UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 7.01 | Regulation FD Disclosure. |
On April 23, 2024, Day One Biopharmaceuticals, Inc. (the “Company”) issued a press release titled “Day One’s OJEMDA™ (tovorafenib) Receives US FDA Accelerated Approval for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma (pLGG), the Most Common Form of Childhood Brain Tumor.” A copy of the press release is attached hereto as Exhibit 99.1.
On April 24, 2024, the Company also updated its corporate presentation. A copy of the updated presentation is attached as Exhibit 99.2 to this report.
The information in this Item 7.01, including Exhibits 99.1 and 99.2 to this report, shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section or Sections 11 and 12(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”). The information contained in this Item 7.01 and in the accompanying Exhibits 99.1 and 99.2 shall not be incorporated by reference into any other filing under the Exchange Act or under the Securities Act, except as shall be expressly set forth by specific reference in such filing.
| Item 8.01 | Other Events. |
On April 23, 2024, the Company announced that the U.S. Food and Drug Administration (the “FDA”) approved OJEMDA (a tablet formulation and powder solution formulation of tovorafenib) for the treatment of patients of 6 months of age and older with relapsed or refractory low-grade glioma (“pLGG”) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. The indication was approved under accelerated approval based on response rate and duration of response. With the approval, the Company received a rare pediatric disease priority review voucher from the FDA.
The accelerated approval of OJEMDA is based on data from the Company’s pivotal open-label Phase 2 FIREFLY-1 trial, which enrolled a total of 137 relapsed or refractory BRAF-altered pLGG patients across two study arms. Arm 1, which accrued 77 patients, was used for the efficacy analyses. Arm 2 provided additional safety data from an incremental 60 patients and was initiated to enable access to tovorafenib once Arm 1 had fully accrued. Details of this trial were presented in November 2023 at the Society for Neuro-Oncology meeting through two oral plenary presentations and in parallel through a publication in Nature Medicine.
The approval of OJEMDA was based, in part, on the major efficacy outcome measure of overall response rate (“ORR”), defined as the proportion of patients with complete response, partial response (“PR”), or minor response (“MR”) by independent review based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (“RAPNO LGG”).
In Arm 1, data from the 76 RAPNO LGG evaluable patients include:
| • | A best ORR of 51% (95% CI: 40 - 63), which included 28% PRs and 11% MRs. |
| • | The ORR for OJEMDA was 52% among the 64 patients with BRAF fusions or rearrangements and 50% for the 12 patients with a BRAF V600 mutation. |
| • | The ORR was 49% among the 45 patients who had received a prior MAPK-targeted therapy, and 55% among the 31 patients who had not received a prior MAPK-targeted therapy. |
| • | As of the June 5, 2023 data cutoff, the median duration of response by RAPNO LGG was 13.8 months (95% CI: 11.3, not estimable). In addition, 66% of patients remained on study and continue on treatment as of this date. |
| • | The median time to response, following initiation of treatment, with OJEMDA was 5.3 months (range 1.6, 11.2). |
| • | Based on RANO LGG criteria, the ORR was 53% [95% CI: (41, 64)]. |
The safety of OJEMDA was evaluated in 137 patients with relapsed or refractory pLGG, with the majority of adverse events being Grade 1 or Grade 2. The most common side effects were rash, hair color changes, tiredness, viral infection, vomiting, headache, fever, dry skin, constipation, nausea, acne and upper respiratory tract infection.
The Company has set a wholesale acquisition cost for a 28-day supply of OJEMDA at $33,916.
Cautionary Note Regarding Forward-Looking Statements
This Current Report on Form 8-K contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: the Company’s plans to develop cancer therapies, plans regarding commercialization of OJEMDA™ including anticipated wholesale acquisition cost, expectations from current clinical trials, the execution of the Phase 3 clinical trial for tovorafenib as designed, any expectations about safety, efficacy, timing and ability to complete clinical trials, release data results and to obtain additional regulatory approvals for tovorafenib and other candidates in development, and the ability of tovorafenib to treat pLGG or related indications.
Statements including words such as “believe,” “plan,” “continue,” “expect,” “will,” “develop,” “signal,” “potential,” or “ongoing” and statements in the future tense are forward-looking statements. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they do not fully materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements.
Forward-looking statements are subject to risks and uncertainties that may cause the Company’s actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties in this press release and other risks set forth in the “Risk Factors” section of the Company’s Form 10-K for the year ended December 31, 2023 and the Company’s other filings with the Securities and Exchange Commission, including the Company’s ability to develop, obtain additional regulatory approval for or commercialize any product candidate, the Company’s ability to protect intellectual property, the potential impact of global business or macroeconomic conditions, including as a result of inflation, rising interest rates, instability in the global banking system, geopolitical conflicts and the sufficiency of the Company’s cash, cash equivalents and investments to fund its operations. These forward-looking statements speak only as of the date hereof and the Company specifically disclaims any obligation to update these forward-looking statements or reasons why actual results might differ, whether as a result of new information, future events or otherwise, except as required by law.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit Number |
Description | |
| 99.1 | Press Release, dated April 23, 2024. | |
| 99.2 | Corporate Presentation. | |
| 104 | Cover Page Interactive Data File - the cover page XBRL tags are embedded within the Inline XBRL document | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
| DAY ONE BIOPHARMACEUTICALS, INC. | ||||||
| Date: April 24, 2024 | By: | /s/ Charles N. York II, M.B.A. | ||||
| Charles N. York II, M.B.A. | ||||||
| Chief Operating Officer and Chief Financial Officer | ||||||
Exhibit 99.1
Day One’s OJEMDA™ (tovorafenib) Receives US FDA Accelerated Approval for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma (pLGG), the Most Common Form of Childhood Brain Tumor
First and only FDA-approved type II RAF inhibitor for patients with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation
RAPNO LGG overall response rate (ORR) of 51%
Day One receives rare pediatric disease priority review voucher
Conference call and webcast to be April 24, 8:30 a.m. Eastern Time
BRISBANE, Calif., April 23, 2024 – Day One Biopharmaceuticals, Inc. (Nasdaq: DAWN) (“Day One” or the “Company”), a commercial-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved OJEMDA (tovorafenib), a type II RAF inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response. With the approval, Day One received a rare pediatric disease priority review voucher from the FDA.
“OJEMDA ushers in a new day for children living with relapsed or refractory pLGG, and we are pleased that we can deliver a new medicine for these patients in desperate need of new treatment options. Moreover, OJEMDA is the first and only FDA-approved medicine for children with BRAF fusions or rearrangements, which are the most common molecular alteration in pLGG,” said Jeremy Bender, Ph.D., chief executive officer of Day One. “We are very proud that our first approved medicine addresses this serious and life-threatening disease of childhood and adolescence. We are grateful to the pLGG community, including patients and their families, study investigators, non-profit organizations, and advocacy groups, for their collaboration and support as we strive to close the innovation gap for children with cancer awaiting new treatments.”
pLGG is the most common brain tumor diagnosed in children, with patients suffering profound tumor- and treatment-associated morbidities that can impact their life trajectory. BRAF is the most commonly altered gene in pLGG, with up to 75 percent of children having a BRAF alteration. Until now, there had been no medicines approved for patients with pLGG driven by BRAF fusions.
