FDA-Approved Drug Therapies for Obstructive Hypertrophic Cardiomyopathy: Endpoints, Trial Designs, and REMS
In a narrow, first-in-class therapeutic area, the earliest approvals set the template that every follow-on program is measured against. For obstructive hypertrophic cardiomyopathy, where oHCM-specific approvals are recent and share a single mechanism, the cleared labels define what regulators accepted on functional-capacity endpoints, safety monitoring, and risk management — precedent that regulatory and clinical teams need when scoping their own trials and submissions.
The analysis below covers each drug product FDA has approved with an oHCM-specific indication. For each, it lays out the pivotal endpoints and trial designs that supported the approval, the labeling restrictions and boxed warnings, and the product-specific REMS governing how the drug is dispensed and monitored.
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FDA-approved drug therapies for obstructive hypertrophic cardiomyopathy: pivotal endpoints, trial designs, and labeling restrictions
Two drug products carry an FDA indication specific to obstructive hypertrophic cardiomyopathy (oHCM), and both belong to the same first-in-class mechanism, the cardiac myosin inhibitor. CAMZYOS (mavacamten), from Bristol Myers Squibb, was the first, approved April 28, 2022 under NDA 214998 1135. MYQORZO (aficamten), from Cytokinetics, followed under NDA 219083 with original approval December 19, 2025 5225. No other active ingredient in Drugs@FDA is indicated for oHCM; the agents historically used in this disease (beta-blockers, non-dihydropyridine calcium channel blockers, disopyramide) are used off-label and are not the subject of an oHCM-specific approval.
Both products were reviewed as new molecular entities (submission Type 1) on the standard review track, and both hold FDA orphan-drug designation for symptomatic hypertrophic cardiomyopathy: mavacamten designated April 27, 2016 and aficamten designated January 5, 2021 51505211. The two labels are structurally parallel: an efficacy claim built on improvement in functional capacity, a boxed warning for heart-failure risk from reduced left ventricular ejection fraction (LVEF), mandatory serial echocardiography, and dispensing restricted through a product-specific REMS.
CAMZYOS (mavacamten)
Indication and population
CAMZYOS is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM to improve functional capacity and symptoms 353637. The dedicated VALOR-HCM program subsequently supported labeling that CAMZYOS reduces the need for septal reduction therapy (SRT) in patients eligible for it 105106.
Pivotal trial design and endpoints
The primary efficacy trial was EXPLORER-HCM, a Phase 3 double-blind, randomized, placebo-controlled, multicenter, international, parallel-group study in 251 adults with symptomatic NYHA class II-III obstructive HCM, LVEF at least 55%, and an LVOT peak gradient greater than 50 mmHg at rest or with provocation 38. Patients were randomized 1:1 to CAMZYOS or placebo and treated for 30 weeks, starting at 5 mg once daily with dose adjustment to optimize the LVOT gradient while maintaining LVEF above 50% 38.
The primary endpoint was a composite functional responder measure at Week 30: either an increase in peak oxygen consumption (pVO2) of more than 1.5 mL/kg/min plus at least a one-class NYHA improvement, or a pVO2 increase of more than 3.0 mL/kg/min with no NYHA worsening 38. The endpoint was met by 37% of CAMZYOS patients versus 17% on placebo (p = 0.0005) 38. At baseline the population was roughly 73% NYHA class II and 27% class III, with mean LVEF 74% and mean Valsalva LVOT gradient 73 mmHg; about 75% were on beta-blockers 38.
VALOR-HCM was a Phase 3, double-blind, randomized, placebo-controlled, 16-week trial in 112 patients with severely symptomatic, drug-refractory obstructive HCM who were SRT-eligible at baseline (93% NYHA class III), randomized 1:1 with allowed doses of 2.5, 5, 10, or 15 mg once daily 105106. The composite primary endpoint (proportion who decided to proceed with SRT by Week 16 or remained SRT-eligible by guideline criteria) occurred in 18% of CAMZYOS patients (10/56) versus 77% on placebo (43/56), a 59% treatment difference (p<0.0001) 105106.
