Summary Basis of Decision for Camzyos

Clinical Pharmacology

Based on non-clinical data, a reduction in the left ventricular ejection fraction (LVEF) may be expected with Camzyos treatment. In clinical studies, concentration-dependent reduction in LVEF was also observed in both single and multiple ascending dose studies in healthy subjects. In the EXPLORER-HCM clinical study, while mean resting LVEF was 74% at baseline in both treatment groups, the mean absolute change from baseline in LVEF was ‑4% in patients treated with Camzyos, and 0% in the placebo-treated patients, over the 30‑week treatment period. At Week 38, following an 8‑week interruption of Camzyos, mean LVEF had returned to baseline levels in both treatment groups.

A population pharmacokinetic analysis, and an exposure response modelling for the relationship between Camzyos exposure and LVEF, as well as between Camzyos exposure and provoked (Valsalva) left ventricular outflow tract (LVOT) gradient, are supportive of the proposed clinical monitoring and dosing strategy for Camzyos in patients with hypertrophic cardiomyopathy.

No thorough QT study was conducted for Camzyos. However, in a Phase I multiple ascending dose study in healthy subjects, sustained exposure to Camzyos at supratherapeutic levels (18.5 mg and 25 mg once daily for up to 28 days) that led to marked depression of systolic function was associated with corrected QT (QTc) interval prolongation. Increased QT interval with Fridericia correction (QTcF; change from baseline between 30 and 60 ms) was observed in 40% and 70% of participants who were administered Camzyos 18.5 mg and 25 mg once daily, respectively. The QT prolongation was induced in a dose and concentration dependent manner. However, in hypertrophic cardiomyopathy patients, the QT interval may be intrinsically prolonged due to underlying disease, in association with ventricular pacing, or in association with drugs with a potential for QT prolongation commonly used in this patient population. An exposure-response analysis across clinical studies in hypertrophic cardiomyopathy patients treated with Camzyos did not demonstrate concentration dependent QTc prolongation in the therapeutic exposure range.

Special Considerations

Hepatic Impairment

In a single‑dose pharmacokinetic study, the area under the plasma drug concentration time curve (AUC) for Camzyos increased 3.2-fold and 1.9‑fold in patients with mild (Child Pugh Class A) and moderate (Child Pugh Class B) hepatic impairment, respectively, compared to subjects with normal hepatic function. There was no effect of hepatic function on the maximum plasma concentration (C_max), consistent with no change in the rate of absorption and/or volume of distribution. A dedicated pharmacokinetic study has not been conducted in patients with severe (Child-Pugh Class C) hepatic impairment. Therefore, use of Camzyos is not recommended for patients with severe hepatic impairment.

Renal Impairment

No dedicated pharmacokinetic study was conducted in patients with renal impairment. A population pharmacokinetic analysis estimated an increase by 1.2-fold in the median steady-state exposure in patients with an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m², relative to reference patients who had a median eGFR of 95 mL/min/1.73 m².

CYP2C19 Metabolizer Phenotype

Following administration of a single dose of 15 mg Camzyos, C_max and the AUC extrapolated to infinity (AUC_inf) increased by 47% and 241%, respectively, in CYP2C19 poor metabolizers compared to CYP2C19 normal metabolizers. Mean half-life is prolonged in CYP2C19 poor metabolizers compared to CYP2C19 normal metabolizers (at 23 days versus 6 to 9 days, respectively).

Drug-Drug Interactions

Mavacamten, the medicinal ingredient in Camzyos, is a cardiac myosin inhibitor. Additive negative effects on cardiac contractility are expected when Camzyos is used with other drugs that reduce cardiac contractility. Co-administration of Camzyos (15 mg) with the weak CYP2C19 inhibitor, omeprazole (20 mg), resulted in a 48% increase in mavacamten AUC_inf with no effect on C_max in combined healthy normal metabolizers and rapid metabolizers of CYP2C19. Co-administration of Camzyos (25 mg) with the moderate CYP3A4 inhibitor, verapamil sustained release (240 mg), resulted in a 16% and 52% increase in mavacamten AUC_inf and C_max, respectively, in combined healthy intermediate metabolizers and normal metabolizers for CYP2C19. No clinical drug‑drug interaction studies have been conducted with strong CYP2C19 or strong CYP3A4 inhibitors or inducers.

