Levoleucovorin

NEW YORK, NY, USA I December 20, 2024 I Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and Drug Administration (FDA) has approved BRAFTOVI ® (encorafenib) in combination with cetuximab (marketed as ERBITUX ® ) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. i The indication was approved based on a statistically significant and clinically meaningful improvement in response rate and durability of response in treatment-naïve patients treated with BRAFTOVI in combination with cetuximab and mFOLFOX6 from the Phase 3 BREAKWATER trial. Continued approval for this indication is contingent upon verification of clinical benefit. This accelerated approval is among the first in the industry to be conducted under the FDA’s Project FrontRunner, which seeks to support the development and approval of new cancer drugs for advanced or metastatic disease. “Historically, treatment options have been limited and outcomes poor for patients diagnosed with metastatic colorectal cancer with BRAF mutations,” said Scott Kopetz, M.D., Ph.D., FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “As the first and only combination regimen featuring a BRAF-targeted therapy for this patient population, usable even in first-line treatment, the encorafenib regimen has demonstrated high response rates that are rapid and durable. This represents an encouraging sign of continued disease control and a source of renewed hope for patients.” The ongoing BREAKWATER trial is evaluating BRAFTOVI plus cetuximab with or without chemotherapy (mFOLFOX6) in previously untreated mCRC patients who harbor a BRAF V600E mutation. It is the only Phase 3 trial for a BRAF-targeted therapy regimen in first-line BRAF V600E -mutant mCRC. The trial met one of the dual primary endpoints of confirmed overall response rate (ORR), with a statistically significant improvement over standard of care: ORR 61% (95% confidence interval [CI]: 52, 70) for BRAFTOVI in combination with cetuximab and mFOLFOX6 compared with ORR 40% (95% CI: 31, 49) for chemotherapy, with or without bevacizumab (p=0.0008). 1 The median duration of response (DoR) was 13.9 months (95% CI: 8.5, not estimable) for the BRAFTOVI combination regimen versus 11.1 months (95% CI: 6.7, 12.7) for chemotherapy, with or without bevacizumab. 1 The Phase 3 BREAKWATER trial is ongoing, and results from the full dataset will be presented at upcoming medical meetings. “For more than a decade, Pfizer has been a pioneer in delivering targeted therapies for molecular-driven cancers. With today’s accelerated approval of the BRAFTOVI regimen, patients with metastatic colorectal cancer with a BRAF V600E mutation now have a first-line treatment option, which contains a targeted therapy specifically for a mutation that is driving their cancer,” said Chris Boshoff, M.D., Ph.D., Chief Oncology Officer, Executive Vice President, Pfizer. “This milestone adds to our legacy of developing innovative medicines in BRAF tumors, some of the hardest-to-treat cancers. We look forward to continuing to expand our portfolio, including the exploration of a next-generation brain-penetrant BRAF inhibitor.” The safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 in the BREAKWATER trial was consistent with the known safety profile of each respective agent. No new safety signals were identified. The most common adverse reactions (≥25%) were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia. 1 Among patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6, 12% experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common adverse reactions (≥1%) included elevated lipase levels. “Finding out that your cancer has spread can be a frightening time for those with colorectal cancer and their loved ones. The prognosis for those receiving a metastatic colorectal cancer diagnosis has improved slightly in recent years, but the same cannot be said for those with a BRAF mutation who unfortunately face an especially aggressive disease and worse outcomes,” said Michael Sapienza, Chief Executive Officer of the Colorectal Cancer Alliance. “Today’s approval of the first combination regimen including a BRAF-targeted therapy for BRAF V600E -mutant metastatic colorectal cancer, which can be used for previously untreated patients, offers new promise for the community and marks an important step forward in our collective mission to end this disease.” This application was granted priority review, used the Real-Time Oncology Review (RTOR) pilot program, and was conducted under Project Orbis , with application reviews ongoing for Project Orbis partners, including Canada and Brazil. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential future additional license applications for the BRAFTOVI combination regimen in this indication. This accelerated approval follows the previous FDA approval for BRAFTOVI in combination with cetuximab for adults with mCRC with a BRAF V600E mutation after prior therapy. About Colorectal Cancer (CRC) CRC is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022. 2 Overall, the lifetime risk of developing CRC is about 1 in 23 for men and 1 in 25 for women. 