Islet Cell Adenoma

FDA lifts partial clinical holds on ersodetug for the treatment of congenital HI; Phase 3 sunRIZE study to proceed in the U.S. Phase 3 study for ersodetug for the treatment of tumor HI expected to commence in the first half of 2025 REDWOOD CITY, Calif., Sept. 19, 2024 (GLOBE NEWSWIRE) -- Rezolute, Inc. (Nasdaq: RZLT) (“Rezolute” or the “Company”), a late-stage biopharmaceutical company dedicated to developing transformative therapies for rare diseases with serious unmet needs, today reported financial results and provided a business update for the fourth quarter and full fiscal year ended June 30, 2024. “We are thrilled to close out the year with FDA alignment to advance ersodetug in two Phase 3 rare disease programs for the treatment of hypoglycemia resulting from congenital and acquired forms of hyperinsulinism,” said Nevan Elam, Chief Executive Officer and Founder of Rezolute. “The Phase 3 sunRIZE study remains on track for ex-U.S. participant enrollment and we expect U.S. enrollment to begin in the first part of 2025. We look forward to progressing both Phase 3 studies and remain excited at the prospect of ersodetug as a best-in-class treatment for hyperinsulinism based on the success we’ve seen to date.” Recent Pipeline Progress and Anticipated Milestones Congenital HI U.S. Food and Drug Administration (FDA) removal of partial clinical holds on ersodetug, a potential treatment for hypoglycemia caused by congenital HI, and authorization of U.S. inclusion in the ongoing Phase 3 sunRIZE study. Commencing study start-up activities in the U.S. with the goal of including U.S. participants in early 2025. Ex-U.S. patient enrollment in sunRIZE is on track. Topline results from sunRIZE expected in the second half of 2025. Tumor HI FDA clearance of Investigational New Drug (IND) application for Phase 3 registrational study for ersodetug for the treatment of hypoglycemia caused by tumor HI. Start-up activities are ongoing for the study, which will be primarily conducted in the U.S., with patient enrollment anticipated to begin in the first half of 2025. Topline results expected in the second half of 2026. Several insulinoma patients have been treated with ersodetug in the Expanded Access Program (EAP). Diabetic Macular Edema (DME) Announced positive topline results in May of 2024 from the Phase 2 proof-of-concept study of RZ402 in patients with DME. The study met primary endpoints, demonstrating good safety and tolerability, and a significant reduction in central subfield thickness (CST) in the Study Eye at all RZ402 dose levels compared to placebo (up to approximately 50 micron improvement). We are actively engaged in conversations with potential partners to take RZ402 into further development. Fourth Quarter and Full Year Fiscal 2024 Financial Results Cash, cash equivalents and investments in marketable securities were $127.1 million as of June 30, 2024, compared with $118.4 million as of June 30, 2023. Research and development (R&D) expenses were $19.1 million for the fourth quarter of fiscal 2024, compared with $10.9 million for the same period a year ago. Full fiscal year 2024 R&D expenses were $55.7 million, compared to $43.8 million in fiscal year 2023. The increase from fiscal year 2023 to fiscal year 2024 was primarily due to (i) increased expenditures in clinical trial activities, (ii) manufacturing costs for ersodetug, (iii) milestone payments due to license agreement partners, and (iv) higher employee-related expenses, which included employee compensation and stock-based compensation. General and administrative (G&A) expenses were $4.0 million for the fourth quarter of fiscal 2024, compared with $3.3 million for the same period a year ago. Full fiscal year 2023 G&A expenses were $14.7 million, compared to $12.2 million in fiscal year 2023. The increase was primarily attributable to employee-related expenses due to increased headcount and professional fees. Net loss was $23.0 million for the fourth quarter of fiscal 2024 compared with a net loss of $12.7 million for the same period a year ago. Full year fiscal 2024 net loss was $68.5 million compared to net loss of $51.8 million for the fiscal year 2023. About Ersodetug Ersodetug is a fully human monoclonal antibody that binds to a unique allosteric site on insulin receptors to counteract the effects of insulin receptor over-activation by insulin and related substances (such as IGF-2), thereby improving hypoglycemia in the setting of hyperinsulinism (HI). Because ersodetug acts downstream from the pancreas, it has the potential to be universally effective at treating hypoglycemia due to any form of HI. About sunRIZE The Phase 3 sunRIZE study is a multi-center, randomized, double-blind, placebo-controlled, parallel arm study designed to evaluate the efficacy and safety of ersodetug in patients with congenital HI who are experiencing poorly controlled hypoglycemia. Participants between the ages of 3 months to 45 years old are eligible to participate. The study is enrolling up to 56 participants in more than a dozen countries around the world. About Rezolute, Inc. Rezolute is a late-stage rare disease company focused on significantly improving outcomes for individuals with hypoglycemia caused by hyperinsulinism (HI). The Company’s antibody therapy, ersodetug, is designed to treat all forms of HI and has shown substantial benefit in clinical trials and real-world use for the treatment