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For the first time in decades, the FDA approves a new drug for the treatment of the most common form of brain cancer in children. That story enough, but it's the result of a whole new way to start a biopharma company. Doctor Sam Blackman is the founder and head of research and development at Day 1 Biopharmaceuticals. Doctor Blackman, welcome to the program.
Dr. Sam Blackman:Oh, thanks, Moira. It's a pleasure to be here.
Dr. Moira Gunn:Now I've been thinking about where to start this interview, this journey of Day One Biopharmaceuticals, And I just started to start with day 1. I mean, why not? You are a pediatric oncologist treating cancer in children. How do you come to found a biopharmaceutical company?
Dr. Sam Blackman:It's a great question. By accident is probably the best way to summarize it. It was not certainly part of any plan that I had. I had been trained as a pediatric oncologist and neuro oncologist and then about 15, 16 years ago decided that I wanted to take my clinical and scientific training and focus on trying to make new cancer medicines and made a move to the biopharmaceutical industry back in 2008. And it was a really interesting time in 2008.
Dr. Sam Blackman:Obviously, I was learning the business but the business was also changing for pediatrics because some of the regulatory authorities, the FDA, here in the United States and the European Medicines Association were starting to pay attention to the lack of new medicines for childhood cancer and starting to put rules in place that forced companies to start doing development work in pediatric cancer. Prior to that, there weren't any clear rules. And as a new physician in the industry, they put me on some of these projects early. And so for the first part of my career, in addition to learning how to develop new cancer medicines for adults, I also began to learn how to use the tools of industry to try to develop new medicines for children. The problem, of course, is that given the choice of making a new medicine for lung cancer or breast cancer or prostate cancer and making a new medicine for a rare pediatric cancer, the business decision is more often than not going to be to focus those resources on the larger adult cancer.
Dr. Sam Blackman:So a lot of the things that I worked on along the way never moved forward and that was very frustrating.
Dr. Moira Gunn:So you were required to work on the pediatric cancers, but not required to bring them to full commercialization and put them in place.
Dr. Sam Blackman:That's correct. The European Medicines Association, which is the European version of the FDA, actually had a rule starting in 2,008 called the pediatric rule that said that all companies that were going to get medicines approved in Europe had to have what's called a pediatric investigation plan in place. And so companies as they're taking new medicines from their earliest stages of discovery all the way forward would write these pediatric plans but if the medicine didn't work for its adult indication and they decided to terminate the program, even if you had a good scientific reason for developing it in children, if there's no incentive to develop it for adults, there's no incentive to develop it at all. So, yes, a lot of the things that I worked on way back in 2008 never saw the light of day. And that was terribly frustrating because you spend all this time and effort trying to figure out exactly what children and and what childhood cancers you could apply these drugs in and then the rug gets pulled out from under you.
Dr. Moira Gunn:So fast forward. What happened then?
Dr. Sam Blackman:Yeah. So so I've been, you know, working on a bunch of different drugs and and therapies over 10 years, and I was spending more time in smaller companies where a lot of the exciting early science was taking place. But of course there's greater risk with, riskier science. So I was working for a small biotech company that was focused on actually a breast cancer program and the the science didn't work out. The company sort of blew up and I ended up being laid off.
Dr. Sam Blackman:But right in the couple of months prior to that, I had met a venture capitalist who was equally interested in unmet need in pediatric oncology drug development. And she and I got to talking and she said to me, you know, if you're ever interested in thinking about trying to find solutions to make new medicines for childhood cancer, let me know. And when I got laid off from my job in 2018, I gave her a call and I said, well, I I happen to have quite a bit of free time on my hands. And she said, well, what are you thinking? And I said, well, I have this idea of taking some of these old drugs that I had worked on that had fallen by the wayside because they didn't work for their adult cancers and buying them and developing them the way that I realized they could be developed in pediatric cancers and trying to get those medicines of actually convinced ourselves that we could we could do it, that there were drugs out there that we could buy from companies that weren't developing them any longer and that we could target them to pediatric cancers.
