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PRINCETON, N.J.--( BUSINESS WIRE )-- Bristol Myers Squibb (NYSE: BMY) today announced the presentation of data across its cardiovascular portfolio at the American Heart Association (AHA) Annual Scientific Sessions, taking place November 16-18, 2024, in Chicago, Illinois. New analyses include updated results from the nearly two-year post-launch evaluation of the CAMZYOS ® (mavacamten) Risk Evaluation and Mitigation Strategy (REMS) Program and real-world and long-term extension data reinforcing the efficacy and safety profile of CAMZYOS, as well as data on behalf of the BMS-Pfizer Alliance on ELIQUIS ® (apixaban) and the BMS-Johnson & Johnson Collaboration on milvexian. “We look forward to AHA where we will share data that build on our 70-year legacy of pioneering cardiovascular research and delivering paradigm-changing medicines to address the growing burden of cardiovascular disease,” said Roland Chen, MD , senior vice president and head of Immunology, Cardiovascular & Neuroscience (ICN) Development at Bristol Myers Squibb. “Data to be presented at the meeting highlight our commitment to improving clinical outcomes for patients around the world by delivering transformational therapies, like CAMZYOS, the first and only approved cardiac myosin inhibitor.” With inclusion in both the ESC and AHA/ACC clinical guidelines as a recommended option for when symptoms persist after first-line therapy, CAMZYOS is a standard of care for NYHA class II-III symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Research to be presented at the meeting supports the growing body of evidence of CAMZYOS, including compliance with the REMS Program. These data include: An updated analysis of results from the post-launch evaluation of the CAMZYOS REMS Program spanning nearly 2-years (22-months). A featured science presentation of the 128-week analysis (nearly 2.5 years) of the VALOR-HCM long-term study analyzing the efficacy and safety profile of CAMZYOS in reducing patient eligibility and/or decision to proceed with septal reduction therapy (SRT) in patients with symptomatic oHCM. New real-world evidence on CAMZYOS’ long-term effectiveness and safety profile, including data from MARVEL-HCM—the largest observational study on CAMZYOS’ effectiveness—and from COLLIGO-HCM, a real-world study examining racially diverse patients and those with higher disease burden than typically seen in clinical trials. Abstracts sponsored by Bristol Myers Squibb, the BMS-Pfizer Alliance and the BMS-Johnson & Johnson Collaboration to be presented at AHA Scientific Sessions 2024 can be found below. Complete abstracts may be accessed online here . Visit this page on BMS.com for more information on Bristol Myers Squibb’s scientific approach and resources on cardiovascular diseases. Abstract Title Primary Author Type Session Title Date/Time (CST) CAMZYOS (mavacamten) Investigating the natural history and