Bristol Myers Squibb Receives European Commission Approval of CAMZYOS® (mavacamten), for the Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy (HCM)
- Category: Small Molecules
- Published on Tuesday, 27 June 2023 10:40
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CAMZYOS is the first and only cardiac myosin inhibitor approved in the European Union
Approval based on two positive Phase 3 trials, EXPLORER-HCM and VALOR-HCM, demonstrating significant benefit in patients treated with CAMZYOS versus placebo
PRINCETON, NJ, USA I June 26, 2023 IBristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has approved CAMZYOS® (mavacamten, 2.5 mg, 5 mg, 10 mg, 15 mg capsules) for the treatment of symptomatic (New York Heart Association, NYHA, class II-III) obstructive hypertrophic cardiomyopathy (HCM) in adult patients. CAMZYOS is the first and only allosteric and reversible inhibitor selective for cardiac myosin approved in all European Union (EU) member states* and is the first cardiac myosin inhibitor that targets the underlying pathophysiology of HCM. The EC approval of CAMZYOS is based upon positive efficacy and safety results from two Phase 3 trials, EXPLORER-HCM and VALOR-HCM.
“This approval marks an important milestone for patients in Europe who will now have a therapeutic option in CAMZYOS, a first-in-class cardiac myosin inhibitor that treats the underlying pathophysiology of symptomatic obstructive HCM,” said Samit Hirawat, M.D., chief medical officer, Bristol Myers Squibb. “We’re proud to bring this innovative treatment to more patients around the world, while reinforcing our ongoing dedication to transforming patients’ lives through science on a global scale.”
Symptomatic obstructive HCM is an often-inherited heart disease that can be a chronic, debilitating, and progressive condition where patients may experience symptoms of shortness of breath, dizziness and fatigue as well as serious, life-altering complications, including heart failure, arrhythmias, stroke and in rare cases (~1%), sudden cardiac death.
“Obstructive HCM is a life-changing disease for many patients who suffer from symptoms that can significantly impact their quality of life. The positive results of both Phase 3 clinical trials showed that CAMZYOS demonstrated efficacy across all primary and secondary endpoints, including improvements in exercise capacity and symptom burden for these patients,” said Iacopo Olivotto, M.D., Professor of Cardiology at the University of Florence and Head of Cardiology at Meyer Children's Hospital, Florence, Italy. “As the lead clinical investigator for EXPLORER-HCM, I am grateful to the patients who played a key role in this approval and look forward to having CAMZYOS available to patients in the EU who have long awaited a new treatment option for this chronic disease.”
Please see important safety information, including Boxed WARNING, from the U.S. prescribing information below.
Bristol Myers Squibb thanks the patients and investigators involved in both clinical trials.
*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland, Wales).
Full European Summary of Product Characteristics for CAMZYOS is available from the EMA website atwww.ema.europa.eu.
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) ≥55% and at least one peak LVOT gradient ≥50 mmHg (at rest or with provocation at diagnosis); in addition, Valsalva LVOT gradient ≥30 mmHg at baseline was required at screening. Ninety-two percent of patients were on background therapies of a beta blocker or calcium channel blocker. At baseline, approximately 73% of the randomized patients were NYHA class II and 27% were NYHA class III. The mean LVEF was 74%, and the mean Valsalva left ventricular outflow tract (LVOT) gradient was 73 mmHg. The baseline mean Kansas City Cardiomyopathy Questionaire-23 (KCCQ-23) Clinical Summary Score (CSS) was 71.
The primary endpoint was a composite functional endpoint, assessed at 30 weeks, and was defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO2) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by ≥3.0 mL/kg/min plus no worsening in NYHA class. Key secondary endpoints include impact on exercise gradient LVOT, pVO2, NYHA Class and Kansas City Cardiomyopathy Questionnaire (KCCQ)* and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ)† at Week 30.
The trial met all primary and secondary endpoints with statistical significance:
- At Week 30, 37% (n=45/123) of patients taking CAMZYOS achieved the composite primary endpoint, defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO2) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by ≥3.0 mL/kg/min plus no worsening in NYHA class, versus 17% (n=22/128) treated with placebo. The difference was 19.4% (95% CI: 8.67, 30.13; p=0.0005).
- Additionally at Week 30, patients receiving CAMZYOS had greater improvement compared to placebo group across all secondary endpoints, including:
- Change from baseline post-exercise LVOT peak gradient [-47 mmHg vs -10 mmHg; -35 difference (95% CI: -43, -28; p<0.0001)]
- Change from baseline in pVO2 [1.4 mL/kg/min vs -0.05 mL/kg/min; 1.4 difference (95% CI: 0.6, 2; p<0.0006)]
- Number (%) of patients with improvement of NYHA class ≥1 [80 (65%) vs 40 (31%); difference of 34% (95% CI; 22%, 45%; p<0.0001)]
- Change from baseline in KCCQ-23 CSS [14 vs 4; difference of 9 (95% CI: 5, 13); p<0.0001]
- Change from baseline in HCMSQ SoB domain score [-2.8 vs -0.9; difference of -1.8 (95% CI: -2.4, -1.2); p<0.0001]
* The KCCQ-23 CSS is derived from the Total Symptoms 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 HCMSQ SoB domain score measures frequency and severity of shortness of breath. The domain score ranges from 0 to 18, with lower scores representing less shortness of breath.