“pLGG is a chronic and relentless cancer that can devastate children and their families, often stealing their vision, balance and speech,” said Dr. Sabine Mueller, pediatric neuro-oncologist, University of California San Francisco Benioff Children’s Hospitals. “The goal of pLGG treatment is to stabilize or shrink the tumor without further disrupting the child’s and family’s life. Historically, there has been no standard of care for children with pLGG who have relapsed. We are excited to welcome a new targeted treatment option with once-weekly oral dosing designed specifically for these kids and their families.”
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OJEMDA is the only systemic therapy for pLGG that offers once-weekly dosing, with or without food, as a tablet or oral suspension.
Approval Based on Multiple Criteria
The accelerated approval of OJEMDA is based on data from the Company’s pivotal open-label Phase 2 FIREFLY-1 trial, which enrolled a total of 137 relapsed or refractory BRAF-altered pLGG patients across two study arms. Arm 1, which accrued 77 patients, was used for the efficacy analyses. Arm 2 provided additional safety data from an incremental 60 patients and was initiated to enable access to tovorafenib once Arm 1 had fully accrued. Details of this trial were presented in November 2023 at the Society for Neuro-Oncology meeting through two oral plenary presentations and in parallel through a publication in Nature Medicine.
The approval of OJEMDA was based, in part, on the major efficacy outcome measure of overall response rate (ORR), defined as the proportion of patients with complete response (CR), partial response (PR), or minor response (MR) by independent review based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO LGG).
“This is a tremendous moment not only for Day One, but also for the broader pediatric brain tumor community. Thanks to the close collaboration between RAPNO and Response Assessment for Neuro-Oncology (RANO) working groups and the patients and families impacted by a pLGG diagnosis, the way we think about measuring response and the goals of therapy for this unique patient population truly evolved,” said Dr. Samuel Blackman, co-founder and head of research and development at Day One. “As a pediatric neuro-oncologist, the approval of OJEMDA is a dream realized.”
In Arm 1, data from the 76 RAPNO LGG evaluable patients include:
| • | A best ORR of 51% (95% CI: 40 - 63), which included 28% PRs and 11% MRs. |
| • | The ORR for OJEMDA was 52% among the 64 patients with BRAF fusions or rearrangements and 50% for the 12 patients with a BRAF V600 mutation. |
| • | The ORR was 49% among the 45 patients who had received a prior MAPK-targeted therapy, and 55% among the 31 patients who had not received a prior MAPK-targeted therapy. |
| • | As of the June 5, 2023 data cutoff, the median duration of response by RAPNO LGG was 13.8 months (95% CI: 11.3, not estimable). In addition, 66% of patients remained on study and continue on treatment as of this date. |
| • | The median time to response, following initiation of treatment, with OJEMDA was 5.3 months (range 1.6, 11.2). |
| • | Based on RANO LGG criteria, the ORR was 53% [95% CI: (41, 64)]. |
The safety of OJEMDA was evaluated in 137 patients with relapsed or refractory pLGG, with the majority of adverse events being Grade 1 or Grade 2. The most common side effects were rash, hair color changes, tiredness, viral infection, vomiting, headache, fever, dry skin, constipation, nausea, acne and upper respiratory tract infection.
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“This is an exciting moment for children and families living with pLGG who previously had few treatment options if their disease progressed,” said Courtney Davies, president and chief executive officer of the Pediatric Brain Tumor Foundation. “The approval of OJEMDA is a testament to the power of community and industry collaboration to address a critical unmet need for children whose day-to-day living and long-term health outcomes are significantly impacted by pLGG. The potential benefit that a new treatment option provides children living with this disease and their families is crucial. There is so much to celebrate here.”
The Company continues its commitment to the pLGG community with the Phase 3 FIREFLY-2/LOGGIC randomized clinical trial evaluating tovorafenib as a potential front-line therapy compared to chemotherapy in patients aged 6 months to 25 years with pLGG, which it believes will satisfy certain post-marketing requirements to the FDA. This study is currently enrolling patients in the United States, Canada, Europe, Australia, and Asia.
Introducing EveryDay Support From Day One™
Day One Biopharmaceuticals is dedicated to helping patients with pLGG access OJEMDA and supporting their families throughout the treatment journey. As part of this commitment, we are pleased to announce EveryDay Support From Day One™, a comprehensive program that offers personalized services for eligible patients and their care teams, including insurance coverage support, financial assistance options, shipping medication to patients’ homes, and educational resources. Caregivers and healthcare providers can visit www.everydaysupport.com or call a patient navigator at 855-DAY1-BIO (855-329-1246) for more information.
OJEMDA will be available in the U.S. through specialty pharmacy partners Biologics and Onco360.
Conference Call
Day One will host a conference call and webcast tomorrow, April 24 at 8:30 a.m. Eastern Time. To access the live conference call by phone, dial 877-704-4453 (domestic) or 201-389-0920 (international), and provide the access code 13745150. Live audio webcast will be accessible from the Day One Investors & Media page. To ensure a timely connection to the webcast, it is recommended that participants register at least 15 minutes prior to the scheduled start time. An archived version of the webcast will be available for replay on the Events & Presentations section of the Day One Investors & Media page for 30 days following the event.
About OJEMDA™
OJEMDA (tovorafenib) is a Type II RAF kinase inhibitor of mutant BRAF V600, wild-type BRAF, and wild-type CRAF kinases.
OJEMDA is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Tovorafenib is under evaluation as a therapy for patients with pLGG requiring front-line treatment (Phase 3 FIREFLY-2/LOGGIC). It is also being studied in combination with the MEK inhibitor pimasertib for adolescent and adult patient populations with recurrent or progressive solid tumors with MAPK pathway alterations (FIRELIGHT-1).
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Tovorafenib was granted Breakthrough Therapy and Rare Pediatric Disease designations by the FDA for the treatment of patients with pLGG harboring an activating RAF alteration, and it was evaluated by the FDA under priority review. Tovorafenib has also received Orphan Drug designation from the FDA for the treatment of malignant glioma and from the European Commission for the treatment of glioma.
For more information, please visit www.ojemda.com.
INDICATION
What is OJEMDA™ (tovorafenib)?
OJEMDA is a prescription medicine used to treat certain types of brain tumors (cancers) called gliomas in patients 6 months and older:
| • | that is a pediatric low-grade glioma (LGG), and |
| • | that has come back after previous treatment or has not responded to previous treatment and |
| • | that has a certain type of abnormal “BRAF” gene. |
IMPORTANT SAFETY INFORMATION
Before taking or giving OJEMDA, tell your healthcare provider about all of your or your child’s medical conditions, including if you:
| • | have bleeding, skin, or liver problems |
| • | are pregnant or plan to become pregnant. OJEMDA can harm your unborn baby. |
Females who are able to become pregnant:
| • | You should use effective non-hormonal birth control (contraception) during treatment with OJEMDA and for 28 days after your last dose of OJEMDA. |
Males with female partners who are able to become pregnant should use effective non-hormonal birth control (contraception) during treatment with OJEMDA and for 2 weeks after your last dose of OJEMDA.
| • | are breastfeeding or plan to breastfeed. Do not breastfeed during treatment and for 2 weeks after your last dose of OJEMDA. |
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
What should I avoid while taking OJEMDA?
Limit the amount of time you spend in sunlight. OJEMDA can make your skin sensitive to the sun (photosensitivity). Use sun protection measures, such as sunscreen, sunglasses and wear protective clothes that cover your skin during your treatment with OJEMDA.
