibitors were a big step, and they basically changed the nature of the disease in the clinic. What are the problems with to solve from the medical perspective?
Austin Kulasekararaj (MD Consultant Hematologist): So I think the first thing is, as you rightly said, the C five inhibitors have been a major change for these patients with improvement in the mortality and morbidity associated with this condition. So these patients do not, do not have the thrombotic complications associated with the activation of the complement system. But obviously, couple of things from a physician perspective is the spatial, quite a number of these patients continue to remain anemic due to the extravascular hemolysis component, and the proportion of these patients or quite symptomatic from their anemia. And also, a proportion of these patients will also need significant blood transfusions with need for transfusions at regular intervals. And obviously, from a from a perspective from patient as well, this is a disease, I say a lifelong or a long term treatment. And sometimes, if you have to weekly injections for for a period of years and decades together, that is having a significant impact on the patients and it is better to have choices out for our patients so that they can they can use the agents available.
Dr. Bill Sheridan (CMO): Okay. Thanks very much, Austin. I think that’s a great grounding. So now let’s move on to discussing the results of that study.
So it’s my pleasure, of course to to be able to do this today. And with that background, as we discuss the results, from our phase one proof of concept study with 9930. What should we focus on? And, you know, I think that with, with the remaining medical challenges, we should focus on the relief of anemia, and the avoidance of transfusions as key outcomes related to control of both intravascular hemolysis and extraterrestrial hemolysis with increases in PNH rates or client size as a key measure of control for Moses. And, as Austin explained, that’s all to do with improving the lifespan of the PNH red cells.
The objectives of this study with typical dose ranging proof of concept studies of a new Investigational Drug, a really important goal was to identify therapeutically active dose regimens, and we therefore selected patients who are anemic with a hemoglobin less than 10, or else transfusion dependent, and that applied to both the naive patient population who had never had a complement inhibitor and to the inadequate response population.
So the main difference in eligibility criteria between the untreated PNH patients and those who had inadequate response to see five inhibitors was required evidence of ongoing intravascular hemolysis in the sci fi inhibitor naive group, we’d like to dehydrogenase or ldh. For short, two times the upper limit of normal
PNH is a serious illness and very rare as to explain. So we designed the dose ranging scheme to maximize efficiency and minimize the duration of dosing of low doses that might prove suboptimal. Each patient enrolled heard the dose increase from a starting dose at day 15. Patients who have benefited from treatment enter the extension phase after day 28. And the treating investigator could titrate the dose up to 500 milligrams twice a day. We also increase the starting dose as we learned about the drugs activity and progress through the cohorts that 9930 was dosed as a single agent in previously untreated patients. Remember our goal in this program is monotherapy for this disease, in this first study of 9913, p and H, we added 9930 to C five inhibitor treatment in the C five inhibitor inadequate response patients. We plan to transition. Responding patients have their c five inhibitor after the responses are stable. All told 16 patients were enrolled, with C five inhibitor naive patients coming on first insight and set their fricka c five inhibitor inadequate response patients were enrolled later in the study in the UK and Austria when the COVID-19 restrictions eased later last year
since our last presentation in September, the C five and hibbott er naive patients have continued with big dosing. We completed enrollment and the average duration of exposure is six months. The Nine patients dose did either 400 milligrams or 500 milligrams twice a day. Were very ill from their disease with a baseline hemoglobin of 8.3 several with evidence of bone marrow failure and a high incidence of transfusion dependence for barkey biomarkers showed ecchymosis. Of course, with high bilirubin AST and ldh. The patients enrolled earliest in the study are now approaching a year on therapy, which is really gratifying to see the duration of treatment the doses that matter is now a median of 22 weeks.
In the C five inhibitor naive group follow up has confirmed it early findings from last September, anemia was relieved with hemoglobin going up by 3.5 grams per deciliter from a mean of 8.3 baseline to mean of 11.8 at the last study visit. And a remarkable increase in grid cell plant size we’re seeing a 40 percentage point increase associated with a large and clinically meaningful reduction in all of the hemolysis biomarkers bilirubin AST ldh and reticulocyte count.
So a key remaining challenge, as we discussed earlier, is the need for continued transfusions, especially in the context of extravascular hemolysis. But also obviously, in people who are naive to complement inhibitors as this group is. And really important and dramatic result from the study is that no transfusions were needed at the doses of 405 100 milligrams twice a day, the rate of transfusions dropped to zero. So 100% of trans patients were transfusion free. By any measure. This is a great result for patients with PNH. The only transfusion in this group was very early on. We discussed that last year, it was off the first two weeks of dosing in patient D in the first cohort.
Here’s a quick summary of that patient updated from last year with now nearly a year of follow up. In the year prior to study, patient D had 13 units of red sauce transfused. We’ve indicated when the doses of 400 milligrams and then 500 milligrams were introduced, with the arrows in the left hand panel at about weeks, 20 and 28, respectively. As a dose was escalated, we gained control of hemolysis. The hemoglobin continued to rise throughout the year on study. In fact, doubling from 6.7 to 13.8. Over 50 weeks, the red cell clan size reached almost 100% more than 99%. We can also see the clinical chemistry biomarkers AST and LDH. Stabilize and the ridiculous side count settle down as the anemia was corrected.
As you mentioned last year. In the discussion in September, the investigator reported rapid symptomatic relief. You can imagine the difference, the hemoglobin of 12 to 14 and avoidance of transfusions makes to well being compared to a hemoglobin of six to seven and repeated transfusions. These dramatic responses in this patient were reflected in an improvement from baseline of eight points in the facet fatigue score. These are great results from our therapy with a normal drug.
Another example patient H is also very instructive. This patient started at 200 milligrams twice a day and showed a prompt response in every measure. With continued dosing at 400 milligrams twice a day from day 15. Through week 20. The client size got to 100%. We can see them in this patient stability in the various biomarkers took some time to be evident. With no transfusions on study. Your hemoglobin rising from just under 10 to nearly 15 and fatigue score improving from baseline by nine points. These are great results for this patient as well.
As we’ll see in the next few slides. The outcome for the C five inhibitor inadequate response patients were very similar. So we have six patients. They all came on study in late 2020. And for the 400 and 500 milligram dose levels, the median duration of dosing is now about 13 weeks.
