RARE Daily

A Drug Developer that Makes Pediatric Cancers a Priority

February 16, 2024

Because of the rarity of childhood cancers, biopharmaceutical companies often don’t pursue therapies to treat these conditions. The problem is that precision therapies developed to treat adult patients often don’t easily translate into treatments for pediatric patients. Day One Biopharmaceuticals is developing targeted therapies to address childhood cancers and then seeks to partner with larger pharmaceutical companies who may be interested in developing them for adult indications. We spoke to Samuel Blackman, head of research and development for Day One Biopharmaceuticals, about childhood cancers, the need for precisions therapies, and Day One’s business model that makes targeting childhood cancers a priority.

Daniel Levine: Sam, thanks for joining us.

Sam Blackman: Happy to be here. Thank you for having me.

Daniel Levine: We’re going to talk about childhood cancers, the challenges of developing therapies for these conditions, and Day One Biopharmaceuticals’ efforts to bring new therapies to treat these conditions to market. Let’s start with the landscape. How large a problem are childhood cancers and why has this patient population generally not benefited from the advances we’ve seen in therapeutic development more broadly?

Sam Blackman: I’m going to answer the question in a couple of ways. It’s a really good question. From a pure numbers perspective, fortunately, and I think we’re all grateful for this, childhood cancer is not a large problem relative to the number of patients diagnosed each year with lung cancer or prostate cancer or breast cancer. In fact, across all different cancer types that affect children, only about 16,000 children per year are diagnosed with a new cancer here in the United States. But, and I say this as a pediatric oncologist, for every single one of those 16,000 children, a diagnosis of cancer is life altering, not just for the child and not just for their family, but cancer really is a disease of communities and you can imagine a serious diagnosis not only affecting a child and his family, siblings or grandparents or parents, but classmates and teachers and friends. In addition, we treat children with the intent to cure, which means we treat them very intensively because our hope is that they’re going to live long lives, but the cost of that intensive treatment is oftentimes a lot of short-term toxicity and lifelong toxicities. And so the problem of childhood cancer at the individual level is enormous, and even though 70 percent of patients do survive their disease, they do so oftentimes with very significant effects. Now the second part of the question, which is why have pediatric cancer patients not in general benefited from the same type of advances that we’ve seen in therapeutic development more broadly? There’s a couple of reasons. One is, at the end of the day, most new cancer drug targets are selected by large pharmaceutical companies to serve the needs of the larger adult markets because drug development is a very expensive, very time consuming and a very risky endeavor. And by that I mean nine out of 10 cancer drugs that enter clinical development never make it through to approval. And so it’s really incumbent upon these companies to develop drugs for larger indications that are going to be able to provide the return on the investment of doing all of that research and development work. The other issue is that childhood cancers and the molecular drivers of childhood cancers are not always identical between adult and pediatric patients. So a drug that is developed for breast cancer may be against the target that is not relevant to any known pediatric cancer. And unfortunately because of the small numbers of patients, there’s not a lot of economic incentive in the way that we finance drug development in this country to do drug development for very small or rare diseases.

Daniel Levine: There may be listeners who wonder why you can’t just adjust an adult cancer drug to treat a pediatric patient, but it’s not that simple. Why can’t we take medicines developed for adults and just use them in pediatric populations? Are pediatric cancers different than adult cancers? Are there other concerns?

Sam Blackman: So actually, we do and have been for a long time treating pediatric cancers with adult cancer drugs and scaling the schedules and doses of those drugs accordingly, but that has more to do with the fact that for a very long time, the only thing that we had for the treatment of any cancer, pediatric or adult, was chemotherapy, which is less specific in its targeting. Chemotherapies often target the mechanisms that drive cell division independent of whether it’s breast cancer or brain cancer. And so for the past 70 years, we’ve been taking adult chemotherapy drugs and figuring out how to use them for pediatric cancer patients. Over the last 20 years, as we’ve developed novel targeted therapies that really address the genetic defects that drive specific cancers and novel immunotherapies that reactivate the immune system, it turns out that your point is correct. Medicines developed for those adult cancers oftentimes won’t work in pediatric cancers because the underlying biology is different. For example, the whole class of what are called PD-1 or PD-L1 inhibitors, these immune reactivating agents that wake up the immune system so that the immune system destroys the cancer work very, very well in specific adult cancers like melanoma and lung cancer, but they work in almost no pediatric cancers. And a lot of that has to do with the fundamental biological differences between adult and pediatric cancers. The other thing that of course you always have to be thoughtful of is some of the medicines that we use for adults have toxicities or side effects, and when you treat children with the intent for them to survive, some of those side effects could be lifelong in children. That is less of a concern from my perspective, the bigger challenges are really the biological differences between adult and pediatric cancers. There is however some overlap and I think in that space where there is overlap, that is really where a lot of progress can be made.