What are the possible side effects of OJEMDA?
OJEMDA may cause serious side effects, including:
| • | bleeding problems (hemorrhage) are common and can also be serious. Tell your healthcare provider if you have any signs or symptoms of bleeding, including: |
| • | headache, dizziness or feeling weak |
| • | coughing up blood or blood clots |
| • | vomiting blood or your vomit looks like “coffee grounds” |
| • | red or black stools that look like tar |
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| • | skin reactions, including sensitivity to sunlight (photosensitivity). OJEMDA can cause skin reactions that can become severe. Tell your healthcare provider if you get new or worsening skin reactions, including: |
| • rash
• bumps or tiny papules
• acne |
• peeling, redness, or irritation
• blisters |
| • | liver problems. Your healthcare provider will do blood tests to check your liver function before and during treatment with OJEMDA. Tell your healthcare provider right away if you develop any of the following symptoms: |
| • yellowing of your skin or your eyes
• dark or brown (tea-colored) urine
• nausea or vomiting
• loss of appetite |
• tiredness
• bruising
• bleeding
• pain in your upper right stomach area |
| • | slowed growth in children. Growth will be checked routinely during treatment with OJEMDA. |
The most common side effects of OJEMDA include:
| • rash
• hair color changes
• tiredness
• viral infection
• vomiting
• headache |
• fever
• dry skin
• constipation
• nausea
• acne
• upper respiratory tract infection |
OJEMDA may cause fertility problems in males and females, which may affect your ability to have children.
These are not all the possible side effects of OJEMDA. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Please see full Product Information and Instructions for Use for more information.
About Pediatric Low-Grade Glioma
Pediatric low-grade glioma (pLGG) is the most common brain tumor with an estimated incidence of 1,100 children per year who are eligible for front-line systemic therapy. BRAF is the gene most commonly altered in pLGG, of which there are two primary types of BRAF alterations – a BRAF gene fusion and a BRAF point mutation. In children with BRAF-altered pLGG, approximately 80 percent have BRAF fusions or rearrangements, while the remaining 20 percent have a V600 mutation.
Pediatric low-grade gliomas can be chronic and relentless, with patients suffering profound side effects from both the tumor and the treatment, which may include chemotherapy and radiation. These side effects can impact their life over the long term, and may include muscle weakness, loss of vision, and difficulty speaking. This type of tumor has a high risk of progression, and many children with pLGG require long-term treatment. While most children with pLGG survive their cancer, children who do not achieve a complete resection following surgery may face years of increasingly aggressive treatment.
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About FIREFLY-1
FIREFLY-1 is evaluating OJEMDA™ (tovorafenib) as once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG harboring a known activating BRAF alteration. The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC). The primary endpoint is overall response rate (ORR), defined as the proportion of patients with confirmed response based upon Response Assessment for Neuro-Oncology High-Grade Glioma (RANO HGG) criteria. Secondary and exploratory endpoints include the overall response rate based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO LGG) criteria, Response Assessment for Neuro-Oncology Low-Grade Glioma (RANO LGG) criteria and volumetric analyses, progression-free survival, safety, functional outcomes, and quality of life measures. RANO HGG, RANO LGG and RAPNO LGG are assessed by blinded independent central review. Additional information about FIREFLY-1 may be found at ClinicalTrials.gov, using Identifier NCT04775485.
About the Pacific Pediatric Neuro-Oncology Consortium
The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is an international consortium with study sites within the United States, Canada, Europe and Australia dedicated to bringing new therapies to children and young adults with brain tumors.
About Day One Biopharmaceuticals
Day One Biopharmaceuticals is a commercial-stage biopharmaceutical company that believes when it comes to pediatric cancer, we can do better. The Company was founded to address a critical unmet need: the dire lack of therapeutic development in pediatric cancer. Inspired by “The Day One Talk” that physicians have with patients and their families about an initial cancer diagnosis and treatment plan, Day One aims to re-envision cancer drug development and redefine what’s possible for all people living with cancer—regardless of age—starting from Day One.
Day One partners with leading clinical oncologists, families, and scientists to identify, acquire, and develop important targeted cancer treatments. The Company’s pipeline includes tovorafenib (OJEMDA™) and pimasertib.
Day One is based in Brisbane, California. For more information, please visit www.dayonebio.com or find the Company on LinkedIn or X.
Cautionary Note Regarding Forward-Looking Statements
This press release contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: Day One’s plans to develop cancer therapies, expectations from current clinical trials, the execution of the Phase 2 and Phase 3 clinical trial for tovorafenib as designed, any expectations about safety, efficacy, timing and ability to complete clinical trials, release data results and to obtain regulatory approvals for tovorafenib and other candidates in development, and the ability of tovorafenib to treat pLGG or related indications.
Statements including words such as “believe,” “plan,” “continue,” “expect,” “will,” “develop,” “signal,” “potential,” or “ongoing” and statements in the future tense are forward-looking statements. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they do not fully materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements.
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Forward-looking statements are subject to risks and uncertainties that may cause Day One’s actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties in this press release and other risks set forth in our filings with the Securities and Exchange Commission, including Day One’s ability to develop, obtain regulatory approval for or commercialize any product candidate, Day One’s ability to protect intellectual property, the potential impact of global business or macroeconomic conditions, including as a result of inflation, rising interest rates, instability in the global banking system, geopolitical conflicts and the sufficiency of Day One’s cash, cash equivalents and investments to fund its operations. These forward-looking statements speak only as of the date hereof and Day One specifically disclaims any obligation to update these forward-looking statements or reasons why actual results might differ, whether as a result of new information, future events or otherwise, except as required by law.