3 In the U.S. alone, an estimated 152,810 people will be diagnosed with cancer of the colon or rectum in 2024, and approximately 53,000 are estimated to die from the disease each year. 4 For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat. 5 BRAF mutations are estimated to occur in 8-10% of people with mCRC and represent a poor prognosis for these patients. 6 The BRAF V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAF V600E mutation is more than double that of patients with no known mutation present. 6,7 Despite the high unmet need in BRAF V600E -mutant mCRC, prior to today there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E -mutant mCRC. 8,9 About BREAKWATER BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with chemotherapy, in participants with previously untreated BRAF V600E -mutant mCRC. In the Phase 3 portion of the study, patients were randomized to receive BRAFTOVI 300 mg orally once-daily in combination with cetuximab (discontinued after randomization of 158 patients), BRAFTOVI 300 mg orally once-daily in combination with cetuximab and mFOLFOX6 (n=236), or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (control arm) (n=243). The dual primary endpoints are ORR and progression-free survival (PFS), as assessed by blinded independent central review (BICR). Key secondary endpoints include DoR as assessed by BICR, time to response by BICR, overall survival, and safety. About BRAFTOVI ® (encorafenib) BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E . Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in certain cancers, including CRC. Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize the product in Japan and South Korea, Medison has exclusive rights to commercialize the product in Israel and Pierre Fabre has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea). U.S. INDICATION AND USAGE BRAFTOVI ® (encorafenib) is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC. View the full Prescribing Information . There may be a delay as the document is updated with the latest information. It will be available as soon as possible. Please check back for the updated full information shortly. About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com . In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer_News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . References 1 BRAFTOVI (encorafenib) Prescribing Information. Array BioPharma, Inc.; December 2024 2 American Cancer Society. Global Cancer Facts & Figures 5th Edition. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-2024.pdf. Last accessed: December 2024. 3 American Cancer Society. Key Statistics for Colorectal Cancer. Available at: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html. Last accessed: December 2024. 4 American Cancer Society. Cancer Facts & Figures 2024. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf. Last accessed: December 2024. 5 Ciardiello F, Ciardiello D, Martini G, et al . Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin . 2022;72:372–40. 6 Djanani A, Eller S, Öfner D, et al . The role of BRAF in metastatic colorectal carcinoma-past, present, and future. Int J Mol Sci . 2020;21(23):9001. 7 Safaee Ardekani G, Jafarnejad SM, Tan L, et al . The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PloS ONE . 2012;7(10):e47054. 8 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer. V.5.2024 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed December 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 9 Cervantes A, Adam R, Roselló S, et al . Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol . 2023;34(1):10–32. SOURCE: Pfizer

Continued progress with both clinical trials of lead program, SON-1010, for solid tumors and Platinum-Resistant Ovarian Cancer (PROC) Executed licensing agreement to support initiation of a Phase 2 clinical trial of SON-080 in Diabetic Peripheral Neuropathy (DPN) Multiple value-driving milestones expected throughout calendar year 2025 as well as pipeline expansion opportunities across the solid tumor market Total annual operating expenses reduced by an approximate 37% as compared to fiscal year 2023 Approximately 43% of total annual operating expenses during fiscal year 2024 were covered by non-dilutive funding received during fiscal year 2024 from the New Jersey Tax Certificate Transfer and Australia R&D Tax Incentive Programs PRINCETON, NJ, Dec. 17, 2024 (GLOBE NEWSWIRE) -- Sonnet BioTherapeutics Holdings, Inc. (the “Company” or “Sonnet”) (NASDAQ: SONN), a clinical-stage company developing targeted immunotherapeutic drugs, reported today financial results for the fiscal year ended September 30, 2024 and provided a corporate update. “We are very pleased with the progress we have made across all facets of the company’s operations. On the financial front, we have delivered on our stated objective of cutting costs through an approximate 37% reduction in total operating expenses versus last year, which will help to extend our cash runway, combined with being able to leverage non-dilutive funding and capital markets financings. Additionally, we have executed on our partnership plans to advance both our SON-080 program and SON-1210 program to their respective next stages of development and continue to believe in their potential to address indications of significant unmet need,” commented Pankaj