These six patients were very ill 300. Bone Marrow failure three had prior blood clots. Five were transfusion dependent at baseline hemoglobin was 8.94. were being treated with eco lism ab with an average dose of 1200 milligrams every two weeks, which is obviously higher than the approved dose and to around revill isn’t that the baseline the virtue profile shows extravascular hemolysis with high bilirubin circulating c three opsonized PNH red blood cells and higher particular site counts adding our old 9930 treatment increases the hemoglobin by 3.2 grams per deciliter and the red cell climb size by 30 percentage points and reduce the lead markers of extravascular hemolysis. Remember, this is a shorter follow up. So these results are strikingly similar. Nevertheless, to those in the C five inhibitor naive subjects, indicating that proximal component inhibition with targeting factor D can control both intravascular hemolysis and extravascular hemolysis.
So even though follow up is much shorter than in the C five inhibitor naive group, the story with red cell opsonization with complement component c three that Austin discussed earlier, is pretty interesting. And in five out of six subjects, these levels have fallen dramatically, even in the first eight weeks of treatment, and the hemoglobin has risen quickly as a result. Just like in the naive population, we have dramatic outcome in transfusion rate, so it’s gone to zero in five or six patients. In the other patient, the transfusion rate was halved. So altered alter, we have five or six patients now transfusion free. Again, this is a really great result.
patient N is one of Austin’s patients and demonstrates the effects of adding 9930 on top of 1200 milligrams of echoluismab at every two weeks, so this person was still not getting control was still anemic. And after only 12 weeks without a 9930 we’re seeing a gratifying response with continued rise in hemoglobin and rising PNH red cell clone size, fallen recoilless side count and fall in the C three opsonized cells. So as you saw before, it can take longer than this for the whole picture to stabilize, but already this patient has done really, really well.
So overall, you know the outcomes on anemia, transfusions and control of hemolysis have been very encouraging. But such as the safety and tolerability profile we’ve seen so far, we haven’t really seen any safety signal. So of course, with any new investigational medicine, we’re very careful about safety monitoring the clinic and in the laboratory. With the thorough investigations. No patient has stopped or interrupted dosing due to related ace. And like in all trials of complement inhibitors. You know, we’ve seen instances of phimosis. These have resolved without changing the dose and the patients have continued on study. As we discussed last year, we have seen a benign drug rash in some patients that goes away without any intervention or changing dosing at 9930. We’ve also seen transient headache more commonly in the C five inhibitor naive group. This is an expected effect of Coplin inhibitors, and happens due to resetting of nitric oxide homeostasis with control with intravascular hemolysis. In essence, it’s confirmation of the on target effect of the drug.
We couldn’t be more pleased with the responses we’ve seen so far anemia was relieved transfusions avoided. And both intravascular and extravascular hemolysis brought under control the consistent effects in both c five inhibitor naive and C five inhibitor inadequate response patients provide confidence for the next steps in this program. And also provide confidence for focusing on monotherapy with 9930.
You know, we didn’t chat about it today, but the PK the PD of PNH in laboratory assays were similar to healthy subjects. Importantly, we’ve got a very good dose range to select for pivotal studies in PNH and also to apply to our broader program in other alternative pathway dysregulation diseases. So we look forward to finalizing this selection after after discussion with regulators, all told these findings plus the safety and tolerability profile in this seriously all patient population strongly support our pivotal study programming PNH and the expansion to study site, just studying selected nephritis indications. So that’s that’s the review of the data. Now I’d now like to invite Austin and Barry to join us and will in a minute get to getting a perspective on on the data coming out of phase one dose ranging study.
1 hour mark time stamp
But, you know, Barry, it’d be really important just to spend a few minutes to educate everybody about what it’s like to experience pain. He has a patient so please go ahead.
Barry Katsof (PNH patient): Thank you. It’s not a good experience to be here. frank and open. But first of all, the journey starts when typically, most patients wake up one morning and see that the urine is, is red blood colored.
That’s pretty frightening in itself. So what do you do, you end up going to your GP, and they end up sending you to your audiologist. In my case, we went through all the workups. And the doctor kept saying, don’t find anything, don’t worry about it. That’s fine for them to say. Meanwhile, every morning when you went to the washroom, you kind of had one eye open one eye closed, because you didn’t know what you were going to see. very frightening. went to another urologist, head of the university and did all the workups. Again, nothing was found.
I came back did all the workups. Again, to make a long story short, we ended up going to a nerf ologists kidney doctor because I was very insistent on wanting to know what was upstream from the bladder. And when you put blood or urine in a centrifuge, what ends up happening is blood will settle and the hemoglobin won’t. And that’s how we determined that I had something other than blood in my urine. And that whole process took nearly two years. Then lying to the hematologist with these findings, they were able to quickly do some tests and determine that I had PNH. That was great. But the treatments at that time weren’t available. And then when they were available in 2007, the C five inhibitors. As was stated, hemoglobin never gets to an optimal level, you end up becoming transfusion dependent. Life with PNH is dependent or revolves around how you feel. Fortunately, I have a very supportive network, family and friends, and you can never make plans. It’s always Yes, we’ll go for dinner. But it’s really going to depend on how I physically feel low hemoglobin severely restricts what you can do in your daily life. Forget about active activity, because in most cases, your hemoglobin doesn’t allow you to do that climbing a set of stairs becomes an issue or a challenge. Then you start to develop the need for transfusions. transfusions in themselves are very problematic. You just don’t go into a blood bank and say give me two units of Type A doesn’t work that way you get your blood tests, you then your doctor determines that you need a top up if you want to call it that, then you have to go back for a cross match. Then after lots of transfusions, you end up building up antibodies, and that they have to get you a proper blood to match what you have or what the patient has all told, besides feeling very sluggish and not well before you need the transfusion with hemoglobin in the 70s. It could take several days until you actually get the transfusion. Then once you get the transfusion, you just don’t walk out of the clinic and feel 100% takes another couple of days until your body adapts to the transfusion.
So again, it’s very time consuming and plays upon patient’s lifestyle, the sequence everything depends upon when you’re going to need a transfusion. If you’re if you’re working you have to take time off it becomes very burdensome on the patient and their lifestyle. being tied to an infusion schedule of every few weeks, or every few months. Again, you have to run your life and manage your life around your infusion schedules and your transfusion schedules. Far from optimal. Granted, it’s eliminating some of the uglier aspects of PNH. But it is still not an optimal lifestyle.
Having options as Austin said, for patients to be able to improve their hemoglobin, to normal levels to lead an active lifestyle that is representative of your age group or demographic is great, enable to eliminate the need for transfusions is more than great transfusions bring with themselves, sure, it makes you feel better. But there’s other medical side effects. Patients typically become iron overload with iron, they need iron creation pills to reduce the iron in their body.