DAY ONE MEDIA
Laura Cooper, Head of Communications
media@dayonebio.com
DAY ONE INVESTORS
LifeSci Advisors, PJ Kelleher
pkelleher@lifesciadvisors.com
#####
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Exhibit 99.2 Day One Biopharmaceuticals Targeted Therapies for People of All Ages April 2024 1
Disclaimer This presentation and the accompanying oral commentary contain forward-looking statements that are based on our management’s beliefs and assumptions and on information currently available to our management. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “should,” “could,” “expect,” “plan,” anticipate,” “believe,” “estimate,” “predict,” “intend,” “potential,” “would,” “continue,” “ongoing” or the negative of these terms or other comparable terminology. Forward-looking statements include all statements other than statements of historical fact contained in this presentation, including information concerning our future financial performance, including the sufficiency of our cash, cash equivalents and short-term investments to fund our operations, business plans and objectives, timing and success of our planned nonclinical and clinical development activities, the results of any of our strategic collaborations, including the potential achievement of milestones and provision of royalty payments thereunder, timing and results of nonclinical studies and clinical trials, efficacy and safety profiles of our products and product candidates, the ability of tovorafenib to treat pediatric low-grade glioma (pLGG) or related indications, the potential therapeutic benefits and economic value of our products and product candidates, potential growth opportunities, competitive position, industry environment and potential market opportunities, our ability to protect intellectual property and the impact of global business or macroeconomic conditions, including as a result of inflation, changing interest rates, cybersecurity incidents, perceived instability in the global banking system, uncertainty with respect to the federal debt ceiling and budget and potential government shutdowns related thereto and global regional conflicts, on our business and operations. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. These factors, together with those that are described under the heading “Risk Factors” contained in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (“SEC”) and other documents we file from time to time with the SEC, may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this presentation, and although we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted a thorough inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and investors are cautioned not to unduly rely upon these statements. Furthermore, if our forward-looking statements prove to be inaccurate, the inaccuracy may be material. In light of the significant uncertainties in these forward-looking statements, you should not regard these statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame, or at all. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. 2
Cancer Therapies for People of All Ages Our Approach • Develop medicines for genomically-defined cancers • Establish first-in-class position through rapid registration pathways • Expand to adolescent and adult populations in parallel and pursue those opportunities with the same commitment we do for children IPO: 2021 Financial Position: Runway into 2026 Nasdaq: DAWN Founded: 2018 3
Our Pipeline Phase 3/ Recent & Anticipated Product Candidate Therapeutic Area Preclinical Phase 1 Phase 2 Approved Registrational Milestones BRAF-altered FDA approval: FIREFLY-1 (pivotal Phase 2) April 2024 Relapsed pLGG Tovorafenib Type II RAF Inhibitor OJEMDA brand name 1 in U.S. Frontline RAF- First patient dosed: FIREFLY-2 (pivotal Phase 3) March 2023 altered pLGG MAPK-altered Recommended Phase 2 dose & Pimasertib † † † schedule expected: FIREFLIGHT-1 solid tumors MEK 1/2 Inhibitor 2H 2024 (Combo w/ tovorafenib) § VRK1 Program Pediatric and In-licensed : August 2023 VRK1 Inhibitor adult cancers 1 † † † § OJEMDA has received accelerated approval by the U.S. Food and Drug Administration. Pimasertib Phase 1 dose escalation and expansion trial previously completed. Includes patients ≥12 years of age. Research collaboration and license agreement with Sprint Bioscience AB for exclusive worldwide rights to a research-stage program targeting VRK1. pLGG, pediatric low-grade glioma. 4 The safety and efficacy of investigational agents and/or investigational uses of approved products have not been established.
TM OJEMDA (tovorafenib) Relapsed or Refractory BRAF-altered pLGG 5
OJEMDA Now Approved In The U.S. OJEMDA is the first and only FDA Approved therapy for the treatment of pediatric patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation * 6 This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.
pLGG Impact On Patients’ Lives Lily was diagnosed with an operable brain tumor at 5 months of age 7 Lily, lives with pLGG.
Pediatric Low-Grade Glioma: The Most Common Type Of Brain Tumor In Children A Serious and Life-Threatening Disease pLGGs are chronic and • For the majority of pLGG patients in the relapsed setting, there is no standard of care and no approved therapies , with patients relentless * • Up to 75% of pLGGs have a BRAF alteration , of those ~80% suffering profound tumor 2-6 are BRAF fusions and ~20% are BRAF V600 mutations and treatment-associated • Despite surgery playing a significant role in treatment, the morbidity that can impact 7,8 vast majority of patients still require systemic therapy their life trajectory over the • Due to high rate of disease recurrence, most patients will 1 long term undergo multiple lines of systemic therapy over the course of their disease 1 2 *Incidence of BRAF alterations varies across pLGG subtypes. Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009;24(11):1397-1408. doi:10.1177/0883073809342005. Penman CL et al. Front Oncol. 8 3 4 5 6 2015;5:54. Cohen AR., N Engl J Med. 2020;386(20):1922-1931. Lassaletta A, et al. J Clin Oncol. 2017;35(25):2934-2941. Faulkner C, et al. J Neuropathol Exp Neurol. 2015;74(9):867-872. Packer RJ, et al. Neuro 7 8 Oncol. 2017;19(6):750-761. Ostrum QT et al., Neuro Oncol. 2015; 16(Suppl 10):x1-x36; De Blank P. et al., Curr Opin Pediatr. 2019 Feb; 31(1):21-27.
Conventional Treatments Can Be Disruptive To Childhood And Can Have Significant Long-Term Consequences Surgery Chemotherapy Radiation • Significant recovery times • Requirement for indwelling • Risk of secondary malignancy catheter and weekly infusions • Risks of complications • Risk of malignant transformation • Risk of neutropenia, • Resection may be limited by • Risk of vascular proliferation and hypersensitivity reactions, location of tumor stroke nausea and vomiting and • Potential for functional deficits • Neurocognitive impact, peripheral neuropathy based on location of tumor depending on location of tumor and extent of resection and radiation field Goal of therapy is to control the tumor, minimize the burden of surgery, chemotherapy, and radiation, and reduce the risk of life-long treatment- and disease-related effects Source: 1. Heitzer AM, Raghubar K, Ris MD, et al. Neuropsychological functioning following surgery for pediatric low-grade glioma: a prospective longitudinal study. J Neurosurg Pediatr. 2019;1-9. doi:10.3171/2019.9.PEDS19357. 2. Bryant R. Managing side effects of childhood cancer treatment. J Pediatr Nurs. 2003;18(2):113-125. doi:10.1053/jpdn.2003.11. 3. Zahnreich S, Schmidberger H. Childhood cancer: occurrence, treatment and risk of second primary malignancies. Cancers (Basel). 2021;13(11):2607. doi:10.3390/cancers/13112607. 4. National Cancer Institute. Fertility issues in girls and women with cancer. http://www.cancer.gov. Accessed June 13, 2022. 5. Alessi I., Caroleo A.M., de Palma L., Mastronuzzi A., Pro S., Colafati G.S., Boni A., Della Vecchia N., Velardi M., Evangelisti M., et al. Short and Long-Term Toxicity 9 in Pediatric Cancer Treatment: Central Nervous System Damage. Cancers. 2022;14:1540. doi: 10.3390/cancers14061540.
TM Overview U.S. Prescribing Information For OJEMDA (tovorafenib) Available in tablet formulation and pediatric-friendly powder for oral suspension INDICATION OJEMDA is indicated for the treatment of pediatric patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation RECOMMENDED DOSE 2 380 mg/m administered orally once weekly (not to exceed a dose of 600mg once weekly); OJEMDA can be taken with or without food For full prescribing information, visit dayonebio.com * 10 This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.
