Nephrotic Syndrome

Retrospective analysis suggests Acthar Gel treatment was associated with similar improvement in health status and overall symptom reduction in African Americans and non-African Americans with symptomatic sarcoidosis1 Findings on treatment response and physician-reported outcomes indicate that Acthar Gel may be a viable treatment option for both African American and non-African American sarcoidosis patients1 DUBLIN, March 11, 2024 /PRNewswire/ -- Mallinckrodt plc, a global specialty pharmaceutical company, today announced the publication of findings from a retrospective chart review of Acthar® Gel (repository corticotropin injection) treatment outcomes for African American and non-African American patients with symptomatic sarcoidosis – including treatment patterns, co-medication use, and overall health outcomes.1 This analysis suggested that Acthar Gel treatment was associated with similar improvements in health outcomes, a reduction in symptoms, and reduced co-medication use in both African Americans and non-African Americans with symptomatic sarcoidosis.1 The manuscript was recently published online in Therapeutics & Clinical Risk Management. This research builds upon findings from a study investigating the clinical and real-world outcomes of Acthar Gel treatment in a subgroup of African Americans with symptomatic sarcoidosis, previously presented at the 2022 American Thoracic Society Annual International Conference in San Francisco, CA, and published in Therapeutic Advances in Respiratory Disease in 2019.2 Acthar is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides.3 Acthar Gel is approved by the U.S. Food and Drug Administration (FDA) for the treatment of several autoimmune disorders and medical conditions known to cause inflammation, including symptomatic sarcoidosis.3 Please see additional indications and Important Safety Information below. "The results of this retrospective medical chart review highlight unmet needs that exist for African American patients with symptomatic sarcoidosis, who are disproportionately affected by the disease, and reinforce Acthar Gel's potential to help improve health outcomes for appropriate patients,"1,4,5 said George Wan, Ph.D., M.P.H., Vice President, Evidence Generation and Data Sciences, Mallinckrodt. "This research reflects Mallinckrodt's commitment to collecting real-world data on the relationship between patient characteristics, treatment patterns, and outcomes to support clinicians' treatment decisions and address disparities in symptomatic sarcoidosis care."1 About the Study:1 In this retrospective analysis, a national database of Acthar Gel prescribers and the American Medical Association Physician Master were merged to obtain a sample of 98 physicians to provide data on the last 6 consecutive patients seen who met the study's eligibility criteria. The medical records were extracted for adult patients (≥18 years) with a diagnosis of advanced symptomatic sarcoidosis, who had ≥1 symptom, and who had either completed at least one course of Acthar Gel or had received Acthar Gel for at least 6 months during data collection. A total of 272 patients with symptomatic sarcoidosis were included in this analysis (African American (AA): n=168; non-African American (non-AA): n=104). Most patients in both race groups were diagnosed with stage 3 or 4 sarcoidosis based on chest imaging and biopsy (AA: 61.3%, n=103 vs. non-AA: 68.3%, n=71; p=0.2453). Per an assessment of patient characteristics and Acthar Gel treatment patterns, this analysis suggests that the average time since the first diagnosis of sarcoidosis was slightly longer among AA than non-AA (mean ± SD: 5.2 ± 7.6 years vs. 4.3 ± 5.1 years; p>0.05).1 Further, a lower proportion of AA vs. non-AA had completed a course of Acthar Gel therapy (44%, n=74 vs. 55.8%, n=58; p=0.0602) during the data collection period,1 and the duration of Acthar Gel treatment was slightly longer among AA vs. non-AA (mean ± SD: 31.7 ± 32 vs. 29 ± 27.4 weeks; p>0.05).1 "This research underscores the importance of conducting real-world studies to provide data that helps to recognize the disparities in symptomatic sarcoidosis care and address unmet needs to better support health outcomes for all appropriate patients," said Mary McGowan, Chief Executive Officer, Foundation for Sarcoidosis Research (FSR). FSR is the leading international organization dedicated to finding a cure for sarcoidosis and improving care for sarcoidosis patients through research, education, and support. Key Findings: Co-Medication Utilization Patterns1 Significantly fewer patients among both race groups were on any co-medication after Acthar Gel initiation (p<0.0001): AA before: 88.1%, n=148 vs. after: 20.2%, n=34 Non-AA before: 83.7%, n=87 vs. after: 24%, n=25 More AA had a reduction in any co-medication use after Acthar Gel initiation (AA: -77% vs. non-AA: -71%; p<0.0001). After Acthar Gel initiation, fewer AA (before: 59.5%, n=100 vs. after: 11.9%, n=20; p<0.0001) and non-AA (before: 65.4%, n=68 vs. after: 14.4%, n=15; p<0.0001) were on glucocorticoids. Overall, the mean prednisone dose reduced after Acthar Gel initiation among AA (before: 18.5 mg/day vs. after: 10.1 