Physiologically based pharmacokinetic (PBPK) modelling and simulation were used to predict drug interactions of Camzyos with modulators of CYP2C19 and CYP3A4. Co‑administration of Camzyos (15 mg) with the strong CYP2C19 inhibitor, ticlopidine (250 mg twice daily) in-silico, resulted in a 98% and 59% increase in mavacamten area under the concentration time curve from time zero to the end of the 24h dosing interval (AUC_tau) and C_max, respectively, in healthy CYP2C19 normal metabolizers. Co‑administration of Camzyos (15 mg) with the strong CYP3A4 inhibitor, itraconazole (200 mg), was predicted to result in an increase of up to 76% and 54% in AUC_tau and C_max, respectively, in healthy CYP2C19 poor metabolizers. In CYP2C19 normal metabolizers, an increase of 29% and 17% in AUC_tau and C_max, respectively, was predicted. Co‑administration of Camzyos (15 mg) with a strong CYP2C19 and strong CYP3A4 inducer, rifampin (600 mg), following a 7-day lead-in induction period, was predicted to result in a decrease of up to 69% and 7% in mavacamten area under the concentration time curve from time zero to the last concentration quantifiable time (AUC_0-T) and C_max, respectively, in CYP2C19 normal metabolizers and poor metabolizers. Significant increases in Camzyos exposure were predicted for concomitant use with moderate or strong CYP2C19 inhibitors, or strong CYP3A4 inhibitors. Considering the steep relationship between concentrations of Camzyos and LVEF, the increased exposure of Camzyos is expected to be associated with significant reduction on cardiac contractility, which may result in life-threatening heart failure due to systolic dysfunction. Many strong CYP3A4 inducers are also strong or moderate CYP2C19 inducers, e.g., apalutamide, enzalutamide, rifampin. Because Camzyos is extensively and predominantly metabolized by CYP2C19, and to some extent by CYP3A4, the impact on mavacamten exposure by the induction of both CYP2C19 and CYP3A4 enzymes are expected to be significant, reducing the efficacy of Camzyos.

Taking into consideration the underlying disease condition and biological variance of pharmacodynamic effects in patients, concomitant use of Camzyos with moderate or strong CYP2C19 inhibitors, strong CYP3A4 inhibitors, and moderate or strong inducers to both CYP2C19 and CYP3A4 is contraindicated.

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

Clinical Efficacy

The efficacy of Camzyos for the treatment of hypertrophic cardiomyopathy was based on a Phase III double blind, randomized, placebo‑controlled, multicentre, international, parallel‑group study (EXPLORER‑HCM) conducted in 251 adult patients with symptomatic NYHA Class II and III obstructive hypertrophic cardiomyopathy. Other key inclusion criteria were left ventricular ejection fraction (LVEF) ≥55% and peak left ventricular outflow tract (LVOT) gradient ≥50 mmHg, at rest or with provocation (Valsalva). Patient demographics and baseline characteristics were balanced across study treatment arms, including blood pressure, body mass index, and heart rate. The mean age of patients in the study was 59 years, and 59% of patients were male. The distribution of CYP2C19 phenotypes was similar between the two arms, at 2% poor metabolizers, 26% intermediate metabolizers, 37% normal metabolizers, 24% rapid metabolizers, and 3% ultrarapid metabolizers. These baseline characteristics reflect well the demographic characteristics of patients with obstructive hypertrophic cardiomyopathy in the real world.

Nearly all enrolled patients (92%) were treated with either a beta blocker (75%) or a non-dihydropyridine calcium channel blocker (17%), verapamil or diltiazem, as background therapy. However, combination background therapy for hypertrophic cardiomyopathy was not allowed. Further, the use of either disopyramide or ranolazine as background therapy was prohibited.

Patients were randomized in a 1:1 ratio to receive placebo or Camzyos at a starting dose of 5 mg once daily for 30 weeks. Camzyos dosing was then adjusted to 2.5 mg, 5 mg, 10 mg, or 15 mg daily, based on regularly scheduled pharmacokinetic monitoring of plasma concentrations of Camzyos, as well as pharmacodynamic monitoring of LVEF and Valsalva LVOT gradient using echocardiography. Several pre-specified criteria for dosing discontinuation were used to maintain patient safety and to avoid excessive pharmacologic effects.

In EXPLORER‑HCM, the primary pre-specified endpoint was a composite endpoint of clinical response, one that included a peak oxygen consumption (pVO₂), as well as a commonly used measure of functional capacity in hypertrophic cardiomyopathy patients, the New York Heart Association (NYHA) Class. Thus, the primary endpoint was met by those patients achieving one of the following: a) an improvement of ≥1.5 mL/kg/min in pVO₂, and a reduction of ≥1 NYHA Class, or b) an improvement of ≥3.0 mL/kg/min in pVO₂ and no worsening in NYHA Class.