Dr. Sam Blackman:And in, November of 2018, we got a little bit of seed capital, about $1,000,000 and founded the company. And we called it Day 1 Biopharmaceuticals. We called it Day 1 because of something that I learned as a fellow to do called the day 1 talk, which is the the talk that you have with a family of a child newly diagnosed with cancer where you walk them through the treatment plan and and all the risks and benefits and really build that relationship with that family. And I I said I wanna start a company that makes new medicines for pediatric oncologists to have it that day one talk, and I want that company to have a relationship with families. I wanted to be a trusted partner in trying to make children with cancer better.
Dr. Sam Blackman:And we got to work.
Dr. Moira Gunn:And you got to work. And, one of those drugs you were able to acquire.
Dr. Sam Blackman:That's correct. About 6 or 8 weeks after we started the company, this is one of my favorite stories because it shows you how important serendipity and and being in the right place at the right time, how that can impact, you know, the the fate of future scientific discoveries. About 6 or 8 weeks after we started the company, I got a call from a friend of mine at a large pharmaceutical company, somebody that I had known for a while. And he worked in a function known as business development, the group that's responsible for bringing in new molecules and sometimes for getting rid of old molecules. And he said, hey.
Dr. Sam Blackman:I heard you have a new company. And I said, yes. And he goes, well, we've got a program for a drug called at the time, it was called TAC 580. He said, we're gonna terminate this program. Would you be interested in looking at it?
Dr. Sam Blackman:And it just so happened that I was very familiar with this drug, very familiar with what it did and immediately interested in it because I knew that this drug could potentially be an important new medicine for children with brain tumors. And so, we, in January of 2019, we flew out to Boston to see some of the initial data for this drug and meet with the team and understand what they were looking for in terms of trying to find a new home for the drug. And also to try to convince them that we could be that new home that day 1 could take on this project and develop this drug all the way through to approval. And, some of that early data showed that this drug had the potential for shrinking brain tumors in the largest subset of pediatric brain cancer.
Dr. Moira Gunn:Well, let's talk about that brain cancer, but let me just stop everybody and say before we do, let's let the cat out of the bag. This has just been approved by the FDA. So this is a good news story. This isn't just a we're trying our best. This literally has just been approved.
Dr. Moira Gunn:So let's talk about that particular cancer in children. What is it, what drives it, and what does your drug do?
Dr. Sam Blackman:Yeah. So so it's a great set of questions. So the disease that we're talking about is a disease called pediatric low grade glioma or pediatric low grade astrocytoma. They're they're interchangeable. This is the most common brain tumor of childhood and it turns out that brain tumors are the most common solid tumor of childhood.
Dr. Sam Blackman:The tumor is named because of the way that the cells look under the microscope. There's high grade brain tumors and then there are low grade brain tumors in terms of the way that the cells look under the microscope. But any brain tumor of childhood has the potential for significant impact on that child's life and on that family's life because a tumor growing inside of an enclosed space like, like like the skull has the potential to be really dangerous to function depending on where it's growing in the brain and and ultimately to life. So pediatric low grade glioma is common it's a fascinating disease because as opposed to high grade tumors pediatric gluagliomas typically start the first 10 years of your life, probably around 6 to 8 years of age, and they grow and grow and grow relentlessly. And then for the vast majority of patients, for reasons that we don't fully understand, when you get to your early twenties, they stop growing.
Dr. Sam Blackman:They don't just magically disappear, but they stop growing. And so here you've got a disease that's really different than other types of cancers. In that if you can control the growth of the tumor over the 10 or 15 years that the patient has to live with it, then you can essentially treat that patient to completion and they can go on and live their lives. And so you're trying to balance safety. You wanna have a treatment that doesn't dramatically impact the child or injure the child to try to keep that tumor in check for as long as possible.
