Amiodarone Hydrochloride

Observed 67% Objective Response Rate (ORR) in frontline HR-MDS patients, primarily with TP53 mutations; initial complete remission (CR)/marrow complete remission (mCR) rate of 58% and median overall survival had not yet been reached Observed 43% ORR in frontline TP53m AML patients, 33% CR/complete remission with incomplete hematologic recovery (CRi) and median overall survival had not yet been reached SL-172154 demonstrated a manageable interim safety pro combination with AZA Focuses clinical development opportunity in HR-MDS and TP53m AML; these indications may offer the fastest path to potential approval; enrollment underway in randomized, controlled HR-MDS cohort Shattuck to host conference call and webcast today, June 14, 2024 at 7:30 a.m. ET AUSTIN, TX & DURHAM, NC, June 14, 2024 (GLOBE NEWSWIRE) -- Shattuck Labs, Inc. (Shattuck) (Nasdaq: STTK), a clinical-stage biotechnology company pioneering the development of bifunctional fusion proteins as a potential new class of biologic medicine for the treatment of patients with cancer and autoimmune disease, today announced updated interim data from the Phase 1B dose expansion clinical trial of SL-172154 in combination with AZA in frontline HR-MDS and TP53m AML patients. These data are to be featured in a poster presentation on June 14, 2024 at 18:00 CEST, during the European Hematology Association (EHA) 2024 Congress. “We are pleased to present additional data from our Phase 1B dose expansion clinical trial, which further supports our differentiated mechanism of action and underscores SL-172154’s emergence as the leading CD47 inhibitor in hematologic malignancies,” said Taylor Schreiber, M.D., Ph.D., Chief Executive Officer of Shattuck. “This update shows that the rate of complete remission has improved since our last data release in December, with additional patients in both cohorts who continue to improve on therapy. As a result of these encouraging data, and our expectation of rapid enrollment and progress in our ongoing randomized, controlled cohort in HR-MDS, we are focusing our efforts on our opportunity in HR-MDS and TP53m AML. These are indications with high unmet need, limited competition, and potential for accelerated paths to approval.” Dr. Lini Pandite, MBChB, M.B.A., Chief Medical Officer of Shattuck added, “We are encouraged by the maturing data that continues to underscore the therapeutic potential, and manageable safety profile, of SL-172154 for patients with previously untreated HR-MDS and TP53m AML. Accumulating clinical evidence now shows the pharmacodynamic contribution of CD40 activation in the peripheral blood, and an emerging correlation between clinical remission and CD40 mediated induction of certain cytokines. The TP53m AML and HR-MDS patients we have treated represent a high-risk group with short duration of complete remission and overall survival when treated with azacitidine alone. Median overall survival and duration of remission have not yet been achieved, and we look forward to sharing additional durability data later this year. Enrollment is now underway for our randomized, controlled expansion cohort in frontline HR-MDS patients, and we expect to engage in regulatory discussions later this year regarding the registrational strategy for SL-172154.” A copy of the EHA poster, titled “Phase 1b Study of SL-172154, a Bi-functional Fusion Protein Targeting CD47 and CD40, in Combination with Azacitidine (AZA) in Previously Untreated Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR- MDS) Patients (pts),” will be made available under posters in the Our Science section of Shattuck’s website. Phase 1B Trial of SL-172154 in Frontline HR-MDS and TP53m AML Key takeaways: Additional interim efficacy observed for SL-172154 in combination with AZA in frontline HR-MDS and TP53m AML. HR-MDS: As of the data cut-off date of April 23, 2024, in 24 treated patients (21 had TP53m, 16 had complex karyotype, and seven had therapy-related MDS), the ORR was 67%. Ten (42%) patients achieved a CR with 3.6 months as the median time to CR. Nine patients are continuing on treatment (five CR, two mCR+HI, one SD+HI, one SD). Three patients proceeded to allogeneic hematopoietic cell transplantation (HCT), all three patients achieved CR prior to HCT. TP53m AML: As of the data cut-off date of June 4, 2024, in 21 treated patients (all 21 had TP53 mutations or deletion, 19 had a complex karyotype, and 14 had secondary AML) the ORR was 43%. Six (29%) patients achieved a CR. One patient achieved a CRi and two patients achieved a partial remission (PR). The median time to CR was 3.8 months and none of the responders progressed as of the data cutoff. Five responders (three CR, one CRi, one PR) were taken to