mg/day) and non-AA (before: 17.6 mg/day vs. after: 10 mg/day). The proportion of patients on prednisone daily dose of <10 mg increased after Acthar Gel initiation among both race groups (AA before: 27.8%, n=27/97 vs. after: 31.6%, n=6/19; non-AA before: 13.6%, n=9/66 vs. after: 60%, n=9/15). Physicians' Assessment of Improvement1 The health status of 95.2% (n=160) of AA and 97.1% (n=101) of non-AA improved following treatment with Acthar Gel, based on physician-provided assessments of patient outcomes. Treatment response to overall symptoms was not statistically significantly different between both race groups (AA: 72.6%, n=122 vs. non-AA: 70.2%, n=73) The most frequently reported changes in symptoms following Acthar Gel treatment in both race groups were: Reduction in inflammation (AA: 33.9%, n=57 vs. non-AA: 32.7%, n=34) Improvement in quality of life (AA: 31.5%, n=53 vs. non-AA: 34.6%, n=36) Improvement in lung function (AA: 30.4%, n=51 vs. non-AA: 53.8%, n=56; p<0.05) Reduction in fatigue (AA: 27.4%, n=46 vs. non-AA: 35.6%, n=37) Limitations:1 Data retrospectively collected from medical charts of patients may have omissions and errors. Completeness of information was assessed to the extent possible to minimize bias resulting from any missing data. In addition, only data available in medical charts or known to be complete to the respondents were extracted. Additional limitations of this study include: Physicians' standards for the interpretation of change in each patient's health status vary which may result in bias due to over- or under-estimation of the effectiveness of Acthar Gel. This study was unable to quantify clinical data such as diagnostic and safety measures, clinical and sustained response after treatment, and reasons for discontinuation or dose adjustments related to Acthar Gel. Due to the exploratory nature of this analysis, data were not collected for other medications besides Acthar Gel. Data on adverse reactions in this population, drivers of the decision to use Acthar Gel, and detailed information on prior therapies were not captured. This study was sponsored by Mallinckrodt Pharmaceuticals. INDICATIONS Acthar Gel is indicated for: Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age Treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation Symptomatic sarcoidosis Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus Treatment during an exacerbation or as maintenance therapy in selected cases of dermatomyositis (polymyositis) Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy); ankylosing spondylitis IMPORTANT SAFETY INFORMATION Contraindications Acthar is contraindicated: For intravenous administration In infants under 2 years of age who have suspected congenital infections With concomitant administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of Acthar In patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, or sensitivity to proteins of porcine origin Warnings and Precautions The adverse effects of Acthar are related primarily to its steroidogenic effects Acthar may increase susceptibility to new infection or reactivation of latent infections Suppression of the hypothalamic-pituitary-adrenal (HPA) axis may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g., trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA axis suppression after stopping treatment Cushing's syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Monitor blood pressure and sodium and potassium levels Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy Acthar can cause gastrointestinal (GI) bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain GI disorders. Monitor for signs of perforation and bleeding Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression to psychosis. Existing conditions may be aggravated Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis Prolonged use of Acthar may produce cataracts, glaucoma, and secondary ocular infections. Monitor for signs and symptoms Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Cases of anaphylaxis have been reported in the postmarketing setting. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH and Acthar activity There may be an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients Decrease in bone density may occur. Bone density should be monitored in patients on long-term therapy Adverse Reactions Commonly reported postmarketing adverse reactions for Acthar include injection site reaction, asthenic conditions (including fatigue, malaise, asthenia, and lethargy), fluid retention (including peripheral swelling), insomnia, headache, and blood glucose increased The most common adverse reactions for the treatment of infantile spasms (IS) are increased risk of infections, convulsions, hypertension, irritability, and pyrexia. Some patients with IS progress to other forms of seizures; IS sometimes masks these seizures, which may become visible once the clinical spasms from IS resolve Pregnancy Acthar may cause fetal harm when administered to a pregnant woman Please see full Prescribing Information for additional Important Safety Information. ABOUT SYMPTOMATIC SARCOIDOSIS Sarcoidosis is a challenging and rare multisystem disease.6 In some cases, the