risk factors underlying deterioration in early-stage hypertrophic cardiomyopathy: Findings from SOLENOID Bradlow, W. Moderated Poster Bulking Up: The Latest in Hypertrophic Cardiomyopathy Saturday, Nov. 16, 3:10 PM – 3:15 PM Beta blockers and calcium channel blockers in asymptomatic patients with hypertrophic cardiomyopathy: Prevalence, discontinuation, and effectiveness Bradlow, W. Moderated Poster Data to Discovery: Novel Methods in Cardiovascular Outcomes Research Saturday, Nov. 16, 3:50 PM – 3:55 PM Identification of obstructive and non-obstructive hypertrophic cardiomyopathy patients using natural language processing in a large integrated healthcare system Solomon, M. Moderated Poster Advances in Identification and Management of Hypertrophic Cardiomyopathy – MDP964 Sunday, Nov. 17, 9:30 AM – 9:35 AM Real-world treatment patterns of mavacamten and associated background therapies in patients with obstructive hypertrophic cardiomyopathy (HCM) in the United States Han, X. Traditional Poster Emerging Interventions for Heart Failure – Su2191 Sunday, Nov. 17, 3:15 PM – 4:15 PM Mavacamten: Real-world experience from 22 months of the Risk Evaluation and Mitigation Strategy (REMS) Program Desai, M. Oral Presentation From Bench to Bedside in Heart Failure Monday, Nov. 18, 9:00 AM – 9:10 AM Mavacamten treatment in patients with obstructive HCM referred for septal reduction therapy: 128-week results from VALOR-HCM trial Desai, M. Oral Featured Science Presentation Featured Science: Amyloid, Hypertrophic, and Danon Cardiomyopathies: Targeted Therapies and Specific Populations Monday, Nov. 18, 9:57 AM – 10:05 AM Long-term effectiveness and safety of mavacamten in a real-world, multi-center, global study: Preliminary results of COLLIGO-HCM from a diverse cohort in the United States MacNamara, J. Moderated Poster Hypertrophy and Heart Failure – MDP1368 Monday, Nov. 18, 11:50 AM – 11:55 AM Early insights on mavacamten usage in Canada: A retrospective cohort of the patient support program Ong, K. Moderated Poster Hypertrophy and Heart Failure – MDP1369 Monday, Nov. 18, 12:00 PM – 12:05 PM Real-world long-term effectiveness of mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy: A multicenter observational study (MARVEL-HCM) Abraham, T. Moderated Poster Hypertrophy and Heart Failure – MDP1370 Monday, Nov. 18, 12:10 PM – 12:15 PM Integrated safety and tolerability of mavacamten treatment over 5 years in patients with obstructive hypertrophic cardiomyopathy Owens, A. Moderated Poster Hypertrophy and Heart Failure – MDP1371 Monday, Nov. 18, 12:20 PM – 12:25 PM Mavacamten in adolescent patients with symptomatic obstructive hypertrophic cardiomyopathy: Design of the Phase 3 SCOUT-HCM trial Rossano, J. Traditional Poster Pediatric Heart Failure, Transplantation, and Long-Term Outcomes – Mo2025 Monday, Nov. 18, 1:30 PM – 2:30 PM ELIQUIS (apixaban) – Sponsored by the Bristol Myers Squibb-Pfizer Alliance Understanding medication