Cumulative analysis of data up to 3.5 years
from EXPLORER-LTE showed consistent and sustained improvements in
echocardiographic measures and symptoms, with no new safety signals
observed
CAMZYOS is the first and only approved
cardiac myosin inhibitor that targets the source of symptomatic
obstructive hypertrophic cardiomyopathy
Not intended for UK and Ireland audiences
Bristol Myers Squibb (NYSE: BMY) today announced new long-term
follow-up results from the EXPLORER-LTE cohort of the
MAVA-Long-Term Extension (LTE) study evaluating CAMZYOS®
(mavacamten) in adult patients with New York Heart Association
(NYHA) class II-III symptomatic obstructive hypertrophic
cardiomyopathy (oHCM).
The long-term follow-up efficacy and safety data, presented
today at the European Society of Cardiology (ESC) Congress in
London, reinforce the established efficacy and safety profile of
CAMZYOS, a first-in-class cardiac myosin inhibitor. With inclusion
in both the ESC and AHA/ACC clinical guidelines as a recommended
option for when symptoms persist after first-line therapy, CAMZYOS
is a standard of care for symptomatic oHCM.
Patients experienced consistent and sustained improvements in
echocardiographic measures and biomarkers after up to 3.5 years
(180 weeks) of continuous treatment, including resting left
ventricular outflow tract (LVOT) gradient, Valsalva LVOT gradient,
left atrial volume index and N-terminal pro B-type natriuretic
peptide (NT-proBNP) levels. They also experienced an improvement in
symptoms and functional capacity as measured by NYHA class and
patient-reported outcomes, including most patients achieving NYHA
class I. The safety profile of CAMZYOS for up to 3.5 years remained
consistent with the established safety profile, with no new safety
signals identified.
“The consistent and sustained improvements in multiple cardiac
measures over more than three years with CAMZYOS shows that this
therapy meets an important treatment need for patients with
symptomatic obstructive HCM,” said Pablo García-Pavia, MD, PhD,
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. “These positive long-term data,
together with the inclusion of CAMZYOS in ESC clinical guidelines
for obstructive HCM, underscore the important role of this medicine
in the long-term care of this lifelong condition that requires
ongoing management.”
At the data cutoff, 211 of 231 patients who enrolled in
MAVA-LTE, of which EXPLORER-LTE is a cohort, were on CAMZYOS; 185
and 99 patients had reached Week 156 and 180, respectively. Key
findings from the EXPLORER-LTE data analysis showed sustained
improvements from baseline to Weeks 156 and 180 in
echocardiographic measures and biomarkers. In echocardiographic
markers, patients experienced a reduction of 55.3 mmHg in Valsalva
LVOT gradient at both Week 156 and 180 and a reduction of 40.2 mmHg
and 40.3 mmHg in mean resting LVOT gradient at Week 156 and 180,
respectively. Improvements from baseline to Weeks 144 and 180 were
sustained in mean left atrial volume index, with patients
experiencing a reduction of 3.5 mL/m2 and 5.5 mL/m2, respectively.
The mean left ventricular ejection fraction (LVEF) decreased by 11%
from baseline to Week 180, and the mean (63.9%) remained within
normal range. Evaluation of biomarker data showed that median
NT-proBNP levels decreased by 504 ng/L at Week 156 and 562 ng/L by
Week 180.
At Week 180, most patients (66.3%) were NYHA class I. Overall,
108 patients (46.8%) achieved a complete response — defined as
achieving NYHA class I and a Valsalva LVOT gradient of ≤30 mmHg
during the study and retained a complete response until the data
cutoff. Patient-reported outcomes as measured by the HCM Symptom
Questionnaire (HCMSQ) found improvement in shortness of breath
score from baseline with treatment during the first 12 weeks and
was sustained through Weeks 156 and 180.
“These results, representing the longest duration of follow up
of the Phase 3 EXPLORER study to date, further reinforce the
established safety and efficacy profile of CAMZYOS,” said Roland
Chen, MD, senior vice president and head of Immunology,
Cardiovascular & Neuroscience (ICN) Development at Bristol
Myers Squibb. “As the first and only approved cardiac myosin
inhibitor for patients with symptomatic obstructive HCM and with
thousands of patients around the world treated to date, CAMZYOS,
which targets the source of symptomatic obstructive HCM, is
redefining the treatment landscape for this patient
population.”
The EXPLORER-LTE analysis found no new safety signals observed
with CAMZYOS treatment. A total of 20 patients (8.7%) experienced
transient reductions in LVEF <50%, all recovered to LVEF ≥50%
following treatment interruption and 14 patients reinitiated
treatment with CAMZYOS.
About the EXPLORER-HCM and MAVA-LTE
Trials
The double-blind, randomized, placebo-controlled, parallel group
EXPLORER-HCM Phase 3 trial (NCT03470545) enrolled 251 adult
patients with symptomatic (NYHA class II or III) obstructive
hypertrophic cardiomyopathy (oHCM). 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. Among study participants, 92%
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 included 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 oHCM 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 (oHCM) to improve
functional capacity and symptoms, and in the European Union,
indicated for the treatment of symptomatic (NYHA, class II-III)
oHCM in adult patients. It has also received regulatory approvals
in countries and regions across five continents including
Argentina, Australia, Brazil, Canada, China, Chile, Great Britain,
Hong Kong, Israel, Macau, Singapore, South Korea, Switzerland, and
the United Arab Emirates. 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. CHCs containing a
combination of ethinyl estradiol and norethindrone may be used with
CAMZYOS. However, CAMZYOS may reduce the effectiveness of combined
hormonal contraceptives (CHC). If these CHCs are used, advise
patients to add nonhormonal contraception (such as condoms) during
concomitant use and for 4 months after the last dose of
CAMZYOS.
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 unless otherwise recommended in the Prescribing
Information.
Certain Combined Hormonal Contraceptives (CHC): Progestin and
ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS
may decrease exposures of certain progestins, which may lead to
contraceptive failure. CHCs containing a combination of ethinyl
estradiol and norethindrone may be used with CAMZYOS, but if other
CHCs are used, advise patients to 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. CHCs
containing a combination of ethinyl estradiol and norethindrone may
be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness
of certain other combined hormonal contraceptives (CHC). If these
CHCs are used, advise patients to add nonhormonal contraception
(such as condoms) during concomitant use and for 4 months after the
last dose of CAMZYOS.
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,
that the results of future post-marketing studies will be
consistent with the results of this study, that CAMZYOS
(mavacamten) may not be commercially successful, any marketing
approvals, if granted, may have significant limitations on their
use, and that continued approval of CAMZYOS for such indications
may be contingent upon verification and description of clinical
benefit in additional 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, 2023, 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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