symptoms may come and go throughout a lifetime.6 This is referred to as symptomatic sarcoidosis.6 In people with sarcoidosis, the immune system overreacts, forming clumps of cells called granulomas that result in inflammation to the body's tissues.7 The disease can impact any organ, but it most often impacts the lungs, lymph nodes, eyes, liver, and skin.8 Nearly 90 percent of people with sarcoidosis will suffer lung problems.8 Concomitant involvement of organs outside of the lungs is common, occurring in more than half of all sarcoidosis cases, according to one study.2 ABOUT MALLINCKRODT Mallinckrodt is a global business consisting of multiple wholly owned subsidiaries that develop, manufacture, market and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, hepatology, nephrology, pulmonology, ophthalmology, and oncology; immunotherapy and neonatal respiratory critical care therapies; analgesics; and gastrointestinal products. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. To learn more about Mallinckrodt, visit CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTS This release contains forward-looking statements, including with regard to Acthar® Gel, its potential to improve health and treatment outcomes, its potential impact on patients. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: the effects of Mallinckrodt's recent emergence from bankruptcy; satisfaction of, and compliance with, regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; issues with product quality, manufacturing or supply, or patient safety issues or adverse side effects or adverse reactions associated with Acthar Gel; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law. CONTACT Media Inquiries Green Room Communications 908-577-4531 mediainquiries@grcomms.com Investor Relations Derek Belz Vice President, Investor Relations 314-654-3950 derek.belz@mnk.com Mallinckrodt, the "M" brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. ©2024 Mallinckrodt. US-2400042 03/24 References ___________________________________ 1 Bindra J, et al. Acthar Gel in African Americans versus Non-African Americans with Symptomatic Sarcoidosis: Physician Assessment of Patient Medical Records. Ther Clin Risk Manag. 2024;20:83-94 . 2Chopra I, et al. Repository Corticotropin Injection in Patients with Advanced Symptomatic Sarcoidosis: Retrospective Analysis of Medical Records. Ther Adv Res Dis. 2019(13);1-11. DOI: 10.1177/1753466619888127. 3 Acthar® Gel (repository corticotropin injection) [prescribing information]. Mallinckrodt ARD LLC. 2023. 4 Judson MA. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Humana Press, New York, NY. 2014. 8;149-186. 5 Hena, K. M. Sarcoidosis Epidemiology: Race Matters. Front Immunol. 2020;11:1-5. 6 Sarcoidosis. American College of Chest Physicians. Available at: . Accessed February 2024. 7 Sarcoidosis Overview. 2019. Cleveland Clinic. Available at: . Accessed February 2024. 8 Judson MA, Boan AD, Lackland DT. The Clinical Course of Sarcoidosis: Presentation, Diagnosis, and Treatment in a Large White and Black Cohort in the United States. Sarcoidosis Vasc Diffuse Lung Dis. 2012. 29(2);119-127. View original content to download multimedia: SOURCE Mallinckrodt plc Company Codes: NYSE:MNK, OTC-BB:MCKPF, OTC-BB:MNKPF, OTC-PINK:MCKPF

– Acthar Gel Single-Dose Pre-filled SelfJect Injector is a self-controlled, pre-filled delivery device1 for appropriate patients with a range of chronic and acute inflammatory and autoimmune conditions2 – – This first-in-class delivery device reduces the steps required for patients and caregivers to administer Acthar Gel treatment1 and underscores Mallinckrodt's mission by advancing Acthar Gel therapeutic modernization efforts to address patient needs – – Acthar Gel Single-Dose Pre-filled SelfJect Injector is expected to launch in the U.S. in the second half of 2024 – DUBLIN, March 1, 2024 /PRNewswire/ -- Mallinckrodt plc, a global specialty pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Mallinckrodt's supplemental New Drug Application (sNDA) for the Acthar® Gel (repository corticotropin injection) Single-Dose Pre-filled SelfJect™ Injector (herein referred to as "SelfJect"), a new delivery device for Acthar Gel for appropriate patients with a range of chronic and acute inflammatory and autoimmune conditions.2 SelfJect is intended to provide the appropriate subcutaneous dose of Acthar Gel, as prescribed by a healthcare professional, and is designed to help give patients control of their administration.1,3 Acthar Gel is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides.2 Acthar Gel is approved by the U.S. FDA for the treatment of several autoimmune disorders and medical conditions known to cause inflammation.2 Please see Indications and Important Safety Information for Acthar Gel below. "We're excited to bring this innovation to U.S. patients with chronic and acute inflammatory and autoimmune conditions. This approval reflects Mallinckrodt's longstanding commitment to clinical research and therapeutic modernization efforts providing a new delivery device for patients, caregivers, and medical professionals managing these challenging conditions," said Peter Richardson, MRCP (UK), Executive