Daniel Levine: There’s long been a recognition of the inequity in the development of cancer therapies for pediatric patients. Almost 20 years ago, the Pediatric Research Equity Act gave the FDA the authority to require drug companies to conduct pediatric studies for certain medicines. What effect has that had?

Sam Blackman: For most of those 20 years, almost none in the field of oncology because there has been this notable loophole in the Pediatric Research Equity Act, or PREA, and that loophole is as follows: if the disease that that drug is being developed for is an orphan disease and orphan diseases in this country are defined as having an incidence of less than 200,000 new cases per year, then the requirements under PREA didn’t apply. And as I told you just a few minutes ago, if you add up all of the pediatric cancer diagnosis per year in the United States, it’s only 16,000 patients per year. So not only is any given pediatric cancer an ultra or ultra orphan disease, but all of pediatric cancer in the aggregate is an orphan disease. And so PREA didn’t apply. More recently with the Race for Children Act, which was introduced a few years ago, that loophole has been closed and there has been more work done with the FDA now requiring pediatric study plans for drugs being developed that target certain targets that are relevant to pediatric cancer. But the yield from that work really has yet to be fully realized since that legislation has only been in effect for a few years.

Daniel Levine: Is the fact that more pharmaceutical companies aren’t pursuing these indications simply a matter of economics or are there other issues?

Sam Blackman: I think economics is one and probably a majority and maybe the most important or biggest reason why drug companies either don’t pursue pediatric indications or don’t pursue them until far later in the drug development process. I think that there are other reasons, some of which are probably real and some of which are maybe a little bit more apocryphal beliefs within the drug development community. What do I mean by that? I think that there is a belief, and it’s mistaken that it’s hard to conduct studies in pediatric cancer patients, and that may have been the case 20 years ago, but over the past 20 years, many pediatric oncology centers now know how to run industry sponsored drug development trials and have the infrastructure to do that. I think there was also a belief that, or a fear that if you had a serious toxicity in a pediatric patient on a pediatric trial, that somehow that could put the entire adult drug development program at risk. And so, nobody wanted to take the risk of a child suffering a bad side effect that would then blow up their multimillion or a hundred or million dollar investment in a drug for lung cancer or breast cancer or prostate cancer. Again, I’ve heard those fears, but I’ve never actually seen an adult cancer drug development program torpedoed by a pediatric adverse event. I think the other big thing is that the work that needs to be done to develop pediatric indications is as expensive as doing the work to develop a drug for adult indications, but the yield on that work in terms of the return on investment is smaller and in the eyes of a big pharmaceutical company, they need to maximize their return on their investment in a drug development program. And so if you think of a drug and maybe it’s going to play a role in liver cancer, maybe it’s going to play a role in gastric cancer, maybe it’s going to play a role in melanoma and there are tens of thousands or a hundred thousand patients in the aggregate who that drug would serve. That’s where you’re going to focus your team and your team’s resources and your clinical trial investment. And if that drug could be used for, I’ll pick alveolar rhabdomyosarcoma, 200 to 300 patients a year, you’re not going to put a full team on that because at the end of the day, that’s not an efficient way for you to use the resources that you have to try to get that drug to patients. The problem is if everybody takes that perspective, then who’s going to make new medicines for kids with alveolar rhabdomyosarcoma or Ewing sarcoma? And that’s a problem that we’ve been facing in the drug development ecosystem for many, many years and it explains why there’s such a yawning gap in the approval of new therapies for pediatric cancer patients.

Daniel Levine: I want to talk about what Day One is doing, but perhaps you can start just by explaining the name.