TM Efficacy Summary From OJEMDA (tovorafenib) Prescribing Information Overall response rate (RAPNO-LGG) in RAPNO-LGG 76 evaluable patients 51% Response (IRC) n n (%) 95% CI ORR, n (%) 76 39 (51) 40-63 BRAF fusion or rearrangement 64 33 (52) 39-64 100 Prior MAPKi BRAF V600 mutation 12 6 (50) 21-79 80 100 MAPKi-naive 60 Prior MAPKi 80 Prior MAPKi use 45 22 (49) 31-64 BRAF mutation 40 * PD MAPKi-naive 20 60 MAPKi-naïve 31 17 (55) 36-73 0 BRAF mutation SD 40 * PD * * -20 MR 20 -40 * * * † Median DOR, months 39 13.8 11.3-NR -60 PR * 0 SD * -80 * * * * CR -20 * -100 * MR -40 Median TTR, months 39 5.3 * * * PR -60 * Range 1.6-11.2 * -80 * * CR * -100 * June 5, 2023 data cutoff. CI, confidence interval; DOR, duration of response; IRC, independent radiology review committee; LGG, low-grade glioma; NR, not reached; ORR, overall response rate; RAPNO, Response Assessment in Pediatric Neuro-Oncology; TTR, time to response; CR, complete response; PR, partial response; MR, minor response; SD, stable disease; PD, 11 † progressive disease. As of the data cutoff, 66% remain on tovorafenib. Maximum change in tumor size (%) Maximum change in tumor size (%) Maximum change in tumor size (%)
TM Safety Summary From OJEMDA (tovorafenib) Prescribing Information Warnings and Precautions TEAEs (≥ 30% of patients [n=137]) Preferred Term, n (%) Any Grade Grade ≥3 • Hemorrhage Any AE 137 (100) 86 (63) Hair color changes 104 (76) 0 • Skin toxicity, including photosensitivity Anemia 81 (59) 15 (11) Elevated CPK 80 (58) 16 (12) • Hepatotoxicity Fatigue 76 (55) 6 (4) Vomiting 68 (50) 6 (4) • Effect on growth Hypophosphatemia 64 (47) 0 • Embryo-fetal toxicity Headache 61 (45) 2 (1) Maculo-papular rash 60 (44) 11 (8) • Use in NF1- associated tumors Pyrexia 53 (39) 5 (4) Dry skin 49 (36) 0 Elevated LDH 48 (35) 0 Increased AST 47 (34) 4 (3) No boxed warnings or Constipation 45 (33) 0 Nausea 45 (33) 0 Upper RTI 43 (31) 2 (1) contraindications Dermatitis acneiform 42 (31) 1 (1) Epistaxis 42 (31) 1 (1) June 5, 2023 data cutoff. OJEMDA safety data (n=137). Treatment-emergent AEs ≥20% any grade in arms 1 & 2. AE, adverse event; AST, aspartate aminotransferase; CPK, creatine 12 phosphokinase; LDH, lactate dehydrogenase; RTI, respiratory tract infection; TEAEs, treatment-emergent adverse events.
Estimated BRAF-Altered pLGG Patient Population In The U.S. ~26,000 Prevalence of Systemically- ~2,000-3,000 Treated Patients 1-5 ~1,100 Under 25 Recurrent/Progressive Total Addressable Incidence of Patient Population Treatment- 6 per Year at Steady Eligible * State Frontline 4,5 Patients 7-14 Up to 75% of pLGG cases are BRAF-altered Incidence of BRAF alterations varies across pLGG subtypes of these cases have of these cases have BRAF fusion, primarily BRAF point mutations, ~80% ~20% † † † KIAA1549-BRAF primarily BRAF V600 1 2 Selt F, van Tilburg CM, Bison B, et al. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol. 2020;149(3):499-510. doi:10.1007/s11060-020-03640-3. Ryall S, Tabori U, Hawkins C. Pediatric low-grade 3 glioma in the era of molecular diagnostics. Acta Neuropathol Commun. 2020;8(1):30. doi:10.1186/s40478-020-00902-z. SEER US complete prevalence counts of patients aged under 25 with Brain and Other Nervous Systems tumors as of January 1, 4 5 2017. CBTRUS, Qaddoumi et al 2009, Schreck et al 2019, ClearView Analysis. US Census. Estimated annual incidence, estimated prevalence, and estimated recurrent/progressive total addressable patient population are Day One calculations based 6 7 8 on publicly available data. Source: Internal market research conducted by EpidStrategies, A Division of ToxStrategies, Inc. on behalf of Day One. Ryall S, et al. Acta Neuropathol Commun. 2020;8(1):30. Behling F, et al. Cancers (Basel). 13 9 10 11 12 13 2019;11(6):794. Penman CL, et al. Front Oncol. 2015;5:54. Packer RJ, et al. Neuro Oncol. 2017;19(6):750-761. Cohen AR, et al. N Engl J Med. 2022;386(20):1922-1931. Ryall S, et al. J Neuropathol Exp Neurol. 2017;76(7):562-570. Lassaletta A, 14 * et al. J Clin Oncol. 2017;35(25):2934-2941. Faulkner C, et al. J Neuropathol Exp Neurol. 2015;74(9):867-872. The estimated addressable pool of recurrent or progressive pLGG patients is based on progression free survival curves modeled from † †† published literature. Predominantly seen in pilocytic astrocytomas. May vary across pLGG subtypes. BRAF, V-Raf murine sarcoma viral oncogene homolog B; MAPK, mitogen-activated protein kinase; pLGG, pediatric low-grade glioma.
What Physicians & Caregivers Are Looking For In A Therapy What HCP’s are Seeking What Caregivers are Seeking Effective in stopping or shrinking tumors Live as normal of a childhood as possible Manageable safety profile Minimal impact from the disease Minimal disruption to child’s life Minimal disruption to child’s life “Our time with our kids is precious and not guaranteed, so the less time with meds and “The goal is not interfering with the child’s life.” doctors the better.” – Ped Onc, Chicago Ad Board – Caregiver for a child under 5 yrs 14
Product Profile Aligns With What Physicians Are Looking For In A Therapy Meaningful tumor stabilization or shrinkage may be possible with OJEMDA. In the clinical trial: Efficacy • 51% of children experienced tumor shrinkage by at least 25% • 82% of children saw their tumors shrink or remain stable Generally well-tolerated therapy, with 9 out of 10 patients staying on treatment in the clinical trial Safety Most common grade 3 / 4 adverse events include: anemia, elevated CPK, maculo- papular rash, fatigue & vomiting Once-weekly, taken with or without food conveniently from home can mean Dosing fewer daily interruptions OJEMDA is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion, rearrangement, or BRAF V600 mutation. 15 Data from Pivotal Phase 2 FIREFLY-1 trial.
Comprehensive Approach For A Successful Launch Physicians Payers Patients & Families TM Objective: Establish OJEMDA as Objective: Provide a positive & Objective: Rapidly establish st 1 choice in relapsed / refractory supportive experience when coverage BRAF-altered pLGG patients initiating therapy MEDICAID 89% 40% 65% COMMERCIAL 60% • SP distribution enables consistent patient • Pre-launch engagement to establish Day experience AIDED INTENT TO One & provide background information AWARENESS TREAT • Comprehensive patient support programs • Plans in place for rapid engagement post- address patient needs and accelerates • Dedicated & experienced sales team to approval access to drug engage HCPs 16 SP, Specialty Pharmacy.