Vice President and Chief Scientific Officer. With this approval, Acthar Gel is the first in its class of medications to offer a self-controlled, pre-filled delivery device for appropriate patients with a range of chronic and acute inflammatory and autoimmune conditions.1,2 SelfJect may allow patients to self-administer Acthar Gel with fewer steps, as prescribed by a healthcare professional.1 The delivery device is pre-filled with the prescribed dose of Acthar Gel in 40-unit or 80-unit versions,1 is designed to help patients with dexterity issues,4 and has additional safety features including a hidden needle to help protect patients against needlestick injury.3 Acthar Gel has an established efficacy and safety profile, as well as a long track record of clinical experience spanning more than 70 years.2 Acthar Gel has been prescribed by over 9,200 healthcare professionals and used by more than 43,500 patients.5 Mallinckrodt is committed to providing therapy for appropriate patients with difficult-to-treat conditions. Mallinckrodt offers a suite of services for eligible Acthar Gel patients including support with insurance coverage, commercial copay assistance, a patient assistance program, injection training services, and customized assistance by a nurse navigator. Mallinckrodt also offers a team of field-based experts who provide education for healthcare professionals on the reimbursement process as well as tools available for patients. For more information about Mallinckrodt's programs and patient support please visit ActharHCP.com. SelfJect is expected to launch in the U.S. in the second half of 2024. Acthar Gel will continue to be available as an injection with a vial and syringe. INDICATIONS Acthar Gel is indicated for: Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age Treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation Symptomatic sarcoidosis Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus Treatment during an exacerbation or as maintenance therapy in selected cases of dermatomyositis (polymyositis) Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy); ankylosing spondylitis IMPORTANT SAFETY INFORMATION Contraindications Acthar is contraindicated: For intravenous administration In infants under 2 years of age who have suspected congenital infections With concomitant administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of Acthar In patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, or sensitivity to proteins of porcine origin Warnings and Precautions The adverse effects of Acthar are related primarily to its steroidogenic effects Acthar may increase susceptibility to new infection or reactivation of latent infections Suppression of the hypothalamic-pituitary-adrenal (HPA) axis may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g., trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA axis suppression after stopping treatment Cushing's syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Monitor blood pressure and sodium and potassium levels Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy Acthar can cause gastrointestinal (GI) bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain GI disorders. Monitor for signs of perforation and bleeding Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression to psychosis. Existing conditions may be aggravated Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis Prolonged use of Acthar may produce cataracts, glaucoma, and secondary ocular infections. Monitor for signs and symptoms Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Cases of anaphylaxis have been reported in the postmarketing setting. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH and Acthar activity There may be an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients Decrease in bone density may occur. Bone density should be monitored in patients on long-term therapy Adverse Reactions Commonly reported postmarketing adverse reactions for Acthar include injection site reaction, asthenic conditions (including fatigue, malaise, asthenia, and lethargy), fluid retention (including peripheral swelling), insomnia, headache, and blood glucose increased The most common adverse reactions for the treatment of infantile spasms (IS) are increased risk of infections, convulsions, hypertension, irritability, and pyrexia. Some patients with IS progress to other forms of seizures; IS sometimes masks theses seizures, which may become visible once the clinical spasms from IS resolve Pregnancy Acthar may cause fetal harm when administered to a pregnant woman Please see full Prescribing Information for additional Important Safety Information. ABOUT MALLINCKRODT Mallinckrodt is a global business consisting of multiple wholly owned subsidiaries that develop, manufacture, market and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, hepatology, nephrology, pulmonology, ophthalmology, and oncology; immunotherapy and neonatal respiratory critical care therapies; analgesics; and gastrointestinal products. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. To learn more about Mallinckrodt, visit . CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTS This release contains forward-looking statements, including with regard to Acthar® Gel, the Acthar® Gel (repository corticotropin injection) Single-Dose Pre-filled SelfJect™ Injector, the potential of these products to improve health and treatment outcomes, their potential impact on patients and the availability of Acthar Gel Single-Dose Pre-filled SelfJect Injector in the U.S. in the future. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: the effects of Mallinckrodt's recent emergence from bankruptcy; satisfaction of, and compliance with, regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; changes in market demand; issues with product quality, manufacturing or supply, or patient safety issues or adverse side effects or adverse reactions associated with Acthar Gel and Acthar Gel Single-Dose Pre-filled SelfJect Injector; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law. CONTACT Media Inquiries Green Room Communications 908-577-4531 [email protected] Investor Relations Derek Belz Vice President, Investor Relations 314-654-3950 [email protected] Mallinckrodt, the "M" brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. ©2024 Mallinckrodt. US-2300898 02/24 References 1 Data on file – ref-05469. Mallinckrodt Pharmaceuticals, Inc. 2 Acthar® Gel (repository corticotropin injection) [prescribing information]. Mallinckrodt ARD LLC. 2024. 3 Data on file – ref-05573. Mallinckrodt Pharmaceuticals, Inc. 4 Data on file – ref-05468. Mallinckrodt Pharmaceuticals, Inc. 5 Data on file – ref-05336. Mallinckrodt Pharmaceuticals, Inc. SOURCE Mallinckrodt plc

ALAMEDA, Calif.--( BUSINESS WIRE )-- Exelixis, Inc. (Nasdaq: EXEL) today announced detailed results from CONTACT-02, a phase 3 pivotal study evaluating cabozantinib (CABOMETYX ® ) in combination with atezolizumab compared with a second novel hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC) and measurable extra-pelvic soft tissue disease who have progressed on one prior NHT. The detailed findings are being presented during Oral Abstract Session A: Prostate Cancer at 7:55 a.m. PST on January 25 at the American Society of Clinical Oncology 2024 Genitourinary Cancers Symposium (ASCO GU). “ Patients with metastatic castration-resistant prostate cancer with prior progression on a novel hormone therapy and who have measurable soft tissue metastasis experience the worst outcomes among advanced prostate cancer patients and have limited treatment options,” said Neeraj Agarwal, M.D., FASCO, Senior Director for Clinical Research at Huntsman Cancer Institute at the University of Utah and the global lead investigator of the trial. “ CONTACT-02 is the only phase 3 study evaluating a tyrosine kinase inhibitor and an immune checkpoint inhibitor to show a statistically significant improvement in progression-free survival and a trend for overall survival in these patients. I am encouraged by these results and the potential for cabozantinib plus atezolizumab to be a widely available treatment option for our patients.” As announced in August 2023, CONTACT-02 met one of its primary endpoints, demonstrating a statistically significant improvement in progression-free survival (PFS) as assessed by a blinded independent radiology committee (BIRC) and per RECIST 1.1. The PFS analysis was conducted in the first 400 randomized patients in the intent-to-treat (PFS ITT) population and per protocol. Similar results were observed for all patients. Detailed results presented at ASCO GU show that at a median follow-up of 14.3 months for the PFS ITT population, the hazard ratio (HR) was 0.65 (95% confidence interval [CI]: 0.50-0.84; p=0.0007); the median PFS (mPFS) was 6.3 months for cabozantinib in combination with atezolizumab compared with 4.2 months for second NHT. This was nearly identical to the PFS for the ITT population (n=507): HR was 0.64 (95% CI: 0.50-0.81, p=0.0002); mPFS was 6.3 months for cabozantinib in combination with atezolizumab and was 4.2 months for second NHT. At a median follow-up of 12.0 months for the ITT population, the median overall survival (OS) was 16.7 months for cabozantinib in combination with atezolizumab compared with 14.6 months for second NHT (HR: 0.79; 95% CI: 0.58-1.07; p=0.13). While a trend toward OS improvement was observed, the data were immature and did not meet the threshold for statistical significance. The study will continue to the next analysis of OS, anticipated in 2024. The PFS benefit and the trend for an OS benefit were observed across subgroups of high-risk populations, as presented in Table 1. TABLE 1 Liver metastasis Prior docetaxel for mCSPC Bone metastasis Cabozantinib + atezolizumab Second NHT Cabozantinib + atezolizumab Second NHT Cabozantinib + atezolizumab Second NHT Median PFS per BIRC, months (95% CI) 6.2 (4.0-9.1) 2.1 (2.0-2.3) 8.8 (6.2-9.2) 4.1 (2.3-4.3) 6.3 (6.0-8.8) 4.1 (2.8-5.7) Patients, n 51 48 45 44 162 155 PFS HR (95% CI) 0.43 (0.27-0.68) 0.57 (0.34-0.97) 0.67 (0.50-0.88) Median OS, months (95% CI) 16.4 (8.3-NE) 9.8 (5.5-11.3) 20.9 (10.1-NE) 11.3 (9.0-NE) 16.4 (11.4-18.8) 11.4 (10.4-14.6) Patients, n 59 60 57 58 206 196 OS HR (95% CI) 0.60 (0.35-1.02) 0.56 (0.29-1.08) 0.74 (0.54-1.02) BIRC = blinded independent radiology committee; CI = confidence