of congenital HI and tumor HI. For more information, visit . Forward-Looking Statements This release, like many written and oral communications presented by Rezolute and our authorized officers, may contain certain forward-looking statements regarding our prospective performance and strategies within the meaning of Section 27A of the Securities Act and Section 21E of the Securities Exchange Act of 1934, as amended. We intend such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and are including this statement for purposes of said safe harbor provisions. Forward-looking statements, which are based on certain assumptions and describe future plans, strategies, and expectations of Rezolute, are generally identified by use of words such as “anticipate,” “believe,” “estimate,” “expect,” “intend,” “plan,” “project,” “seek,” “strive,” “try,” or future or conditional verbs such as “could,” “may,” “should,” “will,” “would,” or similar expressions. These forward-looking statements include, but are not limited to statements regarding the fourth quarter and fiscal year financial results of Rezolute, the full year financial results of Rezolute, the ersodetug Expanded Access Program, ersodetug as a sunRIZE Phase 3 study, the ability of ersodetug to become an effective treatment for congenital hyperinsulinism, the effectiveness or future effectiveness of ersodetug for the treatment of congenital hyperinsulinism, statements regarding clinical trial timelines for ersodetug, the RZ402 study, the ability of RZ402 to become an effective treatment for diabetic macular edema, the effectiveness or future effectiveness of RZ402 to become an effective treatment for diabetic macular edema, and statements regarding clinical trial timelines for RZ402. Our ability to predict results or the actual effects of our plans or strategies is inherently uncertain. Accordingly, actual results may differ materially from anticipated results. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. Except as required by applicable law or regulation, Rezolute undertakes no obligation to update these forward-looking statements to reflect events or circumstances that occur after the date on which such statements were made. Important factors that may cause such a difference include any other factors discussed in our filings with the SEC, including the Risk Factors contained in the Rezolute’s Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, which are available at the SEC’s website at You are urged to consider these factors carefully in evaluating the forward-looking statements in this release and are cautioned not to place undue reliance on such forward-looking statements, which are qualified in their entirety by this cautionary statement. Contacts: Rezolute, Inc. Christen Baglaneas cbaglaneas@rezolutebio.com 508-272-6717 LHA Investor Relations Tirth T. Patel tpatel@lhai.com 212-201-6614 Rezolute, Inc. Condensed Consolidated Financial Statements Data (in thousands, except per share data) Three Months Ended Year Ended June 30, June 30, 2024 2023 2024 2023 Condensed Consolidated Statements of Operations Data: Operating expenses: Research and development $ 19,089 $ 10,933 $ 55,743 $ 43,813 General and administrative 4,013 3,305 14,680 12,177 Total operating expenses 23,102 14,238 70,423 55,990 Loss from operations (23,102 ) (14,238 ) (70,423 ) (55,990 ) Non-operating (expenses) income, net 126 1,510 1,964 4,203 Net loss $ (22,976 ) $ (12,728 ) $ (68,459 ) $ (51,787 ) Basic and diluted net loss per common share $ (0.44 ) $ (0.25 ) $ (1.33 ) $ (1.01 ) Shares used to compute basic and diluted net loss per common share 52,235 51,410 51,465 51,188 June 30, June 30, 2024 2023 Condensed Consolidated Balance Sheets Data: Cash and cash equivalents $ 70,396 $ 16,036 Investments in marketable debt securities 56,741 102,330 Working capital 119,047 99,710 Total assets 132,737 123,721 Accumulated deficit (329,444 ) (260,985 ) Total stockholders’ equity 121,003 116,172

The FDA on Monday released new draft guidance on conducting multi-regional oncology trials, saying its “paramount consideration” is whether the results apply to the intended use population and standard cancer care practices in the US. The draft’s release coincides with the European Society for Medical Oncology’s conference in Barcelona this week, and it comes more than two years after the FDA shut the door on companies only relying on data from China-based trials for new cancer drug approvals. Back in 2022, the regulator issued a complete response letter to Eli Lilly and Innovent’s sintilimab regarding its China-only data. The agency similarly rejected Hutchmed’s surufatinib, a kinase inhibitor that blocks VEGFR and FGFR, as a treatment of pancreatic and extrapancreatic neuroendocrine tumors, citing similar concerns. While the FDA’s new nine-page draft doesn’t specifically mention China, it notes that there has been a “decreasing proportion of US participants” in cancer drug trials. If a sponsor is planning a multi-regional trial to support a new drug approval, the FDA recommends “that such a trial be conducted across major geographical regions (e.g., across several continents) rather than predominantly in a single country or in a single geographical region (e.g., Asia).” The guidance said sponsors should be aware that if a trial’s participant demographics differ significantly from the US population, “foreign data may not be appropriate to