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. The study enrolled 112 patients (mean age of 60 years; 51% men; 93% ≥NYHA class III) randomized on a 1:1 basis to receive mavacamten or placebo. At baseline, 95% of patients were on background therapies of a beta blocker, calcium channel blocker, disopyramide or a combination. The primary endpoint was a composite of the proportion of patients who decided to proceed with SRT prior to or at Week 16 or who remained SRT-guideline eligible (LVOT gradient of ≥50 mmHg and NYHA Class III-IV, or Class II with exertion induced syncope or near syncope) at Week 16. Key secondary endpoints included the change from baseline on exercise gradient LVOT, NYHA Class and Kansas City Cardiomyopathy Questionnaire (KCCQ) and biomarkers at Week 16.
The trial met all primary and secondary endpoints with statistical significance:
- Results showed that CAMZYOS significantly reduced the primary composite endpoint of patient decision to proceed with SRT prior to or at Week 16 or patients who remain SRT eligible (LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) at Week 16, with 82% of patients no longer eligible for the surgical procedure or deciding not to proceed with SRT after 16 weeks of treatment. Only 10 (17.9%) patients treated with CAMZYOS vs 43 (76.8%) patients in the placebo group decided to proceed with SRT prior to or at Week 16 or were SRT-eligible at Week 16; treatment difference (95% CI), 58.9% (44.0%, 73.9%); p<0.0001.
- Results also showed CAMZYOS met secondary endpoints (change from baseline to Week 16) vs the placebo group of:
- Change from baseline post-exercise LVOT peak gradient [-39.1 mmHg vs -1.8 mmHg; -37.2 mmHg difference (95% CI: -48.1, -26.2), p<0.0001]
- Proportion with NYHA Class improvement of at least 1 class [62.5% vs 21.4%; 41.1% difference (95% CI: 24.5%, 57.7%), p<0.0001]
- Change from baseline in KCCQ-23 CSS [10.4 vs 1.8; difference of 9.5 (95% CI: 4.9, 14), p<0.0001]
- Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [0.35 vs 1.13; difference of 0.33 (95% CI: 0.27, 0.42), p<0.0001]
- Change from baseline in Cardiac Troponin I [0.5 vs 1.03; difference of 0.53 (95% CI: 0.41, 0.70), p<0.0001]
EXPLORER-HCM and VALOR-HCM Pooled Safety Data
The most commonly reported adverse reactions of the 179 patients treated with CAMZYOS in two Phase 3 studies were dizziness (17%), dyspnoea (12%), systolic dysfunction (5%) and syncope (5%). In these clinical studies, 5% (9/179) of patients in the CAMZYOS group experienced reversible reductions in LVEF <50% (median 45%: range: 35-49%) while on treatment. In 56% (5/9) of these patients, reductions were observed without other clinical manifestations. In all patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS and they completed the study on treatment. Dyspnoea was reported in 12.3% of patients treated with CAMZYOS compared to 8.7% of patients on placebo. In the EXPLORER-HCM study, most (67%) of the dyspnoea events were reported after CAMZYOS was discontinued, with median time to onset of 2 weeks (range: 0.1-4.9) after last dose.
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. It has also received regulatory approvals in Australia, Canada, Brazil, Switzerland, Macau, South Korea and Singapore. 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 LVOT obstruction and improves cardiac filling pressures.
About Obstructive Hypertrophic Cardiomyopathy
Obstructive hypertrophic cardiomyopathy (obstructive HCM) is a chronic, progressive disease in which excessive contraction of the heart muscle and reduced ability of the left ventricle to fill can make it difficult for blood to circulate to the rest of the body, leading to the development of debilitating symptoms and cardiac dysfunction. HCM can be hereditary and can develop at any age. Patients are typically diagnosed in their 40s or 50s, and as many as 50% of patients have a hereditary predisposition.
In obstructive HCM, which is the most common type of HCM, the left ventricular outflow tract (LVOT) where blood leaves the heart becomes obstructed by the enlarged heart muscle. As a result, obstructive HCM has also been associated with increased risks of atrial fibrillation, stroke, heart failure and, although rare, sudden cardiac death. The most frequent cause of obstructive HCM is mutations in the heart muscle proteins of the sarcomere. Obstructive HCM is estimated to affect 400,000-600,000 people worldwide, however many patients remain undiagnosed and/or asymptomatic.
About CAMZYOS REMS Program
CAMZYOS is only available in the U.S. through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Further information is available at www.CAMZYOSREMS.com or by telephone at 1-833-628-7367.
CAMZYOS(mavacamten) is 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.
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.
SOURCE: Bristol Myers Squibb