Some of these medications have severe side effects with them. So having the option of a treatment that will allow a patient to have an acceptable hemoglobin and reduce or eliminate the need for transfusions, as they say, in the advertisements priceless.
Dr. Bill Sheridan (CMO): Okay, I think that that really explains it perfectly. Austin, can we get two reactions to, you know, the results of this study? And maybe you can frame it as to what are you looking for from proximal complement inhibitors.
Austin Kulasekararaj (MD Consultant Hematologist): So thanks, Bill. So Barry did sum it up Is it because we, I think I think of it as a sort of going through different eras, because in the pre close mabira, the main goal of therapy was to prevent end organ damage, prevent thrombosis and the complications associated with it, which is obviously life threatening, leading onto mortality and morbidity. And I think, which we were all very pleased about. And that is what the C five inhibitors, mainly close Mab did in that So switching gears, I think once you see these patients coming into the clinic, where you tell them, you’re prevented from thrombosis, but still their quality of life is not significantly great, because they still continue to remain anemic and transfusion dependent. And you accumulate this group of patients over a period of years, because these are patients who have remind on C5 inhibitors, but continue to have continued to remain any may continue to remain symptomatic continue to have significant impact on their impact on their quality of life. So, which is where I think the proximal complement inhibitors do significantly play a role. And I think it doesn’t make sense when somebody is on an intravenous every two weekly to give them another subcutaneous or another intravenous so patients once you say that there is a proximal component compliment inhibitor, which is an oral compound with then patients were extremely keen to participate in the studies and more pleasing for for for a trial list and the patient to see is this group of patients as you showed having a significant improvement in the hemoglobin because you showed one of the patients that the patient jumped from a hemoglobin of seven to 14, that’s nearly doubling of the hemoglobin level. And sometimes I jokingly say that you come to a stage of needing needing villi sections, which is coming to Barry’s point of increased red ferritin and you take our installation you don’t need it might even lead out a bit of blood to improve. So I think this is this is an significantly important step forward for this group of patients where oral therapy is is important to improve their quality of life and continue to continue to keep the thromboses at bay as well and live let them lead a lifestyle where you’re not attached to the hospital for too long.
Dr. Bill Sheridan (CMO): Okay, so this is a complicated disease with lots of measures. So we’ve talked about transfusions, hemoglobin, and a bunch of biomarkers, including LDH. In terms of measuring outcomes, how would you rank those in order of importance of what matters to you?
Austin Kulasekararaj (MD Consultant Hematologist): I think I think it’s a really again, we are going through a shifting and changing landscape as well. So LDH for all right purposes, because it’s a marker of intravascular hemolysis. was, was always and it’s important to measure LDH because that’s a simple cheap test to monitor. intravascular hemolysis
See what the LDH is doing Be it one and a half times v two times upper limit of normal. But I always say this patients don’t see LDH patients see their quality of life, you can tell them what their LDH is, but patients might say, but I’m still feeling tired, I’m still needing blood transfusions. So at the end of the day, I keep saying this to all my patients as well. I’m not treating numbers I’m treating you. And that is what is important. If a patient patient’s quality of life improved, I’m not belittling LDH at all. LDH is important. It’s an important biomarker to look at the ability of the complement inhibitor but the in a larger scale, transfusions and hemoglobin or extremely important for patient’s well being and quality of life.
Dr. Bill Sheridan (CMO): Thank you. So that was super, I think, I’d like to move on to one slide that sort of sets up what else we might be able to do with complement inhibitors and also invite Dr. Rovin to join us. So, you know, there’s been an explosion of knowledge about the effective the alternative pathway of different diseases. Dr. Roven, could you maybe expand on this and from the point of view of the nephrology world, what makes you excited about these investigational new drugs and BCX9930 and infected inhibitors.
Dr Brad H. Rovin (Ohio State Univ.): So thanks, Bill, and thanks for having me. Um, you know, it’s been well known in nephrology circles for a really long time that certain diseases that affect the filtering units of the kidney glomerular diseases or glomerulonephritis, such as lupus, systemic lupus erythematosus, activate the complement pathway. And so early on in my investigational career, I had hoped we could look at a complement inhibitor in lupus nephritis. Over the last decade, however, with molecular biology techniques, we really discovered that complement is involved in a whole variety of our glomerular diseases. And I like to think about them as diseases in which compliment is is causative, and these are the C three glomerulopathy is where the alternative pathway is dysregulated and over activated, and these cause direct damage to the filtering units of the kidney, and can progress to end stage kidney disease requiring dialysis and transplantation. A typical hemolytic uremic syndrome is a thrombotic microangiopathy, we’re patients that get clotting. And this is also a dysregulation of the alternative complement pathway. So these two categories of diseases, which are really manifested in several ways clinically, show you where an alternative pathway inhibitor target would be absolutely perfect. Then you have diseases like systemic lupus, which consumes complement, and we know that compliment in in disease like this can be helpful, because if you have early complement pathway loss, you actually get manifestations of lupus. But when you get down to the alternative pathway, that’s an effector pathway that we believe causes damage and organ damage and especially in the kidney, we see complement deposited in the kidney, or within the glimmery eye, and that’s generally associated with considerable inflammation. When we our own group has looked at the transcripts that are elevated within the kidney, in patients with lupus nephritis. We do this by micro dissecting out of from the kidney biopsy that we take clinically. One of the complement components that’s really elevated is factor D. And we’ve shown in our own laboratory that the alternative pathway is is really the pathway that’s doing the damage in the kidney during lupus. You can have another example in which the complement pathway is pro inflammatory within the kidney. And also a very good example for the audience is is Anka vasculitis. Anka vasculitis is not associated with systemic complement consumption like lupus is, and when we look at the kidney, we don’t see a lot of compliment, just, you know, at this sort of gross level of the kidney biopsy, but experimental animals suggested that this was important. And a compliment, see five a inhibitor has now been shown to really reduce inflammation in patients with Anka vasculitis. So those are two really good examples of where compliment is really driving inflammation.
