Results from VALOR-HCM LTE (56 weeks)
demonstrated that with longer follow-up, CAMZYOS continued to
reduce eligibility for invasive SRT at 56 weeks
EXPLORER-LTE data (cumulative analysis up to
120 weeks) showed sustained improvements in LVOT obstruction,
symptoms, and NT-proBNP levels in patients with symptomatic
obstructive HCM, with no new safety signals observed
CAMZYOS was recently approved in the
European Union, following its approval in the U.S. and other
markets worldwide, and is the first and only cardiac myosin
inhibitor approved to treat adult patients with symptomatic
obstructive HCM
Bristol Myers Squibb (NYSE: BMY) today announced new long-term
follow-up results from two Phase 3 studies evaluating CAMZYOS®
(mavacamten), a first-in-class cardiac myosin inhibitor, in adult
patients with symptomatic obstructive hypertrophic cardiomyopathy
(HCM). Results from the 56-week analysis of the VALOR-HCM long-term
extension (LTE) study were presented as a late-breaking oral
presentation, with simultaneous publication in JAMA Cardiology, and
results from the cumulative 120-week analysis of the EXPLORER
cohort of the MAVA-LTE study were presented as an oral presentation
at the European Society of Cardiology (ESC) Congress 2023.
“The new long-term data presented at ESC were consistent with
the primary analyses from each study, further underscoring the
benefit our first-in-class therapy can provide to patients with
symptomatic obstructive HCM,” said Amy Sehnert, M.D., Vice
President, Head of Cardiomyopathy and Heart Failure Clinical
Development, Bristol Myers Squibb. “These positive data reinforce
the clinically meaningful significance of these two Phase 3 trials
that led to the approval of CAMZYOS in the United States, the
European Union and other countries around the globe. We are excited
for the ongoing exploration of the potential of CAMZYOS and remain
dedicated to providing support for obstructive HCM patients
worldwide.”
Key findings from the 56-week analysis of VALOR-HCM LTE
include:
- Treatment with CAMZYOS demonstrated sustained improvements
across key study endpoints in both the original CAMZYOS group over
56 weeks and those transitioned to the placebo cross-over group
over 40 weeks.
- At Week 56, 5 of 56 patients (8.9%) in the original CAMZYOS
group and 10 of 52 patients (19.2%) in the placebo cross-over group
at Week 40 decided to proceed with septal reduction therapy (SRT)
or were SRT-eligible.
- CAMZYOS demonstrated sustained reduction in peak resting LVOT
gradient (-34.0 mmHg for the original CAMZYOS group [95% CI -43.5
to -24.5] and -33.2 mmHg for the placebo cross-over group [95% CI
-41.9 to -24.5]).
- Proportion with NYHA class improvement of ≥1 class was observed
in 93% of patients in the original CAMZYOS group at Week 56 and 73%
of patients from the placebo cross-over group at Week 40.
- On the patient-reported 23-item Kansas City Cardiomyopathy
Questionnaire Clinical Summary Score (KCCQ-23 CSS)*, average scores
of symptom frequency, symptom burden and physical limitation
continued to improve with a 14.1 point increase for the original
CAMZYOS group (95% CI 9.9 to 18.3) and 11.7 point increase for the
placebo crossover group (95% CI 6.9 to 16.4).
- CAMZYOS was also associated with sustained reduction across
biomarkers of cardiac wall stress and myocardial injury including
reduction in N-terminal pro brain natriuretic peptide (NT-proBNP),
with -376 ng/L for the original CAMZYOS group (95% CI -723 to -225)
and -423 ng/L for the placebo cross-over group (95% CI -624 to
-252) and reduction in cardiac troponin I with -7.0 ng/L for the
original CAMZYOS group (95% CI -10 to -2.3) and -6.2 ng/L for the
placebo cross-over group (95% CI -11.5 to -3.3).
- No new safety signals were observed, and safety and efficacy
were consistent across both patient groups.
*The KCCQ‑23 CSS is derived from the Total Symptom 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 56-week late-breaking analysis of VALOR-HCM LTE builds upon
previous findings and demonstrates the consistent impact of this
oral treatment for severely symptomatic obstructive HCM patients by
showing that nearly 9 out of 10 patients treated with this drug
have continued in this long-term extension trial without SRT at
either 40 or 56 weeks of treatment,” said Milind Desai, M.D., MBA,
director, center for hypertrophic cardiomyopathy and vice chair of
education in the Heart, Vascular & Thoracic Institute at
Cleveland Clinic. “These findings are important for our continued
understanding of this treatment and encouraging for patients hoping
for non-surgical options.”
Key findings from the cumulative 120-week analysis of
EXPLORER-LTE include:
- No new safety signals were observed.