HCT and seven patients were still undergoing treatment, including two patients in CR. Additional patients may be bridged to transplant in the coming months. Preliminary analysis indicates clearance of TP53 mutation in four out of five TP53m HR-MDS patients and two out of four TP53m AML patients who achieved CR and were evaluated as of the data cutoff. Median duration of response for OR and CR and overall survival had not yet been reached in either HR-MDS or TP53m AML as of the respective data cutoff dates. Safety Results: As of the data cutoff date of April 23, 2024, SL-172154 showed a manageable safety profile: Infusion-related reactions (IRRs) were the most common SL-172154 treatment-emergent adverse events (TEAEs). There have been no G3 or higher IRRs when patients have been premedicated with dexamethasone. There was no evidence of hemolytic (destructive) anemia. HR-MDS: Grade 3/4 AEs were reported in ten (42%) patients as related/possibly related to SL-172154: IRR (n=3), febrile neutropenia (n=2), anemia, alkaline phosphate increased, chondrocalcinosis, colitis, cytokine release syndrome, decreased appetite, fatigue, hypertension, left ventricular dysfunction, myocardial infarction (MI), neutropenia, pancytopenia, thrombocytopenia, troponin I increase, each in one patient. There was one death due to AE of sepsis, deemed unrelated to SL-172154, and three treatment discontinuations due to AEs, including MI (n=1), IRR (n=1) and sepsis (n=1). As already reported in the Company’s May 2024 EHA abstract, a Grade 4 MI occurred in one patient who first developed sepsis on-study. This patient had a history of coronary artery disease and type II diabetes. The MI occurred eight days after the last dose of SL-172154. Although reported by the investigator as possibly related, Shattuck’s assessment is that this event was unlikely related to SL-172154. TP53m AML: Grade 3/4 AEs were reported in seven patients (33%), as related/possibly related to SL-172154, including neutropenia (n=3), thrombocytopenia (n=2), leukopenia (n=2), ALT increased (n=1), AST increased (n=1), enterococcal bacteremia (n=1), fatigue (n=1), hypoxia (n=1) and pneumonia (n=1). There were three deaths due to AEs deemed unrelated to SL-172154 including sepsis (n=1) and pneumonia (n=2). As already reported in the Company’s December 2023 update for the ASH Annual Meeting, a Grade 5 cardiac arrest occurred in one patient with a history of significant cardiovascular disease, prior MI, prior stenting, prior arrhythmia, hypokalemia in the setting of amiodarone, additional adverse risk factors and other comorbidities. Although reported by the investigator as possibly related, Shattuck’s assessment is that this event was unlikely related to SL-172154. Key Takeaways from Phase 1B Trial of SL-172154 in Platinum-Resistant Ovarian Cancer (PROC) SL-172154 in combination with pegylated liposomal doxorubicin (PLD) or mirvetuximab soravtansine (Elahere) Interim efficacy results as of April 23, 2024, showed four of 21 (19%) treated patients in our Phase 1B study of SL-172154 in combination with PLD have achieved partial responses. The Javelin-200 study reported an ORR of 4% with PLD alone. Two additional patients with stable disease showed maximum tumor reductions of 17% and 27% and were continuing on study. The Company is continuing to follow patients for progression free survival and overall survival. In our cohort combining SL-172154 with Elahere, the Company has completed enrollment. As of the April 23, 2024 data cutoff, the Company has not observed an ORR benefit beyond Elahere alone, and the Company plans to further follow patients for progression free survival and overall survival. Both of these combinations, SL-172154 combined with PLD and SL-172154 combined with Elahere, have shown an acceptable safety pro IRRs as the most common treatment emergent AE as of the data cutoff. The Company is not currently planning to conduct additional clinical development in PROC, in part due to the evolving competitive landscape in this indication. Should progression free survival or overall survival mature favorably in either PROC cohort, we would evaluate further development in PROC at that time. Shattuck will focus all current later-stage clinical development efforts in AML and HR-MDS due to the strength of the emerging efficacy results in those patient populations, the limited competition, and the potential for these indications to be the fastest path to registration. Conference Call at 7:30 a.m. ET Today Shattuck will host a conference call today at 7:30 a.m. ET featuring lead investigator Dr. Naval Daver, MD, (Professor and the Director of the Leukemia Research Alliance Program in the Department of Leukemia and MD Anderson Cancer Center in