Peak oxygen consumption is a direct, objective, and reproducible measure of exercise capacity, and has been endorsed for the clinical evaluation of the efficacy of therapeutic intervention in patients with hypertrophic cardiomyopathy based on its high reproducibility, low variance, and a narrow dynamic range at maximal effort.

The results from the EXPLORER‑HCM study at Week 30 showed that the conditions of the primary composite endpoint were met in 37% of patients treated with Camzyos, compared to 17% treated with a placebo (95% confidence interval of this between‑group treatment difference: 8.7-30.1; p = 0.0005). Camzyos was also observed to be superior to placebo for each of the two component criteria of the primary composite endpoint.

Five secondary endpoints of change from baseline to Week 30 were pre-specified to be tested sequentially in the following order: a) to asses LVOT obstruction, mean post exercise peak LVOT gradient, b) to assess exercise capacity, mean pVO₂, c) to assess patient function, the proportion of patients with at least one class improvement of NYHA Class, d) to assess patient function and quality of life, the Kansas City Cardiomyopathy Questionnaire (23‑item version) clinical summary score, and, e) to assess patient self-reported severity of hypertrophic cardiomyopathy symptoms, the Hypertrophic Cardiomyopathy Symptom Questionnaire shortness of breath domain score.

Results of all pre‑specified secondary endpoints demonstrated statistically significant and clinically relevant superiority of Camzyos over placebo in the intention to treat population. Results of further exploratory endpoint analyses consistently supported the effectiveness of Camzyos, including improvement in the levels of the cardiac biomarker, N‑terminal pro hormone B type natriuretic peptide (NT‑proBNP), and in a variety of measures of cardiac structure, including left atrial volume index, intraventricular wall thickness, and left ventricular mass index.

Overall, treatment of obstructive hypertrophic cardiomyopathy with Camzyos consistently demonstrated superiority of Camzyos over placebo in a variety of measures of patient function and cardiac function.

Indication

The New Drug Submission for Camzyos was filed by the sponsor with the following indication:

Camzyos (mavacamten) is indicated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in adult patients.

Health Canada approved the following indication:

Camzyos (mavacamten capsules) is indicated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM) of New York Heart Association (NYHA) Class II-III in adult patients.

For more information, refer to the Camzyos Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Camzyos was evaluated in the pivotal study, EXPLORER‑HCM (described in the Clinical Efficacy section). Close monitoring of patients was carried out, both clinically and by echocardiography, to mitigate the development of excessive inhibitory effects of Camzyos on cardiac myosin, since several-fold increases in systemic exposure to Camzyos have been shown to occur in patients that are poor metabolizers of CYP2C19 and/or CYP3A4, compared to normal metabolizers.

In the pivotal study, the most commonly reported adverse events that occurred more frequently in Camzyos‑treated patients compared to placebo‑treated patients were dizziness (Camzyos: 17.1%; placebo: 11.7%) and headache (Camzyos: 11.4%; placebo: 7.8%). However, the proportion of patients with serious adverse events and the incidence of major adverse cardiovascular events were not increased with Camzyos, compared to placebo. No increase in QT interval prolongation was noted with Camzyos treatment. In addition, no deaths occurred among patients treated with Camzyos.

While the incidence of resting LVEF <50%, determined by routine regular echocardiographic monitoring, was a protocol specified criterion for temporary study treatment discontinuation, increases in the incidence of adverse events associated with clinically meaningful decreases of LVEF were not observed. During the 30 weeks of study treatment in the EXPLORER‑HCM study, documented episodes of LVEF <50% were observed in 5.7% of patients in the Camzyos treatment arm and in 1.6% of patients in the placebo treatment arm. All Camzyos treated patients who were observed to have LVEF <50% during the on-treatment portion of the study recovered left ventricular function after temporary discontinuation of study drug.