Dr. Sam Blackman:And, certainly, if you've got a treatment that can shrink those tumors, that's even better because I think logically, we believe that carrying around a large tumor in your brain for many years is probably not the greatest thing for you as a patient. So it's a very different type of disease. And then the other thing that makes it unique is that many of these children have tumors that are driven by a single gene alteration. And it turns out that in pediatric glaugr glioma, we understand that gene and those alterations really well. It's a gene called BRAF BRAF.
Dr. Sam Blackman:And alterations in that gene signal the the cells that make up that tumor to grow and grow relentlessly.
Dr. Moira Gunn:You are listening to TECHNATION. I'm Moira Gunn, and my guest today is doctor Sam Blackman, the former associate director of experimental medicine at Merck and director of oncology early clinical development at GlaxoSmithKline, doctor Blackman is the founder and head of research and development at Day 1 Biopharmaceuticals. Now you were telling me there are about 1500, new cases diagnosed each year, some 26,000, people living with this disease or this condition, I should say, now, how have they been treated to date?
Dr. Sam Blackman:Right. So there's about 1500 new pediatric gliobrachealomas a year of which about 70% of them have this BRAF alteration. No matter what genetic alteration you have driving your tumor, the treatment for the most part for these patients is almost always the same. It starts with surgery if you are capable of undergoing surgery. Some tumors are so deep in the brain or within the brain stem that they can't safely be removed.
Dr. Sam Blackman:Similarly, some of these tumors can occur in the nerve or along the path that the optic nerve follows in the brain and you can't remove that tumor without rendering the child blind. And so there are some patients who can't have any surgery, but there's a majority who can have some surgery. Some patients can have the tumor completely removed. Some, patients can have the tumor only partially removed. So depending on whether or not you can have surgery and whether or not if you can you can have the tumor completely removed or not, you may need systemic therapy and by systemic therapy I mean a therapy that's delivered typically as a pill or as a set of pills or as intravenous infusions.
Dr. Sam Blackman:And and to date, most of the systemic therapy for these children who've needed it has been multi agent intravenous chemotherapy, so combinations of drugs that attempt to get the tumor to stop growing. And these are traditional chemo drugs. They have all sorts of toxicities associated with them both in the short term and in the long term. And ultimately, they're not targeted to the genomic or genetic alterations that drive the tumor. They're they're non specific killers of rapidly dividing cells.
Dr. Sam Blackman:And that's pretty much been the standard of care for 20 some years, until recently as we we've now begun to develop more targeted therapies that really address the underlying molecular alterations that drive these tumors.
Dr. Moira Gunn:Now to get an approval, you have to go through a series of phase 1, 2, 3 trials to prove that something is really efficacious and and is not toxic here and is making a a positive difference. And you've got children. This is amazing. Tell us what you did.
Dr. Sam Blackman:Right. So you would think that it's hard to run clinical trials in children. It turns out that it's actually no more or less difficult than running clinical trials in adult cancer patients. It's actually been one of the persistent myths that I think has limited the development of new medicines for childhood cancers. This myth that, oh, it's really hard to run clinical trials in children.
Dr. Sam Blackman:Believe me, pediatric oncologists always prefer to have a patient enrolled on a clinical trial even if it's a clinical trial of 1 standard regimen versus another. So clinical trials are really at the core of the way the pediatric oncology has been practiced for the past 75 years. We when we inherited, our drug, which, has now has the generic name of tovorafenib, When we inherited it, it had already been through adult phase one trials. That's the initial safety testing that's that's done of new medicines. And and these safety trials were originally run-in adult patients with melanoma with skin cancer.
Dr. Sam Blackman:Many of which also have the same B RAF genomic alterations. So we inherited the drug with about 250 or so patients worth of safety data. So we understood approximately what the right dose should be. Certainly for adults, we had to verify that in children. We understood what the safety profile in adults would be, but of course had to verify that in children.