I’ll give you three other examples within the kidney world which are really important. And that is IGA nephropathy and membranous nephropathy, where we think that, at least in IGA nephropathy, the alternative pathway is activated, but it’s action in the kidney is going to be where it comes into the of course into the common pathway, which will be the end of starting with factor D and beyond C, three and beyond. So that’s being targeted right now, in patients with IGA nephropathy, and also in patients with membranous, nephropathy and other rare glomerular disease. And I’m gonna just throw this out there because I think this is important for people to consider. When we’ve done proteomic analysis of microdissected kidney biopsies. One of the things we find in diabetic kidney disease, which of course, is the most common cause of end stage kidney disease requiring dialysis or transplantation. One of the surprising findings we consistently see is C three and other distal complement components. And, and sort of one of my pet hypotheses is that even though this compliment probably doesn’t have anything to do with the pathogenesis of diabetic kidney disease, it may be responsible for the progression once the disease is up and running the progression of the slow progression of kidney injury toward end stage disease, which really suggests or begs the question of whether a complement inhibitor in a disease that’s not rare, could actually slow the progression towards end stage disease or possibly prevent it.
So in my opinion, in summary, blocking at FACTOR D and beyond, is really sort of target that we want to pursue and in fact, are pursuing in several different kidney diseases having a factor D complement inhibitor, which takes out both the the membrane attack complex down the line, as well as the ad deflect toxins that cause inflammation, such as C5A, it really could be a benefit in treating and managing these kidney diseases.
Dr. Bill Sheridan (CMO): Thanks, Brett. It was great. Barry. Before we hand it over to Charlie to talk about the market research that we’ve been conducting. Would you mind just giving us your reaction to the study results that we shared today? What does it mean for your freedom?
Barry Katsof (PNH patient): Freedom from needing transfusions, freedom to be able to go out and do the things I like to do cycle, hiking in the woods, oh, shoot. That’s because my hemoglobin levels will be at an acceptable level to allow me to do that. I won’t need transfusions, I won’t have to worry about the Ivor iron overload.I won’t have to hedge my or manage my travel schedules about when I need infusions in the clinic, and so on. So these numbers are from a patient’s point of view. Bill very, very encouraging. It gives the quality of life back to the patients that we’ve lost for so many years. And as Austin said, he’s treating the patient and not the numbers. If the patient has an very acceptable quality of life, you have PNH but if it’s not affecting what you do and how you live and
model allowing you to do certain things. sum up freedom.
Dr. Bill Sheridan (CMO): Okay. Well with that. I’d like to thank all of our panelists today. That was really super to have you here. And now we’re going to hand it over to Charlie Gaya. He’s out of commercial to talk about our market research.
Charlie Gayer (Commercial Officer): Thanks, Bill. It’s my pleasure to introduce chinky rosselli Genki is the Vice President of global business analysis and operations here and she’s been with by Chris since 20. May 15.
The breadth and depth of customer insight research from Janki and her team was fundamental to shaping our strategy for early bayeaux in HAE. Her research uncovered pent up demand for an oral prophylactic therapy across a broad range of patients. And we are really thrilled to see that demand coming to life in the early days of the Orladeyo launch. In addition to her work at biocryst Genki has extensive experience and other competitive Rare Disease categories like pulmonary hypertension, and alpha one antitrypsin deficiency. I’ll turn it over to Genki to describe the specific insights about pn h patients and physicians that will help shape our strategy for BC9930. Genki.
Jinky Rosselli (Global Bus. Analysis): Well, thank you, Charlie. Move to the next slide.
Great. So, first of all, it’s just so great to hear from Bill Austin and Barry, these these conversations, wherever they end, whenever they happen, are just so critical as we build up our base of insights for PNH. So thank you so much for that conversation. You mentioned a bit about my experiences with alpha one pulmonary hypertension, and most recently with HAE and they’re just a lot of really good learnings there. But we do recognize it every condition is unique. Early in our work with PNH it’s really been about understanding that journey, that the various describing of the patient and and and also the physician with a certain level of depth. And it’s really listening intently for the what, and most importantly, digging for the whys. We started with some secondary work really sort of building up our anecdotes library of anecdotes that there really is no substitute for hearing from for hearing directly from our patients and actively treating physicians and getting some additional confidence from those insights.
So what we did was we conducted structured interviews with 25, PNH specialists, and 23 PNH patients, all currently receiving CE five inhibitor therapy. So all these patients were either on Solaris or ultomiris. And all based in the US some additional context for the for the patients in this study, only three of the 23 patients were still getting transfusions regularly. So by today’s standards, majority of our patient sample could be considered fairly well controlled.
As I walk through the results of this study, I’ll be referencing two patients. The main difference between these two patients is one was transfusion dependent, and the other transfusion free both gave their currency fives, high marks for satisfaction.
So consistent with what Barry was describing. For most of these patients, their journey towards a diagnosis of PNH was quite frustrating. 40% of the patients stated that they were mis diagnosed, mainly because of the rarity of the condition and its ability to really masquerade as other conditions. Imagine going from frustrations with misdiagnosis to the fear of the actual diagnosis, lack of therapeutic options, potentially then finally getting to a C five. So when we ask the patients directly about their directly experiences with C five treatments, these patients are very grateful and generally very satisfied. And it makes perfect sense given the journey they have been on. These therapies are really life changing for them. But as you can see from the scatterplot on the slide, there were also a wide range of satisfaction scores from these patients, most likely due to some of them having ongoing symptoms, like Austin was describing anemia, fatigue and transfusions to help better describe how these patients feel about their c five. Here are a couple clips from the two patients I described earlier. Patient a who’s transfusion dependent, and patient B who is transfusion free.
Patient A audio clip from interview: We have a routine. So right now I can function. I still have issues but I can bleed a life. I can work part time I can get out on my bike and ride I can walk my dogs after a blood transfusion for a couple of weeks. You know I can travel if I need to. I have a life that I’m okay with. Not what it was. But until something else comes along right now. That’s what I got. So when I get a transfusion, I’m like okay, let’s go let’s go do stuff.
Patient B audio clip from interview: Normal as far as my RBC counts are a lot better with ultomiris than they were with Solaris. I used to hover between nine and nine and 11. But now I’m pretty stable around 11-11.2 something like that, not too bad, manageable for sure.
Jinky Rosselli (Global Bus. Analysis): So, as you just heard in the audio clips, these patients are coping. And it’s in the, in the case of many rare diseases, these patients become expert Cooper’s. Again, they are grateful for the benefits of these advancements in therapies and relatively satisfied. But despite this general satisfaction, the majority of patients are still looking for something more, they’re looking for more convenient options and more efficacy. When we probe deeper with these patients, we uncovered a couple points that provide some additional color to these unmet needs. The first point, many patients are still managing the overall disease and symptoms. I’d like to share clips again from these two patients first from patient a, and how he’s dealing with his symptoms. And then from patient B, who speaks about what he desires in terms of incremental benefits from a future therapy.