- Overall, 75.9% of patients improved by ≥1 NYHA class from
baseline at the start of the LTE study to Week 120.
- Of the 14 patients who were in NYHA class I, 12 remained in
NYHA class I at the latest available assessment.
- Treatment with CAMZYOS was associated with sustained
improvements from baseline at the start of the LTE study in
echocardiographic parameters, including E/e’ average and
NT-proBNP.
- Mean LVEF remained within the normal range at all study visits.
- Since the previous interim analysis in August 2021, one new
patient experienced a transient reduction in LVEF <50% resulting
in temporary treatment interruption.
“The presentation of data − the largest and longest analysis of
patients on CAMZYOS to-date − illustrates the promise of this
game-changing treatment for patients with symptomatic obstructive
HCM,” said Pablo García-Pavia, M.D., Ph.D., head of the Inherited
Cardiac Diseases and Heart Failure Unit at the Department of
Cardiology of Hospital Universitario Puerta de Hierro and professor
at the Spanish Cardiovascular Research Institute (CNIC) in Madrid,
Spain. “Studies like EXPLORER-LTE are important for understanding
longer-term results that assess key cardiac measures and support
the use of CAMZYOS in patients living with this chronic
condition.”
About the VALOR-HCM and LTE
Trial
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. Patients
were required to have LVOT peak gradient ≥50 mmHg at rest or with
provocation, and LVEF ≥60%. 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 post-exercise LVOT gradient, NYHA class, Kansas City
Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score and
cardiac biomarkers (NT-proBNP and Cardiac Troponin I) at Week
16.
The group initially randomized to CAMZYOS continued the drug for
32 weeks, and the placebo group crossed over to dose-blinded
CAMZYOS from Week 16 to Week 32. From the 112 randomized patients
with obstructive HCM, 108 (mean age, 60.3 years; 50% men; 94% in
NYHA class III/IV) qualified for Week 32 evaluation (56 in the
original CAMZYOS group and 52 in the placebo cross-over group) and
continued once-daily CAMZYOS until Week 128. During this LTE
period, CAMZYOS dose remained blinded.
About the EXPLORER-HCM and the MAVA-LTE
Trials
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. 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.
EXPLORER-LTE is a cohort of the MAVA-LTE study (NCT03723655), an
ongoing, dose-blinded, 5-year study of CAMZYOS in patients with
symptomatic obstructive HCM who completed the EXPLORER-HCM trial.
All participants in the EXPLORER-LTE cohort started on 5 mg of
CAMZYOS daily and dose adjustments were made at Weeks 4, 8 and 12
based on site-read echocardiography measures of Valsalva LVOT
gradient and LVEF only. Dose adjustment was also possible at Week
24 following site-read echocardiography assessment of post-exercise
LVOT gradient. Subsequent to Week 24, dose adjustment was possible
if site-read Valsalva LVOT gradient was >30 mmHg and LVEF
≥50%.
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, and in the European Union,
indicated for the treatment of symptomatic (NYHA, class II-III)
obstructive HCM in adult patients. It has also received regulatory
approvals in Australia, Brazil, Canada, Great Britain, Macau,
Singapore, South Korea and Switzerland. 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 left ventricular
outflow tract (LVOT) obstruction and improves cardiac filling
pressures.
IMPORTANT SAFETY
INFORMATION
WARNING: RISK OF HEART FAILURE
CAMZYOS reduces left ventricular ejection fraction (LVEF) and
can cause heart failure due to systolic dysfunction.
Echocardiogram assessments of LVEF are required prior to and
during treatment with CAMZYOS. Initiation of CAMZYOS in patients
with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is
<50% at any visit or if the patient experiences heart failure
symptoms or worsening clinical status.
Concomitant use of CAMZYOS with certain cytochrome P450
inhibitors or discontinuation of certain cytochrome P450 inducers
may increase the risk of heart failure due to systolic dysfunction;
therefore, the use of CAMZYOS is contraindicated with the
following:
- Moderate to strong CYP2C19 inhibitors or strong CYP3A4
inhibitors
- Moderate to strong CYP2C19 inducers or moderate to strong
CYP3A4 inducers
Because of the risk of heart failure due to systolic
dysfunction, CAMZYOS is available only through a restricted program
under a Risk Evaluation and Mitigation Strategy (REMS) called the
CAMZYOS REMS PROGRAM.
CONTRAINDICATIONS
CAMZYOS is contraindicated with concomitant use of:
- Moderate to strong CYP2C19 inhibitors or strong CYP3A4
inhibitors
- Moderate to strong CYP2C19 inducers or moderate to strong
CYP3A4 inducers
WARNINGS AND PRECAUTIONS
Heart Failure
CAMZYOS reduces systolic contraction and can cause heart failure
or totally block ventricular function. Patients who experience a
serious intercurrent illness (e.g., serious infection) or
arrhythmia (e.g., atrial fibrillation or other uncontrolled
tachyarrhythmia) are at greater risk of developing systolic
dysfunction and heart failure.