Dr. Sam Blackman:And we had a little bit of clinical data from about 9 patients, 9 9 children with low grade gliomas who had been treated on an academic trial, run at the Dana Farber Cancer Institute in Boston, which coincidentally was the place that I I trained. So once we inherited the drug, the first thing that we did actually was not even to to set up a trial. We designed what we thought would be an appropriate trial. And then we went and we talked to the FDA and told them our plans. And it turns out that this is really what the FDA wants from drug companies.
Dr. Sam Blackman:They want you to come to them early and often to talk with them about what you're planning to do and get into alignment with them around what you think is the right path to get a drug approved and what they think is the right path to get a drug approved. And it was really after that initial meeting that we were able to set up, our trial designed to generate data to get this drug approved, a trial that we called the fire FLY trial that enrolled children with relapsed pediatric glaugriglioma with this BRAF alteration.
Dr. Moira Gunn:So who is in the trial and what was it like to be in this trial?
Dr. Sam Blackman:So we ultimately rolled about a 136 patients in total on in 2 different groups. One group was used to generate the efficacy data to to ask whether or not the drug worked and and shrank tumors or stop them from growing and then one group of about 60 patients that generated additional safety data. The trial was open to children as young as 6 months of age and as old as 25 years. This was actually really, a challenge because when we inherited the drug, we didn't have the drug in a format that could be given to children who couldn't swallow pills. So one of the other things that we had to do in that very first year was try to turn this drug into something that could be administered as a liquid to children who couldn't swallow pills.
Dr. Sam Blackman:That took a lot of work. And then we included patients up to 25 years of age because as I I said before, this tumor can continue to grow into your early 20s. And so we would have patients who were diagnosed when they were 8 or 9 or 10 years old and had been living with this tumor for 10 or 15 years and it was continuing to grow, so we wanted to make sure that our trial could accommodate those patients as well. And being on the clinical trial, certainly was work for the patients and families who are involved and we're incredibly grateful to them. They had to show up and get scanned and have tests to show that they were safe to be on the trial, that they didn't have any other major medical problems that could preclude them from being on the study.
Dr. Sam Blackman:And then they had to, show up frequently for clinic visits to make sure that we were getting all the safety information that we needed, that we could draw blood to check the levels of the drug because we have to characterize how the drug is handled by the body and metabolized by the body. They had to have scans, MRI scans every 3 months. We had to have a piece of their tumor from when they had originally been diagnosed to test and prove that that BRAF alteration was present. We wanted to collect symptom diaries and understand the impact of both the disease and the treatment on their quality of life. So it's it's a lot of work to be in a clinical trial and and again we're immensely grateful to the patients and their families, some of whom had to travel very far to come to clinical trial sites.
Dr. Sam Blackman:We opened up clinical trial sites around the world, in the United States, in Europe, in Asia, and Australia, in order to be able to approve patients as quickly as possible.
Dr. Moira Gunn:And it's clearly a family business at this point.
Dr. Sam Blackman:It's it's certainly, you know, consistent with what I've said for a long time as a pediatric oncologist. You know, childhood cancer is a disease of families. It's a disease of communities. A child with cancer that impacts parents and brothers and sisters and aunts and uncles and grandparents and classmates and teachers. And so the treatment of childhood cancer does require a family effort and and and it's not hard once you think about it a little bit to understand how big of a commitment that is.
Dr. Sam Blackman:If you've got 2 working parents and you've got a child that needs to be seen at a cancer center 2 hours away, that's going to be incredibly disruptive for that family. And so to the extent that we can make that easier for that family, it's certainly something that we always, always try to do.
Dr. Moira Gunn:So initially, it's a liquid, but then it becomes a daily pill?
