Drugs Xagena
The European Commission ( EC ) has approved Camzyos ( Mavacamten, 2.5 mg, 5 mg, 10 mg, 15 mg capsules ) for the treatment of symptomatic ( NYHA, class II-III ) obstructive hypertrophic cardiomyopathy ( HCM ) in adult patients.
Mavacamten is the first and only allosteric and reversible inhibitor selective for cardiac myosin approved in all European Union ( EU ), and is the first cardiac myosin inhibitor that targets the underlying pathophysiology of hypertrophic cardiomyopathy.
Mavacamten 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 hypertrophic cardiomyopathy.
Mavacamten shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state.
In patients with hypertrophic cardiomyopathy, myosin inhibition with Mavacamten reduces dynamic left ventricular outflow tract ( LVOT ) obstruction and improves cardiac filling pressures.
The EC approval of Camzyos is based upon positive efficacy and safety results from two phase 3 trials, EXPLORER-HCM and VALOR-HCM.
EXPLORER-HCM Trial
The EXPLORER-HCM phase 3 trial 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 ) greater than or equal to 55% and at least one peak LVOT gradient greater than or equal to 50 mmHg ( at rest or with provocation at diagnosis ); in addition, Valsalva LVOT gradient greater than or equal to 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 greater than or equal to 1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by greater than or equal to 3.0 mL/kg/min plus no worsening in NYHA class.
Key secondary endpoints included 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:
a) at week 30, 37% ( n=45/123 ) of patients taking Mavacamten has achieved the composite primary endpoint, defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension by greater than or equal to 1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by greater than or equal to 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 );
b) additionally at week 30, patients receiving Mavacamten 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 less than 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 less than 0.0006 ) ]; number ( % ) of patients with improvement of NYHA class 1 or more [ 80 ( 65% ) vs 40 ( 31% ); difference of 34% ( 95% CI; 22%, 45%; p less than 0.0001 ) ]; change from baseline in KCCQ-23 CSS [ 14 vs 4; difference of 9 ( 95% CI: 5, 13 ); p less than 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 less than 0.0001 ].
VALOR-HCM trial
VALOR-HCM was a randomized, double-blind, placebo-controlled, multicenter phase 3 study of patients with symptomatic, obstructive hypertrophic cardiomyopathy ( NYHA class II-IV ) who met guideline criteria for septal reduction therapy ( SRT; LVOT gradient of greater than or equal to 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 or more ) 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 S septal reduction therapy prior to or at week 16 or who remained septal reduction therapy-guideline eligible ( LVOT gradient of greater than 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:
A) results showed that Mavacamten has significantly reduced the primary composite endpoint of patient decision to proceed with septal reduction therapy prior to or at week 16 or patients who remain septal reduction therapy eligible ( LVOT gradient of greater than or equal to 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 septal reduction therapy after 16 weeks of treatment.
Only 10 ( 17.9% ) patients treated with Mavacamten versus 43 ( 76.8% ) patients in the placebo group decided to proceed with septal reduction therapy prior to or at week 16 or were septal reduction therapy-eligible at week 16; treatment difference ( 95% CI ), 58.9% ( 44.0%, 73.9% ); p less than 0.0001.
B) results have also shown Mavacamten met secondary endpoints ( change from baseline to week 16 ) versus 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 less than 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 less than 0.0001 ]; change from baseline in KCCQ-23 CSS [ 10.4 vs 1.8; difference of 9.5 ( 95% CI: 4.9, 14 ), p less than 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 less than 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 less than 0.0001 ].
EXPLORER-HCM & VALOR-HCM Pooled Safety Data
The most commonly reported adverse reactions of the 179 patients treated with Mavacamten 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 Mavacamten group experienced reversible reductions in LVEF less than 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 Mavacamten, LVEF recovered following interruption of Mavacamten and they completed the study on treatment.
Dyspnoea was reported in 12.3% of patients treated with Mavacamten compared to 8.7% of patients on placebo.
In the EXPLORER-HCM study, most ( 67% ) of the dyspnoea events were reported after was Mavacamten discontinued, with median time to onset of 2 weeks ( range: 0.1-4.9 ) after last dose.
Obstructive Hypertrophic Cardiomyopathy
Obstructive hypertrophic cardiomyopathy 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.
Hypertrophic cardiomyopathy 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 hypertrophic cardiomyopathy, which is the most common type of hypertrophic cardiomyopathy, the left ventricular outflow tract where blood leaves the heart becomes obstructed by the enlarged heart muscle.
As a result, obstructive hypertrophic cardiomyopathy 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 hypertrophic cardiomyopathy is mutations in the heart muscle proteins of the sarcomere.
Obstructive hypertrophic cardiomyopathy is estimated to affect 400,000-600,000 people worldwide, however many patients remain undiagnosed and/or asymptomatic. ( Xagena )
Source: BMS, 2023
XagenaMedicine_2023