Sam Blackman: So, it’s a great question. When I was starting the company back in 2018 and we had gotten some seed funding to try and build it, we had to incorporate, and so we had to give the company a name. And I’ll tell you, I was sitting in my dining room at the dining room table in my home in Seattle thinking about what would be a good name for a company focused on pediatric drug development. And the first name that I came up with was Kinder Farm, which is, I will tell you a terrible name. It’s just terrible. And not only is it a terrible name, but it’s somebody else’s terrible name because it actually belonged to another company. I went through every iteration of kinder or PD or you name it, they were all terrible. So, I sort of leaned back in my chair and assumed my deep thinking position and stared at the ceiling and asked myself, why am I doing this? Why am I going to try and start a company focused on pediatric cancer drug development? And my thinking took me back to the very first week of my fellowship in Boston when I was trained to be a pediatric oncologist. And when I arrived in Boston, one of the very first things that they told us they were going to do as part of our orientation was teach us how to do what’s called a day one talk. And I had no idea what a day one talk is. And so, they told us a day one talk is the discussion that you have with a family of a child newly diagnosed with cancer, where you sit down and explain to the family the diagnosis and what the implications are and what the treatment plan is and what that treatment plan is going to look like oftentimes months or years of therapy. And most importantly, it’s where you really build that therapeutic relationship, that bond of trust between you and the family because you’re going to have to carry that family through a lot of ups and downs. And it really is not only just day one of treatment for that patient or that family, but it’s day one of life in a completely new way. It’s life in the uncertainty of being a cancer patient in cancer land for all intents and purposes and surrounded by patients and doctors and nurses and hospitals. And it’s the thing that you’re going to think about all the time. And I thought to myself, if we’re going to make a company that’s going to try and make new medicines, we’re trying to make new medicines for doctors to bring to patients at that day one talk. And I also thought this is really the first day of what I hope would be a new model for making new medicines for pediatric oncology. So, we called it Day One Biopharmaceuticals.

Daniel Levine: Day One, seeking to bridge the gap between pediatric and adult patients. What’s the business model that allows Day One to pursue these therapies for pediatric cancer patients where most biopharmaceuticals don’t make that a priority?

Sam Blackman: So, one thing that we stand to benefit from is that we’re a small company, so the need for a return on the investment that we’re making is smaller. We don’t need to make billions of dollars a year on a cancer medicine. For us to be successful, we need to create a pipeline full of medications that is sustainable and that will allow us to continue this work for many, many years to come. There are some indications, some diseases, pediatric cancer diseases that do occur with enough frequency that if you have a drug that really makes a difference for that disease, then that can actually be a standalone indication where you can get approved for that indication and that indication alone and have a sustainable business as a result. However, those diseases are pretty rare. And so, to solve the problem for diseases like Ewing sarcoma or osteosarcoma or high risk neuroblastoma, rare cancers that might only occur in a few hundred patients per year, the only way that you can get people to invest is if you also have visibility to developing that drug or adult indications where the biology of the drug makes a difference for the pediatric cancer as well as the adult cancer. And that’s really the model that we took is picking targets that are relevant to pediatric cancers where there are drugs that we can bring in and develop, but making sure that those drugs also have the potential for development in adult cancers. And then to pursue both of those lines of work with equal intensity. And if we are successful developing a drug that works for kids, we’re going to bring that drug to patients. If we’re successful in developing a drug for adults as well, there are plenty of people who would be willing to partner with us to make sure that that drug gets to adult patients. And that for us is how we believe we solve the math problem here of incentivizing drug development for pediatric cancer patients.

Daniel Levine: Day one’s lead experimental therapy is in development for both frontline and relapsed pediatric low-grade glioma. For listeners not familiar with the condition, what is it?

Sam Blackman: So low-grade glioma is a brain tumor. In fact, it’s the most common brain tumor of childhood. Glioma refers to a tumor, a brain tumor originating from a set of cells in the brain that are not the neurons, but are supporting cells called glial cells. So glioma means a tumor of the glial cells. Low grade refers to the way that those tumors look under the microscope. They tend to multiply relentlessly because these are tumor cells, but at a slower rate, and low grade gliomas manifest as slow growing, really chronic, relentless brain tumors of childhood. They tend to occur when patients are in their first decade of their life, so somewhere between age zero and age 10, and they grow and grow and grow and grow relentlessly. And then what’s fascinating about these low-grade gliomas is that many of them, when patients get to their early twenties, they simply stop growing for reasons that we don’t fully understand. So you might think, well, that’s pretty great, a brain tumor that only grows for a while and then stops. How dangerous could it be? Well, it’s still a brain tumor. It’s still a mass growing inside of the enclosed space that is the skull, and it grows relentlessly. And the treatment of that tumor is required in a number of patients requiring surgery or chemotherapy. Treatment has side effects. The growth of the tumor, the location of the tumor within the brain can have side effects, and these children are treated for a very, very long time, oftentimes receiving many cycles of therapy. And as a result, they accumulate a great deal of both short and long-term toxicities. So this is a disease where there have been very few drugs approved. In fact, there’s only been one drug recently approved for a very small subset of patients. The drug that we’re developing is for the largest molecularly defined subset of low-grade glioma patients, those with a mutation in a gene called BRAF.