Dr. Sam Blackman:It's actually started out as a pill. So when we inherited the drug, it was only manufactured as tablets and then we created a liquid formulation. Amazingly with this drug, it only needs to be administered once a week either as tablets or as a as a liquid which is pretty incredible for me as a as a physician and as a as a scientist to think that there's a medicine out there that can control or shrink [this type of] brain tumor that you only have to take once a week. When I was training to be a pediatric neuro oncologist, I don't think any of us thought that that would be possible. And the fact that we've identified the responsible gene that we have molecules that can target those genomic alterations, and that we can make molecules that have characteristics that allow it to be administered on this really convenient schedule for families.
Dr. Sam Blackman:It was part of the reason why we so desperately wanted to get a hold of this drug and and develop it for these patients.
Dr. Moira Gunn:And what exactly does it do?
Dr. Sam Blackman:So tovorafenib is technically called a type 2 graft inhibitor. So there's different types of these small molecules and what this one does is it binds to a pocket on the BRAF protein and changes the shape of that BRAF protein in such a way that it can't signal anymore. So it's almost like a key going into a lock but the wrong key so that that lock can't turn. And what that does is it shuts down the signaling of these altered forms of the BRAF gene and keeps the BRAF protein, which is broken in in this disease keeps it from signaling the tumor cells to grow. And ultimately what happens when you turn that off is the tumor cells stop growing and either they stop growing and just sit still in a state of quiescence or the tumor cells die and the tumor shrinks.
Dr. Moira Gunn:And that's what we want. It's pure and simple.
Dr. Sam Blackman:Yeah. Well, historically, the goal of therapy for these patients has just been to hold the tumor in check. And I will have to tell you more when I saw some of the initial data indicating that tumors were shrinking it was deeply satisfying and deeply affecting to me emotionally as a person. One of the privileges of being a pediatric oncologist or a physician sort of in drug development is that when I look at a chart, that's got lots of bars on it showing, you know, whether tumors have gotten bigger or smaller, every one of those bars that I see on those those plots I know is someone's child, that someone's son or daughter or somebody's grandson or granddaughter or somebody's brother or sister. Every one of those bars or points on a line is a person that their parents have hopes and dreams for.
Dr. Sam Blackman:And to see that person having a response to a drug is why I went into this field. It's the thing that allowed me to walk away from taking care of patients one at a time to be able to see a chart that has dozens and dozens and dozens of patients whose tumors have shrunk, you know, really is everything that I dream for when starting this company.
Dr. Moira Gunn:How well did this work in the trials that you did?
Dr. Sam Blackman:So we saw 51% of patients, 52% of patients with tumors that actually shrank to meet the criteria needed to be considered a response by the FDA. And then another 30% of patients whose tumors either stayed still or shrank a little bit, but not enough to officially be called a response. But again, in keeping with the way that this disease has historically been considered, even having a tumor that stays still for a couple of years, and doesn't grow at all is a significant improvement for these patients. So we saw 82% of patients who we asserted had benefit, but really 52% of patients who had shrinkage of at least 25% of their tumor and some about 26% of patients who had shrinkage of almost 50% for their tumor, which is really remarkable.
Dr. Moira Gunn:Well, you did mention that BRAF is involved in other pediatric cancers, although less so, percentage wise. We also don't know if this will work in adults. I mean, there are many places to go from here. What's the plan for day 2?
Dr. Sam Blackman:That's a pretty question.
Dr. Moira Gunn:Now that we got through day 1.
Dr. Sam Blackman:Yeah. So you're right. So the BRAF gene is altered in a number of other diseases in both adult patients and and pediatric patients. Just as a as an anecdote, very early in the life of the company we created our what's called the compassionate use program that would allow physicians to come to us and ask for access to the drug for patients who had diseases driven by the same BRAF gene that weren't brain tumors, where the child really a child had run out of any type of option. And one of the first compassionate use cases that we had and we actually published a paper on this was a little boy who had a fast growing soft tissue tumor called a sarcoma that was growing behind his heart but in front of his spinal cord in a place that could not be, operated on.