Targeted Launch With Highly Experienced Field Team Targeting ~200 centers where 90% Deep oncology experience with of pLGG patients receive treatment relationships at top-tier accounts Average experience: 18 Account 13 years of oncology Managers fully-dedicated 4 years of rare disease to OJEMDA 2 years of pediatric oncology clinical experience Institutional experience and existing relationships with key accounts 17
Patient Support Program Supporting Access DEDICATED PATIENT NAVIGATOR COPAY CARD PHONE & VIDEO PROGRAM CONSULTATIONS COVERAGE PATIENT DELAY ASSISTANCE PROGRAM PROGRAM COVERAGE INTERRUPTION SUPPORT 18
FIREFLY-2 / LOGGIC Pivotal Phase 3 Trial of Tovorafenib in Frontline pLGG 19
FIREFLY-2/LOGGIC Pivotal Phase 3 Trial Of Tovorafenib In Frontline pLGG Trial Design Endpoints • Randomized, global, registrational Phase 3 trial of monotherapy tovorafenib • Primary endpoint: ORR based on RANO-LGG criteria, assessed by vs SoC chemotherapy blinded independent central review ‒ The ORR primary analysis is expected to occur ~12 months after the • Eligibility: Patients aged 6 months to <25 years with LGG harboring a RAF last patient randomized alteration and requiring first-line systemic therapy • Key secondary endpoints: PFS and DoR by RANO criteria, ORR by RAPNO • Tovorafenib available as tablets and pediatric-friendly liquid suspension criteria • Patients who progress after stopping tovorafenib may be re-challenged • Other secondary endpoints: changes in neurological and visual function, safety, and tolerability • Patients who progress in the SoC arm during or post-treatment may cross- over to receive tovorafenib • Key exploratory objectives: QoL and health utilization measures 2 Tovorafenib, 420mg/m QW Non-resectable or (not to exceed 600 mg) Stratified by sub-total resected LGG Long-term AND • Location of tumor follow-up Requiring first-line • Genomic alteration systemic therapy Investigator's choice of • CDKN2A status (48 months) vincristine/carboplatin* or N ≈ 400 • Infant CHG diagnosis vinblastine * COG or SIOPe-LGG regimen. Abbreviations: CHG, chiasmatic, hypothalamic glioma; DoR, duration of response; LGG, low-grade glioma; ORR, objective response rate; QoL, quality of life; QW, once weekly; SoC, standard of care. 20 1:1 Randomization
FIRELIGHT-1 Phase 1b/2 Trials Evaluating Tovorafenib as a Combination with Pimasertib 21
Pimasertib: Investigational Allosteric MEK1/2 Inhibitor With Demonstrated Activity In MAPK-Driven Solid Tumors • Pimasertib is an investigational orally-bioavailable, selective, non- competitive MEK1/2 inhibitor in-licensed from Merck KGaA in February 2021 • Extensive non-clinical and clinical development work through Phase 2, including a solid tumor trial in Japan and combinations with other MOAs • Main AEs typical for all in-class allosteric MEK inhibitors (GI, CPK elevation, skin rash, visual disturbances) • Nearly three-fold higher CNS penetration than other MEKi inhibitors (trametinib or selumetinib) • Pimasertib showed monotherapy clinical activity, including an improvement in median PFS versus dacarbazine in NRAS mutant melanoma • Combination with tovorafenib and other targeted therapies may unlock the full value of pimasertib in advanced solid tumors 22 Sources: Pimasertib Investigator Brochure, v12, 2019; de Gooijer et al., Int J Cancer, 2018; Shaw et al., AACR LB-456, 2012; Lebbe et al., Cancers, 2020.
Vertical MAPK Pathway Inhibition With Tovorafenib And Pimasertib May Unlock Potential Synergy For Adult Solid Tumors TAK-632+pimasertib in KIAA1549-BRAF DAY101+MEKi in KRAS mut tumor mixed Mullerian PDX model ex vivo A BRAF KRAS or NRAS cell lines in vitro NCI-H1792 non-V600 mutant mutant C 10 42.2 86.3 90.4 92.0 93.3 94.0 95.8 5.0 34.0 74.8 85.5 90.3 91.7 92.9 94.5 2.5 30.9 61.3 73.5 84.9 90.0 92.4 94.3 100% inh 1.3 28.0 53.6 61.4 72.3 83.8 90.6 93.3 MEK 0.6 25.4 47.3 53.7 62.3 72.1 84.8 91.7 0.3 22.1 42.4 50.3 55.1 61.6 73.0 87.4 RAF/ PI3K/m PI3K/m 0 0.0 4.7 6.2 12.4 23.1 34.8 50.8 MEK/ERK TOR TOR 50 0 0.3 0.6 1.3 2.5 5 10 DAY101 (μM) ERK Calu-6 BGB-382+pimasertib in KRAS mut Calu6 cell line in vitro 10 53.2 74.0 75.3 76.0 77.3 78.7 81.9 B 5.0 37.6 72.4 73.4 74.5 75.1 76.4 79.3 0 inh 2.5 23.4 68.0 70.3 72.5 73.7 75.1 78.4 1.3 15.2 62.6 66.9 70.5 72.9 74.7 77.6 Proliferation, survival Proliferation, survival 0.6 14.4 54.5 62.1 66.9 71.6 74.5 77.5 0.3 8.7 45.2 53.6 60.8 67.9 73.9 77.7 0 0.0 -2.1 1.5 9.3 21.7 43.8 63.9 Type II RAFi + MEKI Type II RAFi + MEKI 0 0.3 0.6 1.3 2.5 5 10 DAY101 (μM) Type II RAFi + MEKi is synergistic in BRAF fusion melanoma PDX model ex vivo (internal data) A Non V600 BRAF dimers are Targeting multiple nodes of effectively inhibited by type II MAPK pathway will drive deeper Sensitivity of KRAS Q61 mutant cells to pimasertib is enhanced when cells are treated with the type II B RAFi , but not type I BRAFi and more durable response BRAF inhibitor BGB-283 (Yuan et al., Mol Onc 2020) Tovorafenib + MEK inhibitor is synergistic in KRAS G12C and Q61 mutant tumor cells (Venetsanakos et al., C 2021 AACR poster presentation) 23 MEKi-2 (μM) MEKi-2 (μM)
Tovorafenib / Pimasertib Combination In Solid Tumors (FIRELIGHT-1) 1 Trial Design Endpoints 2 • Combination dose escalation, global phase 1b/2 trial • Phase 1b: PK, PD and Safety, MTD/RP2D • Phase 1b, BOIN (adaptive), n = 10/cohort (approximately) • Phase 2: Efficacy (ORR, DOR) • Phase 2, Simon 2-stage, n = 25/cohort (approximately) • Eligibility: Patients aged 12 years and older, dose escalation will be performed in advanced solid tumor patients with any MAPK alteration. Expansion cohorts will focus on indications with a potential path to accelerated approval Phase 1b Phase 2* NRASmut Selected tumors Tovorafenib + Tumors with MAPK Pimasertib Safety BRAF Class 1 (non-E/K) and Class 2 mutant tumors pathway alterations until disease Follow Up 3 progression BRAF-fusion selected tumors Pre-identified patients with advanced solid tumors and available clinical molecular profiling information. *Additional biomarker-selected cohorts may be pursued based on developing data 1 Abbreviations: BOIN, Bayesian Optimal Interval Design; BRAF, B-Raf proto-oncogene, serine/threonine kinase; MAPK, mitogen-activated protein kinase; NRAS, neuroblastoma rat sarcoma viral oncogene. Umbrella 2 master study – DAY101-102 (main protocol) DAY101 and MAPK pathway aberration, Sub-study 1 monotherapy (DAY101-102a), Sub-study 2 MEK combo (DAY101-102b). Intend to open U.S. and ex-U.S. clinical sties. 24 3 DAY101 + Pimasertib until disease progression, intolerable toxicity, withdrawal of consent, or death
Summary 25
Financial Summary: DAWN Cash, cash equivalents and short-term investments as of ~87.4 million shares of common stock outstanding as December 31, 2023: $366.3 million (no debt) of February 21, 2024 Twelve Months Ended Twelve Months Ended $ Millions 12/31/23 12/31/22 R&D Expense $130.5 $85.6 G&A Expense $75.5 $61.3 Net Loss $188.9 $142.2 FIREFLY-1: Pivotal Phase 2 clinical trial of tovorafenib • Data published in Nature Medicine and oral presentations at SNO in November 2023 Projected TM • OJEMDA (tovorafenib) approved in the U.S. and received PRV in April 2024 Cash Runway into 2026 FIREFLY-2/LOGGIC: Pivotal Phase 3 clinical trial of tovorafenib in newly diagnosed pLGG • First patient dosed in March 2023 1 26 All financial and share information is unaudited. NDA data set includes analysis of primary (ORR by RANO-HGG) and secondary (ORR by RAPNO, PFS) efficacy endpoints, safety, and exploratory analyses (including ORR by RANO-LGG). PRV, Priority Review Voucher.
