Welcome to SpringWorks R&D Day. I'm Saqib Islam, CEO of SpringWorks Therapeutics, and I'm delighted to discuss the many exciting opportunities we have to serve a broad range of patients from our portfolio of investigational therapies. Thank you for joining us today. Before we get started, I'd like to draw your attention to our customary forward-looking statements disclosure. As a reminder, if you have to leave us early or if you'd like to revisit anything we present here today, a recording and downloadable copy of our R&D Day presentation will be available on our corporate website following the live event. You'll be hearing today from several members of our team. I'm very pleased to be joined by our Chief Operating Officer, Dr. Badreddin Edris, our Chief Development Officer, Dr. Mary Smith, our Chief Commercial Officer, Bhavesh Ashar, our Head of R&D, Dr. Mike Burgess, and our Chief Medical Officer, Dr. Jim Cassidy. Together, we look forward to sharing our recent accomplishments and discussing how they position us for continued success and value creation for all of our stakeholders. We are also pleased to be joined by Dr. Breelyn Wilky from the University of Colorado in Denver. Dr. Wilky is a leading desmoid tumor physician and key opinion leader who will be discussing the patient's disease journey, treatment considerations, and the unmet need in this indication. In addition, Dr. Neal Rosen from Memorial Sloan Kettering Cancer Center in New York will be presenting. Dr. Rosen is a luminary in the field of MAP kinase biology and drug development, and is also the founding SAB member of MapKure, the joint venture we've established with BeiGene to advance BGB-3245. Dr. Rosen will give an overview of this compound and its potential role in a variety of biomarker-defined cancers. Before we get started on our agenda, I'd first like to take a few moments to share what our goals are here at SpringWorks. Our mission is clear. We are driven to help people suffering from severe rare diseases and cancers live longer, better lives. Our company was founded in 2017, and over the past five years, we have taken our lead program, nirogacestat, through a successful phase III study that has put us on track to file our first new drug application later this year. Our goal is to provide the first approved therapy for patients with desmoid tumors in 2023. Building on this first approval, we expect to have a second marketed product by 2025, and between these two therapies, we see potential to serve patients across four distinct indications in areas of significant unmet need by the end of 2025. Importantly, each of these opportunities are supported by a robust and long-dated intellectual property portfolio. Our efforts have been enabled by a repeatable business model that has helped us to construct a portfolio of opportunities that is both broad in its application as well as capital efficient in its development. We seek to evaluate the therapeutic opportunity for each of our molecules, closely scrutinizing them from every angle to unlock their full potential for patients. We'll have an opportunity to discuss several of those opportunities today. We've also forged collaborations with industry and academic innovators to multiply our opportunities for success and have built our company with exceptional people who work with urgency and tenacity to make a profound impact on the lives of people with devastating cancers. We are well capitalized with a multi-year cash runway to help us execute on our ambitious agenda. We have a leadership team with deep experience in drug development, business development, and commercialization, along with an operational and financial infrastructure to support our efforts on behalf of a broad group of oncology patients. I'll now turn it over to our COO, Badreddin Edris, to talk in more detail about our business model and corporate strategy. Thanks, Saqib. We believe that we have created a repeatable and sustainable business model built upon strategic capital allocation and focused on pursuing opportunities that match translational insights to underserved patient populations where we believe we can have a competitive advantage and an attractive commercial opportunity. We have a rigorous vetting process as it relates both to expanding our existing programs as well as to bringing in new opportunities through business development. We scrutinize product candidates from every angle, looking to construct our portfolio with assets that are validated, versatile, and support the balance of our pipeline across early and late-stage programs with room to explore additional indications over time. Unmet patient need within oncology, small molecules, biomarker-driven development, monotherapy efficacy hypothesis, combination therapy opportunities, viable and rapid paths to regulatory approval. These are just some of the criteria we focused on in building our portfolio to date. Part of this, of course, involves bringing to bear the best thinking and opportunities outside of SpringWorks to help us advance our mission. Accordingly, over the past five years, we've built a robust network of collaborators and partners across academia and industry, some of which we'll be discussing results from today. All of this is in service of our ultimate goal of advancing programs through development in order to deploy our fully integrated commercial organization to deliver important new medicines to patients. Our two lead programs, nirogacestat in desmoid tumors and mirdametinib in NF1-PN, serve as case studies for how we've implemented our approach to unlocking the full potential for differentiated molecules within our core segments. Each of these molecules have advanced initially as monotherapies with clear therapeutic hypotheses and attractive market opportunities conditioned upon clinical success. Following these initial standalone development programs are a series of additional monotherapy and combination therapy opportunities, which we pursue with the utmost capital efficiency by working with collaborators and partners that expand our scientific, operational, and financial strength that we can bring to these programs. An example of this is our BCMA strategy, which you'll hear more about today from our Head of R&D, Mike Burgess. To date, we have signed eight industry collaborations enabling us to generate the broadest GSI combination clinical data sets across the myeloma treatment landscape without any cost incurred by SpringWorks beyond drug supply and intellectual property. Another example is our collaboration with BeiGene, from which initial clinical data will be presented today by our Chief Medical Officer, Jim Cassidy. The cost-sharing and operational sharing structure here has allowed us to unlock several promising development opportunities in an extremely capital-efficient manner. As we continue selectively building out our preclinical portfolio, we intend to bring this exact same approach to bear as molecules earlier in our pipeline, such as those emerging from our TEAD inhibitor or EGFR inhibitor portfolios look to progress into the clinic in the coming years. Here is our pipeline today. We have 19 active R&D programs, including four late-stage trials in rare oncology indications, two of which are potentially registrational. We have a mix of wholly developed and collaboratively advanced programs underway, highlighting our continued focus on generating validating data sets in a capital-efficient manner and gaining subsequent investments upon the achievement of proof of concept. As you can see, we have a roster of leading biopharma and academic collaborators that are helping us to unlock the potential of these approaches. More important than the quantity of programs is the quality of the scientific strategy, the robustness of the unmet need, and the caliber of the data. That's what we'll focus on today. With that, I'll turn it back over to Saqib. Thanks, Badreddin. We work with urgency to find the answers people with cancer need. Just three years ago, we were a newly public company that had just started enrolling patients in two potentially registrational trials in two distinct oncology indications. Since then, we've made remarkable progress that has, among other activities, led to a positive phase III study, which sets us up for our first NDA filing. We've also demonstrated proof of concept across our portfolio and expanded our scope of opportunities to address yet more unmet needs on behalf of oncology patients. All of these efforts are coalescing into an outcome that will provide us with the potential for multiple approvals and revenue streams starting next year. What we'll be sharing with you today is our path toward these approvals and commercial opportunities. First, with nirogacestat and desmoid tumors, we delivered highly statistically significant and clinically meaningful results against our primary and all key secondary endpoints in the DeFi trial, providing clear evidence of a significant benefit to desmoid tumor patients and setting us up for an NDA filing later this year, which will be reviewed under the FDA's Real-Time Oncology Review program. Mary Smith, our Chief Development Officer, will walk you through these data, and Bhavesh Ashar, our Chief Commercial Officer, will share with you why our clearly differentiated product profile paves the way for nirogacestat to become the standard of care treatment for desmoid tumors. This is expected to translate into a meaningful revenue opportunity in an indication with no FDA-approved therapies with our launch slated for next year. Second, with nirogacestat and BCMA combination therapy, we generated important evidence of the benefits of combining our drug with the first of our BCMA partners. The focus of our collaboration with GSK is to maintain the efficacy of BLENREP while improving its ocular toxicity profile, enabling more multiple myeloma patients across lines of therapy to potentially benefit from this drug. We believe that the initial data presented at ASCO this year are very promising, showing a marked reduction in Grade 3 ocular toxicity, which if sustained as the studies advance, has the potential to enable the combination to move into earlier lines of therapy. We look forward to sharing additional data from the nirogacestat plus BLENREP phase II trial with a longer follow-up time and more patients on both the combination and monotherapy control arms, and to initiating new substudies to evaluate this combination with standard of care treatments in multiple myeloma. In parallel, we continue to generate clinical data across our portfolio of collaborations and expect additional clinical data to be forthcoming in the H2 of this year. Mike will share more about our opportunities in multiple myeloma based on the enhanced benefit risk profile that is possible for BCMA therapies when combined with nirogacestat. Third, as mentioned in our press release this morning, we have commenced a phase II study of nirogacestat in patients with ovarian granulosa cell tumors. These tumors account for approximately 5% of all ovarian cancers, and there are no FDA-approved therapies for these patients. This represents yet another meaningful expansion opportunity for nirogacestat, as Badreddin Edris will share with you today. Fourth, in addition to nirogacestat, we have a very high-quality molecule in our MEK inhibitor, mirdametinib. We continue to believe mirdametinib has the potential to bring expanded benefits, including a manageable safety profile to a broad group of patients with NF1 plexiform neurofibromas. The Phase IIb ReNeu trial has been fully enrolled since late 2021, and we plan to engage with the FDA later this year to align on a path towards regulatory approval. Fifth, mirdametinib is also being evaluated in a phase II study in pediatric low-grade glioma, with clinical data expected at a medical meeting later in June. Lastly, we are very pleased with the progress we've made across our solid tumor portfolio. Jim will share additional indications that we believe are quite promising for mirdametinib, along with some new clinical data from our collaborations with BeiGene. We are building a leading targeted oncology company. We believe that we have set a foundation and capital-efficient infrastructure that will allow us to continue to translate the opportunities that we have created into multiple drug launches on behalf of patients in need over the next three years, starting next year with desmoid tumors as our first approval and our first indication for nirogacestat. By 2025, our goal is to establish nirogacestat as a standard of care for patients with desmoid tumors. We expect to have two approved products in this time frame, with the potential to serve patients in four different indications. We have a full agenda today that covers clinical data across our portfolio, as well as our strategic priorities to drive our continued growth. As you can see from this slide, we are in a very meaningful and exciting period in terms of data generation, regulatory discussions, and launch preparations. We expect 2023 to mark our transition into a commercial-stage company, and we expect our research and development expertise to continue to strengthen our ability to execute and innovate. Turning to nirogacestat, this is a potentially first-in-class oral gamma secretase inhibitor that has positive top-line phase III data for desmoid tumors and encouraging proof-of-concept data in our first combination trial with BCMA-targeted therapy in multiple myeloma. We have 11 nirogacestat clinical trials ongoing or on track for initiation in 2022. Nirogacestat has received Fast Track, Breakthrough Therapy, and Orphan Drug designations from the FDA. We expect to file an NDA for nirogacestat in patients with progressing desmoid tumors in the H2 of the year and are very pleased that the FDA plans to review our filing under the RTOR program. Importantly, nirogacestat has been granted several U.S. composition of matter and method of use patents that extend IP protection into 2039. We will begin the nirogacestat section of our agenda by speaking about desmoid tumors. We'll start off by hearing from a desmoid tumor patient, Dana, who was enrolled in the nirogacestat phase II trial that was conducted by the NCI. While each desmoid tumor patient's experience is different, and Dana's is not meant to represent all patients, nor all enrolled in the phase II trial, her story embodies that which many desmoid tumor patients currently face, given the high rates of recurrence following surgery and the lack of FDA-approved therapies available for these patients. Let's play the video. I was diagnosed in 1999 with my first desmoid tumor. It was in my right calf, and I was pretty much living my best life teaching marine biology down in the Florida Keys, and I was training to run a marathon. I was stretching one day, and I just felt this lump in the back of my leg, and honestly didn't think a lot about it. I was 26 years old at the time, and I didn't think that really anything could happen to me. I didn't pursue it too doggedly when it first began, but after a couple of months, it continued to get larger in size and the pain started to settle in, and it became time for me to do some more research. When I was going through the diagnostic process, it was quite terrifying, actually. I had my MRI on a Monday, and I came back in, and they told me on Tuesday that I needed to be prepared to come in for surgery on Friday. I went in for surgery. As it turns out, the tumor that they removed was the size of about a football. It had grown into that size over the course of two years. My first recurrence with a desmoid tumor was almost immediately following my first surgery. It happened within about six to nine months. I had literally just gotten that open wound closed up, and at the top and the bottom of my scar, I felt these two small lumps, and I tried to sell myself on the idea that it was scar tissue, but that's definitely not what it turned out to be. Within a year, I already had two new tumors return, and so at the time, the first line of work was to just surgically remove them. Out came the next two tumors, and it set me off on a course of surgeries for the next several years, where I would take out two tumors and then three would return. Three went out, four came back. After we decided that the surgical approach was no longer working, I was pretty much running out of leg, and my mobility was becoming extraordinarily impaired. I traveled to almost every hospital on the entire Eastern Seaboard. There was pretty much no stone left unturned in my pursuit of trying to find the right treatment for me and my desmoid tumor. My leg was pretty enormous. My calf was twice the size of my thigh, so it became obvious to us at some point that it was time for us to think about amputating. In 2008, my mom was diagnosed with pancreatic cancer and ended up dying in less than eight weeks. She was just 59 years old. That experience, it was horrific and traumatic, but it gave me the courage that I needed to amputate my leg since I watched cancer consume my mother, and I didn't want that to happen to me. For five years, I was relatively desmoid tumor-free. In 2013, five years after I had my leg amputated, I was really struggling again with mobility, and I had significant pain in my hip and pelvis, and I just thought I had injured myself. As it turns out, I had another desmoid tumor that had returned, and it was in my hip and pelvis. I was adamant about finding a treatment that I would hopefully be able to resolve some of my pain and increase my mobility, but still have the ability to live my life. When I found the clinical trial that was being hosted at National Cancer Institute, it seemed like it was the perfect fit for me. On December 9th, 2013, that's the day that my entire life changed. That is my very first day that I ended up being enrolled in the nirogacestat trial. I had