adherence to oral anticoagulants in atrial fibrillation management: Patient and provider perspectives in a mixed methods study Wendt, S. Moderated Poster Data to Discovery: Novel Methods in Cardiovascular Outcomes Research Monday, Nov. 18, 10:30 AM – 11:30 AM Milvexian – Sponsored by the Bristol Myers Squibb-Johnson & Johnson Collaboration Current oral anticoagulation use among patients with atrial fibrillation and risk factors associated with inadequate treatments: A report from a UK population cohort study Kang, A. Poster presentation Medications in Motion: Innovating Pharmacotherapy for Enhanced Treatment Outcomes Monday, Nov. 18, 1:30 PM – 2:30 PM About CAMZYOS ® (mavacamten) CAMZYOS ® (mavacamten) is the first and only cardiac myosin inhibitor approved in the U.S., indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms, and in the European Union, indicated for the treatment of symptomatic (NYHA, class II-III) obstructive HCM in adult patients. It has also received regulatory approvals in countries and regions across five continents. CAMZYOS is an allosteric and reversible inhibitor selective for cardiac myosin. CAMZYOS modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. CAMZYOS shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In HCM patients, myosin inhibition with CAMZYOS reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures. IMPORTANT SAFETY INFORMATION WARNING: RISK OF HEART FAILURE CAMZYOS reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LVEF are required prior to and during treatment with CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status. Concomitant use of CAMZYOS with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of CAMZYOS is contraindicated with the following: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS PROGRAM. CONTRAINDICATIONS CAMZYOS is contraindicated with concomitant use of: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers WARNINGS AND PRECAUTIONS Heart Failure CAMZYOS reduces systolic contraction and can cause heart failure or totally block ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure. Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function. Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. CYP 450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness CAMZYOS is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of CAMZYOS and drugs that interact with these enzymes may lead to life-threatening drug interactions such as heart failure or loss of effectiveness. Advise patients of the potential for drug interactions, including with over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine). Advise patients to inform their healthcare provider of all concomitant products prior to and during CAMZYOS treatment. CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program CAMZYOS is only available through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the CAMZYOS REMS Program include the following: Prescribers must be certified by enrolling in the REMS Program. Patients must enroll in the REMS Program and comply with ongoing monitoring requirements. Pharmacies must be certified by enrolling in the REMS Program and must only dispense to patients who are authorized to receive CAMZYOS. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.CAMZYOSREMS.com or by telephone at 1-833-628-7367. Embryo-Fetal Toxicity CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. ADVERSE REACTIONS In the EXPLORER-HCM trial, adverse reactions occurring in >5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM. Effects on Systolic Function In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS. DRUG INTERACTIONS Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS. Impact of Other Drugs on CAMZYOS: Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors : Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated. Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers : Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated. Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors : Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available. Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates unless otherwise recommended in the Prescribing Information. Certain Combined Hormonal Contraceptives (CHC): Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of certain progestins, which may lead to contraceptive failure. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS, but if other CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. Drugs That Reduce Cardiac Contractility Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved. SPECIFIC POPULATIONS Pregnancy CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or www.bms.com . Lactation The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition. Females and Males of Reproductive Potential Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. Please see U.S. Full Prescribing Information , including Boxed WARNING and Medication Guide . About ELIQUIS ® (apixaban) ELIQUIS ® is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, ELIQUIS decreases thrombin generation and blood clot formation. ELIQUIS is approved for multiple indications in the U.S. based on efficacy and safety data from multiple Phase 3 clinical trials. ELIQUIS is a prescription medicine indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE, following initial therapy. ELIQUIS continues to be developed and commercialized by The Bristol Myers Squibb-Pfizer Alliance. ELIQUIS Important Safety Information Indications ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. ELIQUIS is indicated for the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE following initial therapy. Important Safety Information WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA (A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. (B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of ELIQUIS and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated. CONTRAINDICATIONS Active pathological bleeding Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs. Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage. The anticoagulant effect of apixaban can be expected to persist for at least 24 hours after the last dose (i.e., about two half-lives). An agent to reverse the anti-factor Xa activity of apixaban is available. Please visit www.andexxa.com for more information on availability of a specific reversal agent. Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours. Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients. Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients. Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy : Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (APS): Direct-acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients with triple-positive APS. For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. ADVERSE REACTIONS The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding. TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. DRUG INTERACTIONS Combined P-gp and Strong CYP3A4 Inhibitors: Inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) increase exposure to apixaban and increase the risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or ritonavir). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors. Clarithromycin Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS. Combined P-gp and Strong CYP3A4 Inducers: Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban. Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. PREGNANCY The limited available data on ELIQUIS use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery, and in the fetus and neonate. Labor or delivery: ELIQUIS use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches. LACTATION Breastfeeding is not recommended during treatment with ELIQUIS. FEMALES AND MALES OF REPRODUCTIVE POTENTIAL Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including ELIQUIS should be assessed in these patients and those with abnormal uterine bleeding. Please see U.S. Full Prescribing Information , including Boxed WARNINGS , available at BMS.com . About the Bristol Myers Squibb-Pfizer Collaboration The Bristol Myers Squibb-Pfizer Alliance (the Alliance) is committed to driving education and awareness about atrial fibrillation and deep vein thrombosis (DVT) and/or pulmonary embolism (PE). With long-standing cardiovascular leadership, global scale and expertise in this field, the Alliance strives to implement global, research-driven approaches to illuminate and address the unmet needs around strokes related to non-valvular atrial fibrillation, which are often fatal or debilitating. Through collaborations with non-profit organizations, the Alliance aims to provide patients, healthcare professionals and decision makers with the information they need to understand and take appropriate action on risk