Assess the patient’s clinical status and LVEF prior to and
regularly during treatment and adjust the CAMZYOS dose accordingly.
New or worsening arrhythmia, dyspnea, chest pain, fatigue,
palpitations, leg edema, or elevations in N-terminal pro-B-type
natriuretic peptide (NT-proBNP) may be signs and symptoms of heart
failure and should also prompt an evaluation of cardiac
function.
Asymptomatic LVEF reduction, intercurrent illnesses, and
arrhythmias require additional dosing considerations.
Initiation of CAMZYOS in patients with LVEF <55% is not
recommended. Avoid concomitant use of CAMZYOS in patients on
disopyramide, ranolazine, verapamil with a beta blocker, or
diltiazem with a beta blocker as these medications and combinations
increase the risk of left ventricular systolic dysfunction and
heart failure symptoms and clinical experience is limited.
CYP 450 Drug Interactions Leading to Heart Failure or Loss of
Effectiveness
CAMZYOS is primarily metabolized by CYP2C19 and CYP3A4 enzymes.
Concomitant use of CAMZYOS and drugs that interact with these
enzymes may lead to life-threatening drug interactions such as
heart failure or loss of effectiveness.
Advise patients of the potential for drug interactions,
including with over-the-counter medications (such as omeprazole,
esomeprazole, or cimetidine). Advise patients to inform their
healthcare provider of all concomitant products prior to and during
CAMZYOS treatment.
CAMZYOS Risk Evaluation and Mitigation Strategy (REMS)
Program
CAMZYOS is only available through a restricted program called
the CAMZYOS REMS Program because of the risk of heart failure due
to systolic dysfunction. Notable requirements of the CAMZYOS REMS
Program include the following:
- Prescribers must be certified by enrolling in the REMS
Program.
- Patients must enroll in the REMS Program and comply with
ongoing monitoring requirements.
- Pharmacies must be certified by enrolling in the REMS Program
and must only dispense to patients who are authorized to receive
CAMZYOS.
- Wholesalers and distributors must only distribute to certified
pharmacies.
Further information is available at www.CAMZYOSREMS.com or by
telephone at 1-833-628-7367.
Embryo-Fetal Toxicity
CAMZYOS may cause fetal toxicity when administered to a pregnant
female, based on animal studies. Confirm absence of pregnancy in
females of reproductive potential prior to treatment and advise
patients to use effective contraception during treatment with
CAMZYOS and for 4 months after the last dose. CAMZYOS may reduce
the effectiveness of combined hormonal contraceptives (CHCs).
Advise patients using CHCs to use an alternative contraceptive
method that is not affected by CYP 450 enzyme induction or to add
nonhormonal contraception. Advise females of reproductive potential
about the potential risk to the fetus with maternal exposure to
CAMZYOS during pregnancy.
ADVERSE REACTIONS
In the EXPLORER-HCM trial, adverse reactions occurring in >5%
of patients and more commonly in the CAMZYOS group than in the
placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%).
There were no new adverse reactions identified in VALOR-HCM.
Effects on Systolic Function
In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at
baseline in both treatment groups. Mean (SD) absolute change from
baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the
placebo group over the 30-week treatment period. At Week 38,
following an 8-week interruption of trial drug, mean LVEF was
similar to baseline for both treatment groups. In the EXPLORER-HCM
trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in
the placebo group experienced reversible reductions in LVEF <50%
(median 48%: range 35-49%) while on treatment. In all 7 patients
treated with CAMZYOS, LVEF recovered following interruption of
CAMZYOS.
DRUG INTERACTIONS
Potential for Other Drugs to Affect Plasma Concentrations of
CAMZYOS
CAMZYOS is primarily metabolized by CYP2C19 and to a lesser
extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and
moderate to strong inhibitors or inducers of CYP3A4 may affect the
exposures of CAMZYOS.
Impact of Other Drugs on
CAMZYOS:
- Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4
Inhibitors: Concomitant use increases CAMZYOS exposure, which may
increase the risk of heart failure due to systolic dysfunction.
Concomitant use is contraindicated.
- Moderate to Strong CYP2C19 Inducers or Moderate to Strong
CYP3A4 Inducers: Concomitant use decreases CAMZYOS exposure, which
may reduce CAMZYOS’ efficacy. The risk of heart failure due to
systolic dysfunction may increase with discontinuation of these
inducers as the levels of induced enzyme normalizes. Concomitant
use is contraindicated.
- Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors:
Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4
inhibitor increases CAMZYOS exposure, which may increase the risk
of adverse drug reactions. Initiate CAMZYOS at the recommended
starting dose of 5 mg orally once daily in patients who are on
stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4
inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg,
10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS
treatment and intend to initiate a weak CYP2C19 inhibitor or a
moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic
assessment 4 weeks after inhibitor initiation, and do not
up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid
initiation of concomitant weak CYP2C19 and moderate CYP3A4
inhibitors in patients who are on stable treatment with 2.5 mg of
CAMZYOS because a lower dose is not available.
Potential for CAMZYOS to Affect Plasma Concentrations of
Other Drugs
CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19.
Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may
reduce plasma concentration of these drugs. Closely monitor when
CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9
substrates where decreases in the plasma concentration of these
drugs may reduce their activity.
Hormonal Contraceptives: Progestin and ethinyl estradiol are
CYP3A4 substrates. Concomitant use of CAMZYOS may decrease
exposures of ethinyl estradiol and progestin, which may lead to
contraceptive failure or an increase in breakthrough bleeding.
Advise patients to use a contraceptive method that is not affected
by CYP 450 enzyme induction (e.g., intrauterine system) or add
nonhormonal contraception (such as condoms) during concomitant use
and for 4 months after the last dose of CAMZYOS.
Drugs That Reduce Cardiac Contractility
Expect additive negative inotropic effects of CAMZYOS and other
drugs that reduce cardiac contractility. Avoid concomitant use of
CAMZYOS in patients on disopyramide, ranolazine, verapamil with a
beta blocker, or diltiazem with a beta blocker as these medications
and combinations increase the risk of left ventricular systolic
dysfunction and heart failure symptoms and clinical experience is
limited.
If concomitant therapy with a negative inotrope is initiated, or
if the dose of a negative inotrope is increased, monitor LVEF
closely until stable doses and clinical response have been
achieved.
SPECIFIC POPULATIONS
Pregnancy
CAMZYOS may cause fetal harm when administered to a pregnant
female. Advise pregnant females about the potential risk to the
fetus with maternal exposure to CAMZYOS during pregnancy. There is
a pregnancy safety study for CAMZYOS. If CAMZYOS is administered
during pregnancy, or if a patient becomes pregnant while receiving
CAMZYOS or within 4 months after the last dose of CAMZYOS,
healthcare providers should report CAMZYOS exposure by contacting
Bristol Myers Squibb at 1-800-721-5072 or www.bms.com.
Lactation
The presence of CAMZYOS in human or animal milk, the drug’s
effects on the breastfed infant, or the effects on milk production
are unknown. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for
CAMZYOS and any potential adverse effects on the breastfed child
from CAMZYOS or from the underlying maternal condition.
Females and Males of Reproductive Potential
Confirm absence of pregnancy in females of reproductive
potential prior to initiation of CAMZYOS. Advise females of
reproductive potential to use effective contraception during
treatment with CAMZYOS and for 4 months after the last dose. Use of
CAMZYOS may reduce the effectiveness of CHCs. Advise patients using
CHCs to use an alternative contraceptive method or add nonhormonal
contraception.
Please see U.S. Full Prescribing Information, including Boxed
WARNING and Medication Guide.
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.
Cautionary Statement Regarding
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on current expectations and projections about our future
financial results, goals, plans and objectives and involve inherent
risks, assumptions and uncertainties, including internal or
external factors that could delay, divert or change any of them in
the next several years, that are difficult to predict, may be
beyond our control and could cause our future financial results,
goals, plans and objectives to differ materially from those
expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
whether results of future post-marketing studies will be consistent
with the results of this study, whether CAMZYOS® (mavacamten) for
the indication described in this release, will be commercially
successful, that any marketing approvals, if granted, may have
significant limitations on their use, and that continued approval
of such product candidate for such indication described in this
release may be contingent upon verification and description of
clinical benefit in confirmatory trials. No forward-looking
statement can be guaranteed. Forward-looking statements in this
press release should be evaluated together with the many risks and
uncertainties that affect Bristol Myers Squibb’s business and
market, particularly those identified in the cautionary statement
and risk factors discussion in Bristol Myers Squibb’s Annual Report
on Form 10-K for the year ended December 31, 2022, as updated by
our subsequent Quarterly Reports on Form 10-Q, Current Reports on
Form 8-K and other filings with the Securities and Exchange
Commission. The forward-looking statements included in this
document are made only as of the date of this document and except
as otherwise required by applicable law, Bristol Myers Squibb
undertakes no obligation to publicly update or revise any
forward-looking statement, whether as a result of new information,
future events, changed circumstances or otherwise.
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