done radical things. I had had my leg amputated. I had done 5,000 rads of radiation. I had done countless chemotherapy treatments, and none of them had done really anything besides leave me with less body parts. Here was my first chance to try this drug specifically targeted for us. Even removing my entire leg with good margins did not prevent it from coming back in my hip and pelvis. But here was this medication, just a pill I got to take on my own. I could live at home. I didn't have to go to the hospital for the treatment. Twice a day, take a pill. My experience with nirogacestat really was life-altering for me in every way, shape, and form. It reduced my tumor. Prior to taking nirogacestat, I was struggling with mobility. I was in significant pain. I couldn't wear my prosthesis, and my quality of life was challenging. Once I got onto the drug, the pain was beginning to diminish and everything was starting to move again. My mom and I were both runners, and we swore we were gonna run a marathon together once I got rid of that desmoid tumor. In June of 2021, it's so amazing, I ended up doing all 26.2 miles on my forearm crutches. Took me 11 hours. I had an amazing team of people with me. I think one of the biggest lessons that came out of being on the nirogacestat trial for me was that I kind of changed my whole approach because finally, for the first time, I had taken a medication that had provided me with an improvement in my quality of life, and it reduced my pain, and it increased my mobility. I'm super hopeful that this becomes an FDA-approved drug that other patients can have access. Our team is working with urgency to transform the lives of people like Dana. Now we'll hear from Dr. Breelyn Wilky, Director of Sarcoma Medical Oncology at the University of Colorado, Denver, who has experience with nirogacestat through the clinical trials as well as the SpringWorks Expanded Access Program. Dr. Wilky, thank you for being with us today to share more about desmoid tumors, the patient journey, and treatment considerations for these patients. Good morning. I'm Dr. Breelyn Wilky from the University of Colorado School of Medicine, where I'm the Director of Sarcoma Medical Oncology. I'd like to thank SpringWorks for the opportunity to spend some time with you today talking about rare diseases called desmoid tumors. I'm gonna walk you through a day in the life not only of a physician who takes care of patients with these diseases and has to make treatment decisions, but I also wanna share with you the patient perspective, what it's like to live with desmoid tumors. Desmoid tumors are also known as desmoid fibromatosis or aggressive fibromatosis. These are very unique neoplasms of fibroblasts, which are the structural cells that hold us together, connective tissue cells that commonly make up structures like scar tissue or tendons. These are not considered a cancer because they cannot metastasize or spread to other organs. They can occur anywhere head to toe and can be locally aggressive, infiltrative, and destructive. The particular behavior and nature of the individual desmoid tumor really depends on the location and its proximity to other important structures. Even though that these are not cancer, these tumors can have an incredible impact on function and quality of life for otherwise young and healthy patients. This is a picture of a patient's back that you can see here, and you can see this very large mass coming out of the side. This is a desmoid tumor. Overall, desmoid tumors are very rare. The incidence is estimated at only two-four cases per million per year. They can occur in all age groups, but are most common in young people between 10-40 years of age, and they're twice as common in women. Most desmoid tumors are sporadic. Think of these as a disorder of wound healing and scar tissue pathways. It's not uncommon that a patient may have a prior injury, a trauma, a surgery scar, or a foreign body that might trigger the formation of a desmoid tumor. However, the majority of patients with sporadic tumors, we don't know a cause. They're unelicited. It is important to note that about 10%-15% of patients develop desmoid tumors associated with a syndrome called Familial Adenomatous Polyposis. This is an inherited condition where patients lack a gene called APC in all of their cells. In addition to having essentially a 100% chance of developing colon cancer, which requires early colectomy or removal of the colon to prevent cancer, about 10%-20% of FAP patients will also go on to develop desmoids that can be multiple, and notoriously occur in the abdominal cavity, which is very challenging to deal with. Here is a photo of the biologic pathways we're talking about. Sporadic desmoids are driven by activating mutations that lead to constant activation of beta-catenin, which triggers the fibroblast growth and the tumor formation. As I mentioned, APC, which is lost in familial adenomatous polyposis or FAP, is actually the negative suppressor for beta-catenin. There are other pathways that are important that we don't completely understand, but particularly estrogen, which can also have an effect on desmoid growth, as we mentioned, and then a pathway called Notch, which we'll hear a lot about today and is regulated by gamma secretase, which is being inhibited by the drug nirogacestat. Patients can present with symptoms based on the location of the desmoid. In extremity sites or on the abdominal wall, most commonly, patients will notice a firm, large mass that can be painful or limit the range of motion if it's in a joint. However, desmoids that occur inside the abdominal cavity or the thoracic cavity may not be found until they start to develop symptoms that are different, like weight loss, GI symptoms like nausea, vomiting, or a change in bowel habits, and even in severe cases, complete obstruction of the bowel, a hole in the bowel or a rupture called perforation or bleeding. You might think that the immediate solution for a desmoid tumor, like other types of cancer, is to remove it surgically, to cut it out. It turns out this is actually not always the best option for desmoid tumors. Even a patient like the one I showed you with the picture of the very large desmoid tumor on his back, to remove that surgically is going to require an extensive mutilating surgery. In the abdominal cavity or other locations, the desmoid wraps around structures like spider webs. Big blood vessels, organs, these are impossible to remove with surgery. Because fundamentally desmoids are a disorder of wound healing, after surgery, even with complete removal, there's up to a 50% chance that the desmoid will just regrow because it's stimulated by the same wound healing pathways that we've been talking about. Interestingly, we have learned that about 20% of desmoids can resolve completely or at least become dormant and not grow with no treatment at all. Based on this, for asymptomatic desmoids or desmoids that are not in a dangerous location, the standard guideline is a watch and wait approach, and to reserve any treatment in case the desmoid does start to grow or if it becomes symptomatic. Now, medical therapy is actually the standard recommendation for almost all desmoid tumors, except for the ones that occur in the abdominal wall where surgery is not morbid and the tumor can easily be removed. Life-threatening surgeries are also performed in case of catastrophic complications from the desmoid tumor. In general, we are focused primarily on medical therapies rather than surgery based on these guidelines. What are our treatment options then from a medical perspective? Well, we discussed the watch and wait approach, and we discussed when we would consider surgery. Again, small abdominal wall tumors. What about radiation therapy? It's very effective for desmoid tumors, but the problem with radiation is there's a small but significant risk of a secondary cancer, a full-blown cancer of fibroblasts called sarcoma. This is not great for young and healthy patients. Radiation treatment causes long-term fibrosis, which is a thick scarring that occurs in the area where radiation is given. We try to avoid this whenever possible. New strategies that we're using include ablation, which is where a needle is placed into the desmoid tumor, and then you can either freeze it, you can electrocute it, or you can use high-frequency ultrasound waves to try to neutralize it as well. These are more exploratory, but we are increasingly using these techniques for the right tumors at the right time. In medical therapies, the oldest therapies we used were traditional chemotherapy. This contained all of the usual side effects, including long-term risk of secondary cancers like leukemia, toxicity of the heart and other organs, risks of serious infections, and so on. Now, liposomal doxorubicin does avoid many of these toxicities, and this is one of the standard medications that we frequently will use in our management of desmoid tumors. It still has significant side effects for the patient. We are in the age also of targeted therapies. There was recently a large phase III trial of a targeted therapy pill called sorafenib versus placebo for desmoid tumors that showed significant improvement. This is very similar to other drugs in the class, including imatinib and pazopanib. Although these are not traditional chemotherapies, there are still significant toxicities associated with this group of agents, including high blood pressure, risks of bleeding and blood clot formation because of the effects on normal blood vessels, as well as nuisance side effects such as diarrhea, also a lightening of the hair or pigmentation. They can also get significant thyroid dysfunction, and importantly, pregnancy and breastfeeding are contraindicated not only with these agents, but fertility can be impacted by traditional chemotherapy as well, long term. Previously, we've also used estrogen-blocking therapy, which again, we found has had a similar response rate as a placebo, so only less than 20%. Based on this, we rarely use these drugs anymore. The two newest agents under investigation include nirogacestat, which we'll learn much more about, as well as a drug called tegavivint. These are all in clinical trials. Tegavivint is a beta-catenin inhibitor, and we don't have much data available yet. Of note, there are no approved drugs specifically for desmoid tumors. How do we choose a treatment? Well, it all comes down again to the symptoms, the location, and the risk to surrounding structures and organs. We also need to consider how badly we need to have a response, and this can not only be because of these other factors, but patient preferences. Some patients have significant anxiety over doing nothing, or they may want a quicker response to get treatment over with, based on goals and other things going on in their lives. We want to know if shrinking a tumor with medical therapy might create another option like surgery or the ability to freeze the tumor. What is the expected function or consequences after a desmoid tumor surgery? For medical therapies, patients will have strong preferences, particularly side effect profiles or other medical conditions that might drive the decision between oral drugs or traditional chemotherapy as well. It's a huge discussion that requires a lot of considerations of multiple aspects. What is not unclear is that these tumors, again, despite not being cancer, have a significant impact on patient quality of life. This is a scale, a survey that was reported in this paper from 31 desmoid tumor patient interviews. You can see some of the medical complications in this table, that patients reported not infrequently as a result of either their tumor or the treatment. Additionally, this is other impacts that are primarily psychosocial, and you can see that these are highly impactful, issues, including medical uncertainty, problems with self-esteem, problems living their lives and working, as well as other family, interactions and psychological side effects as well. What I will tell you is that the patients that have struggled the most have had surgery, for their abdominal desmoid tumors, often before even realizing the diagnosis. It was assumed to simply be a cancer. Although the desmoid is gone, the long-term issues, including chronic pain, opiate dependency, chronic bowel issues, including change in bowel movements, can be permanently life-altering. This causes a huge amount of distress for the patients, more so than the tumor ever did. Importantly, these scales and these actual factors from patients were incorporated in the phase III trial of nirogacestat. We'll actually have data in the near future measuring true impact on patient life, not just the shrinkage of the desmoid tumor from nirogacestat. For the rest of this talk, I figured I would walk you through 3 representative cases of desmoid tumor patients and how we talk about treatments and some of the challenges that come up with managing these patients. The first patient was a 35-year-old female, emergency room physician. She noted cramping and abdominal pain and could actually palpate a mass on herself. Because she was an ER physician, she performed an ultrasound and showed a 4.5 cm mass in her abdomen. When we got the CT scan, which I'll show you on our next slide, there was a large mesenteric mass. This is deep in the abdominal cavity that was wrapped around a major vein called the inferior mesenteric vein that supplies a decent amount of intestine. There were also satellite nodules and lymph nodes that appeared suspicious. The biopsy did confirm that this was a desmoid tumor, and she went on to have a colonoscopy to rule out polyps that might suggest FAP or familial adenomatous polyposis. She noted that she had three children, and her last baby was born four months before her symptoms started, and she had used in vitro fertilization and hormone exposure. At the time I met her, she did not desire any more children. This is a picture of a CT scan of the desmoid tumor. This is a slice through the middle of the abdominal cavity, and you can see this large firm mass, that is not supposed to be there on both the cross-section view as well as the frontwards view or the coronal view. The pain was thought to be related to blockage of that vein being able to drain from the intestine, and this was confirmed on colonoscopy. We took her to tumor board. A tumor board is basically a meeting we have weekly with about 30 different experts in sarcoma and desmoid tumors, including surgeons, radiation oncologists, and so on. We review all the options I talked to you about. Because of her symptoms, she was not a candidate for watch and wait. A surgical option was considered, but it was thought that she was unlikely to get negative margins because it was wrapped around the vein, and she was at major risk for long-term complications. Radiation therapy, again, there's a concern for secondary cancers in a young woman, so we reserved that as well. For ablation, the tumor was too big. It was close to important structures where an ice ball or freezing would not be ideal. The tumor was difficult to see where it stopped and started, so it was not an option at this time either. That left us with medical therapies. We discussed all of the options that we previously talked about with the patient. At the end of the day, her biggest concern was to get a quick response to relieve her pain, as well as to give her the highest chance of not having to deal with this ever again. At the time that I met her, the nirogacestat trial was not yet enrolling patients, but she would have been an excellent candidate. After thorough discussion, she opted for the most aggressive traditional chemotherapy, doxorubicin and dacarbazine. She received four treatments. She was actually treated out of state, so we were really working with her local treatment team to try to get her through therapy. Her pain did resolve with treatment, but she had significant side effects, including significant nausea and vomiting, low blood pressure, low counts requiring blood transfusions, and her menses were disrupted. We ultimately tried to adjust the treatment doses, but she was still having so much toxicity that she stopped after four cycles of treatment. You can see when comparing the baseline and the after three cycle scans that the tumor had shrunk considerably, flattened out, and actually was becoming a little bit darker, which is a classic sign of a desmoid turning into normal scar tissue. Just to kind of touch on some of these other issues, this is another patient I recently saw. 25 years old, again, had just given birth to her third child under the age of five and was actively breastfeeding her three-month-old new baby and mentioned that she was hoping for more children. Over the past several months, she had noted a mass in her left wrist, and this was increasingly getting bigger and causing the charley horse type of pain, a shooting pain through her entire hand. Her fingers were seizing up, and she was actually dropping items, worried and she was worried about potentially issues with holding her baby. We got imaging for her, and these scans show a desmoid tumor that's wrapped around all the tendons and the bones in the wrist. This is a very tight area, and a surgical option was absolutely not on the table to try to remove this without significant function. We were left again with medical therapy. Again, she's highly symptomatic. We talked about these treatment options. She was worried because she was on her feet all day running around after her kids and was worried she might forget to take pills, so just opted against sorafenib. She did decide that liposomal doxorubicin probably met her needs the best with a less intense schedule, the only once-a-month infusions. She's gonna have to stop breastfeeding now at three months with her new baby, and she needs to get onto contraception to avoid a pregnancy