Daniel Levine: And what’s the prognosis for kids with this condition today and how are they generally treated?

Sam Blackman: The prognosis is good if you’re referring to prognosis only in terms of survival, about 90 percent of patients with low-grade gliomas will survive, but the morbidity that is the accumulated toxicities of both disease and treatment for these patients is extremely high and can include things like profound visual loss or blindness, profound effects on the endocrine system and growth effects on motor function and balance and effects on learning and executive function. The treatment of low-grade gliomas is complicated. Patients all present to the hospital when they are diagnosed with a low-grade glioma with the symptoms of a growing brain tumor, headache, vomiting, double vision or loss of vision, dizziness, seizures. There’s a number of different ways the tumor manifests clinically depending on where it is in the brain, and for about 80 percent of patients, surgery is going to be some part of their treatment. In some cases, you can remove all of the tumor, and in those cases, the vast majority of patients don’t require any additional therapy, but at least two thirds of patients either can’t have their tumor resected at all or can only have a portion of their tumor resected. And then the tumor, of course, does what tumors do. It keeps growing and those patients require chemotherapy or some type of systemic therapy. And oftentimes these patients will have one or more lines, we call them, or courses of systemic therapy. It could be chemotherapy, it could be targeted therapy, it could be targeted agents as part of a clinical trial. In rare cases, we will use radiation. It’s something we don’t like to do. Radiation has very significant short and long-term side effects, including a risk of turning low-grade gliomas into high grade gliomas. And radiation also has in young children especially very profound effects on brain development. So right now we treat these children with primarily surgery and chemotherapy, but we’re in this age now where we understand the biology of these tumors better and the potential for developing new targeted therapies that target the underlying gene defect that drives the tumor are within grasp, and that’s what we’re really focused on.

Daniel Levine: You alluded to your experimental therapy. This is tovorafenib. What is tovorafenib and how does it work?

Sam Blackman: tovorafenib is a small molecule. It’s an investigational therapy, so it’s still undergoing study and has not yet been approved by the FDA, although our application is under review with the FDA. By small molecule therapy, I mean a chemical that can be delivered in pill form or liquid form. And what tovorafenib does is it’s a what’s called a type II RAF inhibitor. It’s a molecule designed to block RAF signaling proteins, which are critical proteins for signaling growth in cells. There’s different types of RAFs, there’s ARAF, BRAF, and CRAF, and it’s BRAF that really drives the majority of low-grade gliomas and the BRAF mutations that occur in low-grade glioma patients come in two different flavors. One’s what’s called a point mutation where just one letter of the gene has changed and the other is called a fusion where the gene actually is broken and gloms onto to a piece of a different gene and then allows for signaling to drive that cancer. Tovorafenib has the ability to block the signaling function of both the point mutated BRAF and the fusion BRAF and shut down the signaling that makes these tumors grow.

Daniel Levine: Are you seeking approval with a companion diagnostic?

Sam Blackman: We are for targeted therapies like this. The Food and Drug Administration oftentimes does require sponsors or companies like ours to ensure that there is an FDA approved diagnostic test to identify patients and make sure that that test is reliable and repeatable. We have been very lucky to be able to partner with Foundation Medicine that makes a gene panel test that’s widely used called Foundation One, and our partnership with them allows us to ensure that their test works in low-grade glioma tissue and can properly identify both the BRAF fusions and the BRAF point mutation. So our hope is to have the companion diagnostic approved essentially in parallel or shortly after we hopefully see tovorafenib approved.

Daniel Levine: What’s known about tovorafenib from the studies you’ve conducted to date?