support an FDA regulatory decision.” However, the agency also said there are some circumstances in which it may be acceptable for a sponsor to conduct a multi-regional trial. That includes enrolling “a substantial proportion of participants in a single foreign geographical region if such a trial is conducted as part of an overall program that includes one or more additional pivotal trials in the premarket setting that will enroll a population that is representative of the US population.” For trials of drugs intended to treat cancers that are common in the US like colorectal or breast cancer, the FDA recommends “equal allocation of study participants across the selected major geographical regions, including North America.” Equal allocation is defined as using equal numbers of subjects from each region. And for studies in cancers that occur “much less commonly in the US compared to regions outside the US (e.g., squamous cell esophageal cancer), FDA recommends a proportional allocation approach.” Proportional allocation is defined by the draft as the allocation of subjects to regions in proportion to the size of the region and disease prevalence. The FDA also said companies should take into account patient-related factors like disease risk and genetic background in addition to disease-related and socio-cultural factors, including diet, when deciding if a multi-regional trial is appropriate. Sponsors should request a meeting with the regulator if and when the treatment landscape changes during a trial to determine the most efficient approach to incorporating those changes into an ongoing trial.

ALAMEDA, Calif.--( BUSINESS WIRE )-- Exelixis, Inc. (Nasdaq: EXEL) today announced updated and final data from CABINET, a phase 3 pivotal trial evaluating cabozantinib (CABOMETYX ® ) versus placebo in two cohorts of patients with previously treated neuroendocrine tumors: one cohort with advanced pancreatic neuroendocrine tumors (pNET) and one cohort with advanced extra-pancreatic NET (epNET). These data are being presented today at the 2024 European Society for Medical Oncology Congress (ESMO 2024) during the Proffered Paper Session: NETs and Endocrine Tumours at 2:45 p.m. CET and were simultaneously published in the New England Journal of Medicine ( NEJM ). “ The phase 3 CABINET study, which was conducted through the National Cancer Institute's National Clinical Trials Network, reflects real-world clinical practice in that it enrolled a wide and heterogeneous range of patients regardless of primary tumor site, grade, somatostatin receptor expression and functional status,” said Jennifer Chan, M.D., M.P.H., study chair for the CABINET trial, Clinical Director of the Gastrointestinal Cancer Center and Director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute. “ I’m encouraged by these final results showing that cabozantinib provided a clinically meaningful treatment benefit for patients with previously treated advanced neuroendocrine tumors, including across all major clinical subgroups. The findings suggest that cabozantinib has the potential to become a new standard of care for these patients greatly in need of new treatment options.” The final results from the CABINET study presented today at ESMO and published in NEJM demonstrate continued improvement with cabozantinib in the primary endpoint of progression-free survival (PFS) by blinded independent central review (BICR) through the data cutoff of August 24, 2023. In the pNET cohort (n=95), at a median follow-up of 13.8 months, the hazard ratio (HR) was 0.23 (95% confidence interval [CI]: 0.12-0.42; p<0.0001); median PFS was 13.8 months for cabozantinib versus 4.4 months for placebo. In the epNET cohort (n=203), at a median follow-up of 10.2 months, the HR was 0.38 (95% CI: 0.25-0.59; p<0.0001); median PFS was 8.4 months versus 3.9 months, respectively. Upon disease progression, patients were unblinded, and those receiving placebo were permitted to cross over to open-label therapy with cabozantinib. Additional analyses suggest benefits with cabozantinib across all clinical subgroups examined, including primary tumor site, grade and prior systemic anticancer therapy. In the pNET cohort, the objective response rate (ORR) by BICR was 19% with cabozantinib compared with 0% with placebo. In the epNET cohort, the ORR by BICR was 5% with cabozantinib compared with 0% with placebo. Similar interim overall survival (OS) results for cabozantinib compared to placebo were observed in both cohorts; HRs for OS were 0.95 (95% CI: 0.45-2.00) for the pNET cohort and 0.86 (95% CI: 0.56-1.31) for the epNET cohort. “ Patients with advanced neuroendocrine tumors face a poor prognosis with limited treatment options. These updated data reinforce the potential of cabozantinib as a new treatment to significantly delay disease progression,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “ We believe the CABINET data indicate that cabozantinib could be practice-changing in NET, and we are working closely with the FDA to bring this differentiated option to patients with advanced NET as quickly as possible.” The safety profile of cabozantinib observed in each cohort was consistent with its known safety profile; no new safety signals were identified. A majority of patients treated with cabozantinib required dose modifications or reductions to manage adverse events. These results were the basis for Exelixis’ supplemental new drug