while on these treatments. Even if we go on and treat her now, she'll have a good chance of a response. However, there's a high risk that if she does get pregnant again, the desmoid tumor will get reactivated, and we'll be back in the same boat. Finally, the last case. This is a case where we actually did use nirogacestat. This is a 36-year-old female who presented with multiple large abdominal wall masses two years after a C-section and her pregnancy. Unfortunately, she was diagnosed with new FAP. She did not inherit this in her family. This was a new mutation. She was at risk not only for colon cancer but for multiple other desmoids down the road. She was initially treated outside at a different hospital and was started on sorafenib but developed hepatic abscesses that were difficult to explain and not able to be managed. She was changed over to tamoxifen and had progression of disease, not surprisingly. She received six cycles of a liposomal doxorubicin. While she did have some modest benefit with the doxorubicin, she had cognitive changes, severe chemo brain, fatigue, and difficulty taking care of her daughter, and so her quality of life was really disrupted. She still had a very firm mass that was causing pain and issues with her clothes fitting as well that were upsetting to her. She came to see me, and we actually applied for compassionate use nirogacestat. You can see in the scan on the top, which is a baseline prior to starting nirogacestat, that she had this very large, bright white mass that was protruding out towards her abdominal wall. She actually, after only six months of therapy, had a significant shrinkage. She can no longer feel the mass unless she palpates deeply. This is still continuing to shrink. She has not yet plateaued. Now, I'm not in a place to comment on whether or not this is a typical response for nirogacestat, but this was quite impressive, at least in her case, given the modest responses from our other agents. Importantly, the only side effects she complains of are hot flashes and the loss of her menses. She's been able to manage this with a supplement called SAMe and is experiencing excellent quality of life on treatment. She no longer has any cognitive issues or fatigue from her leftover chemotherapy, and she remains excited to stay on therapy, and we're hopeful that she'll continue to respond. The summary and take home, I hope I've convinced you that even though they are not cancer, desmoid tumors have significant impact on quality of life and in bad locations can threaten life and limb just like the worst cancer. For patients and providers, it's hard to offer traditional chemotherapy with its long-term risks and toxicity, as well as extensive surgeries that can be mutilating for the rest of their lives or radiation therapy that can cause cancers later. We're increasingly evolving towards observation and medical therapies and avoiding these sorts of interventions, but we still need an ideal future treatment for desmoid tumors. Ideally, this treatment will be highly effective but would spare patients from the toxicity and a profile that's more acceptable for young patients in their prime of life without long-term impacts or risks. I'm anxious to see, like everyone, the global data for how nirogacestat has performed, but I've treated somewhere around 20 patients either on the trial or with the compassionate use program. I've been really impressed that the benefits far outweigh the downsides. If nirogacestat's approved, I believe in my practice it will be a rare patient who goes on to receive traditional chemotherapy for desmoid tumors. Thank you, Dr. Wilky. We appreciate your overview on desmoid tumors, how they're treated today, and the unmet need from a clinician's perspective. I'm pleased to share more today about our clinical experience with nirogacestat in patients with desmoid tumors. As Saqib shared, we have over 10 years of clinical history with nirogacestat, including in our lead indication of desmoid tumors. I'd like to start with a summary of the phase II trial conducted by the National Cancer Institute, which enrolled 17 heavily pretreated and progressing desmoid tumor patients. The results from this study showed a 100% disease control rate, with five of 17 patients achieving an objective response. Clinical benefit was demonstrated regardless of the number or type of prior lines of therapy or the specific underlying mutational status. Because no patients progressed on study, median progression-free survival was not reached at the time of the publication in 2017. Long-term follow-up data from this study were just presented by the NCI investigators at ASCO. With maturation of the trial, the 2022 data cut demonstrated a median time on treatment of 4.4 years, with four patients remaining on nirogacestat after more than seven years on treatment. With long-term follow-up, no disease progression has been observed for any patient while on study. Nirogacestat was generally well-tolerated in this trial, with the most commonly reported adverse events considered related to nirogacestat, including diarrhea, fatigue, nausea, AST increased, lymphocyte decreased, hypophosphatemia, and rash. This phase II study served as the basis for our phase III DeFi trial, which enrolled a similar patient population and is using the same dose and schedule of 150 milligrams BID dosed continuously. Now turning to DeFi. This trial was designed to demonstrate the clinical benefit of nirogacestat in patients with progressing desmoid tumors. Here is the DeFi trial design. It is a double-blind, placebo-controlled, event-driven trial that randomized 142 adult patients 1:1 to receive either nirogacestat or placebo. Eligible patients had desmoid tumors that had grown by at least 20% as measured by RECIST within 12 months prior to study screening. DeFi also includes an open label extension for patients that had progressed radiographically while in the double-blind portion of the trial, or for those who were still ongoing in the double-blind phase of the study at the time of the primary analysis. The primary endpoint is progression-free survival as assessed by blinded independent central review, and this applied both to radiographic and clinical progressions. Key secondary and exploratory endpoints include safety and tolerability, objective response rate, duration of response, changes in tumor volume as assessed by MRI, and changes in patient-reported outcomes, including pain, physical functioning, and health-related quality of life. In late May, we were very pleased to report top-line data from our DeFi trial. DeFi met its primary endpoint of improving progression-free survival. This result was statistically significant with a hazard ratio of 0.29 and a P value of less than 0.001. This corresponds to a 71% reduced risk of tumor progression for nirogacestat treated patients. In addition, the study also met all of its key secondary endpoints, including objective response rate and several patient-reported outcome measures. Nirogacestat was also generally well tolerated in the DeFi trial with a manageable safety profile. The majority of women of childbearing potential had adverse events consistent with ovarian dysfunction. Other adverse events were generally consistent with safety data reported in earlier trials of nirogacestat. We received highly encouraging feedback from the investigators on this study. They were very impressed by the top-line results and are excited to have the opportunity to offer nirogacestat to patients pending approval. We believe that the top-line DeFi data provides compelling evidence of the clinical benefit that nirogacestat may offer patients with desmoid tumors. We thank the DeFi study investigators and most importantly, the patients who participated in the trial, and we look forward to a comprehensive data presentation at an upcoming medical conference. Now I'd like to talk a little bit more about ovarian dysfunction since we've received a lot of questions about this from investors after making the top-line announcement. As we heard from Dr. Wilky, an effect on ovarian function and embryo fetal toxicity has been described for many anti-cancer therapies, including cytotoxic drugs. When there is a disruption of follicular cycling, this has frequently been termed primary ovarian insufficiency, ovarian failure, or early menopause in these settings. Based on animal studies in rodents and a review of the literature, ovarian dysfunction associated with nirogacestat and other gamma secretase inhibitors is thought to be due to the disruption of follicular cycling as well as follicular depletion. Ovarian dysfunction may result in clinical manifestations such as irregular menses or sensation of menses and hot flashes. Laboratory findings may include any of the following, increased follicle-stimulating hormone and luteinizing hormone and decreased estradiol and anti-Mullerian hormone. In the NCI-sponsored phase II open label clinical trial, symptoms suggestive of ovarian dysfunction were reported in women receiving nirogacestat. We continue to analyze the DeFi data to assess overall impact of ovarian dysfunction and the dynamics around resolution. Our analysis for participants who displayed adverse events consistent with ovarian dysfunction will include baseline demographics, prior therapies, potential for resolution, time to onset and duration of events, concomitant medications, dose modifications, and hormone levels. As you can see, this will be a comprehensive analysis, and we intend to share more information at a medical conference in the months ahead. On the regulatory front, nirogacestat has already been granted Fast Track, Breakthrough Therapy, and Orphan Drug designations from the FDA. Following our positive top-line data announcement, we submitted an application for nirogacestat to be reviewed under the FDA's Real-Time Oncology or RTOR program. This is an initiative of the FDA's Oncology Center of Excellence that aims to provide a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. Under the RTOR program, the FDA is able to have access to clinical data before the information is formally submitted to the agency. We are very pleased to share that our application has been accepted and our NDA will be reviewed under RTOR. We look forward to having discussions with the agency and to submitting our NDA, which is planned for the H2 of this year. Thank you for your attention today. Now I'll turn to Bhavesh, our Chief Commercial Officer, to speak about the company's commercial plans for nirogacestat in desmoid tumors. Thank you, Mary. I'm excited to present to you today the important opportunity for nirogacestat to fulfill a significant unmet need, the associated commercial opportunity, and to provide a preview of our ongoing launch preparations following our positive DeFi readout and upcoming regulatory submission plans. I'd like to start by thanking Dana for sharing her journey and Dr. Wilky for her presentation. As we heard from both the physician and patient perspective, desmoid tumors are complex, sometimes heterogeneous tumors that can be debilitating, disfiguring, and in rare cases, even life-threatening. These tumors can cause substantial pain and often impact function, mobility, and overall quality of life for patients of all ages, but most commonly young and otherwise healthy patients. With no truly effective treatment options, this patient population has been left underserved and frustrated. There is a clear and important need for new therapeutic advances, therapies that not only address tumor growth but also alleviate symptoms and improve quality of life. We at SpringWorks Therapeutics feel privileged to have the opportunity to provide what we hope and expect to be the first approved therapy for desmoid tumors. Over the past year, we've begun our commercial preparations in anticipation of bringing a therapy for desmoid tumors to market. We've learned a great deal from our medical affairs team, who've been in the field supporting investigators and gathering important insights from physicians. As the commercial team was formed, one of the first things we set out to do was to build on these insights and develop our commercial strategy. We've worked to thoroughly understand the desmoid tumor patient journey, both through the eyes of patients and the physicians treating them. Here you see select verbatims from patients on the right in blue and from physicians on the left in green. Our findings unequivocally point to the significant unmet need. Patients speak to despair because there is no end and no solution or resolution. They live with fear that their desmoid tumors will come back. There are many stories of regret for having undergone surgery and the morbidity that has resulted from some of these surgeries, and they also describe that current treatment options come with severe side effects that can sometimes be just as bad as the desmoid-related symptoms. We've also conducted qualitative research with over 500 physicians who consistently report dissatisfaction with currently available off-label systemic treatment options. They speak to the aggressiveness of the disease and the same shortcomings of systemic therapies that are currently used. They also speak to the challenges of surgery to treat desmoid tumors, worrying about whether they got it all and the need to better understand the potential recurrence post-surgery. For those affected by them or working on behalf of those who are, desmoid tumors truly are anything but benign. Their morbidities are malignant. Against this backdrop, we believe SpringWorks Therapeutics has an important responsibility and a significant opportunity ahead of us for nirogacestat in desmoid tumors. First, there are about 1,000-1,650 new cases diagnosed in the U.S. each year. That said, the estimated prevalent pool is three-seven times the incident pool due to the high recurrence rate and the long course of the disease, implying a total of 5,500-7,000 patients undergoing active treatment for desmoid tumors each year in the U.S. We estimate approximately 50% of them are currently treated with a systemic therapy, and we expect nirogacestat to be an important option for those patients. Beyond that, we also see this patient population growing as desmoid tumor experts and guidelines have moved away from surgery as a default post-intervention due to the invasive nature of the tumors and high recurrence rates of up to 77%. The first joint global consensus guidelines suggesting avoidance of initial surgery were published in 2020, and we anticipate these guidelines to have a meaningful impact on the frequency of initial surgical intervention. We believe that over time, and with the support of our educational efforts and with the availability of more effective options, the role of systemic therapies in the treatment of desmoid tumors will continue to grow. This is supported by the experience in Denmark, where the 2014 European Consensus Guidelines suggesting avoidance of initial surgical intervention led to a drop in initial surgeries from 75% to 32% over a time span of three-four years. Second, we are pleased that there is already a high degree of awareness of nirogacestat among physicians. Over 70% of oncologists that we surveyed were aware of nirogacestat on an aided basis. Additionally, a key to success in any launch is having strong data from a rigorous study with expert KOL involvement. Over 90% of U.S. DeFi sites are registered sarcoma centers, which are institutions with multidisciplinary sarcoma expertise. This means that leading sarcoma specialists already have experience with nirogacestat. Similarly, many DeFi clinical sites were also leading NCCN centers. Third, we have the potential to bring the first FDA-approved therapy to this underserved patient population with the strongest overall profile generated to date. We now have positive top-line data from the phase III DeFi study, a rigorously designed study that enrolled a population with progressing desmoid tumors. As Mary mentioned, in addition to meeting the primary endpoint of improving progression-free survival, the DeFi trial achieved significance on all key secondary endpoints, including ORR and quality of life measures. In addition, phase I and phase II trials demonstrate evidence of long-term treatment durations. While we certainly believe in the strength of the DeFi data, it is of course important to understand the perspective of treating physicians. When presented with a blinded product profile commensurate with the results achieved in DeFi, physicians expressed substantial enthusiasm for nirogacestat, with 80% of oncologists seeing the profile as more favorable overall than sorafenib. Approximately 90% of medical oncologists and surgeons expressed an intent to switch patients to nirogacestat if approved. We believe this confirms that nirogacestat has a profile that has the potential to become the standard of care in this setting. All of these factors set the stage for strong uptake by clinicians upon approval and underscore the potential of a substantial commercial opportunity for SpringWorks Therapeutics. We've also done work to understand what matters most to prescribing physicians when selecting a treatment for patients with desmoid tumors. We asked 100 oncologists that treat desmoid tumors to rank their top treatment goals. The results underscore that first and foremost, clinicians prioritize efficacy-related attributes. The top-ranked goals are improving quality of life, achieving durable responses, avoiding severe outcomes of disease progression, improving function and mobility, reducing tumor volume, and improving pain. Importantly, as indicated in the blue bars on the slide, all of the top seven priorities are addressed through primary, secondary, or exploratory endpoints in the DeFi trial, positioning us well to offer an evidence base that specifically addresses the priorities of treating physicians. Turning