Mohan, Ph.D., Founder and Chief Executive Officer of Sonnet. “Looking ahead, our focus is on advancing our lead program, SON-1010, and we are pleased to be on track for key data readouts from our ongoing SB101 trial for solid tumors and our SB221 trial for PROC. We look forward to the upcoming data readouts to help further unlock the intrinsic value of our FHAB technology platform.” Recent Highlights Announced topline safety data following successful completion of SON-1010 monotherapy dose escalation in the Phase 1 SB101 trial;Announced the publication of extensive discovery, development, and preclinical data regarding SON-1010, demonstrating its mechanism of action in a paper entitled, “SON-1010: an albumin-binding IL-12 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy,” in Frontiers in Immunology;Granted U.S. Patent No. 12,134,635 covering two of its novel drug candidates, SON-1411 (IL-18BPR-FHAB-IL12) and SON-1400 (IL-18BPR-FHAB), each containing a modified version of recombinant human interleukin-18 (BPR = Binding Protein Resistant);Entered into a licensing agreement with Alkem Laboratories Limited for the research, development, manufacturing, marketing, and commercialization of the SON-080 molecule for the treatment of DPN in India;Received preliminary approval for the sale of tax credits from the New Jersey Technology Business Tax Certificate Transfer Program administered by the New Jersey Economic Development Authority (NJEDA); andEntered into a Master Clinical Collaboration Agreement with the Sarcoma Oncology Center to advance the development of SON-1210 in combination with chemotherapy for the treatment of metastatic pancreatic cancer. Lead Clinical Programs Update SON-1010: Targeted Immune Activation Cancer Therapy, Turning ‘Cold’ Tumors ‘Hot’, Initially Targeting Solid Tumors and Platinum-Resistant Ovarian Cancer (PROC) Phase 1 Trial (SB101 Trial): Advanced Solid Tumors (Monotherapy) This first-in-human study is primarily designed to evaluate the safety, tolerability, PK, and PD of multiple ascending doses of SON-1010 in cancer patients and is being conducted at several sites across the United States. The Company recently completed enrollment and dose escalation in the Phase 1 SB101 clinical trial of SON-1010 (IL12-FHAB) in adult patients with advanced solid tumors. Additionally, the Company reported that results of SON-1010 at the highest dose have been formally evaluated by the Safety Review Committee. The study has enrolled 24 subjects to date. Primary outcome measures for the study were to evaluate the safety and tolerability of SON-1010 and establish the MTD. For more information about the SB101 clinical trial, visit clinicaltrials.gov and reference identifier NCT05352750. Phase 1b/2a Trial (SB221 Trial): Advanced Solid Tumors and PROC (Combo with Atezolizumab) The second trial is a global Phase 1b/2a multicenter, dose-escalation and randomized proof-of-concept study to assess the safety, tolerability, PK, PD, and efficacy of SON-1010 administered subcutaneously (SC) in combination with atezolizumab given intravenously (IV) (in collaboration with Genentech, a member of the Roche Group). This study was recently expanded to include the MTD of SON-1010 from SB101. Enrollment remains ongoing and an update on safety at the MTD in that trial is expected in Q1 2025. For more information about the SB221 clinical trial, visit clinicaltrials.gov and reference identifier NCT05756907. SON-1010 Upcoming Milestones Phase 1: Solid Tumors (Monotherapy)​ H1 calendar year 2025: Topline Efficacy Data​ Phase 1b/2a: PROC (Combo with Atezolizumab)​ Q1 calendar year 2025: Additional Safety Data​H2 calendar year 2025: RP2D & Topline Efficacy Data SON-1210: Proprietary, Bifunctional Version of Human Interleukins 12 (IL-12) and 15 (IL-15), Configured Using Sonnet's Fully Human Albumin Binding (FHAB®) platform, in Combination with Chemotherapy for the Treatment of Advanced Solid Tumors and Metastatic Pancreatic Cancer As previously announced, the Company successfully completed two IND-enabling toxicology studies of SON-1210 in non-human primates (NHPs), which demonstrated no overt toxicity in the GLP study apart from the expected and mild, on-target changes in hematology and clinical chemistry parameters that resolved completely within 14 to 21 days post-dosing. A significant increase in interferon gamma (IFNγ), which was controlled and prolonged, was noted as early as one day following administration, with no apparent increase in other proinflammatory cytokines. IFNγ is a well-known pharmacodynamic biomarker that is required for anti-tumor efficacy in preclinical models. Other signs of cytokine imbalance, or uncontrolled increase of pro-inflammatory cytokines (including TNF-α, IL-1β, and IL-6) were notably absent from all dose levels tested in the study. In August 2024, the Company entered into a Master Clinical Collaboration Agreement with the Sarcoma Oncology Center, to conduct an investigator-initiated Phase 1/2a clinical study to evaluate SON-1210 in combination with several chemotherapeutic agents including but not limited to NALIRIFOX (the combination of liposomal irinotecan, 5-fluorouracil/leucovorin, and oxaliplatin) for the specific treatment of metastatic