Regulatory Decision Summary for Camzyos

Hypertrophic cardiomyopathy (HCM) is a rare disease, and the most common inherited disorder of the myocardium. To date, pharmacological treatment has consisted primarily of beta-blockers and non-dihydropyridine calcium channel blocker (CCB) to improve symptoms and patient function. There is no current approved drug therapy available that is directed at the primary myocardial derangement of HCM. Camzyos, is a first-in-class allosteric inhibitor of cardiac myosin.

The sponsor has provided safety, efficacy and quality data for Camzyos in the treatment in patients with obstructive HCM (oHCM). The key efficacy and safety data were derived from EXPLORER-HCM, a pivotal Phase 3 trial that assessed the effects of Camzyos in patients with oHCM. The primary endpoint consisted of a composite endpoint of patient function, as measured by change in New York Heart Association (NYHA) Class, and of a key pharmacodynamic variable in HCM, peak oxygen uptake (pVO₂), which reflects patient exercise capacity. Five individual secondary endpoints were also pre-specified to be tested sequentially, in this order: a) post-exercise left ventricular outflow tract (LVOT) peak gradient, b) pVO₂, c) NYHA Class improvement, d) Kansas City Cardiomyopathy Questionnaire 23-item version (KCCQ-23) clinical summary score (CSS) to assess patient function, and, e) the Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) shortness of breath (SoB) domain score to assess patient self-reported severity of HCM respiratory symptoms.

Results of all of these endpoints demonstrated statistically significant and clinically relevant superiority of Camzyos over placebo when used in the treatment of oHCM, in addition to background therapy of either a beta-blocker or a non-dihydropyridine CCB. Results of further exploratory endpoint analyses of cardiac function and cardiac structure are also supportive of Camzyos over placebo.

The most common adverse events in patients receiving Camzyos were fatigue, dizziness and headache being reported moderately more frequently than with placebo. Moreover, due to its mechanism of action, use of Camzyos can lead to excessive decreases of myocardial contractile function, manifesting as a decrease in left ventricular ejection fraction (LVEF), leading to the potential occurrence of overt heart failure. Accordingly, throughout the clinical drug development programme, the sponsor has used an explicit dosing algorithm for Camzyos, based on regular assessment of achieved mavacamten plasma concentrations, and/or LVEF and LVOT gradient measurements by echocardiography. During the conduct of the pivotal clinical trial, EXPLORER-HCM, both pharmacokinetic and pharmacodynamic measures were monitored routinely and used to titrate Camzyos doses, while later during its open-label extension trial, a greater reliance on clinical assessment and echocardiographic monitoring only was instituted. The sponsor has shown that regular patient monitoring of LVEF and LVOT gradient echocardiographically, along with patient clinical status, is an acceptable approach to be used to optimise dosing of Camzyos in oHCM in the post-market setting to limit the risk of inducing episodes of drug-related cardiac failure. Accordingly, an explicit dosing algorithm and patient monitoring schedule have been developed for post-market use as outlined in the Camzyos Product Monograph. Further, the initiation of Camzyos will be limited to use under the supervision of a physician experienced in the treatment of HCM. Both patient and prescriber educational materials have also been developed. 

Increased plasma concentrations of mavacamten leading to reductions in LVEF and heart failure can be caused by drug interaction. However, the sponsor has shown that regular routine monitoring of LVEF by echocardiography is an effective way to monitor and manage patient risk for this adverse drug reaction, without the need for additional monitoring with regular mavacamten plasma concentrations testing, including for patients who are slow metabolisers of CYP 2C19 and CYP 3A4, or taking drugs that inhibit these CYP isozymes that play an important role in the biotransformation of Camzyos. However, concomitant use of moderate to strong CYP 2C19 inhibitors or strong CYP 3A4 inhibitors has been contraindicated to limit the risk of significant increase of mavacamten plasma concentrations.

Camzyos has been shown to cause fetal toxicity and teratogenicity in pre-clinical models. Accordingly, Camzyos use is contraindicated during pregnancy.

In summary, the sponsor has demonstrated consistent clinical benefits of Camzyos across a wide array of functional and pharmacodynamic endpoints when used as a treatment for oHCM. Although generally tolerated, Camzyos use has the potential to result in significant decreases in LVEF in individual patients. To manage this risk, an explicit Camzyos dosing algorithm and patient monitoring regimen is provided in the Camzyos Product Monograph. Overall, the information provided by the sponsor supports a favorable overall benefit-harm-uncertainty profile for Camzyos, when used as indicated.

For further details about Camzyos, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.