now to the treatment landscape. Today, there is substantial variability in how patients with desmoid tumors are treated. We heard in Dr. Wilky's presentation that traditional chemotherapies and other systemic therapies that are being used off-label to treat desmoid tumors carry risks and toxicities. The lack of a systemic therapy that offers strong efficacy, improves quality of life, and has a manageable tolerability profile has resulted in a rather fragmented treatment landscape. Looking specifically at sorafenib, the phase III data was from an investigator-sponsored study that assessed ORR locally, not centrally, did not collect on many of the important endpoints we just discussed, and enrolled a less severe patient population than our DeFi study, with only 40% of patients having had radiographic progressing tumors at the time of study entry, compared to 100% in the DeFi study. In addition, sorafenib's ORR was not statistically significant as compared to placebo. Nirogacestat will have the most robust and comprehensive data package in desmoid tumors, as Mary has already described. Detailed results from DeFi will more fully describe the profile of nirogacestat in this indication. As mentioned, we believe that the strength of the product profile should support the opportunity for nirogacestat to become the standard of care for patients with desmoid tumors upon approval. As with any medication, there are risk-benefit considerations that physicians and patients will have to consider when making treatment decisions. Mary provided context earlier regarding reproductive toxicity, and Dr. Wilky shared her perspective as a treating physician. I'd like to provide an additional perspective on what this means in terms of the potential addressable patient population. We've assembled a variety of epidemiological and market research to inform our assessment of the market potential in light of these considerations. For context, I'd like to highlight that epidemiology research has shown that the typical desmoid tumor patient is a woman who initially presents in her fourth decade of life. Specifically, we found that the median age at diagnosis was 38 years, and the interquartile range was 31-50 years old. When looking at the prevalence data, of the 5,500-7,000 desmoid tumor patients actively seeking or receiving treatment in any given year in the U.S., we estimate that 60%-70% of these individuals are female. Based on our research, we estimate that approximately 20% will have female reproductive toxicity concerns, but approximately three-quarters of this group will eventually require or choose an active intervention given the nature of their tumors or the symptoms that they are experiencing. This means that the totality of the patients who may elect to forego treatment due to reproductive concerns represents less than 10% of the overall eligible population. Importantly, as you can see on the right-hand side of this slide, all current therapies, including surgery, chemotherapeutic agents, and TKIs, are associated with female reproductive toxicities. All of which require family planning considerations to be taken into account. Our market research shows that a majority of medical oncologists are frequently talking to their female patients about fertility concerns for all of these therapies. With positive DeFi results in hand, our focus now is squarely on preparing the market, the organization, and the brand ahead of this important launch. Our medical team has already supported a number of key medical education programs around which we've seen strong engagement. In the coming months, we will launch a robust disease education campaign geared towards increasing awareness of desmoid tumors, shortening the timeframe to, and improving the accuracy of diagnosis, and educating on the importance of a multidisciplinary consultation, which is especially important in the community setting, where patients today are often still referred to a general surgeon instead of a sarcoma specialist. We have actively engaged with the thought leader community, important patient advocacy organizations like the Desmoid Tumor Research Foundation, community oncology associations, payers, and other important stakeholders. We are building critical teams and infrastructure. We've hired a commercial leadership team with deep experience in oncology and rare diseases. We are building our distribution model for commercial supply and preparing a patient support program to enable desmoid tumor patients who can benefit from nirogacestat to have access to the treatment once approved and prescribed. We are concurrently advancing our customer segmentation and targeting activities, as well as initiating sales manager hiring as a precursor to onboarding the sales rep team. Of course, now that we have the DeFi data, we are rapidly accelerating the key brand-building activities. Our US pre-launch activities, commercial infrastructure, and commercial supply readiness are fully on track for an approval in 2023. We're advancing our activities at a rapid pace and are energized and eager to serve patients with desmoid tumors. In summary, nirogacestat has the potential to address a large and unmet need for patients with desmoid tumors and represents a significant business opportunity for SpringWorks. There is a large pool of prevalent patients actively receiving treatment annually in the US, and the propensity to treat is high, with over 90% of US desmoid tumor patients receiving an active intervention. Desmoid tumor experts and guidelines are moving away from surgery as a first approach for these tumors, and we believe that nirogacestat has the potential to become the systemic therapy of choice based on its differentiated efficacy, tolerability, quality of life improvements, and oral convenience that supports the potential for extended duration of treatment. Our ambition is to change the paradigm of treatment and provide the first FDA-approved therapy for patients with desmoid tumors, one that offers truly meaningful efficacy, improving a patient's quality of life, and has a tolerability profile that enables people in the prime of their life to be able to work, take care of their children, and live without significant comorbidities associated with desmoid tumors. These patients have been waiting too long. They need new advances right now, and it would be our honor and our privilege to serve them. Thank you for your attention today. It's my pleasure to turn the presentation over to Badreddin Edris, who will discuss a new expansion opportunity for nirogacestat. Thank you, Bhavesh. As I shared at the outset, we have been intensely focused on unlocking further opportunities for nirogacestat, given its best-in-class tolerability profile and first-in-class potential. In addition to the significant opportunities we see for nirogacestat to serve patients with desmoid tumors and multiple myeloma, we are incredibly excited to share more about a monotherapy expansion of nirogacestat into ovarian granulosa cell tumors. Ovarian granulosa cell tumors account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord tumors, representing 70% of all cases. At the time of diagnosis, patients typically report severe abdominal pain and abnormal or post-menopausal bleeding alongside a large pelvic or abdominal mass. There are similarities here to the desmoid tumor market. The estimated incidence of ovarian granulosa cell tumors in the US is on the order of 1,500-2,000 patients annually. Given that patients can live for years following diagnosis, we estimate a significant prevalent pool of approximately 10,000-15,000 patients with this cancer in the U.S. There are currently no FDA-approved therapies, and limited treatment options exist for these patients who are faced with the prospect of using off-label options that we believe poorly balance efficacy and safety. The alternative for these patients involves undergoing invasive surgeries with high recurrence rates. Today, there are no biologically rational targeted treatments for ovarian granulosa cell tumors, and based on emerging data and discussions with leading KOLs in the gynonc space, we are very excited by the opportunity for nirogacestat to potentially become a treatment option for these patients. I'll spend a moment on the biology and current bar for success in the clinic. Nearly all ovarian granulosa cell tumors are driven by a mutation in the FOXL2 gene, which preclinical data have shown results in sensitivity to gamma secretase inhibition. Nirogacestat is therefore expected to inhibit Notch-induced granulosa cell growth and activity, providing a rational underpinning for the therapeutic strategy and potentially leading to meaningful outcomes for these patients. Importantly, there are currently no approved therapies for ovarian granulosa cell tumors. Feedback from our KOLs suggests that the threshold for inclusion in NCCN guidelines would be quite low for a novel agent, given the precedents and limited therapeutic options available today. As you can see on this slide, single agent and combination regimens utilizing chemotherapy and anti-angiogenic therapy have shown only modest clinical activity and durability in these patients to date. These studies set the bar we aim to clear in nirogacestat phase II trial, which I'll discuss in a few moments. Before getting to the study, I wanna orient you to some of the insights we've gained from our initial market research efforts, which highlight multiple potential advantages for nirogacestat over existing off-label treatments. First, our market research indicates that patients are looking for a less invasive alternative to surgery with potentially lower risks of recurrence. Second, existing systemic treatments used off-label show low efficacy and come with challenging adverse event profiles, making them difficult to use over long periods of time. This is an especially important limitation for a tumor type that can oftentimes be slower growing and where longer-term therapy may be required. Third, there's strong physician appetite for an oral therapy to replace IV chemotherapy and IV anti-angiogenic options that they typically use for these patients. All of this speaks to the high unmet need in ovarian granulosa cell tumors and nirogacestat's opportunity to become an attractive oral systemic treatment option on the back of an FDA approval in desmoid tumors and positive results from our upcoming phase II trial in ovarian granulosa cell tumors. On this side, you see the design for the phase II trial, which is set to begin this month. Our principal investigator will be Dr. Panagiotis Konstantinopoulos, the Director of Gynecologic Oncology Translational Research at Dana-Farber Cancer Institute and Harvard Medical School. This is a single-arm open label study evaluating nirogacestat as a monotherapy in patients with recurrent ovarian granulosa cell tumors. The study is expected to enroll approximately 40 patients who will receive 150 milligrams of nirogacestat twice daily. This was the same dose and schedule used in our DeFi study. Eligible patients will have recurrent ovarian granulosa cell tumors and one or more prior lines of systemic therapy. The primary endpoint is objective response rate as measured by RECIST 1.1, and patients will be assessed for response every two months. Secondary endpoints include PFS, OS, duration of response, safety and tolerability, and quality of life assessments, all of which we believe will be important measures in evaluating the total clinical benefit to these patients. We are very encouraged by this new meaningful opportunity for nirogacestat to potentially be the first targeted oral therapy for ovarian granulosa cell patients. We anticipate dosing our first patient very soon, and we look forward to sharing more as the study accrues patients and the data set matures. I will now turn the call over to Mike Burgess to discuss our development programs for nirogacestat as a BCMA combination therapy for patients with multiple myeloma. Thank you, Badreddin. I'm delighted to be here today to speak to our BCMA programs, which are evaluating nirogacestat as a potential cornerstone of BCMA combination therapy across all key therapeutic modalities. For some brief background, this became a significant area of focus for us in 2020, driven by the encouraging preclinical and clinical data presented at ASH in 2019, which showed that gamma secretase inhibition is emerging as a validated mechanism to potentiate BCMA therapies. We have since advanced a broad collaboration strategy with leading BCMA players to generate a diverse data set to position nirogacestat as a potential cornerstone for BCMA combination therapy in multiple myeloma. This is a significant opportunity as there are approximately 40,000 multiple myeloma patients receiving first and second-line therapy and about 15,000 relapsed refractory patients receiving third-line or higher therapy annually in the U.S. We believe there is potential for nirogacestat in combination with all BCMA-targeted therapy modalities and for combination use alongside standard of care agents across lines of treatment. Over the next few slides, I'll walk through our BCMA combination approach, the mechanistic rationale, and some of the encouraging emerging data from our collaborations that have been generated to date. Multiple myeloma is the third-largest oncology revenue opportunity as a consequence of the prevalence of the disease and the long durations of treatment across multiple lines of therapy. Approximately three-quarters of the sales are in the first- and second-line setting. The vast majority of patients are treated in the community, where drug use is determined by efficacy, but most importantly, safety. BCMA therapies are likely to be adopted as the new standard of care, but their use may be limited by their toxicity profile, whether that's ocular toxicity in the case of antibody drug conjugates or cytokine release syndrome neurotoxicity or administration complexities in the case of T-cell engagers and CAR T-cell therapies. Myeloma development typically starts with monotherapy development in relapsed refractory disease and moves forward to frontline combinations with standard of care over time. Nirogacestat has the potential to unlock opportunities for all BCMA therapies, particularly in the community setting as part of effective, tolerable, and convenient regimens. Here you will see that we now have eight ongoing clinical collaborations, which span all key BCMA modalities and are non-interventional. All costs associated with studies are assumed by our collaborators other than expenses related to manufacturing of nirogacestat and certain expenses related to IP filings, making these programs a capital-efficient way for SpringWorks to collect a broad set of clinical data across a range of therapeutic modalities. Five studies are currently in the clinic, and three others are planned. As a reminder of the mechanistic rationale, gamma-secretase has been shown to cleave BCMA, which is specifically expressed on multiple myeloma cells. By inhibiting gamma-secretase with nirogacestat, membrane-bound BCMA can be preserved on the surface of myeloma cells, thereby increasing target density while simultaneously reducing levels of soluble BCMA, which may interfere with the activity of BCMA-directed therapies. Nirogacestat has been pre-clinically validated to reduce BCMA shedding and profoundly increase cell surface BCMA levels to improve the activity of BCMA-targeted therapies against myeloma cells. This has been shown across all key modalities, as you can see from the data panels that show profound synergy in combination with ADC, CD3 bispecific, CAR T-cell therapy, and a monoclonal antibody. In addition to clear preclinical validation, we believe that nirogacestat has several differentiated advantages over other gamma-secretase inhibitors, including the tolerability profile that enables it to be dosed continuously, which is important for providing continuous pharmacodynamic engagement with BCMA since the target turns over so rapidly. Damian Green and colleagues at Fred Hutchinson Cancer Center have previously demonstrated that gamma-secretase inhibition leads to increased membrane BCMA in patients with multiple myeloma in a study evaluating the gamma-secretase inhibitor crenigacestat in combination with a BCMA-targeted CAR T-cell therapy. An increase in membrane-bound BCMA was demonstrated in myeloma cells in the bone marrow after one week of GSI monotherapy run-in, as evidenced by both greater percentage of cells that were positive for BCMA, as well as a profound increase in the median surface density. Follow-up data presented more recently at ASH last year underscored the consistency of the effect on membrane-bound BCMA in additional patients. These data represent proof of concept for gamma-secretase inhibitors, leading to an increase in BCMA target on multiple myeloma cells in patients. Our objective is to generate clinical data to evaluate the role of nirogacestat in combination with all key BCMA modalities, with the ultimate goal of meaningfully improving clinical outcomes for patients with multiple myeloma across lines of therapy. Reflecting on data generated with nirogacestat in combination with CAR-T, I'd like to share a data vignette that was presented last December at ASH by our collaborator, Precision BioSciences, which begins to show clinically the profound impact that nirogacestat potentially had on BCMA-targeted therapies. As shown on this slide, when combined with nirogacestat at a dose of 100 milligrams twice daily, a low dose of Precision's allogeneic BCMA CAR T-cells achieved a similar level of expansion and persistence as a seven-fold higher dose of CAR T-cells administered as a monotherapy. This further supports our hypothesis that nirogacestat has the ability to be the cornerstone of BCMA combination therapy across modalities, and we look forward to