Camzyos was also studied in MAVA‑LTE, an open‑label extension study with a planned treatment duration of 104 weeks. This study included 224 patients with obstructive hypertrophic cardiomyopathy who were previously enrolled in EXPLORER‑HCM, 112 of whom had been in the placebo group of the parent study. Mean duration of treatment in the interim dataset, filed initially as part of this submission with a data cut off date of October 30, 2020, was 32 weeks. Fatigue (6.7%), atrial fibrillation (4.9%), headache (4.9%), dyspnea (4.5%), dizziness (4.0%), and diarrhea (3.1%) were among the most commonly reported adverse events. Serious adverse events were reported in 8.5% of patients, including three cases of heart failure, and two cases of atrial fibrillation (considered to be not related to treatment with study drug), with no cases of ventricular arrhythmias. All three cases of heart failure resolved. One patient died due to bacterial endocarditis, considered not related to treatment with the study drug. Treatment with Camzyos was temporarily interrupted in nine patients due to an adverse event, with three of these due to documented decreases in LVEF, and one due to atrial fibrillation. Extension data with a cut off date of August 31, 2021, was requested during the submission review and was found to be consistent with results reported for the initial interim analysis. No new safety signal was detected.

As demonstrated in the pivotal study, EXPLORER‑HCM, and in the open‑label extension study, MAVA‑LTE, the safety profile of Camzyos, obtained while following a strict dosing algorithm, is acceptable for use in the treatment of obstructive hypertrophic cardiomyopathy. An explicit dosing algorithm and a patient monitoring schedule have been developed for the post marketing setting to mitigate the risk of drug induced left ventricular dysfunction, with or without heart failure. Treatment of obstructive hypertrophic cardiomyopathy with Camzyos is recommended to be initiated only by physicians experienced in the diagnosis and treatment of hypertrophic cardiomyopathy. Also, to limit the risk of excessive systemic exposure to Camzyos, concomitant use of Camzyos with drugs that are moderate or strong CYP2C19 inhibitors, or strong CYP3A4 inhibitors is contraindicated.

Since Camzyos has been shown to induce teratogenicity in non‑clinical studies, its use during pregnancy is contraindicated.

For more information, refer to the Camzyos Product Monograph, approved by Health Canada and available through the Drug Product Database.

Mavacamten (the medicinal ingredient in Camzyos) is a selective and reversible inhibitor of cardiac myosin adenosine triphosphatase (ATPase). Mavacamten binds cardiac myosin ATPase of various mammals, including rats, dogs, and humans. This binding inhibits the hydrolysis of adenosine triphosphate to adenosine diphosphate, which prolongs the relaxed state of myosin, and thus lowers the strength of cardiomyocyte contractions.

Mavacamten is extensively and rapidly distributed to tissues, including the myocardium, where it accumulates, and is metabolized nearly exclusively by the liver (mainly by the cytochrome P450 [CYP] enzymes CYP2C19 and CYP3A4), then cleared slowly through the biliary tract into the feces in rat. In vitro, mavacamten was a weak time dependent inhibitor of CYP2C19 and CYP2D6 and an inducer of CYP3A4 and CYP2B6. It led to no other pharmacokinetic interactions. Observed adverse effects in dogs and rats (heart failure sometimes correlated with liver and lung injury) were related to mavacamten’s pharmacodynamic activity; these effects were seen at doses below clinical therapeutic exposures, which constitutes a main limitation of the non-clinical programme. Fertility and developmental toxicology studies indicated a high risk of adverse effects in exposed offspring (post implantation loss, visceral and skeletal malformations, early postnatal deaths), however, occurring at exposures below the range considered therapeutic in humans. Mavacamten transferred to embryo fetal tissues. Transfer to maternal milk is unknown, but possible since the drug is hydrophobic.

While all the necessary studies were conducted, reaching a margin of safety compared to clinical use was not feasible since the systemic exposures that are therapeutic in patients were either lethal or toxic to animals. Since this non‑clinical toxicity is directly related to the desired pharmacologic effect of mavacamten, this did not hinder clinical development. Clinical studies accounted for this risk by strictly monitoring plasma drug concentrations and pharmacodynamics effects in patients, as measured by regular repeated echocardiographic assessments, which led to mavacamten dose adjustments when required. The only non-clinical toxicity observed was cardiac toxicity in healthy animals and embryo fetal toxicity in gestating animals. Thus, the toxicological data package supports short term use of mavacamten. However, due to the absence of safety margins and the known increase in toxicity associated with progressive accumulation of mavacamten in tissues, long term safety is not supported by the submitted non‑clinical data package and relies on the clinical data and pharmacovigilance. The Camzyos Product Monograph adequately reflects remaining uncertainties and risk mitigation strategies.

For more information, refer to the Camzyos Product Monograph, approved by Health Canada and available through the Drug Product Database.

The chemistry and manufacturing information submitted for Camzyos has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

The sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The gelatin used in the capsule shells is of animal origin. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.