Patient A audio clip from interview: For pain is improved every now and then I’ll get rollin. And it lasts for about 15-20 minutes, I recognize the symptoms now, I could feel it coming on the way it resolves itself, as I have to lay on my stomach flat on a hard floor. And it takes about 15-20 minutes, and then it subsides. But I’ve learned the symptoms and you know, it hurts like crazy, it’s pretty unbearable, but I know it’s gonna pass. So I just have to, you know, bite my lip, if you will, and just knuckle under and get through it.
Patient B audio clip from interview: Love to have my blood count be a little higher, absolutely love that pretty good. They’re better than they’ve ever been in a long time. So, you know, if I could incrementally improve, I’d like that, I don’t really notice fatigue that often does. If I could be less fatigued and have more energy, I would take that all day too.
Jinky Rosselli (Global Bus. Analysis): So in addition to greater efficacy, the research overwhelmingly shows patients desire for oral therapy, they want relief from their injectables, reducing their burden of treatment. So let’s hear again, from patient B regarding what he’s looking for in a new therapy.
Patient B audio clip from interview:And how to do it, it didn’t take so long to administer, what I would like to see in the future is like something like I could do daily. Or I rather like take a pill daily than go every eight weeks to get an infusion. Because that would just I would just take it with my vitamins. You know, it just takes it just takes I get there and o’clock is the process of getting set up and getting stuck and then mixing the drug, having the right blood work done, get the results back and then getting it it’s just that’s that’s cumbersome. That takes forever. I wish it wasn’t that long. I wish it I wish it was a little bit easier than that, but it’s not so.
Jinky Rosselli (Global Bus. Analysis): So now we turn to our 25 PNH treating physicians, compared to the patient’s physician satisfaction is slightly higher. When asked about current treatments. This is not unexpected, especially as these physicians are looking to gain a relatively acceptable level of stability with these patients. And it’s really a judgment call for them what that level of stability is. Keep in mind for the 20 through 23 patients who participated in our research, their mean hemoglobin for the group was around 9.3 ranging from about 7-12. So with the tools these physicians currently have, they’re really shooting to take these patients from bad to okay. While these physicians are generally satisfied, they do recognize that there’s still room for improvement. And as they are very much aware that these patients are still experiencing symptoms.
So when we asked about their desires for future therapies, physicians indicate on an unaided basis, greater efficacy really centered around hemoglobin, which echoes what we heard from from Austin and Barry, and having an oral option. These physicians are doing their best, but do desire more for the patients. They recognize that their patients are continuing to experience burden, whether it’s disease related or treatment related.
A core exercise in the research was really showing patients and physicians and early profile of 9930, which we called product x. Just for some additional context, the product profile we showed them was very similar to the profile that bill described earlier in this presentation. Reactions to the profile were overwhelmingly positive 91% of patients indicate an interest in switching to 9930 after reviewing the profile, and this is across all the patients in our research, regardless of whether the patient is stable transfusion free or not, physicians were also enthusiastic about the profile with some signs of hesitation to switching. They’re well controlled patient. But this is fairly common at this stage with many rare diseases. In addition, these physicians indicate from the research that if asked by their patient, they would prescribe. This is very similar to what we saw in HAE and what I’ve seen in other rare diseases. So for patients, what really drives their desire to switch is one the availability of a world to the potential improved hemoglobin and pre symptom control. When we did some additional analysis of the data, we did see that there’s really no correlation between their satisfaction with current treatment that I discussed earlier, and patients desire to switch to 9930.
I’m now at the end of my presentation. So I just wanted to thank you all for your attention and time today. And hope you found the presentation helpful. I would like to end However, with a final clip from patient B. If you remember, remember, he is transfusion free, and very satisfied with the C fives. This clip is a reaction when we showed him the early profile of 9930.
Patient B audio clip from interview: That’s exactly the kind of thing that I’ve been looking for is something like this. Basically, my like, pie in the sky dream scenario is taking a pill twice a day, rather than going and getting any kind of sticks and infusions. I would much rather do this, especially when he improves my quality of life, which is paramount to me. So that, that all that stuff. This would be my dream scenario, is what we’re describing right here. I’d switch in the heartbeat. I just take it all like something orally like take a pill every day. I’d be in so quick. Yes.
Charlie Gayer (Commercial Officer): Thank you Genki biocryst. This is why we do what we do. We hear these heartfelt expressions all the time from people with HAE, PNH people with serious life threatening diseases. They’re happy for any drug that helps them makes their lives better, maybe even keeps them alive. But to be able to do that with an effective oral drug. For so many of these people with rare diseases that is truly their dream.
You heard today from Dr. Babu and our discovery team in Birmingham. You heard their passion and saw their skill. You heard Bill’s excitement about the clinical results for bc x 9930. At this stage, you heard expert opinions from Austin Barry and Brad about the opportunities for 9930. And what a difference a drug like this could make for people living with PNH rare kidney diseases and beyond.
We have a commercial team out there right now. Working hard to bring Orladeyo out to people living with HAE We can’t wait to bring more oral medicines like 9930 to other people who have the same dream. This is why we do what we do.
I’d like to invite my colleagues back now for the q&a session.
John Bluth (CCO): Just a reminder, if you do have a question, please enter it for us in the question and answers box in the lower left hand portion of your screen. First question we have for you, Bill. Now that you have more data, what dose Do you plan to use in your PNH pivotal is and have you considered a higher dose? And will the dose in the PNH pivotal be the same dose for the renal proof of concept trial.
Dr. Bill Sheridan (CMO): Thanks, John. So we’ll finalize the first selection with the regulators. So the way we work it out is based on PK PD modeling. And that evidence supports what we’ve seen. What we showed today is that the 400 to 500 milligram dose level looks like the right dose level to go for. So one of the really useful things about targeting factor D is it’s not the mutated protein in PNH or for that matter any of the renal diseases. So we can translate the dose directly over to the other indications and that’s what we intend to do.
John Bluth (CCO): Great, thanks, Bill. And another one for you. Can you explain why the relative PNH clone size is an important metric.
Dr. Bill Sheridan (CMO): It’s something that’s been written about by academics in the literature and the proportion of the bone marrow production, that is PNH production. You can measure with white cell client size with the canvas icon size and so if as the red cell client size is only a fraction of that, that’s telling you that the red cells have a very short lifespan, as Austin explained. So if we can get that number, that relative number to look just like the white cell colony size, then we’ve normalized the red cell lifespan is what it’s telling us. So it’s an interesting metric, and something that we should look at more.