generating and reporting additional clinical data with our patients in 2022. Turning to a phase I and II study evaluating nirogacestat in combination with GSK's antibody-drug conjugate, BLENREP, which is our most advanced BCMA program. The goal of this study is to lower ocular toxicity while preserving efficacy compared to single-agent BLENREP when dosed at its approved dose and schedule of 2.5 milligrams per kilogram every three weeks. When BLENREP is used at its approved monotherapy dose and schedule, it exhibits antitumor activity with an objective response rate of 31% that is associated with ocular toxicity in a high proportion of patients, presenting a potential barrier to developing BLENREP in first-line therapy. The key thesis we are operating on is that the combination of nirogacestat with lower-dose BLENREP will preserve the activity of BLENREP at its approved dose while reducing ocular toxicity. The lower dose of BLENREP being taken forward in this study is 0.95 milligrams per kilo. As a reminder, this dose is expected to have no clinical activity as a monotherapy, as per the DREAMM-1 data. Here on this slide, you see the development plan for nirogacestat in combination with BLENREP. The study, which is a sub-study of GSK's DREAMM-5 platform trial, began with a dose exploration arm evaluating 0.95 milligrams per kilo BLENREP Q-3 weekly, combined with a 100-milligram BID nirogacestat dosed continuously and subsequently moved into a phase II randomized cohort expansion based on data from the initial dose exploration cohort. The target enrollment for the cohort expansion arm is 70 patients, with 35 patients randomized either to BLENREP 2.5 mg/kg Q3 weekly monotherapy, the control arm, or low-dose BLENREP plus nirogacestat using the same dose as the dose exploration cohort. Sub-studies are underway to evaluate the combination of nirogacestat plus BLENREP with dexamethasone and either Revlimid or pomalidomide to enable future development in first- and second-line myeloma, respectively. Enrollment in these sub-studies is expected to commence imminently. Interim data from the DREAMM-5 study were presented at ASCO last weekend and included data on patients from the dose exploration cohort, as well as from the randomized cohort expansion arms. 10 patients were enrolled in the dose exploration and interim data from 28 patients in the phase II cohort expansion, 14 in each arm were presented. At the time of the March 4th, 2022 data cut-off, the median follow-up in the low-dose BLENREP plus nirogacestat dose exploration cohort was approximately 35 weeks, and the median follow-up of both cohort expansion arms was 12 weeks. The study enrolled patients with relapsed refractory multiple myeloma who had failed multiple prior lines of therapy. The adverse event profile for non-ocular events was as expected, based on the known profile for both monotherapy BLENREP and nirogacestat. The combination did not result in any clear exacerbation of either toxicity profile. However, when you look at the ocular adverse events, there was a substantial reduction in the rate of severe events. In the cohort expansion, which utilized the KVA ocular toxicity grading scale, grade 3 ocular adverse events occurred in 7% of patients in the nirogacestat combination, compared to 50% in the BLENREP monotherapy arm, which is consistent with previous studies for BLENREP at this dosing schedule. These data were very early, as evidenced by the median number of cycles at the time of the interim data cut, and we look forward to closely evaluating the safety profile in each arm as more patients are evaluated and more follow-up time is achieved. This data from ASCO showed that six of 10 patients in the dose escalation had a response. This data led to the opening of the randomized phase II cohort expansion. Taken together with the data from the 14 patients in the cohort expansion, the objective response rate in these 24 patients was 38%. 17% of patients achieved a very good partial response. The objective response rate of the BLENREP monotherapy control arm was 50%, which is at the higher end of the response rate for monotherapy BLENREP, which is consistently in the 30%-40% range, which may simply reflect the small numbers of patients reported in this interim analysis. Looking more closely at the responding patients in the dose exploration arm, for which there is a longer duration of follow-up, there is emerging evidence of durable responses over one year. Furthermore, some variability in the time to onset of response is noted as well, based on this early interim analysis. We will learn more with regards to the time to response as well as the response durability as more patients are enrolled and the data mature. We expect that the more data from this study will be presented at a future meeting. In summary, this interim data analysis of the DREAMM-5 study indicates that nirogacestat in combination with low-dose BLENREP may provide an attractive benefit-risk profile compared to BLENREP monotherapy at the approved doses, given the reduced incidence of grade 3 ocular toxicity while maintaining comparable efficacy. One of the things that has us most excited is the potential for the reported clinical activity in the late-line to be additive on top of the standard of care agents in earlier lines of therapy. The improvement in efficacy is facilitated by combination with current standard of care treatments. Indeed, there are precedents for therapies exhibiting a response rate of approximately 30% in relapsed refractory multiple myeloma, moving into earlier line treatment settings in combination with standard of care. For example, daratumumab exhibited a 29.2% ORR as a monotherapy in relapsed refractory population and subsequently demonstrated significantly enhanced activity in combination with lenalidomide and dexamethasone in the POLLUX study. Demonstration of greater antitumor activity in combination with standard of care in relapsed setting preceded the evaluation of the ultimate approval of daratumumab in earlier line treatment. Similarly, BLENREP is now being evaluated in combination with standard of care across lines of therapy in multiple myeloma. An interim analysis of DREAMM-9 study was presented at ASH last year, in which BLENREP was given in combination with bortezomib, lenalidomide, and dexamethasone in transplant-ineligible, newly diagnosed multiple myeloma patients. A response rate of 83%-100% was noted across various doses and schedules of BLENREP, thereby demonstrating proof of concept that BLENREP similarly has additive efficacy to standard of care in first-line patients. In this same study, the rate of grade 3 ocular toxicity was 33%-83%. Therefore, preserving BLENREP monotherapy efficacy while significantly improving ocular safety profile via combination with nirogacestat could support development in combination with standard of care agents across lines of therapy. As previously mentioned, nirogacestat and BLENREP are being evaluated in combination with Revlimid and dexamethasone, as well as pomalidomide and dexamethasone in the additional sub-studies on the DREAMM-5 protocol. We view these initial data from the GSK study as proof of concept for combining nirogacestat with BCMA-directed agents. While we think the specific benefit of adding nirogacestat to a BCMA-directed therapy will differ based on the individual modality and molecule, overall, we believe we have the potential to improve the risk-benefit profile across BCMA-targeted therapeutic modalities. We are very encouraged by the emerging clinical profile of nirogacestat with low-dose lenalidomide, given the efficacy and safety profile that we have seen to date. We look forward to the maturation of the phase II portion of the study later this year and to the initiation of new substudies evaluating this combination with standard of care treatment to support the development in earlier lines of therapy. We are also simultaneously advancing nirogacestat in combination with additional BCMA-targeted therapeutic modalities, four bispecific antibodies, two CAR T-cell therapies, and a monoclonal antibody. These studies are at various stages of development, and we are looking forward to sharing updates as they become available. Thank you very much for your attention today. We'll now take a short five-minute program break before getting back into our nirogacestat programs. The next portion of our agenda will focus on our MAPK pathway programs, starting with our MEK inhibitor, mirdametinib. Mirdametinib is an investigational oral small molecule MEK inhibitor with over 10 years of clinical experience. We believe that mirdametinib is a differentiated MEK inhibitor due to its potency, limited DDI liabilities, significant CNS exposure, manageable tolerability profile and lack of food effect. The compound is in late-stage development for children and adults with NF1-associated plexiform neurofibromas via our potentially registrational phase II-b ReNeu trial, which is fully enrolled as of the end of last year. Mary will speak more about NF1-PN in a few moments, but I'll highlight that we believe there is a significant opportunity here to make a meaningful difference for patients. While some of these patients may be addressed by selumetinib, which is currently the only approved therapy available to physicians in the pediatric setting, our feedback has been consistent that physicians and patients are looking for a more convenient compound without a food restriction. That said, selumetinib has had a rapid uptake with $123 million of sales in their last twelve months, which validates MEK inhibition in this disease and underscores the substantial commercial opportunity and the high unmet need that remains. Building on this differentiated profile is a growing set of opportunities that we are pursuing not only in rare tumors, but also in highly prevalent biomarker-defined tumors, and both as a monotherapy and in combination therapy settings, including low-grade glioma, MAPK mutant breast cancer, RAS/RAF mutant cancer and other solid tumors. We currently have five clinical trials ongoing or on track for initiation in 2022, and similar to our IP strategy for nirogacestat, we have U.S. composition of matter patent protection for mirdametinib, which extends into 2041. In aggregate, we believe that mirdametinib has a total potentially addressable population of over 150,000 patients on an annual basis from these current programs alone, representing a very meaningful opportunity to help patients and one that we have the potential to build on even further as we and our collaborators formulate additional avenues for mirdametinib's development. Data are expected across these studies throughout 2022, including some that we will highlight for the first time today. I'll now turn it over to Mary, who will start with our mirdametinib program in NF1-PN. Thank you, Saqib. Turning to our most advanced program with our MEK inhibitor, the ReNeu trial is evaluating mirdametinib as monotherapy for children and adults with NF1-PNs, which are tumors that can grow aggressively along peripheral nerves and that can lead to extreme pain and disfigurement. NF1 is one of the most common genetic tumor predisposition syndromes, with an estimated 100,000 patients in the United States. Throughout their lifetime, approximately 30%-50% of individuals with NF1 will develop plexiform neurofibromas, which can undergo malignant transformation and lead to dire prognoses. Historically, these tumors were treated with surgery. However, their infiltrated growth pattern along nerves makes successful surgical resection challenging, and these operations can oftentimes lead to permanent nerve damage and disfigurement. MEK inhibitors are a validated class for the treatment of NF1 plexiforms. Now I'll provide a brief overview of the design of our ReNeu trial. ReNeu is an open label study that enrolled 114 patients in two cohorts, a pediatric and an adult cohort. Patients received 2 mg/m² of mirdametinib twice daily, up to 4 mg twice daily on an intermittent dosing schedule of three weeks on, one week off for up to 24 cycles or approximately two years. Participants who completed 24 cycles of treatment can enter the long-term extension phase of the study. The primary endpoint for ReNeu is objective response rate as measured by MRI, and secondary endpoints include safety and tolerability, duration of response, quality of life, and physical functioning assessments, all of which are important in defining the total clinical benefit for mirdametinib. We believe that mirdametinib has the opportunity to benefit a broad set of NF1-PN patients. MEK inhibitors are a proven therapeutic approach for NF1-PNs, and this population is rapidly emerging as a validated commercial market. Both pediatric and adult patients, the latter of whom does not have an approved therapy, are looking for a durable, tolerable and convenient treatment option. This is where we believe mirdametinib has a tremendous opportunity to serve these patients due to the availability of a pediatric formulation, the absence of a food effect, limited drug-drug interaction liabilities, and a dosing scheme that allows patients to take the drug for three out of every four weeks. Together, we believe that mirdametinib's features represent a potentially best-in-class product profile that can greatly decrease patient burden and increase access to therapy. The ReNeu study is fully enrolled and participants completing 24 cycles of therapy have started to enter the long-term extension phase of the study. The ReNeu study design was previously reviewed with the FDA and our planned regulatory interactions later this year are intended to confirm the pivotal nature of the study and to align on the data required for regulatory approval. Now I'm happy to turn it over to Jim to walk through the additional expansion opportunities we're pursuing for mirdametinib. Thank you, Mary. I'm now going to spend a few minutes discussing some additional indications that we think are very promising for mirdametinib, along with the presentation of some novel clinical data from our collaborations with BeiGene. Before starting, I just want to orientate you. We will begin the discussion with some of the programs that are less advanced. I will briefly walk through the rationale for our approach to these programs, focusing on those that have already started dosing and that are nearing initial data releases, then turn our attention to the more mature BeiGene collaborations. The first indication I'll highlight is pediatric low-grade glioma. These are the most prevalent CNS tumors in children, accounting for approximately 30% of all cases and are associated with significant morbidities, including seizures and cognitive decline. In addition, the current cases do have a propensity to become malignant and deadly. There are no approved therapies for low-grade gliomas, and patients with unresectable disease or residual disease following surgery often receive increasingly aggressive chemotherapy regimens. Importantly, approximately 70% of patients with low-grade gliomas harbor genetic alterations that upregulate the MAP kinase activity, making MEK inhibitors an attractive therapeutic strategy, as shown in a number of small studies with other MAP kinase pathway inhibitors. Given mirdametinib's unique CNS exposure and our experience dosing the agent in pediatric patients through our NF1 program, we were approached by St. Jude to collaborate on a phase I, phase II trial, which has now kicked off. The phase I portion of this investigator-sponsored trial commenced last year and is currently in dose escalation. After determining a recommended dose, our collaborators at St. Jude's will plan to enroll three expansion cohorts in the phase II portion of the study. We're delighted that an initial look at these data will be presented next week at the International Symposium on Pediatric Neuro-Oncology. Next, we have a clinical collaboration with Memorial Sloan Kettering. The collaboration is a platform study evaluating mirdametinib in combination with fulvestrant in ER-positive breast cancers harboring MAP kinase pathway mutations, especially NF1 loss of function. We also have a separate cohort evaluating mirdametinib as a single agent in tumors with activating mutations in MEK1 and MEK2. The scientific rationale supporting the fulvestrant combinations in ER-positive breast cancer patients with MAP kinase-mediated resistance is shown here. Despite the broad success of endocrine therapies for ER-positive breast cancers, a significant proportion of patients progress on therapy. The thesis here is that MAP kinase mutations, which are found in up to 15% of these cancers, can contribute to fulvestrant resistance and that using a MEK inhibitor along with hormonal therapy can potentially improve the efficacy of the latter. Along the bottom of the slide, you see some preclinical data that support that thesis. On the left panel, the combination of fulvestrant and a MEK inhibitor cause durable tumor control in an in vivo model of ER-positive NF1 loss of function breast cancer, supporting the enhanced tumor activity. On the right panel, combination of fulvestrant and a MEK inhibitor lead to a more complete inhibition of the MAP kinase pathway. Turning to the opportunity for the second cohort of our ongoing trial and collaboration with MSK, activating mutations in MEK1 and MEK2 have been described in approximately 2% of solid tumors. Preclinically, mirdametinib has shown potent activity against class one and class two mutations, namely those that are RAF-dependent or regulated, and published case reports with MEK inhibitors are supportive of the use of mirdametinib in these patients. Mirdametinib's potentially best-in-class profile has set the stage for us to advance promising combination opportunities in collaboration with BeiGene. In our clinical evaluation of the mirdametinib and lifirafenib, the