factors associated with stroke and other cardiovascular conditions. About Milvexian * Milvexian is an investigational oral, highly selective Factor XIa (FXIa) inhibitor, part of a new class of anticoagulants in development aimed at preventing harmful clotting that restricts blood flow (thrombosis) while preserving the normal clotting process (hemostasis). As a result, milvexian could potentially reduce major cardiovascular events due to harmful clotting without significantly increasing the risk of bleeding. It is currently being studied in the Phase 3 Librexia program, the most comprehensive FXIa clinical development program to date, for the prevention and treatment of major thrombotic conditions. * Milvexian is an investigational agent and has not been approved for use in any country, for any indication. About the Bristol Myers Squibb-Johnson & Johnson Collaboration Bristol Myers Squibb and Johnson & Johnson, two unsurpassed leaders in cardiovascular care, are determined to close the gap in unmet needs in thrombosis management by overcoming the limits of today’s treatments. The collaboration to develop and commercialize milvexian aims to leverage the combined scientific expertise and world-class commercial capabilities of each company, to improve patient outcomes. The alliance is uniquely equipped to deliver on the promise of FXIa inhibitors and is working diligently to ensure cutting-edge safe and effective treatment options are available for patients. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , X , YouTube , Facebook and Instagram . Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that milvexian may not receive regulatory approval for the indications described in this release, any marketing approvals, if granted, may have significant limitations on their use, and, whether CAMZYOS (mavacamten), ELIQUIS (apixaban) or milvexian, if approved, for such indications described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news

点击蓝字 关注我们 引用本文：卢丽婷，王晰程，巴一．家族性腺瘤性息肉病的化学预防药物进展与展望[J/CD]．肿瘤综合治疗电子杂志，2024，10（4）：101- 108． 通信作者：王晰程 E-mail：xicheng_wang2024@163.com 家族性腺瘤性息肉病（familial adenomatous polyposis，FAP）是一种由APC基因胚系突变引起的常染色体显性遗传病，APC基因突变位置与结肠息肉病的发病年龄、严重程度、癌症风险等级及有无结肠外表现密切相关[1-2]。经典型FAP大多与发生在密码子169～1 393之间的突变相关，通常在青少年时期即出现数百甚至数千个结直肠腺瘤样息肉，未经治疗的患者会进一步发展为结直肠癌[3-4]。FAP患者也可能表现出多种结直肠外症状，如硬纤维瘤、十二指肠腺瘤、骨瘤、先天性视网膜色素上皮肥大、甲状腺癌、肝胆胰及上消化道恶性肿瘤等[5]。鉴于高发结直肠癌风险，2020年美国胃肠内镜学会指南推荐患者从10～12岁进行内镜下监测及息肉切除[6]。但内镜监测间隔期内仍有癌症发生的风险。目前，根据患者的腺瘤负荷和个人偏好，预防性手术如全结肠切除术＋回肠直肠吻合术（ileoanal anastomosis，IRA）或全结肠直肠切除术＋回肠储袋肛管吻合术（ileal pouch-anal anastomosis，IPAA）是标准治疗方案。与IRA相比，尽管IPAA降低了残余直肠癌变的风险，但二者均不能完全消除FAP相关肠外肿瘤发生风险，且2种术式患者术后肠功能障碍和硬纤维瘤发生率相当[7-9]。因此患者需终身进行内镜监测和进一步干预，严重影响生活质量。 化学预防旨在通过药物减少息肉数量和大小，从而延迟或避免手术，减少内镜检查和息肉切除的频率，降低手术相关并发症发生率，并防止癌症的进展。对于息肉负担尚未严重到需要进行结肠切除的青少年患者，化学预防可以减轻患者的心理和生理负担，使其达到更成熟的决策年龄[10]。此外，硬纤维瘤是FAP的第二大死因，与手术、创伤及雌激素相关[11-12]。对于APC基因突变位点更易发生硬纤维瘤的患者，通过化学预防延迟甚至避免手术有利于患者的生存[13]。更长时间的术前监测也有助于更清楚地了解腺瘤负荷，制订更好的个性化治疗方案。