Priorities as a Commercial-Stage Company TM Advance Portfolio Expand Pipeline Launch OJEMDA (tovorafenib) • Expand awareness amongst • FIREFLY-2: Study tovorafenib as a • Grow Day One into a leading, physicians and establish broad frontline therapy for treatment- biopharmaceutical company that is coverage to enable patient access naive patients with pLGG the partner of choice for oncology drug development • Establish OJEMDA as the standard • FIRELIGHT-1: Evaluate of care for relapsed or refractory tovorafenib in combination with • Explore selective partnerships as a pLGG harboring a BRAF alteration pimasertib in adolescent and source of capital and risk sharing adult populations • Provide a positive and supportive • Further invest in business experience when initiating • Advance early stage VRK1 development activities to expand our OJEMDA therapy for patients and program to clinical development multiple asset portfolio for both families children and adults 27
Appendix 28
Tovorafenib Inhibits Both BRAF Fusions And BRAF V600 Mutations MAPK pathway RAS-independent activation of the MAPK pathway Tovorafenib is an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor that was designed to inhibit both RAS monomeric and dimeric RAF kinase • Activity in tumors driven by both RAF fusions and BRAF V600E mutations RAF RAF RAF Tovorafenib mutation fusion • Tablet and pediatric-friendly liquid suspension • Once weekly dosing MEK Currently approved type I BRAF inhibitors are indicated for use in patients with tumors bearing BRAF V600 mutations ERK • Type I BRAF inhibitors cause paradoxical MAPK activation in the setting of wild-type RAF, increasing the risk of tumor growth in BRAF fusion-driven Proliferation and survival Proliferation and survival Proliferation and survival 29 Source: 1. Sun Y et al., Neuro Oncol. 2017; 19: 774–85; 2. Sievart AJ et al., PNAS. 2013; 110:5957-62; 3. Karajannis MA et al., Neuro Oncol 2014;16(10):1408-16.
Pivotal Phase 2 Trial Of Monotherapy Tovorafenib In Relapsed Or Progressive pLGG (FIREFLY-1) Trial Design Endpoints (Pivotal Arm 1) 1 • Three arm, open-label, global registrational phase 2 trial • Primary endpoint: ORR based on RANO-HGG , assessed by blinded independent central review • Pivotal Arm 1 (recurrent/progressive pLGG, n=77): harboring a KIAA1549- BRAF fusion or BRAF V600E mutation 2 • Secondary endpoints: ORR by RAPNO-LGG assessed by blinded independent • Arm 2 (expanded access recurrent/progressive LGG, n=60): harboring an central review; PFS, DoR; TTR, CBR; safety activating RAF alteration 3 • Exploratory analyses: ORR and CBR by RANO-LGG assessed by blinded • Arm 3 (extracranial solid tumors): harboring an activating RAF fusion independent central review rd Clinical and radiological evaluations at baseline, and every 3 Key Inclusion Criteria nd cycle for pLGG and every 2 cycle for solid tumors • 6 months – 25 years of age Day –28 to 0 • RAF-altered tumor Enrollment/ • ≥1 prior line of systemic Screening Baseline End of Trial Study Drug Administration After Cycle 27: patients may either C27D1 therapy with radiographic (C1D1) 2 continue treatment or enter drug 420mg/m QW (not to exceed 600mg), progression holiday period at any time (at QW in 28-day cycles discretion of investigator) • Prior use of MAPK pathway targeted therapy was permitted Eligibility evaluation Treatment period: minimum of 2 years or until progression or toxicity/intolerability 1 2 3 June 5, 2023 data cutoff. Wen PY, et al. J Clin Oncol. 2010;28(11):1963-1972. Fangusaro J, et al. Lancet Oncol. 2020;21(6):e305–316. van den Bent MJ, et al. Lancet Oncol. 2011;12(6):583-593. Abbreviations: CBR, 30 clinical benefit rate; IRC, independent review committee; C, cycle; D, day; LGG, low-grade glioma; ORR, objective response rate; PFS, progression-free survival; DoR, duration of response; QW, once weekly; TTR, time to response; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology; MAPK, mitogen-activated protein kinase. For more information, please refer to NCT04775485
Data from Pivotal Phase 2 FIREFLY-1 Trial June 5, 2023 data cutoff 31
FIREFLY-1 Baseline Patient Characteristics Characteristic Arm 1 (n=77) Location (n=77) Deep midline structures Optic pathway Median age, years (range) 8 (2-21) 12% 51% Sex, n (%) Other Male 40 (52) † 16% Female 37 (48) Cerebral hemisphere 8% Race, n (%) Cerebellum Brain stem White 41 (53) 6% 8% Asian 5 (6) Black 2 (3) Multiple 3 (4) Other 6 (8) BRAF alteration (n=77) Not specified 20 (26) Number of lines of prior systemic therapy 17% Median (range) 3 (1-9) 1, n (%) 17 (22) 2, n (%) 21 (27) ≥3, n (%) 39 (51) 83% Prior MAPK pathway targeted therapy, n (%) Prior MEK inhibitor 43 (56) Prior BRAF inhibitor 8* (10) ‡ Prior BRAF and MEK inhibitors 5 (7) BRAF V600E BRAF Fusion* Any MAPK inhibitor 46 (60) * † June 5, 2023 data cutoff. Includes 6 patients with BRAF duplication and 2 with BRAF rearrangement per fluorescence in situ hybridization or in situ hybridization. Includes tumors that were 32 extending into multiple regions of the brain, leptomeningeal disease, and/or spinal disease. ‡The 5 patients that had previously received both a MEK inhibitor and also a BRAF inhibitor are recorded in both the “Prior MEK inhibitor” and “Prior BRAF inhibitor” groups. MAPK, mitogen-activated protein kinase.