Labeling restrictions and REMS
CAMZYOS carries a boxed warning: it reduces LVEF and can cause heart failure due to systolic dysfunction; LVEF echocardiograms are required before and during treatment; initiation is not recommended when LVEF is below 55%; and treatment must be interrupted if LVEF falls below 50% at any visit or with heart-failure symptoms or worsening clinical status 34353637. The boxed warning also flags CYP450 interaction risk and states that the drug is available only through the CAMZYOS REMS Program 342421.
Contraindications are defined by CYP interactions. In the 2022 to 2024 labeling, CAMZYOS was contraindicated with moderate-to-strong CYP2C19 inhibitors or strong CYP3A4 inhibitors, and with moderate-to-strong CYP2C19 inducers or moderate-to-strong CYP3A4 inducers; the 2025 label update revised this to strong CYP2C19 inhibitors and to moderate-to-strong CYP2C19 inducers or moderate-to-strong CYP3A4 inducers 34353722. Weaker inhibitors trigger required dose reduction and additional monitoring rather than contraindication 2122.
The CAMZYOS REMS is a fully operational restricted-distribution program. Only certified prescribers may prescribe, and certification requires reviewing the prescribing information and program materials, passing a knowledge assessment, and submitting an enrollment form 8283. Only certified pharmacies may dispense 7887. Before initiation the prescriber must counsel the patient, assess cardiovascular status, obtain an echocardiogram, screen for interacting medications, and enroll the patient 8290. For ongoing therapy, echocardiogram results must be documented on a Patient Status Form at defined intervals; if the form is not received within 3 calendar days of the last day of the week an echocardiogram is due, the patient is not authorized to receive further drug until it is submitted 7791.
MYQORZO (aficamten)
Indication and population
MYQORZO is indicated for the treatment of adults with symptomatic obstructive HCM to improve functional capacity and symptoms 25. Notably, the labeled indication statement does not specify an NYHA class, although the pivotal trial enrolled NYHA class II/III patients 2543.
Pivotal trial design and endpoints
The pivotal trial was SEQUOIA-HCM, a Phase 3 multicenter, randomized, double-blind, placebo-controlled study in adults with symptomatic obstructive HCM (NYHA class II/III, LVEF at least 60%, resting LVOT gradient at least 30 mmHg and post-Valsalva LVOT gradient at least 50 mmHg) 43. A total of 282 adults were randomized 1:1 (142 aficamten, 140 placebo) to once-daily treatment for 24 weeks, stratified by beta-blocker use and CPET modality 4339. Dosing started at 5 mg once daily with titration at Weeks 2, 4, and 6 in 5 mg increments up to a maximum of 20 mg once daily if the Valsalva gradient remained at least 30 mmHg and LVEF stayed at or above 50% 3942.
The primary endpoint was change from baseline in peak oxygen uptake (pVO2) by CPET at Week 24: a least-squares mean of +1.7 mL/kg/min with MYQORZO versus 0.0 with placebo, a difference of 1.7 mL/kg/min (95% CI 1.0 to 2.4; p<0.0001) 39. Key secondary endpoints all favored MYQORZO at Week 24, including KCCQ Clinical Summary Score (difference +7.3; p<0.0001), Valsalva LVOT gradient (difference -48.8 mmHg; p<0.0001), NYHA improvement of at least one class (58.5% vs 24.3%; p<0.0001), proportion with Valsalva gradient below 30 mmHg (49.3% vs 3.6%; p<0.0001), duration of SRT eligibility (35 vs 113 days; p<0.0001), and total CPET workload (difference +12.2 W; p<0.0001) 40.
Labeling restrictions and REMS
MYQORZO carries a boxed warning for risk of heart failure: it reduces LVEF and can cause heart failure due to systolic dysfunction; echocardiography is required before and during treatment; and it is available only through the MYQORZO REMS Program 3325. Labeling directs that treatment not be initiated when LVEF is below 55% 3325. Dose is decreased by 5 mg (20 to 15, 15 to 10, 10 to 5 mg) when LVEF is below 50% and at least 40%, and interrupted for at least 7 days when LVEF falls below 40% or with worsening clinical status; the REMS monitoring form requires documented LVEF of at least 55% before resuming at 5 mg 5557335365.