目前关于FAP的化学预防的探索已有40余年，但FAP的化学预防还处于早期阶段，尚无药物被批准。本文旨在对FAP化学预防的现有文献及研究进展作一综述，以期对其有全面了解并为未来开展临床试验提供方向。 1. 非甾体抗炎药 非甾体抗炎药（nonsteroidal anti-inflammatory drugs，NSAIDs）通过抑制环氧合酶（cyclooxygenase，COX），尤其是COX-2，减少前列腺素的合成，具有抗炎、镇痛和解热作用。COX-2的过表达与结直肠癌的增殖、侵袭、血管生成及抗凋亡等过程密切相关[14]。NSAIDs能抑制COX-2活性，减少前列腺素E2的生成，抑制息肉增生和血管生成，诱导癌细胞凋亡，影响Wnt/β-catenin信号通路。此外，COX-2的异常表达与APC基因突变相互影响[15]，表明COX抑制剂可能对FAP患者具有预防作用，其安全性和有效性已在临床试验中得到探究。 1.1 舒林酸 舒林酸是一种非选择性NSAIDs，可竞争性抑制COX-1和COX-2，是最早用于FAP化学预防研究的药物之一。1991年，Labayle等[16]的研究显示，在10例先前接受过结肠切除术的FAP患者中，服用舒林酸组（300 mg/d）与安慰剂组相比，息肉消退率比较差异有统计学意义（P＜ 0.01）。后续研究显示，舒林酸能显著减少未接受手术FAP患者的息肉数量和直径，但一旦停药，患者息肉数量、直径均增加[17]。低剂量舒林酸栓剂（50 mg/d）连续治疗33个月可使87%的直肠息肉患者腺瘤逆转，且安全性良好[18]。多项研究均表明，舒林酸治疗有效性不受APC基因突变位点影响，且对十二指肠息肉也有效果，但对壶腹周围息肉无效[19-20]。一项针对8～25岁APC突变携带者的研究结果显示，尽管舒林酸组黏膜前列腺素水平低于安慰剂组，但息肉直径和数量的获益无统计学意义[21]。此外，尽管在舒林酸治疗中进行密切内镜随访，但仍有患者进展为结直肠癌。这些研究均为小样本研究，且多数患者仅评估了直肠病变，其能否转变为临床获益尚需进一步研究证实。 舒林酸的代谢产物显示出一定的抑制肿瘤的潜力，但在一项研究中，6个月治疗后对息肉数量无显著影响，且因其肝脏毒性也限制了剂量增加[22]。 1.2 阿司匹林 阿司匹林作为广泛应用的非选择性NSAIDs，美国胃肠病学会指南建议50～69岁有心血管疾病风险的人群使用低剂量阿司匹林以降低结直肠癌和心血管疾病风险[23]。CAPP1研究纳入了206例10～21岁的FAP患者，发现阿司匹林片联合抗性淀粉组中位治疗17个月后，与安慰剂组相比，息肉负荷有减小趋势，差异无统计学意义，但阿司匹林组在用药超过1年后最大息肉直径显著减小（P＝0.02）[24]。日本一项研究[25]评估了阿司匹林（100 mg/d）与安慰剂的疗效，亚组分析显示，治疗前平均基线息肉直径为≤2 mm的受试者经阿司匹林干预后息肉直径和息肉数量均显著减少，但阿司匹林联合抗性淀粉组组有18%受试者出现严重不良反应。J-FAPP-Ⅳ研究[26]纳入104例患有超过100个大肠腺瘤性息肉且未接受结肠切除术的患者，在研究前，患者接受了内镜切除所有直径至少5 mm的结直肠息肉，结果显示，服用阿司匹林8个月的患者结肠息肉复发率显著降低，而美沙拉嗪组未见明显效果。但该研究入组患者中位年龄为30岁以上且无结直肠癌，可能为较轻表型，且阿司匹林仅给药8个月，长期使用的安全性仍是限制其广泛应用的主要问题。 1.3 塞来昔布 鉴于非选择性NSAIDs的胃肠道不良反应，塞来昔布作为一种选择性COX-2抑制剂在FAP中的化学预防作用得到广泛关注。Steinbach等[27]的研究将77例18～65岁的FAP患者分为安慰剂组、低剂量塞来昔布组（100 mg，2次/d）和高剂量塞来昔布组（400 mg，2次/d），与安慰剂组相比，6个月内高剂量塞来昔布组患者结直肠息肉总数减少了28% （P＝0.003），息肉直径之和下降30.7%（P＝0.001），各组间不良事件发生率相似。而低剂量塞来昔布组相对于安慰剂组无显著差异。进一步分析显示，对于初始十二指肠黏膜受累超过5%的患者，服用塞来昔布（400 mg，2次/d）可将十二指肠受累面积减少31%[28]。另一项Ⅰ期剂量递增试验评估了短期塞来昔布治疗FAP患儿的安全性和有效性，塞来昔布（16 mg/kg，1次/d）对FAP患儿是安全且耐受良好的，安慰剂组受试者在第3个月时息肉数量增加了39.1%，而最高剂量塞来昔布组患者中，息肉数量减少了44.2%（P＝0.01）[29]。Burke等[30]进行的CHIP研究，将10～17岁的FAP患儿随机分配至塞来昔布组（16 mg/kg，1次/d）或安慰剂组，持续干预5年。结果显示，塞来昔布组患儿疾病进展（最早出现≥20个直径＞2 mm息肉）的中位时间为2.1年，安慰剂组患儿为1.1年，无患者发展成结肠直肠癌。由于观察到的终点率低，长期影响尚不明确。对于高剂量塞来昔布长期治疗的安全性（尤其是心血管事件风险）和效果，以及与其他药物联合使用的潜在协同效应，仍需进一步的研究来确认。 1.4 基于NSAIDs药物的组合疗法 1.4.1 联合依氟鸟氨酸 多胺是一类含氨基的小分子代谢物，在细胞生长中发挥核心作用。在FAP患者中，多胺合成的关键酶鸟氨酸脱羧酶（ornithine decarboxylase，ODC）活性及黏膜多胺水平在正常和腺瘤组织中均显著升高[31]。依氟鸟氨酸是一种强效ODC抑制剂，在ApcMin/+小鼠中，依氟鸟氨酸联合NSAIDs可使肠道肿瘤数量减少超过80%（P＜0.000 1）；与单独使用舒林酸相比，其联合治疗可以显著减少高级别腺瘤的发生（P＝0.003）[32]。Ⅲ期临床试验评估了依氟鸟氨酸（750 mg/d）与舒林酸（150 mg/d）联合治疗与单药治疗在成人FAP患者的疗效和安全性[33]。该研究持续48个月，纳入171例患者，主要研究终点为疾病进展。结果显示，联合用药组并未显著降低疾病进展发生率[34]，但在延迟下消化道手术方面表现出显著优势（P＝0.02）[35]，但需要注意依氟鸟氨酸的耳毒性。另一项随机Ⅱ期试验显示，塞来昔布（400 mg，2次/d）联合或不联合依氟鸟氨酸在预防息肉病患者腺瘤方面无显著差异[36]。 1.4.2 联合厄洛替尼 体细胞APC失活和表皮生长因子受体（epidermal growth factor receptor，EGFR）信号转导可促进COX-2表达和随后的腺瘤-癌发展[37]。厄洛替尼是一种抗EGFR活性的口服酪氨酸激酶抑制剂。FAPEST研究显示，舒林酸（150 mg，2次/d）联合厄洛替尼（75 mg/d）可在6个月后显著降低FAP患者结直肠及十二指肠息肉负荷[38-39]。但联合治疗可能引发痤疮样皮疹等不良反应，长期使用还与心脏毒性相关[38-40]。一项Ⅱ期单臂试验评估了厄洛替尼（350 mg，1次/周）干预能否有效降低息肉负荷并改善不良事件状况。结果表明，厄洛替尼干预6个月后，十二指肠息肉负荷显著减轻，平均百分比变化为-29.6%，12%的患者Spigelman评分降级，且整体不良事件可接受，但仍需更多数据证实其长期安全性[41]。 