John Bluth: Great. Thanks. And another one for you. Have you withdrawn the C five inhibitor in any patients? And what are your plans to do so in report data?
Dr. Bill Sheridan (CMO): So I’ll ask Austin to comment on this as well. So the protocol absolutely plans to do that. And no, it’s the data in the night patient population, from that perspective strongly supports that strategy, because it’s monotherapy in the naive, and fundamentally, the disease is the same crisis and whether or not you’ve had a good response or a poor response to a C five inhibitor. So our objective is to keep things stable, and then withdraw the C five inhibitor, you haven’t done it yet. We look forward to seeing that data hopefully later in the year. Austin, would you like to comment about? You know, I’m a you’re an investigator I’m studying with several patients are interested to hear your perspective.
Austin Kulasekararaj (MD Consultant Hematologist): Yeah, so. So I agree with you, Bill, because the protocol allows, it allows us to withdraw the baseline c five inhibitor and just leave them on 9930. And the couple of reassuring things for me, or the good data coming out from the naive study from from from South Africa, saying that these patients are continuing to remain stable with a hemoglobin improvement as well. So that is a very reassuring aspect. And the second thing is, obviously, all our patients are more or three out of my four patients are on a higher dose 215 100 milligram of aqueles map. So there is a there is a there is a possibility of gradually and slowly withdrawing these patients rather than abruptly stopping them as well. So there is there is a potential of doing that. And going forward, that’s probably what is going to be because we don’t want patients to be on multiple different complement inhibitors at the same time, or am I wrong? Is that going to be what it’s going to be in the future? I don’t know. But from the cost perspective, and every perspective, I think a single drug is going to be better is going to be better specific for patients and economically makes sense as well.
John Bluth (CCO): Great. Well, Austin, I’ll follow up with another question sort of in that category. For you and and bill in the panel. Also, how do you feel the the data supports monotherapy? For 9930?
Austin Kulasekararaj (KOL): I think I think it does, obviously, it’s a rare disease. But smaller numbers or smaller numbers are always going to be a problem even if it’s rare disease, but the confidence and the additional data from the add on therapy, and the ability to use it in our patients makes gives us a bit more confidence. The patient’s knee, having a stability in their hemoglobin also gives an added complex added reassurance as well. And I always say that as well, the reassurance that these patients have not a developed thrombosis with significant disease activity during the course of the disease is also important because we should not we should not forget about it. So all in all in all it it looks for looks, looks very promising. Obviously, we need to talk about the slightly higher LDH than expected in all the other programs and what the what is the reasoning but as I said, if if you ask a patient and obviously Barry’s here, we do have a normal LDH or a transfusion independency. But with a good hemoglobin I probably will take the later rather than earlier I think so.
John Bluth (CCO): Yeah, Barry, we’ve gotten that question for you, too. You know how to add from a patient perspective. What do you find most important?
Barry Katsof (PNH Patient): hemoglobin and transfusion independence. All the other numbers really to most patients don’t mean anything. And the more they dwelve into them, the more nervous they may get. patient wants to know that they don’t need transfusions, and their hemoglobin is at a very acceptable if not near normal level to allow them to have a great quality of life.
John Bluth (CCO): Great. Thank you. Bill, start with you on this one. Given the excellent results around transfusions and hemoglobin. Why did LDH only go to two times up for limited normal?
Dr. Bill Sheridan (CMO): You know, I think it’s it’s an interesting question. And I think we’re learning about what happens when the hemoglobins get really high. And they’re all made up of peonysymbols, and massive transformation can see a couple of the subjects we talked about today and doubling the hemoglobin from seven to 14. And all of the cells of P cells now. So even a slight bit of trauma in taking a blood sample or a movie that from Alesis, will put the LDH up. What does it mean? I think that it may mean nothing, actually. And, you know, one of the interesting discussions we’ve been having with your advisors is where did the, you know, where did that target level of LDH come from in the first place? And it’s actually pretty obscure when you delve into the literature. But also, maybe you’d like to answer that question, because in a query hemoglobin is what Moti metrologist care more.
Austin Kulasekararaj (MD Consultant Hematologist): I think the ldh baseline LDH level comes from a South African, sorry, South Korea and registry data where they looked at the this is all three occlusion map where they looked at the baseline ldh and, and abdominal pain, chest pain and predicting the risk of thrombosis and end organ damage. And that is where the cutoff of 1.5 times upper limit of normal terms, and it’s a gradated view of 1.5 to three and more than three and going up I think so. But there is no data, post the complement a therapy, I bought in C five and C three inhibitor in the context of correlating LDH with a clinical response from the patient perspective. And secondly, just to add, add a point as well, it is even if it’s two times upper limit of normal of LDH, this is definitely not in the range of when patients get proper breakthrough hemolysis when the LDH goes up to four times to six times upper limit of normal with significant symptoms. So this is this, this is again, something to look up. And there was one additional question, john on that as well. Where are we sure that all the LDH is coming from the red cells? Or are there going to be other sources of LDH as well, so potential.
Dr. Bill Sheridan (CMO): So in summary, it was an interesting prognostic marker in the era before CE five inhibitors, it’s a very useful biomarker for selection of dose in those rankings. environment, the study we just talked about today. But actually, it’s never been validated as a prognostically, useful after the complement inhibitors have been applied. So we need to keep that in mind.
Jon Stonehouse (CEO): Hey, Bill, just want to add on question would be some of these studies have had ldhs an endpoint in the trials? And what’s your view on how we do in that situation?
Dr. Bill Sheridan (CMO): Yeah. So I think it depends on the situation. And certainly in the case of the naive patient population that who’ve never had a complement inhibitor, it’s really easy to measure, and it’s an accepted surrogate marker for clinical benefit. The key clinical benefits are transfusion avoidance and rising hemoglobin, as we’ve discussed repeatedly, today. So it’s still a useful input. It’s easy to show that you can affect that endpoint. So it’s commonly used in clinical studies.
Jon Stonehouse (CEO): And it’s different from placebo, right? It’s not some choice.
Dr. Bill Sheridan (CMO): You’ve always had to control whether or not the control group so as a difference in control, yep.
Jon Stonehouse (CEO): Great. Thanks.
John Bluth (CCO): Bill. When you look at the competitive landscape, how would you compare BCX930, based on this data to other therapies on the market or in development?