Sam Blackman: So overall, what we know about tovorafenib is that it is a well-tolerated and active agent in terms of its anti-tumor activity in relapsed, low-grade glioma patients. We’ve conducted two trials at Day One, one of which is in the process of really spooling up. But the main trial that we have conducted is called Firefly One, and it’s a study of tovorafenib as a single agent in patients with relapsed low-grade gliomas that have relapsed after or progressed after at least one line of therapy. In this trial, we enrolled 77 patients. These are all children who had on average three or more prior lines of treatment. So they’re coming to this trial after having had their tumor grow through three prior lines of therapy. And all of these children had tumors with either a BRAF fusion or BRAF point mutation. And what we saw in our study is that tovorafenib shrank tumors to a point of 25 percent or more from baseline in more than 50 percent of patients. That is to say 50 percent or more of patients, depending on the way that you look at these tumors, the different measurements that you employ radiographically have tumor shrinkage of 25 percent or more, which qualifies as a response under the different response assessment criteria used, either a set of criteria called RAPNO-LGG, or a response assessment criteria called RENO-LGG. We found that these responses are durable with the median duration of response really now 14 months and growing. This is still is an ongoing trial, and the drug, as I say, is generally well tolerated with the side effects all being to date things that we think are monitorable and reversible, the most common ones being hair color change. Tovorafenib can make your hair turn platinum blonde temporarily. That’s reversible. Skin rash and anemia are the other two most common side effects that we’re seeing.

Daniel Levine: Are you considering any adult indications for the drug?

Sam Blackman: We are. We have a number of other studies ongoing, including an adult study. We actually have presented data showing that tovorafenib has anti-tumor activity in adult cancers that have the same type of BRAF fusions that we see in pediatric cancers. So, in some melanoma patients and sarcoma patients we’ve seen some really interesting responses, and we have an ongoing trial of tovorafenib in combination with a second drug called pimasertib, which we own as a MEK inhibitor, looking at a variety of adult cancers that are driven by gene alterations in the same family as BRAF.

Daniel Levine: Is the expectation that you would commercialize the pediatric indications on your own? And if so, have you started to build a commercial team?

Sam Blackman: So yes and yes. Once we knew that tovorafenib looked like a drug that had the strong potential to be filed with the FDA for approval, we made the decision to build a commercial team to meet the needs of pediatric patients directly. And not only have we started to build out our commercial team, we have now hired and fully staffed our commercial team. As you may be aware, Daniel, tovorafenib, our new drug application has been accepted for review by the FDA with priority review status and the FDA assigned a potential approval date of April 30th of this year—so to be ready to meet the needs of patients from day one, every pun intended there. We’ve been building our commercial team internally for about two years and then recently hired out our salesforce. And I have to say, just as a personal anecdote, it’s been immensely satisfying to see as we’ve been building out the commercial team, how many people want to come and help us address the needs of these patients. We posted 18 sales positions and we had over 1500 people apply. It was one of the most in demand pharmaceutical sales jobs that we’ve seen recently. And I think a lot of it is because of the mission of the company and I think the potential for this drug to make a difference in patients’ lives. And so we’re really, really proud of and excited by the team that we’ve hired that’ll be interfacing directly with physicians and nurses and hospital pharmacists.

Daniel Levine: Day One is a public company. In June 2023, raised 172.5 million through a public offering. How far will existing cash take you and what’s the plan for raising additional capital?

Sam Blackman: So yes, we went public in 2021 and raised capital in a couple of follow-on offerings. We’re very fortunate. We have a very strong balance sheet with about $400 million as of the last reporting period. That cash will take us into 2026, and will be used for a variety of things, including the commercial launch of tovorafenib, as well as trying to build out our pipeline and bring in new programs. We are not going to stop with just tovorafenib, and we’re not going to stop with just low-grade glioma. The potential I think, is there for Day One to be an enduring company focused on the needs of pediatric cancer patients and patients of all ages. So we’ll continue to grow the company and depending on our needs and the financing environment, we will certainly look to the markets for additional capital as needed. But we are in a pretty good position right now.

Daniel Levine: Sam Blackman, co-founder and head of RD for day one, biopharmaceuticals. Sam, thanks so much for your time today,

Sam Blackman: Daniel. Thank you very much. I really enjoyed the conversation.

This transcript has been edited for clarity and readability.

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