application (sNDA) for cabozantinib for the treatment of adults with advanced NET. The FDA accepted the sNDA in August and assigned a Prescription Drug User Fee Act target action date of April 3, 2025. In August of 2023, CABINET was stopped and unblinded early due to a dramatic improvement in PFS observed at an interim analysis in both of the trial’s cohorts, per a unanimous recommendation of the Alliance for Clinical Trials in Oncology independent Data and Safety Monitoring Board; all patients were unblinded, and those on placebo were given the option to cross over to active treatment with cabozantinib. Cabozantinib demonstrated a statistically significant and clinically meaningful improvement in PFS versus placebo based on results of both local review and available BICR. Initial results by investigator were presented at ESMO 2023. About CABINET (Alliance A021602) CABINET (Randomized, Double-Blinded Phase III Study of CAB ozantinib versus Placebo I n Patients with Advanced NE uroendocrine T umors After Progression on Prior Therapy) is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology with participation from the NCI-funded National Clinical Trials Network as part of Exelixis’ collaboration through a Cooperative Research and Development Agreement with the NCI’s Cancer Therapy Evaluation Program. CABINET is a multicenter, randomized, double-blinded, placebo-controlled phase 3 pivotal trial that had enrolled a total of 298 patients in the U.S at the time of the final analysis. Patients were randomized 2:1 to cabozantinib (60 mg) or placebo in two separately powered cohorts (pNET, n=95; epNET, n=203). The epNET cohort included patients with the following primary tumor sites: gastrointestinal (GI) tract, lung, unknown primary sites and other. Each cohort was randomized separately and had its own statistical analysis plan. Patients must have had measurable disease per RECIST 1.1 criteria and must have experienced disease progression or intolerance after at least one U.S. FDA-approved line of prior therapy other than somatostatin analogs. The primary endpoint in each cohort was PFS per RECIST 1.1 by blinded independent central review. Secondary endpoints included overall survival, radiographic response rate and safety. More information about this trial is available at ClinicalTrials.gov . About NET NET are cancers that begin in the specialized cells of the body’s neuroendocrine system. 1 These cells have traits of both hormone-producing endocrine cells and nerve cells. 1 In the U.S., it is estimated that 161,000 to 192,000 people are living with unresectable, locally advanced or metastatic NET. 2 The number of people diagnosed with NET has been increasing in recent decades. 3 Functional NET release peptide hormones that can cause debilitating symptoms, like diarrhea, hypertension and flushing which may require focused treatment, while symptoms of non-functional NET are related primarily to tumor growth. 4,5 Most NET take years to develop and grow slowly, but eventually all patients with advanced or metastatic NET will develop refractory and progressing disease. 6,7 NET can develop in any part of the body, but most commonly start in the GI tract or in the lungs, where they have historically been referred to as carcinoid tumors and are more recently called epNET. 1 The five-year survival rates for advanced GI and lung NET tumors are 68% and 55%, respectively. 8,9 NET can also start in the pancreas, where they tend to be more aggressive, with a five-year survival rate of only 23% for advanced disease. 1,10 For advanced NET patients, treatment options include somatostatin analogs, chemotherapy, targeted therapy and peptide-receptor radionuclide therapy. 11 About CABOMETYX ® (cabozantinib) In the U.S., CABOMETYX tablets are approved as monotherapy for the treatment of patients with advanced renal cell carcinoma (RCC) and in combination with nivolumab for patients as a first-line treatment for patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib, and; for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. CABOMETYX tablets have also received regulatory approvals in over 65 countries outside the U.S. and Japan, including the European Union. In 2016, Exelixis granted Ipsen Pharma SAS exclusive rights for the commercialization and further clinical development of cabozantinib outside of the U.S. and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the U.S. CABOMETYX is not indicated as a treatment for NET. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation. Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention. Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis. Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose. Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE. Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity. Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity. Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC. Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency. Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome. Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose. Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients. Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated. Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN. In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients. Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity. Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose. ADVERSE REACTIONS The most common (≥20%) adverse reactions are: CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. DRUG INTERACTIONS Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice. Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose. Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment. Please see accompanying full Prescribing Information https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf . You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. About Exelixis Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care. Powered by drug discovery and development excellence, we are rapidly evolving our product portfolio to target an expanding range of tumor types and indications with our clinically differentiated pipeline of small molecules, antibody-drug conjugates and other biotherapeutics. This comprehensive approach harnesses decades of robust investment in our science and partnerships to advance our investigational programs and extend the impact of our flagship commercial product, CABOMETYX ® (cabozantinib). Exelixis is driven by a bold scientific pursuit to create transformational treatments that give more patients hope for the future. For information about the company and its mission to help cancer patients recover stronger and live longer, visit www.exelixis.com , follow @ExelixisInc on X (Twitter), like Exelixis, Inc. on Facebook and follow Exelixis on LinkedIn. Exelixis Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the presentation of final results from the CABINET trial at ESMO 2024; the therapeutic potential of cabozantinib to become a new standard of care for patients with previously treated NET who are greatly in need of new treatment options, and Exelixis’ belief that cabozantinib could be practice-changing and significantly delay disease progression; Exelixis’ plans to work closely with the FDA to bring cabozantinib as a treatment option to patients with advanced NET as quickly as possible, as well as the FDA’s regulatory review process with respect to Exelixis’ sNDA submission, including the Prescription Drug User Fee Act target action date assigned by the FDA; and Exelixis’ scientific pursuit to create transformational treatments that give more patients hope for the future. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ continuing compliance with applicable legal and regulatory requirements; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating cabozantinib; Exelixis’ dependence on its relationships with its cabozantinib commercial collaboration partners, including the level of their investment in the resources necessary to pursue regulatory approvals and successfully commercialize cabozantinib in the territories where approved; Exelixis’ dependence on third-party vendors for the development, manufacture and supply of cabozantinib; Exelixis’ ability to protect its intellectual property rights; market competition, including the potential for competitors to obtain approval for generic versions of CABOMETYX; changes in economic and business conditions; and other factors affecting Exelixis and its development programs detailed from time to time under the caption “Risk Factors” in Exelixis’ most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and in Exelixis’ future filings with the Securities and Exchange Commission. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law. Exelixis, the Exelixis logo and CABOMETYX are registered U.S. trademarks of Exelixis. ___________________________________ 1 Neuroendocrine Tumors. Cleveland Clinic website. Available at: https://my.clevelandclinic.org/health/diseases/22006-neuroendocrine-tumors-net . Accessed September 2024. 2 Population Estimate: Unresectable, Locally Advanced or Metastatic Extra-Pancreatic NET. June 2024 (internal data on file). 3 Pathak, S., Starr, J.S., Halfdanarson T., et al. Understanding the increasing incidence of neuroendocrine tumors. Expert Rev Endocrinol Metab. September 2023;18(5):377-385. 4 Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ ® )–Patient Version. NCI website. Available at: https://www.cancer.gov/types/pancreatic/patient/pnet-treatment-pdq . Accessed September 2024. 5 What Is a Pancreatic Neuroendocrine Tumor? ACS website. Available at: https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/about/what-is-pnet.html . Accessed September 2024. 6 McClellan, K., Chen. E.Y, Kardosh A., et al. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers. 2022, 14(19), 4769. 7 What is a Gastrointestinal Carcinoid Tumor? ACS website. Available at: https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/about/what-is-gastrointestinal-carcinoid.html . Accessed September 2024. 8 Survival Rates for Gastrointestinal Carcinoid Tumors. ACS website. Available at: https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html . Accessed September 2024. 9 Survival Rates for Lung Carcinoid Tumors. ACS website. Available at: https://www.cancer.org/cancer/types/lung-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html . Accessed September 2024. 10 Survival Rates for Pancreatic Neuroendocrine Tumor. ACS website. Available at: https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/detection-diagnosis-staging/survival-rates.html . Accessed September 2024. 11 Neuroendocrine Tumor (NET). NCI website. Available at: https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/carcinoid-tumor . Accessed September 2024.