Dr. Bill Sheridan (CMO): I think it’s crystal clear what the challenges are to improve on the current situation with markers, C five inhibitors. And we discussed that a lot today, I have no doubt that if we can bring forward a safe and effective effective D inhibitor YPC x 9930, that we can do make a whole whole lot of difference to a lot of patients in terms of transfusion avoidance, and feeling normal, with great hemoglobins. They’re the problems to address. You know, it’s all of the alternative pathway inhibitors under development and other proximal inhibitors under development. You can expect with adequate doses, that we can do this, but it’s very early. So I think the opportunities great with regard to the commercial aspects here. Maybe john or Charlie could answer that.
Jon Stonehouse (CEO): I mean, listen, it’s a huge market. It’s is massive. And when you add more and more layers of indications, we’re happy to compete in that space. These are tough targets as I talked about before, so we all have a ways to go before We really know how the competitive landscape plays out. But it’s huge. And maybe Brad, I throw a question to you is, what do you what do you think with a oral profile? Or your Defreitas? patients? What do you think we don’t have a patient representative here for that, but what do you think their view would be on effector D inhibitor?
Dr Brad H. Rovin (Ohio State Univ.): So we really do like to have most of our patients on oral medications if we possibly can, especially the group, you know, C, three, G. And lupus patients, they’re generally younger people who are, you know, working or going to school, etc. And coming in for infusions continuously is is really a little bit really impacts their lifestyle. Some of the folks with membranous nephropathy or diabetes, you know, if we ever went to diabetes, which is, you know, they’re older. So that may make less difference, but I don’t think so. I mean, most people don’t really want to come in
on a weekly or bi weekly basis, to get an infusion.
Dr. Bill Sheridan (CMO): In answer to the question of how do we, you know, have the can the field of investigation or compliment inhibitors? And what does that data mean?
transfusion avoidance in every patient in the 90s, and almost every patient response cohort, that sets up a fantastic pivotal program, if we can get anywhere close to that, in larger studies. That’s a magnificent result. Right. So the, the, you know, this could be a revolution in medical care as a way of approaching it. So it’s all full speed ahead to set up the pivotal trials.
John Bluth (CCO): Thanks, Bill. And another question about the renal opportunity for Bill. Maybe you and Brad, both. Brad, you just touched on this a bit. Which of the renal complement diseases Do you plan to study in which ones make the most sense to study in your proof of concept trial?
Dr. Bill Sheridan (CMO): So I’ll set it up first, you know, when we start our proof of concept study, later in the year, we’ll talk about the selection of diseases, it’s, you know, we want to get through the regulatory steps first, before making that announcement, however, they’re all attractive. Things thing to say here. So Brad, like to add anything.
Dr Brad H. Rovin (Ohio State Univ.): So well, my favorite topic is lupus nephritis. And that’s, you know, something we’ve been looking at for years. It’s a fairly complicated disease, and the drug would be an add on to standard therapy, simply because you can’t do a single therapy that’s unproven. Having said that, just to make a point, where I think this would fit in dramatically in a lupus population would be its anti inflammatory effects might considerably decrease or eliminate the need for glucocorticoids, which, again, if we had a patient representative, they would tell you that that’s probably the worst part of lupus therapy, because of all the acute side effects that they experience, as well as the long term health effects that, you know, over the years and years, they accumulate. However, one of you know, we were talking about this in the context of PNH is model therapy, one of the disease groups that where you could look at this as monotherapy, in the renal domain would be the C three glomerulopathy ease, which are driven by alternative pathway disease, and for which there’s absolutely no therapy now. And that would be a very exciting concept. And then you could do this against standard of care, which is just supportive care. So even though that population is ultra rare, we’ve had about two to three studies in this already. And we’ve been able to recruit sufficient patients. And this is a group that’s by and large, young people that really really need this therapy. So that might be the favorable one that I would start with, but I would hope that we would consider lupus and lupus nephritis as well.
John Bluth (CCO): Great, thanks very much. So for Bill, Barry and Austin, how much do you worry about a PNH patient missing a dose with an oral medicine? And what was compliance like in your trial maybe bill, you can talk about the compliance piece first.
Dr. Bill Sheridan (CMO): Sure, compliance is really excellent in the study, and it wasn’t a surprise to us. And people have had no trouble taking the twice daily medicine in the clinical trial.
Austin Kulasekararaj (MD Consultant Hematologist): I think I’ll also agree the common concept is like obviously, you worry about compliance in this condition because it’s a long term treatment.
But I use a slightly different anecdote for these kinds of things. Because if you’re a CML patient until you know what the BCR Abel is, the patients will know what the responses here in tnh patient, the body clock of complement activation, is your is your check on it, patients will, unfortunately tried to miss a dose type of thing. And they will know if they miss a dose they’re getting going to get him realizes and they will take the next dose. That’s my personal take on it. Because patients know what is happening to their disease. So they it’s unlikely to miss a dose.
Barry Katsof (PNH Patient): Yep. Yeah. So I think what Austin is saying is is definitely correct. We’re going to patient’s going to know pretty soon if they stop taking their medication. I think in today’s day and age of with everybody having a smartphone, I’m sure somewhere down the line, an app can be put together to kind of ding dong you to like, you know, Hey take your pill. So I wouldn’t look at that as being an issue.
Jon Stonehouse (CEO): Yeah, Barry jinki and Charlie are already on that.
Jinky Rosselli (Global Bus. Analysis): JOHN did just add that I think we’ve seen that consistently to insert of any of these chronic rare diseases where patients are super motivated, right? I mean, they know it. They know that if they do messages, there is that good chance of a breakthrough. What Austin and Barry were describing it to be had HAE and rare diseases that they managed.
John Bluth (CCO): So thanks, Frankie, a question for you. Dr. Babu. Why did you choose factor d over factor? sure you’re on mute. We can come back here in a minute bamboo with that one. Bill, did you measure facet fatigue scores in the study?
Dr. Bill Sheridan (CMO): Sure. You know, it’s a very interesting, patient reported outcome tool. It’s been used in other studies PNH. And you know, I mentioned a couple of anecdotes today. And we’ll finish analyzing that data and look forward to presenting it at a scientific Congress.
John Bluth (CCO): Yeah, we got you loud and clear. So what why, why factor D versus factor B?
