U.S. FDA has assigned a target action date
of June 16, 2023
Application based on results from the Phase
3 VALOR-HCM study
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S.
Food and Drug Administration (FDA) has accepted its supplemental
new drug application (sNDA) for CAMZYOS® (mavacamten) for an
expanded indication to reduce the need for septal reduction therapy
(SRT). CAMYZOS is currently FDA approved 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. The FDA assigned a Prescription
Drug User Fee Act (PDUFA) goal date of June 16, 2023.
“Currently, it is recommended that many patients with severe
symptomatic obstructive hypertrophic cardiomyopathy undergo SRT.
This often requires either an open-heart surgical procedure or
septal ablation procedure – both specialized care options,” said
Roland Chen, MD, senior vice president and head of cardiovascular
development, Global Drug Development at Bristol Myers Squibb. “The
approval of CAMZYOS earlier this year marked a significant
milestone for patients. FDA acceptance of the filing for this
expanded indication has the potential to strengthen the profile of
CAMZYOS, while further reinforcing our commitment to delivering
transformative cardiovascular therapies to patients.”
The sNDA submission was based on the results of the Phase 3
VALOR-HCM study, a randomized, double-blind, placebo-controlled
study, which evaluated CAMZYOS in patients with symptomatic,
obstructive HCM (NYHA class III-IV) who met the 2011 ACC/AHA
guideline criteria for SRT and who have been referred for an
invasive procedure. VALOR-HCM met its primary and all secondary
endpoints with a high degree of statistical significance, with no
new safety signals observed.
About the Phase 3 VALOR-HCM
Trial
VALOR-HCM (NCT04349072) is a randomized, double-blind,
placebo-controlled, multicenter Phase 3 study of patients with
symptomatic, obstructive HCM (NYHA class III-IV) who meet guideline
criteria for septal reduction therapy (SRT) and have been referred
for an invasive procedure. The study enrolled 112 patients
randomized on a 1:1 basis to receive mavacamten or placebo.
VALOR-HCM includes three treatment periods over 128 weeks: a
16-week placebo-controlled period, a 16-week active treatment
period where all patients received mavacamten and a 96-week
long-term extension period where all patients received
mavacamten.
The primary endpoint of VALOR-HCM is a composite of the number
of patients who decide to proceed with SRT prior to or at Week 16
and the number of patients who remain SRT-guideline eligible (LVOT
gradient of ≥50mmHg and NYHA Class III-IV) at Week 16 in the
mavacamten group compared with the placebo group. Key secondary
endpoints include impact on exercise gradient LVOT, NYHA Class and
Kansas City Cardiomyopathy Questionnaire (KCCQ) and biomarkers at
Week 16.
About Obstructive Hypertrophic
Cardiomyopathy
Obstructive hypertrophic cardiomyopathy (obstructive HCM) is a
chronic, progressive disease in which excessive contraction of the
heart muscle and reduced ability of the left ventricle to fill can
make it difficult for blood to circulate to the rest of the body,
leading to the development of debilitating symptoms and cardiac
dysfunction. HCM can be hereditary and can develop at any age.
Patients are typically diagnosed in their 40s or 50s, and as many
as 50% of patients have a hereditary predisposition.
In obstructive HCM, which is the most common type of HCM, the
left ventricular outflow tract (LVOT) where blood leaves the heart
becomes obstructed by the enlarged heart muscle. As a result,
obstructive HCM has also been associated with increased risks of
atrial fibrillation, stroke, heart failure and, although rare,
sudden cardiac death. The most frequent cause of obstructive HCM is
mutations in the heart muscle proteins of the sarcomere.
Obstructive HCM is estimated to affect 400,000-600,000 people
worldwide, however many patients remain undiagnosed and/or
asymptomatic.
About CAMZYOS
(mavacamten)
CAMZYOS (mavacamten) is the first and only cardiac myosin
inhibitor approved by the U.S. Food and Drug Administration (FDA)
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.
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 LVOT
obstruction and improves cardiac filling pressures.
About CAMZYOS 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 CAMZYOS 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 by telephone at
1-833-628-7367.
INDICATION
CAMZYOS (mavacamten) is 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.
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
were excluded from EXPLORER-HCM. Concomitant use of CAMZYOS with
disopyramide in combination with verapamil or diltiazem has been
associated with left ventricular systolic dysfunction and heart
failure symptoms in patients with obstructive HCM.
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%).
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 with disopyramide in combination with verapamil or
diltiazem. 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 US 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 CAMZYOS (mavacamten) for the indication described in this
release will be commercially successful, 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,
2021, 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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