Houston, TX) to discuss the data from the poster presentation featured at the EHA 2024 Congress, including an interim safety and efficacy update from the frontline expansion cohorts in HR-MDS and TP53m AML. To listen to the live webcast, please visit the Investor Relations page of the Shattuck Labs website here. Participants may register for the call here. While not required, interested participants are encouraged to join 10 minutes prior to the start of the event. A replay of the webcast will be available following the conclusion of the live call and will be accessible on the Company’s website. About SL-172154 SL-172154 (SIRPα-Fc-CD40L) is an investigational Agonist Redirected Checkpoint (ARC®) fusion protein designed to simultaneously inhibit the CD47/SIRPα checkpoint interaction and activate the CD40 costimulatory receptor to bolster an anti-tumor immune response in patients with advanced cancer. Multiple Phase 1 clinical trials are ongoing for patients with platinum-resistant ovarian cancer (NCT04406623, NCT05483933) and patients with AML and HR-MDS (NCT05275439). About Shattuck Labs, Inc. Shattuck Labs, Inc. (Nasdaq: STTK) is a clinical-stage biotechnology company pioneering the development of bi-functional fusion proteins as a potential new class of biologic medicine for the treatment of patients with cancer and autoimmune disease. Compounds derived from Shattuck’s proprietary ARC® platform are designed to simultaneously inhibit checkpoint molecules and activate costimulatory molecules with a single therapeutic. The company’s lead SL-172154 (SIRPα-Fc-CD40L) program, which is designed to block the CD47 immune checkpoint and simultaneously agonize the CD40 pathway, is being evaluated in multiple Phase 1 trials. Shattuck has offices in both Austin, Texas and Durham, North Carolina. For more information, please visit: Forward-Looking Statements Certain statements in this press release may constitute “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, statements regarding: future presentations of clinical data; clinical development plans and strategies for SL-172154; timing of anticipated clinical data; future plans for Shattuck’s pipeline; and Shattuck’s strategies. Words such as “anticipate,” “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “develop,” “plan” or the negative of these terms, and similar expressions, or statements regarding intent, belief, or current expectations, are forward-looking statements. While the company believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to the company on the date of this release. These forward-looking statements are based upon current estimates and assumptions and are subject to various risks and uncertainties (including, without limitation, those set forth in Shattuck’s filings with the U.S. Securities and Exchange Commission (SEC)), many of which are beyond the company’s control and subject to change. Actual results could be materially different. Risks and uncertainties which could cause such outcomes to change include: global macroeconomic conditions and related volatility; expectations regarding the initiation, progress, and expected results of Shattuck’s preclinical studies, clinical trials and research and development programs; the potential failure of a clinical trial to provide sufficient results to merit further development; expectations regarding the timing, completion and outcome of the company’s clinical trials; the unpredictable relationship between preclinical study results and clinical study results; the timing or likelihood of regulatory filings and approvals; liquidity and capital resources and other risks and uncertainties identified in Shattuck’s Annual Report on Form 10-K for the year ended December 31, 2023 and subsequent disclosure documents filed with the SEC. Shattuck claims the protection of the Safe Harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. Shattuck expressly disclaims any obligation to update or alter any statements whether as a result of new information, future events or otherwise, except as required by law. The Company intends to use the investor relations portion of its website as a means of disclosing material non-public information and for complying with disclosure obligations under Regulation FD. Investor & Media Contact: Conor Richardson Vice President of Investor Relations Shattuck Labs, Inc. InvestorRelations@shattucklabs.com