vertical combination, so far we have observed clinical activity in several tumor types and in a variety of different oncogenic RAF alleles, noting these outside of G12C. Just as importantly, we have clinical evidence that this combination can be tolerated by patients with a meaningful number of patients in our study dosed for over two years. I'll show you those data in just a few moments. For the novel pan-RAF dimer inhibitor, BGB-3245, we have all successfully progressed the dose finding study with safety tolerability profile and early clinical signals demonstrated in mutational backgrounds that are not addressed with currently available therapies. Encouraged by the early-phase clinical data of BGB-3245, we in Beijing have completed the next equity investment in the MapKure joint venture to enable an expanded BGB-3245 development strategy with a focus on selected tumor types and mutations. I'll walk through those data plans as well after Dr. Neal Rosen, whose lab at MSK did much of the foundational work around this molecule, introduces some of the preclinical data that got us and Beijing excited about moving the program into the clinic. These data demonstrate that preclinically mirdametinib and lifirafenib show compelling synergy. In vitro screens of RAF mutant cancer cell lines show large improvements in anti-proliferative potency with the addition of mirdametinib to lifirafenib across different RAF isoforms. Similar combination activity is seen in vivo, leading to more robust tumor regressions with the combo. Now moving into the clinical data. 35 patients were treated using a standard novel-novel phase I dose escalation scheme. Of these 35 patients, 13 remained on therapy as of the November 2021 cutoff date, with more patients having been enrolled since then as well. These were patients with advanced disease and were heavily pre-treated. The majority of patients had tumors with a RAS mutation as their primary driver. One additional point to call out here is the high prevalence of gynecological tumors, which in this study were primarily low-grade serous ovarian cancers. The investigators were excited by some early responses we saw in these patients, and so we're highly motivated to get more patients on trial given the lack of an approved therapy for these patients. Here you see the waterfall of best tumor responses from across the dose escalation cohorts. We were encouraged to see clinical activity across mutation types with an overall response rate of 30% in the escalation phase. The observed activity included some deep responses. As mentioned, we've continued to enroll patients since this data cutoff date, and encouragingly, we've seen more responses in priority tumor types. We expect these updated data will be presented at a medical conference later this year. On this slide, we see the swimmer plot for patients with low-grade serous ovarian cancer treated on study. Given that this was the largest subset enrolled in the dose escalation portion of the trial, LG-SOC is a subset of ovarian cancer that is enriched for MAP kinase alterations and is molecularly strictly distinct from high-grade serous ovarian cancer. The objective response rate in these patients was 73%, with one CR and seven PRs out of 11 LG-SOC patients. We saw a lot of responses deepened or remained stable over time, and of note, there were also three long-duration stable diseases. By May of this year, we had a disease control rate of 100%, with 10 of 11 patients remaining on therapy, with time on treatment between 13-34 months and a median duration of treatment over two years. Clinical responses were seen across a range of MAP kinase alterations, including in patients with KRAS G12V and G12D, NRAS Q61R, and BRAF V600E mutations. Overall, the duration of response and disease control in this subset was highly encouraging and it compares favorably with other data sets in this indication. Additionally, the time that these patients remained on therapy illustrates that this regimen can have a favorable tolerability profile, which was one of the open questions around this mechanistic combination at the outset. Here we see a patient vignette from the study which illustrates both depth of response and tolerability. This patient presented with LG-SOC with a KRAS G12D mutation and had three lines of prior treatment. The patient achieved a PR in the time of her first scan, which was eight weeks, and this response deepened over time to a 77% reduction in the target lesion by week 48. We also observed marked reductions in CA-125 levels on treatment. We believe these data are very encouraging, with the patient remaining on therapy as of May 2020. On this slide, we highlight the safety and tolerability profile for the combination treatment. As you can see, all grade three or higher treatment-emergent AEs are shown on the left. We view these as generally consistent with what you would expect to see in a typical heavily-treated, relapsed, or refractory phase I cancer population. On the right are the related grade three or higher AEs, which were generally manageable. We note that there have been relatively few discontinuations due to AEs, and as mentioned before, we see a manageable safety profile of the combination that is amenable for the prolonged dosing, given multiple patients who have been treated for over two years. I'm going to switch gears now and talk about the pan-RAF dimer inhibitor BGB-3245, which we are advancing with BeiGene through a joint venture called MapKure. Starting with some background, BGB-3245 is an oral selective small molecule RAF dimer inhibitor that was designed with the goal of improving on the potency and selectivity profile of lifirafenib. BGB-3245 has demonstrated greater kinome selectivity compared to lifirafenib. We believe this enhanced selectivity could lead to improvements in both activity and tolerability. MapKure holds global rights to the asset outside of Asia and is leading the clinical development program. The program is supported by cross-functional collaboration using resources and teams from both SpringWorks and BeiGene. Importantly, MapKure Scientific Advisory Board is comprised of leading industry and academic experts, including Dr. Neal Rosen from Memorial Sloan Kettering Cancer Center, who is here with us today. I'll now turn over to Neal for a scientific presentation on BGB-3245 before presenting the clinical data. Neal? Hi, my name is Neal Rosen. I'm a pharmacologist and molecular biologist and oncologist at Memorial Sloan Kettering Cancer Center, and I work on signaling, especially signaling through the RAS RAF MEK pathway. These are my disclosures. I'm on the SABs of BeiGene, MapKure, Ribon Therapeutics, Zai Lab, and AstraZeneca. I get research support from AstraZeneca and Revolution Medicines. I'm an advisor to Chugai, and I have equity in the designated compounds in this slide. Okay. What I'm gonna talk about today is feedback reactivation of the ERK pathway. As you can see from the cartoon, this is a standard cartoon where RTKs, receptor tyrosine kinases, activate RAS. They activate RAS, they activate MEK and ERK, and ERK phosphorylates a variety of substrates that ERK phosphorylates a variety of substrates that mediate the effects of ERK signaling. The other thing that ERK activation does is it causes feedback inhibition of the reactivated pathway. You can see here that, for instance, the protein DUSP is induced by ERK, and DUSP dephosphorylates ERK. The proteins in the Sprouty family are induced, and they turn off upstream signaling to RAS. ERK itself phosphorylates RAF and CRAF and turns them off, phosphorylates SOS and turns it off. The net result of this is that the receptor activation of ERK is self-limiting. It has a certain duration. That's normal signaling. See the other side. On the other hand, in tumors in which this pathway is hyperactivated, the feedback is hyperactive. You have lots and lots of DUSPs and Sproutys and upstream phosphorylation, and you turn off a lot of signaling pathways, normal signaling pathways. The net result of this is hyperactivated ERK signaling controls much of cell function, many functions in the cell, and that creates oncogene addiction. It creates addiction to this pathway, and that's why RAF inhibitors can work. Tumors are very sensitive to inhibition of RAF inhibitors. However, when you give a drug, like vemurafenib, and you inhibit the pathway, you reactivate the inhibited pathways, and that causes adaptive resistance, especially to current RAF inhibitors because they dimerize. When you reactivate RAS induces dimerization of BRAF V600E to itself and to other RAF molecules, and vemurafenib does not work anymore. You need a dimer inhibitor. In collaboration with BeiGene, I will not talk about this. This was a group of papers, probably the most informative of which was written by Zan Yao in 2015 in Cancer Cell. Zan figured out, isolated from BeiGene's stock of RAF inhibitors, a RAF inhibitor that would inhibit dimers. The prediction was you would hit BRAF V600E by itself, which is a monomer. You would predict you would inhibit class two BRAF mutants and fusions which act as dimers. But also, when you inhibit the pathway and you reactivate RAF dimers because you reactivate RAS, you will not cause adaptive resistance because this drug inhibits those reactivated dimers. To test this, we looked in three types of cancer cell. Melanomas, where the rebound that causes adaptive resistance is very, very slight. Colon and thyroid cancers with BRAF V600, where the rebound is very great. This just next slide shows what I'm talking about. If you give vemurafenib to a melanoma line, you inhibit ERK signaling, ERK very well, but then at the end, you have this mild increase in ERK. This is due to relief of feedback. This may not look like much, but it accounts for a large increase in output, and it vitiates, it attenuates the effect of the drug. In contrast, 3245 has much less rebound. This is just another sign you see the same thing. You cannot fully inhibit ERK with vemurafenib in this melanoma, but you fully inhibit it with 3245. In contrast, in colon cancer, where current RAF inhibitors don't work nearly as well as they work in melanoma. In fact, they don't work pretty much at all if you give them by themselves. That's because you get this very robust rebound. That rebound is caused by activation of receptors which activate RAS, which cause RAF dimers to appear that are not inhibited by standard drugs. They are inhibited by 3245, which can really cut down the rebound. One would predict from that, and here it is same thing in this model, and you'd predict from that that it would work better against those tumors. In the thyroid, in the colon, 3245 works to inhibit growth much better than standard RAF inhibitors. Okay, BGB-3245 is insensitive to upstream reactivation. Let me reiterate because it inhibits the dimers that are induced by feedback. Let's look at this a little more carefully, and I'll tell some members of my audience who know me that this is my favorite slide. You can see it on both sides. This is what's going on inside the cell. When you inhibit this colon cancer with vemurafenib, you induce RAS, induction of RAS. When you do it with BGB-3245, the same thing happens. The BGB-3245 reactivates RAS even better than vemurafenib does, and I'll explain that in a minute. If you look at CRAF, if you look at CRAF dimers, this is a measure of BRAF, CRAF dimers. You can see you induce those dimers with vemurafenib, and you can see those dimers are not so sensitive to vemurafenib. You start off by inhibiting the pathway, but you get that rebound that prevents anti-tumor activity. Here's what's cool about this block. You see that you induce many more, much more BRAF, CRAF dimer with BGB-3245 than vemurafenib, but you only have very slight reinduction of ERK compared to the vemurafenib. Why is this? Because the rebound does not cause ERK reactivation. You inhibit the pathway upstream much better. Because you're inhibiting much better, you relieve the feedback better, and you get much more RAF dimer. But though you have that amount of RAF dimer, you only have a slight increase in MEK. The adaptive resistance to current RAF inhibitors occurs because you reactivate receptor tyrosine kinases, which activate a complex that includes SHP2 and SOS1 and SOS2. That's why you get this adaptive resistance. If you look at what happens with vemurafenib, you add SHP2, and you prevent the rebound, as can be seen here. The problem is that SHP2 is not particularly tolerated. You don't need this in high dose for 3245. You can see that 3245 works whether or not SHP2 or SOS is in there. The summary of this is SHP2, SOS prevents feedback-induced RAF dimerization, but it has minimal effect on ERK rebound following 3245. As a result, if you give vemurafenib, it doesn't work in a colon cancer, but you have to add SHP2 or SOS for it to work. You don't need that. 3245 by itself inhibits these models. This is an example of 3245 in a colon cancer. Now, it works well in the colon cancer, but upstream inhibition in this mouse model, you can get a little bit of mileage by adding something else, either a MEK inhibitor or cetuximab. The drug works pretty well by itself. In this model, the inhibitor works just as well with or without SOS1. Finally, if you take tumors which are driven by dimers, the vemurafenib with a RAF mutant that is a dimer, vemurafenib does not work at all. BGB-3245 works quite well, as can be seen here. Now, RAF fusions are dimers as well. RAF fusions are more and more common. You can see black is the control of melanoma with the BRAF fusion. You can see vemurafenib does nothing. BGB-3245 by itself gives a complete response, a stable complete response. Here's another example of a type two BRAF dimer mutant. Vemurafenib works almost not at all. If you add cetuximab, it still doesn't work at all. The BGB-3245 works quite well. The net result of this data is that BGB-3245 inhibits BRAF monomers and dimers equipotently. It inhibits ERK signaling driven by RAS-independent BRAF mutants, and it inhibits feedback reactivation of RAS-driven dimers in BRAF V600E mutants, colon and thyroid tumors. This explains some but not all of the initial clinical data. In the initial clinical data, the patients treated were all patients who had already gotten RAF and MEK for V600 V600 melanomas. Now, we have published in the past that resistance to these tumors is often mediated by dimers. These tumors, we have not been able to treat these tumors effectively with any other regimens. We are now starting to see responses in these patients with BGB-3245, which is a validation of the preclinical data. The second thing I showed you today, I don't think we've really tested yet, and that is the use of this drug in colon and thyroid cancers with mutant BRAF. Finally, this work would predict that this drug would work against RAS tumors, which are driven by a RAS that mostly works by activating RAF. Now, KRAS works by activating RAF and other targets. But NRAS mostly works by activating RAF. NRAS-driven melanomas and colon cancers are not able to be treated with targeted therapy. It's gratifying. I'm not showing the data in NRAS, but the clinical data, which you will see, shows responses of NRAS tumors hitherto untreatable by this kind of drug with BGB-3245. In summary, the results, the preclinical results show that this drug is capable of inhibiting RAF dimers and ERK similarly thereof, and that results in sensitivity of tumors that are driven by the pathway, and that is now being validated in patients. With Neal's presentation as a backdrop, I'll dive into the clinical data with BGB-3245. We're initially studying BGB-3245 as a single agent in a phase I A/B study. The phase I A portion is enrolling patients with advanced solid tumors with MAP kinase mutations, enriching for BRAF-driven cancers. After establishing our recommended phase II dose, we plan to enroll cohorts of patients with tumors harboring non-V600 BRAF mutations, BRAF V600 melanoma patients that have progressed on prior BRAF/MEK inhibitors, and patients with NRAS-mutant melanoma. Neal's presentation just gave you the scientific underpinnings of BGB-3245 and highlighted what got us excited about moving this program forward into the clinic. I'm pleased to share that even in dose escalation, we are seeing monotherapy objective responses in tumors and mutation types of interest with doses that have been well-tolerated so far. Before I get there, let me start by telling you a bit more about the trial. Here we see the baseline characteristics of the patients, which are typical of dose-escalation studies in heavily pretreated patients. As of February 2022, 38 patients were enrolled across our five clinical sites, all places you'll recognize as high quality phase I units, Memorial Sloan Kettering Cancer Center, MD Anderson, Mass General, the Peter MacCallum Cancer Centre, and St. Vincent's Hospital. Of these 38 patients, 14 remained on therapy as of the time of data cutoff. Patients have received a median of five prior lines of therapy and present with a range of tumor types, the most common being GI tumors and skin cancers. The majority of patients have a RAF mutation, but about 30% have a RAS mutation, consistent with our approach to look broadly at MAP kinase pathway-activating mutations early in development before honing in on more selected populations and expansion cohorts. Here's the waterfall showing best tumor response observed in dose escalation. Six out of 25 refractory patients achieved a PR for a 24% objective response rate. Five out of 6 responders had previously been treated with MEK/RAF inhibition and/or immunotherapy. Three of the responders had BRAF V600E mutations, all of whom had received prior MEK/RAF-targeted therapy. These responses, in particular, were incredibly encouraging to us as this has not only validated our scientific hypothesis that a potent pan-RAF dimer