Dr. Sam Blackman:And the tumor was too big to be able to get radiation, and his tumor had already grown through 3 prior treatment regimens. So this little boy unfortunately had no other treatment options and was noted when they looked at his tumor to have a unique BRAF alteration and so the treating physician came to us and said can we get access to your drug and of course we said yes and I was astounded when I was told a few months later that, about 2 months after starting our drug, this child's tumor had completely disappeared on scans to the point where he was able to get radiation focused just on the area where the tumor had been. And then he got some additional treatment with toberafenib and has since been off drug without any recurrence of tumor. So, you know, certainly there are places where tovorafenib can be studied in other tumors beyond pediatric glomeranglioma. And we have trials of tovorafenib going on in a disease called longer Hansel Histiocytosis, which is a really rare disease of immune cells.
Dr. Sam Blackman:We've got a study in another type of brain tumor called craniopharyngioma. And then we have a trial open for adult patients with tumors driven by different alterations, including, alterations in the BRAF gene, but other related genes as well, patients with, melanoma and lung cancer. So we continue to do work to develop tovorafenib in other areas where we think that it could be helpful to patients.
Dr. Moira Gunn:And you continue your compassionate use program?
Dr. Sam Blackman:Well, now that the drug is approved, the nice thing is that physicians can write prescriptions for tovorafenib for pediatric glaucoma patients. Many times, children are treated with new cancer medicines or with cancer medicines, for which there aren't FDA indications, but that's really a physician decision. We only can, support or promote, the use of toberafenib in pediatric glomerangloma patients.
Dr. Moira Gunn:Now I've written down several quotes from you over the conversations we had prior to this interview. One is, in terms of treating children, it's a business solution for a moral problem. And also, drug development is an exercise in hope. It seems to me that both describe the work of day 1.
Dr. Sam Blackman:Yeah. I I think so. I mean maybe on the latter point first, you know, when I chose to go into pediatric oncology, I chose to do it because for me it was the place where I felt that I could be the best physician that I could possibly be. I always viewed taking care of children with cancer as a privilege and an exercise in hope. What was really interesting to me more is that, you know, as I got farther on in my career and people had asked me what I did for a living, I said, well, I'm a pediatric oncologist or a pediatric brain tumor doctor.
Dr. Sam Blackman:They would look at me like I told them that my dog had just run away. They looked at me like I should be sad. And I would tell them, like, you don't understand. Like, if you go to the clinic where I used to see patients and you walk into the waiting room, you see way more people smiling than you do crying. I truly believe that the care of children with cancer or any life threatening disease is really an absolutely an exercise in hope.
Dr. Sam Blackman:We we go into treating patients with cancer with the intent of trying to cure. And in fact, you know, 70 plus percent of children diagnosed with cancer do achieve a cure, a long term durable remission of their disease. So I'm always hopeful. I think it's the only way you can survive is to have hope that the science that you're applying, is going to make people better. I firmly believe that we as a country, we as as a society, we as as human beings deserve, need, require companies that are focused on making new medicines for childhood cancer and other life threatening diseases of childhood.
Dr. Sam Blackman:Independent of whether or not the business model works, you can't you can't just give up. We have to find ways to make new medicines for children. We can't let age or rarity of disease be the deciding factor as to who gets a new medicine or who doesn't or who gets to benefit from emerging science or who doesn't. There has to be a company out there or companies out there that are able to solve these problems because, you know, we tell ourselves and we tell the world, right, that children are our most precious resource. They are our future.
Dr. Sam Blackman:And if that's the case, that is all children, including those who have very serious illnesses, and we need to remember that all of the amazing new science that we are generating and applying that those children deserve access to it as well.
Dr. Moira Gunn:Well, doctor Blackman, thank you so much for coming in. I hope you'll come back, see us again.
Dr. Sam Blackman:I hope, Maura, that we will have new medicines to tell you about, in the years to come. Thank you very much for having me.
Dr. Moira Gunn:Doctor Sam Blackman is the founder and head of research and development at Day One Biopharmaceuticals. More information is available on the web at dayonebio.com.