pancreatic cancer. The NALIRIFOX regimen is U.S. FDA-approved for the treatment of metastatic pancreatic cancer in the front-line and refractory settings. SON-1210 Upcoming Milestones Q1 calendar year 2025: IND SubmissionH1 calendar year 2025: 1st Patient Dosed in Investigator-Initiated Phase 1/2a Study SON-080: Low dose of rhIL-6 for Chemotherapy-Induced Peripheral Neuropathy (CIPN) and Diabetic Peripheral Neuropathy (DPN) In October 2024, the Company entered into a licensing agreement (the “Licensing Agreement”) with Alkem Laboratories Limited (“Alkem”) for the research, development, manufacturing, marketing, and commercialization of its SON-080 molecule for the treatment of DPN in India and the manufacturing, marketing, and commercialization of SON-080 for chemotherapy induced neuropathy (CIPN) and autonomic neuropathy in India. Alkem will conduct all clinical trials it believes appropriate to obtain regulatory approval in India of SON-080 for the treatment of DPN. Summary of Financial Results for the Fiscal Year 2024As of September 30, 2024, Sonnet had $0.1 million cash on hand. The Company believes that based on cash on hand at September 30, 2024, together with the approximate $7.7 million recently received through the sale of common stock and warrants in November and December 2024, $0.7 million received from the R&D Tax Incentive Program in Australia in November 2024 to satisfy the Company’s incentive tax receivable, and $0.5 million received in October 2024 as an upfront payment related to the License Agreement, which after tax withholdings resulted in a net payment of $0.4 million, it has sufficient funds for projected operations into July 2025. Research and development expenses were $5.7 million for the year ended September 30, 2024, compared to $11.8 million for the year ended September 30, 2023. General and administrative expenses were $6.1 million for the year ended September 30, 2024, compared to $7.1 million for the year ended September 30, 2023. About Sonnet BioTherapeutics Holdings, Inc. Sonnet BioTherapeutics is an oncology-focused biotechnology company with a proprietary platform for innovating biologic drugs of single or bifunctional action. Known as FHAB (Fully Human Albumin Binding), the technology utilizes a fully human single chain antibody fragment (scFv) that binds to and "hitch-hikes" on human serum albumin (HSA) for transport to target tissues. Sonnet's FHAB was designed to specifically target tumor and lymphatic tissue, with an improved therapeutic window for optimizing the safety and efficacy of immune modulating biologic drugs. FHAB is the foundation of a modular, plug-and-play construct for potentiating a range of large molecule therapeutic classes, including cytokines, peptides, antibodies, and vaccines. Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the outcome of the Company’s clinical trials, the Company's cash runway, the Company's product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management's current beliefs and assumptions. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential,” "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Investor Relations Contact:JTC Team, LLCJenene Thomas 908-824-0775SONN@jtcir.com Sonnet BioTherapeutics Holdings, Inc.Consolidated Balance Sheets September 30, 2024 2023 Assets Current assets: Cash and cash equivalents $149,456 $2,274,259 Prepaid expenses and other current assets 1,206,409 1,677,396 Incentive tax receivable 762,078 786,574 Total current assets 2,117,943 4,738,229 Property and equipment, net 20,523 33,366 Operating lease right-of-use asset 123,417 193,689 Deferred offering costs 15,000 49,988 Other assets 494,147 414,206 Total assets $2,771,030 $5,429,478 Liabilities and stockholders’ deficit Current liabilities: Accounts payable $2,183,416 $2,201,999 Accrued expenses and other current liabilities 942,489 3,230,922 Current portion of operating lease liability 84,291 73,048 Deferred income — 18,626 Total current liabilities 3,210,196 5,524,595 Operating lease liability, net of current portion 46,573 130,863 Total liabilities 3,256,769 5,655,458 Commitments and contingencies (Note 5) Stockholders’ deficit: Preferred stock, $0.0001 par value: 5,000,000 shares authorized; no shares issued or outstanding — — Common stock, $0.0001 par value: 125,000,000 shares authorized; 650,284 and 218,786 issued and outstanding at September 30, 2024 and 2023, respectively 65 22 Additional paid-in capital 117,195,181 110,017,751 Accumulated deficit (117,680,985) (110,243,753)Total stockholders’ deficit (485,739) (225,980)Total liabilities and stockholders’ deficit $2,771,030 $5,429,478 Sonnet BioTherapeutics Holdings, Inc.Consolidated Statements of Operations Years ended September 30, 2024 2023 Collaboration revenue $18,626 $147,805 Operating expenses: Research and development 5,737,252 11,814,690 General and administrative 6,130,845 7,125,732 Total operating expense 11,868,097 18,940,422 Loss from operations (11,849,471) (18,792,617)Foreign exchange gain (loss) 84,293 (40,077)Other income 4,327,946 — Net loss $(7,437,232) $(18,832,694) Per share information: Net loss per share, basic and diluted $(11.35) $(145.13)Weighted average shares outstanding, basic and diluted 655,240 129,760