inhibitor, it also provides potential targeted therapy options for patients with very limited treatment options and therefore could support an accelerated development path. The remaining responding patients had KRAS G12D, NRAS G12S, and NRAS Q61K mutations respectively, with the NRAS subset in particular representing an exciting development avenue as well, given the significant number of such driver mutations and the lack of targeted agents. These two patient vignettes from the dose escalation illustrate rapid and deep responses to BGB-3245, even in patients failing available MEK/RAF therapies. Both patients were diagnosed with BRAF V600E melanoma and had previously received BRAF/MEK doublets, in this case, dabrafenib and trametinib. In addition, these patients had also received previous immunotherapy in the form of ipi and nivo combos. Both patients started on 40 milligrams per day, continuous dosing of BGB-3245, and each saw meaningful activity with decreases in their lesions after eight weeks of treatment. BGB-3245 was also tolerated, with both patients remaining on treatment as of the data cutoff. We believe these responses are highly encouraging and. Hello, Howard's team. Monotherapy recommended phase II dose declaration in the H2 of this year and expansion cohorts to commence thereafter. Here we have the grade three or higher all-cause and related treatment-emergent adverse events. Howard, can you hear us? Of note, we believe BGB-3245 has a manageable safety profile and one that's very consistent with other MAP kinase pathway agents. We see this profile as very conducive to further development, both as a single agent and in combination with mirdametinib. Looking to the future with our BeiGene collaboration, we expect to complete the current phase of the mirdametinib plus lifirafenib combination in the H2 of this year, at which point we'll be able to make decisions around expansion studies. Data from the trial expected to be presented at a medical meeting in the H2 of this year. For BGB-3245, given the activity that we've already seen in dose escalation, our recommended phase II dose determination is expected in the H2 of this year, with updated data and associated biomarker results expected to also be presented at a conference in the H2 of this year. In parallel to progressing BGB-3245 monotherapy into expansion cohorts based on the exciting clinical responses we've already observed in MEK/ RAF failures and in RAS melanoma, we'll also be embarking on the evaluation of BGB-3245 in combination with mirdametinib, a study that will be sponsored and led by SpringWorks Therapeutics. In addition, we plan to explore BGB-3245 with an anti-EGFR monoclonal antibody in GI tumors with RAF and RAS mutations. Having walked through our portfolio of activities in the MAPK-driven indications beyond NF1-PN, I can say that we are enthusiastic about the data we're seeing and the opportunities we are pursuing. We're looking forward to advancing these programs and to sharing additional clinical data at various conferences later this year. Now I'd like to invite Mike to give a brief overview of our preclinical programs. Thanks, Jim. We have been intensely focused on enhancing our R&D capabilities so that we can further explore the potential of our molecules and expand our opportunity sets. We have taken a targeted, efficient, and strategic approach to the build-out of our early-stage pipeline, and I'll now take a few moments to provide an overview of our TEAD and EGFR portfolios, both of which were in-licensed last year. Starting with our TEAD inhibitor, the program is geared towards treating cancer types driven by the Hippo pathway mutations, which have emerged as validated de novo oncogenic drivers, as well as a resistance mechanism to various targeted therapies and have been implicated in up to 10% of cancers, including subsets of meningioma, non-small cell lung cancer, and head and neck cancers, as well as kidney cancer. All of these initial indications of primary interest for this program are covalent binders in the TEAD palmitoylation pocket that have shown potential and selective inhibition of TEAD-dependent transcriptional programs, which translates to a robust proliferative control in Hippo-altered tumor cell lines. Importantly, these compounds do not impact proliferation in Hippo wild type cell lines, so this is truly targeted approach. In vivo, these compounds exhibit good drug-like properties, and we have seen that they are well-tolerated and induce dose-dependent tumor inhibition. While our initial focus will be on monotherapy applications in biomarker-defined subsets, we are also very interested in pursuing potential rational combinations, deploying TEAD inhibition with, for example, MEK inhibition or EGFR inhibition, each of which represents a mechanism of action within the SpringWorks portfolio. Moving on, EGFR mutational status is one of the most prevalent biomarker tests performed to guide patient therapy today, and small molecule EGFR inhibitors have transformed the treatment of EGFR mutant lung cancer. That being said, resistance to existing therapies is prevalent, as are suboptimal responses to initial therapy based on specific mutational characteristics. Our EGFR portfolio is designed to address high unmet need that remains. We are excited to continue working with our collaborators at Stanford and Dana-Farber and add momentum to advance this portfolio and further our strategy of developing differentiated, leading-edge targeted therapies on behalf of cancer patients. With that, I'll turn it back over to Saqib for some closing remarks. Thanks, Mike. We believe that our foundation and infrastructure will allow us to continue to build on the multiple opportunities we have created at SpringWorks Therapeutics. Our strong execution across our R&D programs, our disciplined, rigorous approach to business development, and our focused commercial build-out will drive our success in 2022 and beyond. Our commercial team is moving assertively on launch preparations for nirogacestat in patients with desmoid tumors based on our very positive top-line data and our clinical development capabilities, and those of our partners are set up to advance our existing pipeline as well as execute against a series of new opportunities. SpringWorks Therapeutics is at a very exciting juncture, and we are well-positioned for continued success. Our first potential commercial launch is expected in 2023, and by 2025, we could potentially have two marketed products with the ability and opportunity to serve patients across four distinct diseases. We have a strong financial position, a disciplined capital allocation strategy, and a multiyear cash runway that will enable us to execute on our goals on behalf of the patients we aim to serve, as well as our other stakeholders. In terms of near-term milestones, 2022 continues to be a year of data sharing and consistent execution across our pipeline. We have tremendous conviction in the data that we shared today. With nirogacestat and desmoid tumors, the DeFi top-line data delivered highly statistically and clinically meaningful results against the primary and all key secondary endpoints, providing clear evidence of a significant benefit for patients with desmoid tumors and setting us up for an NDA filing later this year under the FDA's RTOR program. We look forward to presenting detailed DeFi data at an upcoming medical meeting and in a journal publication as well. With nirogacestat and BCMA combination therapy, we generated important evidence of the synergistic potential of including nirogacestat with the first of our BCMA partners. We expect to share additional data from the nirogacestat plus low-dose BLENREP phase II trial with a longer follow-up time and more patients on both the combination and monotherapy control arms later this year. We look forward to initiating new substudies very soon to evaluate this combination with standard of care treatments in multiple myeloma. In parallel, we will be generating clinical data from our seven other collaborations. We also see significant opportunity for our MEK inhibitor, mirdametinib, both as a monotherapy in rare tumors like NF1-associated plexiform neurofibroma and low-grade glioma, as well as combination therapy in biomarker-defined metastatic solid tumors. In addition, we are very encouraged by the initial data with BGB-3245 and expect to present additional data at a conference in the H2 of 2022. In closing, we have great confidence in the high-quality molecules we are privileged to advance in indications with substantial unmet need via patient-focused and capital-efficient drug development. On the back of our first expected drug launch in 2023, we will continue to build a unique company that is driven to unlock the full potential of targeted oncology. I want to thank you for your time and your attention today. We will now take questions. We'll give people a moment to dial into the toll-free number you see on this slide, or you can ask a question via the webcast chat. Thank you. Ladies and gentlemen, if you have a question or comment at this time, please press star then one on your telephone keypad. If your question has been answered or you wish to remove yourself from the queue, simply press the pound key. Again, if you have a question or comment at this time, please press star then one on your telephone keypad. Please stand by as we accumulate the queue. Thank you all for joining us today. Before we turn to the teleconference line Q&A, we are going to begin with a question from Anupam Rama from J.P. Morgan that was sent through our email portal. With the first question. Based on the known data for nirogacestat in desmoid tumors, how do you think about treatment duration, treat to progression or more acute in nature? How do you view nirogacestat within the treatment paradigm? That's an incredibly important question. And thank you for sending that through, Anupam. We agree that the clinical experience from the phase I and phase II trial provide informative context for how we're thinking about duration of treatment of nirogacestat in the commercial setting. In our phase 1 study, the median duration of treatment was over four years, with the patients who remained on therapy for 10 years. In the phase II study conducted by the NCI, as of the 2022 data cut, which was just presented at ASCO last week, the median time on therapy was 4.4 years, with four of the 17 patients from the initial study cohort still remaining on nirogacestat after more than seven years. Ultimately, these are small patient populations, but it's illustrative of what we've experienced in the clinic with nirogacestat. Now turning to DeFi, as we highlighted in our top-line results release, nirogacestat was generally well-tolerated, and all of this speaks to our robust clinical experience with nirogacestat and supports our view that the safety profile of nirogacestat can be suitable for a long-term dosing regimen and is favorable as compared to other agents in the class of GSIs, as well as therapies currently being used and tried off-label for desmoid tumor patients like sorafenib or chemotherapy. Now, as a reminder, this is a relatively young patient population, as compared to other diseases, with tumors more commonly diagnosed in the fourth decade of life. We believe that a therapy that is well-tolerated over a long period of time will be very clinically meaningful for patients and their treating physicians. To this point, as we discussed and highlighted during today's presentation, physicians are expressing substantial enthusiasm for nirogacestat. Based on a recent physician survey, 80% of oncologists seeing the profile as more favorable overall than sorafenib, and approximately 90% of medical oncologists and surgeons expressed an intent to switch patients to nirogacestat if approved. We believe this confirms that nirogacestat has a profile to become the standard of care in this setting, and we look forward to having the opportunity to bring this drug to patients. Thank you, Saqib. Now we have just one more question from Anupam Rama from J.P. Morgan. We live in a difficult capital markets environment currently. How are you thinking about non-dilutive partnership opportunities across the spectrum of the portfolio? You've seen full steam ahead on the pipeline, but what are the other levers you can pull to extend cash runway? Thank you for the question. We continue to have a strong financial position with over $380 million of cash as of our Q1 filing. We believe that this capital provides us with a multi-year cash runway into 2024 to support the advancements of our current studies as well as commercial readiness for our late-stage rare oncology programs. As we discussed today, we have pursued a capital-efficient development strategy, working with collaborators and partners that expand the scientific, operational, and our financial strength that we can bring to these programs. I'll remind you, as you look at our portfolio in multiple myeloma, our partners are responsible for all costs incurred outside of nirogacestat drug supply and joint intellectual property filings and prosecution. With BeiGene, the cost-sharing and operational sharing structure here has allowed us to unlock several promising development opportunities that we went through this morning in extremely capital-efficient manner. Thank you. With that, operator, we'll now turn it over to the teleconference line Q&A. Thank you. Our first question or comment comes from the line of Peter Lawson from Barclays. Your line is open. Great. Thank you so much. Saqib Islam, again, it's Dr. Wilky still on the line, but just wanted to ask whether nirogacestat kind of opens up the addressable population in terms of less patients in the kind of bottom weight load versus therapeutics. Dr. Wilky is not on the line, but we can give you our perspective on that. Listen, we believe that what we have laid out, as Dr. Wilky addressed, is actually quite a compelling product profile for patients. As Bhavesh walked you through in the commercial survey work and our readiness for launch execution, we believe this will be compelling. We currently are in an environment without an approved therapy that is justifiably fragmented as the patient journey takes people from surgery to chemos, to TKI, to opioids, all of it with the goal of managing clinical outcomes, managing pain, managing functional mobility and quality of life. We believe with the data we've shared with a very meaningful top line result, as well as hitting all key secondary endpoints, which include ORR and patient-reported outcome tools that address these specific issues, will allow nirogacestat to not just be the standard of care, but potentially open the aperture for patients who would otherwise be waiting for treatment. Thank you. Just on the new ovarian indication for niraparib, if you could provide the registration, when we could see the initial data and what that trial design would look like from? Sure, Peter. This is Badreddin Edris. Happy to take that question. As we think about where things stand with nirogacestat development overall, I'll remind you that obviously we are well on our way to filing our first NDA with an expectation of approval in desmoid tumors by next year. What that enables is a whole series of more rapid paths to getting this product to patients with other indications using a set of mechanisms at our disposal. As we think about the phase II precedents in ovarian granulosa cell tumors, as we discussed earlier today, the objective response rates and PFS rates here are very, very modest. However, those precedent agents such as IV chemo, IV Avastin, have been sufficient to get on guidelines. One possibility here is for us to be able to use phase II data on the back of an approval in desmoid within the ovarian granulosa cell tumor population for guideline listing for earlier adoption. Obviously, as the dataset matures, we'll have the opportunity to scrutinize it closely and the opportunity to engage with regulators should we want to go for a more comprehensive path to market here via a supplemental NDA to our first NDA. A couple of different ways it can play out, but certainly on the back of an approved agent in desmoid tumors, we have a lot of flexibility here in terms of label expansion, indication expansion through both approvals and compendia listings. Thank you. Our next question or comment comes from the line of Corinne Jenkins from Goldman Sachs. Your line is open. Yeah. Good afternoon, everyone. How should we think about out-year revenues in desmoid tumors, given I think you could think about it sort of as a bolus of prevalent patients and then the market opportunity shifting more towards, like, an incidence-driven population? Just how are you thinking about out-year revenue given that context? Well, we think it's going to be, as in most rare diseases, we believe that you know, it should be a steady add of patients over time, including in the out years, because you will not convert everybody right at the outset. Now, cutting against that is the chance of us actually, given the awareness of nirogacestat, the absence of an approval, and the need for treatment for desmoid tumor patients that could result in an acceleration with respect to our early year revenues. Certainly, we believe that there is an opportunity not just to capture out-year patients, but as we talked about before, we believe that there is an opportunity to expand the use as people shift away from surgery and other and other mechanisms for treating desmoid tumor patients with the availability of an approved on-label therapy. I think, Corinne, it's tough to tell at the moment. The data certainly supports us having a reasonable launch, but certainly in a rare disease, you know, it isn't the same thing as having a bolus of immediate patients. As we said, you know, with the only approved therapy we expect with all of the