1.4.3 其他  近年来研究表明，FAP患者的肠道菌群谱与正常人及腺瘤患者不同，致瘤菌群可能通过DNA损伤、慢性炎症等机制促进FAP进展[42]。一项舒林酸联合双歧杆菌三联活菌治疗FAP的临床试验表明，舒林酸联合双歧杆菌三联活菌组疗效优于单纯服用舒林酸组和双歧杆菌三联活菌组[43]。其原因可能与降低Bcl-2基因表达、减少对凋亡的抑制、改善肠内环境菌群等有关。以上研究表明，调节肠道菌群，维持肠道微生态平衡可能成为FAP预防的新途径。 2. 二十碳五烯酸 二十碳五烯酸（eicosapentaenoic acid，EPA）是ω-3多不饱和脂肪酸的一种，属于人体必需脂肪酸，主要来源于鱼油。临床前研究显示，EPA可减缓结直肠腺瘤病史患者的隐窝细胞增殖，促进正常结肠黏膜的细胞凋亡[44]。其作用机制可能涉及作为COX-2的替代底物减少前列腺素E2生成，改变T淋巴细胞与结肠细胞膜的脂筏功能并调节信号转导，以及增强氧化应激以促进细胞凋亡[45]。在多中心、随机seAFOod试验[46]中，28例接受过结肠切除术的FAP患者接受EPA（2 g/d）治疗6个月后，息肉数量平均减少22.4%（P＝0.012），息肉直径总和平均减少29.8%（P＝0.027），与选择性COX-2抑制剂塞来昔布的效果相似。同时EPA耐受性良好，不良事件发生率与安慰剂相似。EPA在结直肠腺瘤治疗中显示出潜在效益，特别是在减缓息肉生长方面。 3. 西罗莫司 西罗莫司是一种大环内酯类免疫抑制剂，仅抑制哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）C1的活性，不影响mTORC2。研究表明，西罗莫司可使ApcMin/+小鼠的肠道肿瘤细胞停止生长和分化，甚至可能导致息肉消退[47]。有病例报道了低剂量西罗莫司（0.05～0.1 mg/kg）在2例FAP患儿中的成功应用[48]。该病例治疗1年后，1例患儿显示壶腹周围息肉完全消退，结直肠息肉减小，黏膜发育异常程度降低；另1例患儿的结肠息肉负荷降低，但胃息肉负荷未发生变化，2例患儿均未出现严重不良反应。随后一项纳入5例FAP患者的前瞻性Ⅱ期临床试验显示，4例FAP患者接受西罗莫司治疗6个月后，直肠回肠袋息肉数量明显减少，但不良事件发生率高，1例患者因不能耐受中途退出试验[49]。考虑到西罗莫司的不良反应与血药浓度呈正相关，目前的ⅡA期试验使用封装西罗莫司，以更一致且更低剂量的药物探索其能否预防FAP患者的疾病进展（NCT04230499）。以上研究表明，西罗莫司及其衍生物在FAP化学预防中具有潜力，但其不良反应需要引起高度重视。 4. 二甲双胍 Meta分析显示，长期使用二甲双胍能够降低结直肠腺瘤及癌症风险[50]。Ⅲ期临床研究发现，对非糖尿病患者在息肉切除术后给予低剂量二甲双胍（250 mg/d）干预1年，可减少腺瘤或息肉复发[51]。然而，与一般人群的散发性腺瘤不同，FAP患者的腺瘤数量更多。一项纳入34例韩国FAP患者的随机研究表明，每日口服二甲双胍500 mg或1500 mg治疗7个月并未显著改变结直肠和十二指肠的总体息肉负荷[52]。我国学者发现，1年二甲双胍治疗FAP安全有效，与安慰组相比，试验组患者（每日口服250 mg二甲双胍）的息肉平均数和特定区域的平均息肉负荷显著减少（P＜0.05），且二甲双胍可能通过调节肠道菌群抑制FAP中腺瘤性息肉的发展[53]。在临床上，二甲双胍联合内镜检查被证实优于单独内镜检查治疗FAP。二甲双胍在非糖尿病患者中的应用显示了其在预防腺瘤复发方面的潜力，未来研究应在FAP患者中进一步探索调节肠道菌群与二甲双胍的联合作用，不同的膳食模式也可能对研究结果产生影响。 FAP化学预防随机对照试验汇总如表1所示。 5. 正在进行的试验 lorpucitinib（JNJ-64251330研究）是一种口服小分子泛Janus激酶（Janus kinase，JAK）抑制剂，可阻断信号转导和转录激活因子蛋白（signal transducer and activator of transcription，STAT）的磷酸化，从而抑制与炎症性疾病进展相关的基因转录。2023年美国临床肿瘤学会年度会议报告了lorpucitinib在FAP患者中的Ⅰb期研究（NCT05014360）结果，结果显示，lorpucitinib在FAP患者中表现出肠道选择性分布，虽然息肉负荷的减少在临床上并不显著，但lorpucitinib降低了几种血清炎症生物标志物的水平，有助于改善FAP相关的临床症状，且其具有良好的安全性和耐受性[54]。 REC-4881是一种人工智能辅助开发的口服MEK1和MEK2的非ATP竞争性的小分子别构抑制剂。据推测，REC-4881可能是通过抑制FAP腺瘤中异常的丝裂原激活蛋白激酶（mitogen activation protein kinase，MAPK）信号转导而使肿瘤消退或减慢其生长。目前，一项多中心的评估其在FAP患者中的疗效和安全性的Ⅰb～Ⅱ期试验正在进行（NCT 05552755）。 奥贝胆酸是一种经美国食品药品监督管理局批准用于治疗原发性胆汁性胆管炎的选择性胆汁酸受体激动剂，已显示出减轻炎症和纤维化的潜力[55]。一项Ⅱa期安慰剂对照随机研究正在招募，旨在评估奥贝胆酸干预6个月对FAP患者肠息肉负荷的影响（NCT05223036）。 锂在apcMin/+小鼠中显示出抑制肠干细胞扩增的作用，尽管尚无锂在FAP患者中的应用报道，但已有研究表明，其可降低双相情感障碍患者的结直肠癌和其他癌症发病率[56]。一项前瞻性Ⅱ期单臂试验正在探讨低剂量锂对FAP患者的干细胞动力学、息肉数量和大小的影响（NCT05402891）。 白细胞介素-23（interleukin-23，IL-23）通过激活JAK/STAT3通路维持结直肠癌进展的炎症特征已被证实[57]。一项针对FAP受试者的Ⅰb期临床研究评估靶向IL-23的guselkumab单抗的疗效已完成招募，结果尚未发布（NCT03649971研究）。 6. 总结与展望 FAP的治疗与预防是一项复杂的挑战，涉及基因、药物和肠道环境等多个层面。迄今为止，化学预防研究尚未在临床实践中常规使用，因为先前研究样本量有限且存在矛盾，同时常伴随不良事件。FAP主要与APC基因突变相关，不同的突变类型及位点对疾病表型有显著影响。精确的基因分型和全基因组测序对于实现个体化的风险评估和预防策略至关重要。此外，对于携带特定突变的患者，可以考虑更为针对性的药物干预，如针对特定突变的小分子抑制剂，以提高治疗的针对性和有效性。此外，肠道菌群的调节和特定炎症途径的药物干预也显示出预防FAP的潜力。未来研究需整合这些信息以优化治疗方案，实现个体化治疗，提高治疗的针对性和有效性。 参考文献 [1] HEINEN C D. 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