Long-Term Follow-Up Data from Two Phase 3 Studies of CAMZYOS® (mavacamten) Demonstrate Consistent and Durable Response in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy (HCM)
- CAMZYOS demonstrates sustained improvements in patients with symptomatic obstructive HCM
- CAMZYOS reduces eligibility for invasive SRT and shows improvements in LVOT obstruction, symptoms, and NT-proBNP levels
- No new safety signals observed
- CAMZYOS approved in multiple markets worldwide
- None.
Results from VALOR-HCM LTE (56 weeks) demonstrated that with longer follow-up, CAMZYOS continued to reduce eligibility for invasive SRT at 56 weeks
EXPLORER-LTE data (cumulative analysis up to 120 weeks) showed sustained improvements in LVOT obstruction, symptoms, and NT-proBNP levels in patients with symptomatic obstructive HCM, with no new safety signals observed
CAMZYOS was recently approved in the European Union, following its approval in the
“The new long-term data presented at ESC were consistent with the primary analyses from each study, further underscoring the benefit our first-in-class therapy can provide to patients with symptomatic obstructive HCM,” said Amy Sehnert, M.D., Vice President, Head of Cardiomyopathy and Heart Failure Clinical Development, Bristol Myers Squibb. “These positive data reinforce the clinically meaningful significance of these two Phase 3 trials that led to the approval of CAMZYOS in
Key findings from the 56-week analysis of VALOR-HCM LTE include:
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Treatment with CAMZYOS demonstrated sustained improvements across key study endpoints in both the original CAMZYOS group over 56 weeks and those transitioned to the placebo cross-over group over 40 weeks.
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At Week 56, 5 of 56 patients (
8.9% ) in the original CAMZYOS group and 10 of 52 patients (19.2% ) in the placebo cross-over group at Week 40 decided to proceed with septal reduction therapy (SRT) or were SRT-eligible. -
CAMZYOS demonstrated sustained reduction in peak resting LVOT gradient (-34.0 mmHg for the original CAMZYOS group [
95% CI -43.5 to -24.5] and -33.2 mmHg for the placebo cross-over group [95% CI -41.9 to -24.5]). -
Proportion with NYHA class improvement of ≥1 class was observed in
93% of patients in the original CAMZYOS group at Week 56 and73% of patients from the placebo cross-over group at Week 40. -
On the patient-reported 23-item Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-23 CSS)*, average scores of symptom frequency, symptom burden and physical limitation continued to improve with a 14.1 point increase for the original CAMZYOS group (
95% CI 9.9 to 18.3) and 11.7 point increase for the placebo crossover group (95% CI 6.9 to 16.4). -
CAMZYOS was also associated with sustained reduction across biomarkers of cardiac wall stress and myocardial injury including reduction in N-terminal pro brain natriuretic peptide (NT-proBNP), with -376 ng/L for the original CAMZYOS group (
95% CI -723 to -225) and -423 ng/L for the placebo cross-over group (95% CI -624 to -252) and reduction in cardiac troponin I with -7.0 ng/L for the original CAMZYOS group (95% CI -10 to -2.3) and -6.2 ng/L for the placebo cross-over group (95% CI -11.5 to -3.3). - No new safety signals were observed, and safety and efficacy were consistent across both patient groups.
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At Week 56, 5 of 56 patients (
*The KCCQ‑23 CSS is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ‑23. The CSS ranges from 0 to 100 with higher scores representing better health status.
“The 56-week late-breaking analysis of VALOR-HCM LTE builds upon previous findings and demonstrates the consistent impact of this oral treatment for severely symptomatic obstructive HCM patients by showing that nearly 9 out of 10 patients treated with this drug have continued in this long-term extension trial without SRT at either 40 or 56 weeks of treatment,” said Milind Desai, M.D., MBA, director, center for hypertrophic cardiomyopathy and vice chair of education in the Heart, Vascular & Thoracic Institute at Cleveland Clinic. “These findings are important for our continued understanding of this treatment and encouraging for patients hoping for non-surgical options.”
Key findings from the cumulative 120-week analysis of EXPLORER-LTE include:
- No new safety signals were observed.
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Overall,
75.9% of patients improved by ≥1 NYHA class from baseline at the start of the LTE study to Week 120.- Of the 14 patients who were in NYHA class I, 12 remained in NYHA class I at the latest available assessment.
- Treatment with CAMZYOS was associated with sustained improvements from baseline at the start of the LTE study in echocardiographic parameters, including E/e’ average and NT-proBNP.
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Mean LVEF remained within the normal range at all study visits.
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Since the previous interim analysis in August 2021, one new patient experienced a transient reduction in LVEF <
50% resulting in temporary treatment interruption.
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Since the previous interim analysis in August 2021, one new patient experienced a transient reduction in LVEF <
“The presentation of data − the largest and longest analysis of patients on CAMZYOS to-date − illustrates the promise of this game-changing treatment for patients with symptomatic obstructive HCM,” said Pablo García-
About the VALOR-HCM and LTE Trial
VALOR-HCM (NCT04349072) was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic, obstructive HCM (NYHA class II-IV) who met guideline criteria for septal reduction therapy (SRT; LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) and had been referred or under active consideration (within the past 12 months) for an invasive procedure. Patients were required to have LVOT peak gradient ≥50 mmHg at rest or with provocation, and LVEF ≥
The group initially randomized to CAMZYOS continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded CAMZYOS from Week 16 to Week 32. From the 112 randomized patients with obstructive HCM, 108 (mean age, 60.3 years;
About the EXPLORER-HCM and the MAVA-LTE Trials
The EXPLORER-HCM Phase 3 trial (NCT03470545) was a double-blind, randomized, placebo-controlled, parallel group trial that enrolled a total of 251 adult patients with symptomatic (NYHA class II or III) obstructive hypertrophic cardiomyopathy. All participants had measurable left ventricular ejection fraction (LVEF) ≥
EXPLORER-LTE is a cohort of the MAVA-LTE study (NCT03723655), an ongoing, dose-blinded, 5-year study of CAMZYOS in patients with symptomatic obstructive HCM who completed the EXPLORER-HCM trial. All participants in the EXPLORER-LTE cohort started on 5 mg of CAMZYOS daily and dose adjustments were made at Weeks 4, 8 and 12 based on site-read echocardiography measures of Valsalva LVOT gradient and LVEF only. Dose adjustment was also possible at Week 24 following site-read echocardiography assessment of post-exercise LVOT gradient. Subsequent to Week 24, dose adjustment was possible if site-read Valsalva LVOT gradient was >30 mmHg and LVEF ≥
About CAMZYOS (mavacamten)
CAMZYOS® (mavacamten) is the first and only cardiac myosin inhibitor approved in the
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 <
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 <
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. CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHCs). Advise patients using CHCs to use an alternative contraceptive method that is not affected by
ADVERSE REACTIONS
In the EXPLORER-HCM trial, adverse reactions occurring in >
Effects on Systolic Function
In the EXPLORER-HCM trial, mean (SD) resting LVEF was
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 where decreases in the plasma concentration of these drugs may reduce their activity.
Hormonal Contraceptives: Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by
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. Use of CAMZYOS may reduce the effectiveness of CHCs. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception.
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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, Twitter, 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, whether results of future post-marketing studies will be consistent with the results of this study, whether CAMZYOS® (mavacamten) for the indication described in this release, will be commercially successful, that any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of such product candidate for such indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials. 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, 2022, 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.
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