Tumor Response To Tovorafenib Using RAPNO-LGG, RANO-LGG and RANO-HGG 100 Prior MAPKi 80 MAPKi-naive 100 RAPNO-LGG 60 Prior MAPKi BRAF mutation 80 40 * PD MAPKi-naive 60 20 RAPNO-LGG RANO-LGG RANO-HGG BRAF mutation 0 SD 40 * Response (IRC) PD * * -20 n=76 N=76 N=69 20 MR -40 * * * 0 SD PR -60 * * * * -20 ORR,* n (%) 39 (51) 40 (53) 46 (67) -80 * * CR MR * -100 * -40 * * * 95% CI 40-63 41-64 54-78 -60 PR * * -80 * * CR * -100 * CBR,* n (%) 62 (82) 63 (83) 64 (93) SD of any length of time 43 (57) 46 (61) 54 (78) SD ≥12 months 180 100 Prior MAPKi 80 MAPKi-naive RANO-LGG 60 BOR,* n (%) BRAF mutation 100 40 * PD 20 80 0 0 12 (17) CR 0 SD 60 * * -20 40 28 M (37) R 20 (26) 34 (49) PR -40 P*D * * 20 -60 PR * * -80 11 (14) 20 (26) n/a SD MR * 0 * CR * -100 * * -20 23 (30) 23 (30) 18 (26) MR SD -40 * * * * PR -60 * * * 19 (25) 17 (22) 10 (14) SD <12 months * -80 * CR * * -100 4 (5) 6 (8) 8 (12) SD ≥12 months 13 (17) 11 (14) 4 (6) PD 100 1 (1) 2 (3) 1 (1) NE Prior MAPKi 80 100 MAPKi-naive RANO-HGG 60 80 BRAF mutation 40 * Median DOR, months 13.8 14.4 16.6 PD 60 20 40 0 SD PD 95% CI 11.3-NR 11.0-NR 11.6-NR * * -20 20 MR -40 * * * 0 -60 PR * Median TTR, months 5.3 5.5 3.0 * SD -20 -80 * * * CR * -100 * -40 Range 1.6-11.2 1.6-11.3 2.6-16.6 PR -60 -80 CR * -100 * * * * * * * 33 June 5, 2023 data cutoff. BOR, best overall response; CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; HGG, high-grade glioma; IRC, independent radiology review committee; LGG, low-grade glioma; MR, minor response; n/a, not applicable; NE, not evaluable; NR, not reached; ORR, overall response rate; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology; SD, stable disease; TTR, time to response. * ORR, CBR and BOR for RAPNO-LGG and RANO-LGG included MRs. Maximum change in Maximum change in Maximum change in tumor size (%) tumor size (%) tumor size (%) Maximum change in tumor size (%) Maximum change in tumor size (%) Maximum change in tumor size (%) Maximum change in tumor size (%) Maximum change in tumor size (%) Maximum change in tumor size (%)
Duration Of Tovorafenib Therapy For All Patients With RAPNO-LGG Evaluable Lesions 5.3 Median time to response Months Median duration of 13.8 treatment Months Overall treatment duration (months) 34 June 5, 2023 data cutoff. Patients
Duration Of Tovorafenib Therapy For All Patients With RANO-HGG Evaluable Lesions 3.0 Median time to response Months Median duration of 16.6 treatment Months Overall treatment duration (months) 35 June 5, 2023 data cutoff. Patients
Duration Of Tovorafenib Therapy For All Patients With RANO-LGG Evaluable Lesions 5.5 Median time to response Months Median duration of 14.4 treatment Months Overall treatment duration (months) 36 June 5, 2023 data cutoff. Patients
Tumor Response To Tovorafenib Across Three Assessment Criteria Were Consistent Across BRAF Fusion And Mutation Patients, and Patients With Prior MAPK Treatment 2 3,4 1 RAPNO-LGG RANO-LGG RANO-HGG Response (IRC) n n n ORR,* n (%) 76 39 (51) 76 40 (53) 69 46 (67) BRAF fusion 64 33 (52) 64 33 (52) 59 41 (69) BRAF mutation 12 6 (50) 12 7 (58) 10 5 (50) Prior MAPKi 45 22 (49) 45 23 (51) 41 29 (71) MAPKi-naive 31 17 (55) 31 17 (55) 28 17 (61) CBR,* n (%) (SD of any length of time) 76 62 (82) 76 63 (83) 69 64 (93) BRAF fusion 64 53 (83) 64 53 (83) 59 55 (93) BRAF mutation 12 9 (75) 12 10 (83) 10 9 (90) Prior MAPKi 45 38 (84) 45 38 (84) 41 37 (90) MAPKi-naive 31 24 (77) 31 25 (81) 28 27 (96) CBR,* n (%) (SD ≥12 months) 76 43 (57) 76 46 (61) 69 54 (78) BRAF fusion 64 37 (58) 64 39 (61) 59 49 (83) BRAF mutation 12 6 (50) 12 7 (58) 10 5 (50) Prior MAPKi 45 25 (56) 45 26 (58) 41 33 (80) MAPKi-naive 31 18 (58) 31 20 (65) 28 21 (75) Median DOR, months (95% CI)** 39 13.8 (11.3-NR) 40 14.4 (11.0-NR) 46 16.6 (11.6-NR) BRAF fusion 33 13.8 (11.3-NR) 33 16.3 (11.0-NR) 41 16.8 (11.6-NR) BRAF mutation 6 NR (8.4-NR) 7 12.0 (8.4-NR) 5 15.1 (8.3-NR) Prior MAPKi 22 13.8 (11.3-NR) 23 12.0 (8.5-NR) 29 15.1 (9.0-16.8) MAPKi-naive 17 NR (8.4-NR) 17 16.3 (8.4-NR) 17 NR (11.6-NR) 1 2 3 June 5, 2023 data cutoff. Fangusaro J, et al. Lancet Oncol. 2020;21(6):e305–316. Fangusaro J, et al. Lancet Oncol. 2020;21(6):e305–316. van den Bent MJ, et al. Lancet Oncol. 2011;12(6):583- 37 593. 4. Wen PY, et al. J. Clin Oncol. 2017;35(21),2439-2449. * ORR, CBR for RAPNO-LGG and RANO-LGG included MRs. ** the 95% CI were calculated using Kaplan-Meier method.
Tovorafenib Safety Data (n=137) TEAEs TRAEs Preferred Term, n (%) Any Grade Grade ≥3 Any Grade Grade ≥3 Any AE 137 (100) 86 (63) 134 (98) 58 (42) Hair color changes 104 (76) 0 104 (76) 0 • The most common reasons Anemia 81 (59) 15 (11) 67 (49) 14 (10) Elevated CPK 80 (58) 16 (12) 77 (56) 16 (12) for discontinuation were Fatigue 76 (55) 6 (4) 60 (44) 6 (4) tumor hemorrhage (3 Vomiting 68 (50) 6 (4) 28 (20) 3 (2) patients) and decrease in Hypophosphatemia 64 (47) 0 48 (35) 0 growth velocity (2 patients) Headache 61 (45) 2 (1) 29 (21) 0 Maculo-papular rash 60 (44) 11 (8) 56 (41) 11 (8) • 33 patients (24%) had TRAEs Pyrexia 53 (39) 5 (4) 17 (12) 1 (1) leading to dose reduction; 50 Dry skin 49 (36) 0 45 (33) 0 patients (37%) had TRAEs Elevated LDH 48 (35) 0 42 (31) 0 Increased AST 47 (34) 4 (3) 41 (30) 4 (3) leading to dose interruption Constipation 45 (33) 0 31 (23) 0 • Median duration of dose Nausea 45 (33) 0 25 (18) 0 Upper RTI 43 (31) 2 (1) 2 (1) 0 interruption was 2 weeks Dermatitis acneiform 42 (31) 1 (1) 41 (30) 1 (1) Epistaxis 42 (31) 1 (1) 27 (20) 0 • 9 patients (7%) had TRAEs Decreased appetite 39 (28) 5 (4) 28 (20) 4 (3) leading to discontinuation Paronychia 36 (26) 2 (1) 32 (23) 2 (1) Pruritus 35 (26) 1 (1) 32 (23) 1 (1) COVID-19 34 (25) 0 0 0 June 5, 2023 data cutoff. Treatment-emergent AEs ≥25% any grade in arms 1 & 2. AE, adverse event; ALT, Alanine transaminase; AST, aspartate aminotransferase; COVID-19, Coronavirus 38 disease 2019; CPK, creatine phosphokinase; LDH, lactate dehydrogenase; RTI, respiratory tract infection; TEAEs, treatment-emergent adverse events; TRAEs, treatment-related adverse events.