Yarlagadda Babu, PHD (CDO): Thanks, john. That’s a good question. I think when we select, in fact, today, as the time that we went through a thorough review, a thorough assessment of faculty, its position in the alternative pathway, its role and the structural information we have at that said that if you look at the faculty position in the alternative pathways, the very first enzyme, so that’s a good place to start if you want to control the AP pathway cascade. And also it is the de trumpeting step in the alternative pathway cascade. So controlling faculty at that stage is quite attractive to your impact on the alternative pathway. And also, as I said in the beginning, the fact that he normally circulates in the inactive form, and becomes active only when it binds to the dude’s medical substrate. So if you target the inactive form with SR cacti site, it gives us an opportunity to design and select the molecule producing the off target toxicity. Finally, over the years, we have built a coordinate with quite a good amount of structural expertise on the faculty. It’s actually site. It’s 3d structure, and the conformation changes that take place going from the active to the inactive form. All that experience is quite critical for us in designing a potent molecule to the factor d. So all those factors satisfied as to select the faculty as an actor to target for us for drug discovery. And also all the data you’re seeing today validates that confirms that selection of factor D is is a good target to go after.
John Bluth (CCO): Great, thanks, thanks, Babu. What, Bill, maybe you want to start and then Austin as well? What’s your perspective on the rash?
Dr. Bill Sheridan (CMO): Sure, so I mentioned it in my remarks. The most important consideration here is that it was benign and went away by itself without any intervention. And that scene was continued and the investigators didn’t change the dose, the dosing regimen, they follow the protocol. So from that perspective, it’s a tolerability phenomenon and not a safety issue.
Austin Kulasekararaj (MD Consultant Hematologist): So just john to add in, I think I agree with, because it’s a sometimes when you talk to patients, it’s better to have a predictable side effect, which is self resolving, rather than to have an unpredictable side effect is that so to predict it and to know it happens at a particular date, and it’s not something which we are worried about. And sometimes when you’re doing these kind of early trials, it’s mostly worry is about unpredictable side effects and complications. So if you know what to expect, that’s going to be better.
John Bluth (CMO): Great, awesome. Another question for you. Could you provide some more details about the overall experience your patients had with BCX930 in the trial?
Austin Kulasekararaj (MD Consultant Hematologist): Yeah, so So I would say it’s still early days, three months, but can’t be more pleased with themselves and ourselves. So going on so so all of them three out of the four patients are transfusion independent, one of the patients is a long standing patient who had three PNH for probably 40 years on a extremely high dose of salaries of 1500 milligram, but at least he said, 50% reduction in the need for transfusions, that is a big, big change, because he’s been transfusion dependent for 15 years. And it’s a heavy transfusion burden as well. So to have such a big reduction is a big, big improvement, while the rest of the three patients have got remarkable hemoglobins of 13, 14 and 15. So quite pleased, and obviously being an early phase trial touchwood till date no no side effects, which I’m worried about, or concerned or no side effects at all at the moment, other than the predictable rash.
John Bluth (CCO): Great, thank you, Austin. For Barry, what did you think about the market research commentary that the company described and into the comments of those patients reflect your experience?
Barry Katsof (PNH Patient): I would say I agree with everything that was said. And one of the patients summed it up perfectly. If it’s available, he’ll grab it. And like I said earlier, it’s priceless, if there’s a treatment that will be available to a) improved hemoglobin to allow patients at their age group to be fully active and have a great quality of life, to eliminate the need for transfusions and all the negatives that go along with transfusions. Why not?
John Bluth (CCO): Great. Thanks, john, for you, company’s shown a lot of drug discovery and development capabilities. How do you plan to get the capital to scale and build the way you want to? Do you plan to commercialize 9930 on your own? Or will you look for a partner?
Jon Stonehouse (CEO): So another transformation that’s going on in the company is financially, I mean, we are in a completely different place than we’ve ever been. The fact that we have revenue coming in for more than a day, oh, you know, what the peak sales potential globally of north of $500 million, makes our life a lot easier in terms of being able to fund more research. And then the capital that we brought in at the end of last year, you know, puts us in a really strong situation. So the bottom line is we have a lot of different levers to pull that we never had before. And then the rest of it’s just scale. Right? One of the beauties of being and oral drugs for rare diseases is that, you know, these aren’t 10,000 patients studies, right, they’re, you know, the pivotal are a couple 100 at the end of the day, and so these are things that we can manage, and you know, we’re now up to I think 260 employees a year ago, you know, we were probably more like 100, and something low hundreds, and we’re attracting amazing talent into the company. I mean, Helen, you know, first row seat, you know, to see what we were doing and jumped on board. And you know, we’re getting that from other parts of the organization as well. So it’s a matter of scale and getting good people and we’re doing that.
John Bluth (CCO): Great, thanks, Charlie. Why are you going after p nh first, since it’s a more crowded market when it makes sense to go after another disease first?
Charlier Gayer (Commercial Officer): Great, great question. Well, first of all, we’re going after PNH. But we’re also going after many of these other complement mediated diseases. So it’s not just PNH, as you heard bill described going after PNH first makes a lot of sense. Just because we can do it quickly. We can identify the dose quickly. We’re going straight from phase one to pivotal trials. So that’s great. And then you heard from jinkies research, you heard it from Barry, you heard it from Austin. There’s there’s a real need for the patients out there. And it’s you know, it’s a tube already a $2 billion global market and we believe there’s room for that to grow as well. So all that together makes it a great first target but we look forward to going after numerous diseases in the coming years.
John Bluth (CCO): Great, thanks very much. We’re starting to get tight on time. Maybe one more question, john, john to you. What other rare diseases are you working on beyond he compliment in FOP?
Jon Stonehouse (CEO): Yeah, the short answer is there are a lot more targets and we’re pursuing them. The lengthier answer is, you know, it’s going to be rare disease. It’s got to be a validated target, and then it’s got to fit where, you know, Babu and his team using structure based drug design can get the potency selectivity and bioavailability. And as far as we can see, right now, there’s a number of targets. So we’re going to be doing it again and again and again and filling up our pipeline.
John Bluth (CCO): Great. Thanks very much. I think that brings us to the end of the q&a session. If we didn’t get to your question, please reach out to me by email Jay Bluth at Biocryst.com We’re happy to get back to you.
Jon Stonehouse (CEO): And we’ll get back to john to wrap us up. Sure. Thanks, john. So first off, let me thank Barry, Austin and Brad, I mean, we’ve been working with Barry quite a while now and Austin as well. And Brad, we’re going to be working a lot more with you soon. So really appreciate you taking the time to give investors patient and physician perspective and educating all of us on complement mediated diseases. So thank you very, very much. Our goal this morning was to give you the investor deeper understanding of our drug discovery capability, what’s most important, and treating complement mediated diseases and the exciting potential of our faculty program and the promise that it has for patients. The transformation of our company will continue. We look forward to updating you on our progress as the year unfolds. So thanks for your interest in our company and have a great day.