OPSYNVI ® combines two proven treatments with established efficacy and safety profiles into one tablet to be taken once daily, offering an option that helps to support the implementation of clinical guideline recommendations for early use of combination therapy.1 The comprehensive PAH portfolio at Johnson & Johnson now includes treatments that address all three foundational and guideline-recommended pathways for this rare, progressive disease.2 Approval is based on the results from the pivotal Phase 3 A DUE study, which met its co-primary endpoints, demonstrating significant pulmonary hemodynamic improvement.1 RARITAN, N.J., March 22, 2024 /PRNewswire/ -- Johnson & Johnson today announced that the U.S. Food and Drug Administration (FDA) has approved OPSYNVI® – a single-tablet combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor – for the chronic treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group I) and WHO functional class (FC) II-III.1 OPSYNVI ® may be used in patients with PAH who are treatment-naïve or who are already on an ERA, PDE5 inhibitor or both. OPSYNVI ® may be used in patients who are currently treated concomitantly with stable doses of macitentan 10 mg and tadalafil 40 mg (20 mg x 2) as separate tablets.1 PAH is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation that eventually leads to right heart failure.2 An estimated 500 to 1,000 new cases of PAH are diagnosed each year in the U.S., classifying the disease as a rare condition.3 The 2022 European Society of Cardiology (ESC) / European Respiratory Society (ERS) clinical guidelines recommend initial combination therapy of an ERA and a PDE5 inhibitor for patients with idiopathic PAH, heritable drug-associated PAH, or PAH-associated with connective tissue disease without cardiopulmonary comorbidities at low or intermediate risk.2 "Clinical guidelines recommend treating patients with initial and sequential dual-combination therapy, regardless of risk at initial diagnosis and follow-up. Historically, this required patients to take multiple pills because no single-tablet combination therapy targeting two or more pathways was available," said Kelly Chin, M.D., Professor of Internal Medicine and Director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, and an investigator in the A DUE study.* "As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients." The FDA's approval of OPSYNVI ® is based on the results from the pivotal Phase 3 A DUE study, in which OPSYNVI ® demonstrated greater reduction in Pulmonary Vascular Resistance (PVR) after 16 weeks versus tadalafil or macitentan monotherapy. OPSYNVI ® has a Boxed Warning due to the risk of embryo-fetal toxicity and requires female patients to enroll in the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) program.1 With the approval, Johnson & Johnson now offers a PAH portfolio addressing all three foundational and guideline-recommended pathways – nitric oxide, endothelin, and prostacyclin. "People with PAH often live with the burden of taking many pills each day, which can pose challenges," said James F. List, M.D., Ph.D., Global Therapeutic Area Head, whose team oversees a portfolio of programs including Pulmonary Hypertension at Johnson & Johnson. "We're thrilled to bring this single-tablet combination therapy to patients, as it has the potential to optimize disease management and fulfill a significant unmet need in supporting recently updated treatment guidelines that call for initial or early combination treatment." About OPSYNVI®1 OPSYNVI ® is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor indicated for the chronic treatment of pulmonary arterial hypertension (PAH, WHO Group I) in adult patients of WHO functional class (FC) II-III. Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability. About the A DUE Study1,4 The A DUE study was a double-blind, randomized, active-controlled, multi-center, adaptive, parallel-group study designed to compare the efficacy and safety of OPSYNVI ® to macitentan and tadalafil monotherapies in adult patients with PAH (WHO FC II or III). The three-arm trial enrolled patients from across 76 sites in 16 countries/territories worldwide who were treatment-naïve or on a stable dose of an endothelin receptor antagonist (ERA), or a phosphodiesterase 5 (PDE5) inhibitor, for at least three months. The primary endpoint was change from baseline in PVR at the end of double-blind treatment at 16 weeks and was considered met if macitentan and tadalafil fixed-dose combination (FDC) treatment was superior to both monotherapies. Following the treatment period, patients transitioned to the open-label treatment period for 24 months. INDICATION OPSYNVI® is the combination of macitentan and tadalafil indicated for the chronic treatment of adults with pulmonary arterial hypertension (PAH, WHO Group I and WHO Functional Class [FC] II-III). Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Pregnancy: OPSYNVI® may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. If OPSYNVI® is used during pregnancy, advise the patient of the potential risk to a fetus. Hypersensitivity: OPSYNVI® is contraindicated in patients with a history of a hypersensitivity reaction to macitentan, tadalafil, or any component of the product. Concomitant Organic Nitrates: OPSYNVI® is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of OPSYNVI®. Concomitant Guanylate Cyclase (GC) Stimulators: OPSYNVI® is contraindicated in patients using GC stimulators such as riociguat. WARNINGS AND PRECAUTIONS Embryo-fetal Toxicity and Macitentan-Containing Products REMS: Due to the risk of embryo-fetal toxicity, OPSYNVI® is available for females only through a restricted program called the Macitentan-Containing Products REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests. Notable requirements of the Macitentan-Containing Products REMS Program include: Prescribers must be certified with the program by enrolling and completing training. All females, regardless of reproductive potential, must enroll in the Macitentan-Containing Products REMS Program prior to initiating OPSYNVI®. Male patients are not enrolled in the REMS. Females of reproductive potential must comply with the pregnancy testing and contraception requirements. Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSYNVI®. Hepatotoxicity ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In the double-blind arm of the A DUE study, the incidence of elevated aminotransferases >3 x ULN was 1.0%, and >8 x ULN was 1.0% for OPSYNVI®. In the combined double-blind/open-label arm, the incidence was 3.4% and 1.1%, respectively. Discontinuations for hepatic adverse events in the double-blind and combined double-blind/open-label arms study for OPSYNVI® were 0.9% and 2.2%, respectively. Obtain liver enzyme tests prior to initiation of OPSYNVI® and repeat during treatment as clinically indicated. Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSYNVI®. Consider re-initiation of OPSYNVI® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity. Do not initiate OPSYNVI® in patients with elevated aminotransferases (> 3 x ULN) at baseline. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied; therefore, avoid use of OPSYNVI®. Hypotension OPSYNVI® has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing OPSYNVI®, physicians should carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with pre-existing hypotension, autonomic dysfunction, or left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators. Hemoglobin Decrease Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSYNVI® and OPSUMIT®. These decreases occurred early and stabilized thereafter. In the placebo-controlled study of OPSUMIT® in PAH, OPSUMIT® 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® 10 mg group and in 3.4% of the placebo group. Similar results were observed in the trial with OPSYNVI®. Decreases in hemoglobin seldom require transfusion. Initiation of OPSYNVI® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated. Worsening Pulmonary Veno-Occlusive Disease (PVOD) Since there are no clinical data on administration of OPSYNVI® tablets to patients with veno-occlusive disease, administration of OPSYNVI® tablets to such patients is not recommended. Should signs of pulmonary edema occur when OPSYNVI® tablets are administered, the possibility of associated PVOD should be considered. If confirmed, discontinue OPSYNVI®. Visual Loss and Hearing Impairment Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION. Use of OPSYNVI® in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, is not recommended. Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. Fluid Retention Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs, and heart failure has been reported in patients taking OPSYNVI®. In the clinical study of OPSYNVI® in PAH, the incidence of peripheral edema/fluid retention was 20.6% in the active-controlled and 17.3% in the double-blind/open-label arm. Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. Monitor for signs of fluid retention after OPSYNVI® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSYNVI® or underlying heart failure, and the possible need to discontinue OPSYNVI®. Combination With Other PDE5 Inhibitors Tadalafil, a PDE5 inhibitor and a component of OPSYNVI®, is also indicated for erectile dysfunction. Instruct patients taking OPSYNVI® tablets not to take other PDE5 inhibitors. Decreased Sperm Counts and Prolonged Erection Macitentan may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility. There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors like tadalafil. Patients with conditions that might predispose them to priapism, or in patients with anatomical deformation of the penis are at an increased risk. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. ADVERSE REACTIONS The most common adverse reactions (occurring in ≥ 10% of the OPSYNVI®-treated patients) from the double-blind study data were edema/fluid retention (21%), anemia (19%), and headache/migraine (18%). The incidence of treatment discontinuations due to adverse events among patients receiving OPSYNVI® in the double-blind phase of the study was 8%. The most frequent adverse reactions leading to discontinuation were anemia and hemoglobin decreased (2% grouped) and peripheral edema and peripheral swelling (2% grouped). DRUG INTERACTIONS Nitrates: Administration of nitrates within 48 hours after the last dose of OPSYNVI® is contraindicated. Strong CYP3A4 Inducers: Strong inducers of CYP3A4, such as rifampin, significantly reduce macitentan exposure. Use of OPSYNVI® with strong CYP3A4 inducers should be avoided. Strong CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors like ketoconazole, increases exposure to both macitentan and tadalafil. Avoid concomitant use of OPSYNVI® with strong CYP3A4 inhibitors such as ritonavir, ketoconazole and itraconazole. Use other PAH treatment options when strong CYP3A4 inhibitors are needed. Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors: Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole, is predicted to increase macitentan exposure approximately 4-fold. Avoid concomitant use of OPSYNVI® with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone). Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSYNVI® should be avoided. Alpha-Blockers: PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. Therefore, the combination of OPSYNVI® and doxazosin is not recommended. Antihypertensives: PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Small reductions in blood pressure occurred following coadministration of tadalafil with selected antihypertensive medications compared with placebo. Alcohol: Substantial consumption of alcohol in combination with OPSYNVI® can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. USE IN SPECIFIC POPULATIONS Pregnancy OPSYNVI® is contraindicated during pregnancy. Macitentan, a component of OPSYNVI®, may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female. If the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus. Lactation There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breastfed infants from OPSYNVI®, advise women not to breastfeed during treatment with OPSYNVI®. Females and Males of Reproductive Potential Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating OPSYNVI®, monthly during treatment and one month after stopping treatment with OPSYNVI®. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. Contraception: Female patients must choose one highly effective form of contraception (intrauterine devices [IUD]), contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) during treatment with OPSYNVI® and for 1 month after treatment with OPSYNVI®. If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Male Infertility: Based on findings in animals, macitentan may impair fertility in males of reproductive potential. There have been no studies evaluating the effect of tadalafil on fertility in men or women. Pediatric Use The safety and efficacy of OPSYNVI® in children has not been established. Renal Impairment The use of OPSYNVI® is not recommended in patients undergoing dialysis. Avoid use of OPSYNVI® in patients with severe renal impairment (creatinine clearance 15-29 mL/min). Hepatic Impairment OPSYNVI® must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (> 3 × ULN). Please read Important Safety Information and full Prescribing Information , including Boxed WARNING, for OPSYNVI ® . About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at or at . Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC and Actelion Pharmaceuticals US, Inc., are both Johnson & Johnson companies. *Dr. Chin was compensated for her participation on the steering committee for the A DUE study. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of OPSYNVI ®. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC; Actelion Pharmaceuticals US, Inc., and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of Janssen Research & Development, LLC, Actelion Pharmaceuticals US, Inc. nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 1. OPSYNVI® Prescribing Information. Titusville, NJ: Actelion Pharmaceuticals US, Inc. 2. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. 3. American Lung Association, PAH, 23.10.2020, "Learn About Pulmonary Arterial Hypertension", lung.org, . 4. Grünig E, et al. JACC. 2024; 83(4): 473-484. DOI:10.1016/j.jacc.2023.10.045. Media Contact: Shelly Orlacchio Phone: +1 717-471-3888 [email protected] Investor Contact: Raychel Kruper [email protected] SOURCE Johnson & Johnson