interval; HR = hazard ratio; mCSPC = metastatic castration-sensitive prostate cancer; NE = not evaluable; NHT = novel hormone therapy; OS = overall survival; PFS = progression-free survival Treatment-emergent adverse events (AEs) occurred in 97% of patients treated with cabozantinib in combination with atezolizumab (n=248) compared with 87% of patients treated with a second NHT (n=253), 48% and 23% of which were grade 3/4, respectively. Grade 5 treatment-emergent AEs occurred in 8% of patients treated with the combination regimen compared with 12% of patients treated with a second NHT; no grade 5 treatment-related AEs occurred in either arm. Treatment-related AEs led to the discontinuation of any treatment component in 13% of patients treated with the combination regimen and 2% of patients treated with a second NHT. For all treatment components, the treatment-related AEs leading to discontinuation were 5% vs. 2%, respectively. “ Given there are limited options after progression on novel hormonal therapy, we recognize the need for a regimen that can delay disease progression, that has an acceptable tolerability profile and that is widely available to patients who may not have the means or desire to travel to specialized centers for other therapies,” said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. “ Our decision to conduct CONTACT-02, based upon a signal we observed in COMET-01, underscores our commitment to patients with advanced prostate cancer and to improving their standard of care. We look forward to discussing these important results with the U.S. Food and Drug Administration, and to learning more in the next analysis of overall survival, anticipated this year.” About CONTACT-02 CONTACT-02 is a global, multicenter, randomized, phase 3, open-label study that randomized 507 patients 1:1 to the experimental arm of cabozantinib in combination with atezolizumab and the control arm of a second NHT (either abiraterone and prednisone or enzalutamide). The two primary endpoints of the trial are PFS and OS. The study included patients with mCRPC who have measurable extra-pelvic soft tissue metastasis and who have progressed on one prior NHT. The secondary endpoint is objective response rate per BIRC. The trial is sponsored by Exelixis and co-funded by Ipsen, Roche and Takeda Pharmaceutical Company Limited (Takeda). Takeda is conducting the trial in Japan. More information about CONTACT-02 is available at ClinicalTrials.gov . About CRPC According to the American Cancer Society, approximately 299,000 new cases of prostate cancer will be diagnosed in the U.S., and over 35,000 people will die from the disease in 2024. 1 Prostate cancer that has spread beyond the prostate and does not respond to androgen-suppression therapies – a common treatment for prostate cancer – is known as mCRPC. 2 Men diagnosed with mCRPC often have a poor prognosis, with an estimated survival of 1-2 years. 3,4 About CABOMETYX ® (cabozantinib) In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced renal cell carcinoma (RCC); for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib; for patients with advanced RCC as a first-line treatment in combination with nivolumab; 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 the European Union and additional countries and regions worldwide. 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 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 in combination with atezolizumab is not indicated as a treatment for mCRPC. 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 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. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the presentation of detailed results from the CONTACT-02 trial at ASCO GU 2024; the therapeutic potential of cabozantinib in combination with atezolizumab as an additional and readily available treatment option for patients with mCRPC and measurable extra-pelvic soft tissue disease who have progressed on one prior NHT; Exelixis’ commitment to patients with advanced prostate cancer and to improving their standard of care; Exelixis’ plans to discuss the CONTACT-02 results with the U.S. Food and Drug Administration, and Exelixis’ anticipation that the next analysis of overall survival will be available in 2024; 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; the potential failure of cabozantinib in combination with atezolizumab to demonstrate safety and/or efficacy in future clinical testing; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating cabozantinib; the costs of conducting clinical trials; 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 Cancer Facts & Figures 2024. ACS website. 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 . Accessed January 2024. 2 Prostate Cancer: Types of Treatment. Cancer.Net. Available at: https://www.cancer.net/cancer-types/prostate-cancer/types-treatment . Accessed January 2024. 3 Moreira, D. M., et al . Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer . 2017; 15: 60–66.e2. 4 Freedland, S. J., et al. Real-world treatment patterns and overall survival among men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the US Medicare population. Prostate Cancer Prostatic Dis . 2023.