awareness that is currently there and the enthusiasm around this drug, we hope to be proven wrong. Helpful. Thanks. How should we think about component contributions in the combination of lifirafenib and binimetinib, particularly in the low-grade serous ovarian carcinoma? How should we think about regulatory requirements related to showing component contributions as you progress into additional studies? Hey, Corinne, this is Badreddin Edris. Thanks for the question. Obviously that's an important question we have to ask ourselves in any situation where we're looking at a combination therapy development. For us, we're looking for the data to continue to mature. So far, it's been very favorable from what we've seen in terms of efficacy, in terms of durability, and ultimately that'll drive how we engage with regulators and how we might be able to negotiate moving forward in that indication. Contribution of parts is certainly one thing the regulators look for, but there's also a broader set of components here as they think about the overall clinical profile of a given combination. More to come there as those data mature, and we've pointed folks to the H2 of the year, as a time point when we'll be able to get a lot more clear on, specifically which cohorts, which patients, which mutations we wanna invest more heavily behind, within the BeiGene collaboration. Thank you. Our next question or comment comes from the line of David Nierengarten from Wedbush Securities. Your line is open. Thanks for taking my questions. I had two. First off, you know, I think we've all read the sorafenib paper for desmoid tumors and know the discontinuation rate in that context. Do you have, you know, any real world data on a real median or typical time on therapy with sorafenib for desmoid patients? My second question is, biologically speaking, going to myeloma and BCMA combinations, is there any reason or data that you have to show, you know, an increase over time in terms of BCMA expression or proportion of cells expressing BCMA? In other words, can we expect, you know, maybe a difference in response rate, you know, with a longer duration of treatment, in future studies, with other BCMA-targeted agents? Thanks. Thanks, David. I'll take the first question. I'll turn it over to Dr. Burgess to take the second. It's ultimately a question about differentiating relative to sorafenib, right? I think there are things that I can answer, there are things that I can't answer with respect to kind of where we are, but I'd highlight that we believe that just as we were incredibly pleased with the overall data set and confident that what we saw would lead to a positive top line heading into the phase III readout, we are equally, if not more confident that once the full phase III data set is available, it's clear that nirogacestat is gonna show a meaningful differentiated benefit to desmoid tumor patients and will become the standard of care. I think as we think about this relative to sorafenib, you can look to the feedback from the clinicians and the investigators being incredibly positive. You can look to the top line data. Beyond the primary endpoint of progression-free survival, we saw significant improvements on all key secondary endpoints, including ORR and these multiple PROs. These relate to key parameters such as quality of life, physical functioning, and pain experienced by desmoid patients. While we don't have head-to-head data relative to sorafenib, it stands in stark contrast where sorafenib in that one study didn't achieve statistical significance on either ORR or any patient-reported outcome endpoints, despite being tested in a less severe patient population. These outcomes are incredibly meaningful to patients. We think that they're gonna be meaningfully differentiating relative to sorafenib. You know more to come as we share all the data. As I said at the outset, as confident as we were, you know, in the wave of questions about how we felt about the top line, we feel at least as confident having seen the full data set on the ability to differentiate relative to sorafenib. With that, I'm gonna turn it over to Dr. Burgess to answer your BCMA question. Thanks, Saqib. Before diving into your specific question, I'll just take a step back on the mechanistic rationale for our combination. Nirogacestat has been validated preclinically to prevent BCMA shedding and significantly increases surface BCMA levels to improve the activity of BCMA-targeted therapies against myeloma. This has been shown across all key modalities with profound synergy in combination with BCMA ADC, CD3 bispecific, CAR T-cells, and monoclonal antibodies. Just turning to the data that was presented last weekend at ASCO, we're seeing a 38% ORR for nirogacestat plus low-dose lenalidomide combination, with about half of those being VGPRs and above. We have evidence in that dose escalation cohort of the first responses being achieved after a prolonged period of stable disease and initial responses deepening over time. We think this is due in part to the fact that we are not challenged by frequent interruptions or dose delays associated with high-grade ocular toxicities, which are higher with high doses of lenalidomide are present. Keeping up patients on therapy may well be an important aspect. On the slides that were presented earlier, you saw from data from Damian Green at the Fred Hutch, that there's both an increase in the amount of membrane BCMA present on myeloma cells after treatment with gamma secretase inhibition, as well as an increase in the proportion of cells that are now expressing BCMA. Most of these treatments are totally dependent on the antigen being expressed, and the level at which that antigen being expressed is important. Again, Damian Green's data from ASH also highlighted the fact that you could resensitize patients that had a prior failure to BCMA-directed therapies. taking it all together, we believe that increasing the duration of therapy and increasing both the proportion of BCMA cells which are positive and the degree to which they are positive should translate out to meaningful benefit in the clinic. Thank you. Our next question or comment comes from the line of Yaron Werber from Cowen. Your line is open. Hi, this is Gina dialing in for Yaron. Thank you for taking our questions. I actually have a couple of questions on your mirdametinib program. To start off with, AstraZeneca's Koselugo was approved in April 2020 as the first drug indicated for pediatric NF1-PN based on the phase II SPRINT study. Could you discuss mirdametinib's differentiation from the Koselugo and what you believe would be meaningful differentiation in the phase II-b data? My second question is how can you fine-tune the therapeutic window for mirdametinib combination with lifirafenib, given that lifirafenib is a kinase with broader coverage of TKIs and more toxicity than other RAF kinases? Thank you. Hey, this is Badreddin Edris. I'll take both questions. Thanks to you and Yaron for sharing those. On the first point, in terms of differentiation versus selumetinib, a couple of points to call your attention to. The first is the fact that this is proving itself to be a very robust commercial market. In the second year of launch, we're already seeing a run rate approaching $200 million per year for Koselugo, and that's with a label that's restricted to the pediatric population and also a number of what we believe to be important limitations, which I'll get into in a second. That's kind of the backdrop to the indication and where things stand. As it relates to differentiation, there are a couple of very important vectors that we think about here in terms of making mirdametinib a best-in-class treatment for these patients. Really, it comes down to the properties of the molecule, first and foremost. We're differentiated in terms of our potency, in terms of our lack of a food effect and lack of a drug-drug interaction liabilities. In terms of the product formulation itself, we have a dispersible tablet formulation that really is important for ease of administration in the pediatric population and also for plexiform neurofibroma patients who have the you know, challenges swallowing capsules. That's really important in this indication when you think about the high proportion of patients that have, for example, head and neck tumors. You know, in contrast to those properties that mirdametinib has, the selumetinib label, you know, underscores a challenging tolerability profile. There's a fasting requirement of six hours per day. When you think about that fasting requirement, you think about the tolerability profile, you think about their product format, which really our feedback from clinicians has been it's suboptimal and poses meaningful compliance challenges. We really have an opportunity to come in here and have a best-in-class therapy. The ReNeu data are obviously continuing to mature with more patients, more cycles on treatment, but the study has now been fully enrolled for over six months in both the pediatric and adult populations. We've been pleased with everything we've seen so far. We think that we have line of sight into multiple advantages, as we've talked about over selumetinib, and we look forward to, you know, engaging with regulators on the path to approval. That's, you know, hopefully rounds out the response to your first question. As it relates to your second question, in terms of lifirafenib and its combination with mirdametinib as well as broader development opportunities in the RAF kinase portfolio, I think certainly, as we talked about, 32-45 has a more circumscribed kinome inhibitory profile than does lifirafenib, which we think has some potential advantages here. Keep in mind, you know, we showed you data today with mirdametinib plus lifirafenib that had patients sustaining responses for years on end. Certainly, you know, there were questions out of the gate from folks around can this, an agent like this be tolerably dosed with the mirdametinib? I think we've shown that absolutely that is the case. We can do that. We have multiple-year responses with a really favorable tolerability profile. In sensitive tumor types, we're seeing deep and durable responses, which we think is really important here. You know, as we think about mirdametinib plus lifirafenib, as we think about the really exciting monotherapy data that we showed with BGB-3245 today and some of the really unique features of that molecule as it relates to not only the ability to have standalone responses, but the lack of feedback reactivation and other key features that Neal shared, we're really gonna continue to accrue data and make portfolio decisions as to where we wanna place our bets across this portfolio of collaboration, and that's gonna dictate next steps. I think a lot of that will be contemporaneous with our planned medical conference presentations along with our collaborators at BeiGene and the investigators obviously, which are slated for the H2 of this year. More to come. Thank you. We'll take our last question from Robert Burns from H.C. Wainwright. Your line is open. Hi, guys. Thanks for taking my questions, and congrats on all the data. I got two questions regarding BCMA and then two regarding some of your earlier stage pipeline. While we're still with BCMA, you know, considering the fact that we saw a 50% response rate for BLENREP 2.5 mg/kg in the DREAMM-5 study, you know, it's assumed that we're gonna see a reversion back to that relative 31% response rate seen in DREAMM-2. Considering that potential magnitude of decline in that response rate cohort, you know, how should we be thinking about the potential decline in the response rate for low-dose BLENREP plus nirogacestat in DREAMM-5 as the data matures? Yeah, I'm happy to take that one, Rob. So I think all we can say right now about the data is the following. One is from the phase II portion of the trial, it is a very early data cut from a very small proportion of patients. Just to get factual on it, we're looking at a median of three cycles of therapy from about a third of the patients enrolled on study. I think what we would expect is over more time, the response profiles are going to mature to a place that is more reflective of reality. We know that in the phase I portion of the study we saw a very robust response rate of 60%. That's something that took time to come together. Where the ultimate response rate is going to net out is a function of time, but we think it should reflect reality here. I'll remind you that the expectation or the approach here is really to maintain BLENREP-like efficacy with the combination of low-dose BLENREP plus NIRO. In so doing, being able to avoid the severe ocular toxicity rate that's been seen with BLENREP, and that's been really an impediment for that agent and room to improve. That's really the goal here, and we think that we have every reason to believe that that goal is achievable. More importantly, that goal then opens up the opportunity for line advancement on top of standard of care, where you're gonna be able to get into newly diagnosed patients and into the community setting, where the commercial opportunity is really quite vast. The second point I'll highlight is, you know, just as you pointed out, BLENREP's 2.5 mg per kg two, three-week efficacy really has hovered between 30% and 35% across different studies. I think that's a fair assumption for where things are could ultimately settle. This is a study that is ongoing. We had a very early data cut from a very small number of patients, and we would expect more data based on what's been disclosed publicly to be shared later in the year. You know, we think the data will mature in a way that continues to support our thesis. We're enthusiastic about everything we've seen and more to come. Awesome. Thank you for that. My second question regarding BCMA. You know, we recently saw that Novartis does not intend to exercise its option for AL-102 in multiple myeloma, which is AL-102's gamma secretase inhibitor. I'm just sort of curious how investors should be thinking about that potential read-through or if there is even a read-through there, with regards to niro and the BCMA CAR T-cell agents. Yeah, no, it's a good pick-up there, Rob. Ultimately, we don't think there's gonna be. Ladies and gentlemen, please stand by. You still there? Go ahead, sir. Yes. Hey, Rob. We got disconnected. Sorry. No, it's okay. Let me rewind just to answer the question comprehensively. Ultimately, we think there's no read-through here. AL-102 is a different drug than nirogacestat. Obviously, historically they've had a very tough tolerability profile that has limited them to an intermittent dosing schedule given that tolerability profile. Just as Mike laid out in response to a previous question, you need to maintain presence of a gamma secretase inhibitor in patients in order to maintain that sustained impact on BCMA and keep the membrane levels high and the soluble levels low. Everything we've seen with AL-102 shows that you're unlikely to be able to do that given an intermittent dosing schedule with a lot of time in between doses. In addition, Novartis' BCMA bispecific program, to our knowledge, has yet to disclose any monotherapy clinical data. When you consider that many others are much more advanced in the bispecific space, including, you know, our four current collaborators in Pfizer, J&J, AbbVie, and Regeneron, this may also be driving Novartis' view on their relative competitive position and likelihood for success even without considering the GSI element of it altogether. Ultimately, we don't think there is any read-through here, certainly not to anything we're doing with niraparib based on this announcement. That's our outside-in assessment for sure. Awesome. Thank you for that. Shifting towards your earlier stage pipeline. You know, congrats on the lifirafenib plus mirdametinib data. It's quite encouraging from my view. Obviously, you know, broader data, you and I have had discussions regarding the competitor VS-6766 and the potential lead time there that it has within LG-SOC as well as, you know, RAS-mutated NSCLC. I'm sort of curious, are there any levers you could pull here with which you could sort of catch up to the lead that Verastem has in that development pathway? Yeah, I think it's a good question. I mean, I think all we can say today without speaking out of turn is the fact that we really like our data. Obviously, we've continued to accrue patients and data well past the data cutoff date, which will be the subject of a medical conference presentation, which we expect to be in the H2 of this year. Within that indication, obviously, we have to make decisions around the regulatory path forward and the commercial attractiveness, and rest assured that those are all analyses and discussions that are underway. Obviously, we're looking much broader than LG-SOC with our MAP kinase portfolio. We saw some data today with the ability to potentially treat patients that have failed prior MEK/RAF with melanoma, treat patients with NRAS that currently have no targeted therapy options. As we continue development with mirdametinib as well as with BGB-3245 in its monotherapy expansions as well as the mirdametinib combination there, we think that we're gonna have a lot of informative data to help us make portfolio decisions that take into account the competitive landscape, the commercial opportunity, and the amenability to rapid development paths. All of that's gonna continue to coalesce. We're really pleased with the data that we put out showing exactly what we guided to, objective responses at doses that are well-tolerated and that can be sustained across a variety of RAS mutations, RAF mutations, and tumor types. More to come there, but we're pleased with the progress to date. Thank you. Ladies and gentlemen, this concludes today's presentation. You may now disconnect. Everyone, have a wonderful day.