The single formal contraindication in the aficamten label is concomitant use of rifampin 56. Drug-interaction warnings extend to agents inhibiting multiple elimination pathways, strong CYP2C9 inhibitors, and moderate-to-strong CYP3A inducers, which may increase heart-failure risk and require dose reduction and additional monitoring 25. The titration and monitoring schedule specifies starting at 5 mg once daily, up-titration by 5 mg every 2 to 8 weeks to a 20 mg maximum, with echocardiography 2 to 8 weeks after initiation, after any dose change, and after any interruption; once a maintenance dose is set, LVEF and Valsalva gradient are assessed every 6 months, or every 3 months if LVEF is between 50% and 55% 5559545758. A dedicated REMS supplement for MYQORZO was approved February 5, 2026 12.
Side-by-side comparison
| Attribute | CAMZYOS (mavacamten) | MYQORZO (aficamten) |
|---|---|---|
| Sponsor / application | Bristol Myers Squibb, NDA 214998 11 | Cytokinetics, NDA 219083 52 |
| Original approval | April 28, 2022 11 | December 19, 2025 52 |
| Class / submission type | Cardiac myosin inhibitor; Type 1 NME, standard review 11 | Cardiac myosin inhibitor; Type 1 NME, standard review 52 |
| Orphan designation | Symptomatic HCM, designated Apr 27, 2016 51 | Symptomatic HCM, designated Jan 5, 2021 50 |
| Indication | Adults, symptomatic NYHA II-III oHCM, improve functional capacity/symptoms 35 | Adults, symptomatic oHCM (NYHA class not specified in indication), improve functional capacity/symptoms 25 |
| Pivotal trial(s) | EXPLORER-HCM (n=251, 30 wk); VALOR-HCM (n=112, 16 wk) 38105 | SEQUOIA-HCM (n=282, 24 wk) 43 |
| Primary endpoint | Composite pVO2 + NYHA responder at Wk 30: 37% vs 17%, p=0.0005 38 | Change in pVO2 at Wk 24: +1.7 vs 0.0 mL/kg/min, p<0.0001 39 |
| SRT-related endpoint | VALOR-HCM SRT composite 18% vs 77%, p<0.0001 105 | SRT eligibility duration 35 vs 113 days, p<0.0001 40 |
| Boxed warning | Heart failure from reduced LVEF; mandatory echo; REMS 3435 | Risk of heart failure from reduced LVEF; mandatory echo; REMS 3325 |
| LVEF initiation threshold | Not recommended if LVEF <55% 35 | Do not initiate if LVEF <55% 25 |
| Contraindications | CYP-based (strong CYP2C19 inhibitors; moderate-to-strong CYP2C19 / CYP3A4 inducers, per 2025 label) 3722 | Rifampin (concomitant use) 56 |
| REMS | CAMZYOS REMS Program (prescriber + pharmacy certification, patient enrollment, echo documentation) 827890 | MYQORZO REMS Program (echo-driven monitoring form) 3353 |
Practical takeaways for regulatory review
Both approvals rest on the same evidentiary spine: a Phase 3, double-blind, placebo-controlled trial with a peak-VO2-based functional primary endpoint, supported by NYHA and LVOT-gradient secondary endpoints, and both are conditioned on a boxed warning and REMS built around serial LVEF echocardiography 38393433. The clinically meaningful labeling differences are narrow but worth flagging: the CAMZYOS indication specifies NYHA class II-III while the MYQORZO indication omits an NYHA qualifier 3525; the contraindication architecture differs, with mavacamten governed by CYP2C19/CYP3A4 interaction limits and aficamten carrying a single rifampin contraindication 3756; and mavacamten has a dedicated SRT-reduction dataset from VALOR-HCM that aficamten addresses through an SRT-eligibility secondary endpoint within its pivotal trial 10540. A natural follow-up for readers is the operational detail of each REMS (certification steps, dispensing gates, and monitoring-form timing), and the pharmacogenomic dosing implications of the mavacamten CYP2C19 metabolizer status, both of which Rhizome can pull directly from the current labeling and REMS documents.