VIVUS, Inc. (Nasdaq: VVUS; the “Company”), a biopharmaceutical
company, today announced that results from a new study evaluating
the cardiovascular safety of Qsymia® (phentermine and topiramate
extended-release) capsules CIV will be published in the February 1,
2019 issue of The Journal of Clinical Endocrinology &
Metabolism and are currently available online.1 This retrospective
study, conducted using medical claims databases, was prompted by
the observation in clinical trials that participants taking Qsymia
had higher heart rates than those taking placebo. The new findings
indicate that the combined risk of major adverse cardiovascular
events (MACE) was not elevated in patients currently taking Qsymia,
or concurrently taking both phentermine and topiramate, compared
with former users of these medications. The number of MACE events
(3 events during 3,245 person-years of follow-up) was too few to
draw a definitive conclusion from the data. Results from the study
were previously presented in a poster at the 34th International
Conference on Pharmacoepidemiology & Therapeutic Risk
Management in August 2018.
“The results of this study provide some
assurance that, despite the increase in heart rate seen in the
clinical trials, current use of phentermine in combination with
topiramate did not appear to be associated with a higher
cardiovascular risk. We note that the confidence intervals for this
observation were broad, indicating that the data were imprecise and
compatible with a considerable range of possible effects,” said
Peter R. Kowey, MD, Emeritus Chief, Cardiology at Lankenau
Heart Institute, Professor of Medicine and Pharmacology
at Jefferson Medical College in Philadelphia, and an
author on the publication.
“Obesity is a significant and growing problem in
the United States. Safe and effective tools for managing body
weight and body mass index are critical for helping patients reduce
the risks of overall cardiovascular and diabetes-related mortality,
which are increased in obese individuals. Qsymia provides a safe
and efficacious option for patients seeking to manage body weight
and body mass index,” said Santosh T. Varghese, MD, Chief Medical
Officer at VIVUS.
More than 500,000 patients were included in this
retrospective study, which evaluated risk of MACE among current
users of Qsymia, phentermine and topiramate in combination
(PHEN/TPM), phentermine (PHEN), and topiramate (TPM), compared to
the risk among patients who were former users who had discontinued
these medications. MACE was defined as hospitalization for acute
myocardial infarction (AMI) or stroke or in-hospital
cardiovascular-related death, as determined via discharge status
and ICD-9-CM diagnoses.
“Qsymia is an effective tool as a component of
body mass index management regimens. These study results provide
additional evidence that its use does not increase MACE risk,” said
John Amos, Chief Executive Officer at VIVUS. “We intend to
include these findings in our ongoing discussions with the U.S.
Food and Drug Administration related to our requested label
modification for Qsymia. The requested modification would allow for
the safe and effective short-term use of Qsymia and could
potentially reduce or modify the need for a cardiovascular outcomes
study.”
The efficacy and safety of Qsymia have been
demonstrated in multiple clinical trials and peer-reviewed
publications, including:
- A Phase 3 randomized, placebo-controlled Phase 3 trial
conducted in 1,267 obese adults with body-mass index (BMI) ≥ 35
kg/m2 (EQUIP).2 Patients were randomized to placebo,
phentermine/topiramate controlled release (PHEN/TPM CR) 3.75/23 mg,
or PHEN/TPM CR 15/92 mg, added to a reduced-energy diet. At 56
weeks, patients lost 1.6%, 5.1% and 10.9%, respectively, of
baseline body weight (p<0.0001). A significantly higher
proportion of patients achieved at least 5% weight loss in the
PHEN/TPM CR groups compared with placebo (p<0.0001). Study
authors suggest that the beneficial effects of PHEN/TPM CR on
weight, blood pressure, lipids, and glycemic measures mitigate any
adverse effects on heart rate.
- A Phase 3 randomized, placebo-controlled 56-week trial
conducted in 2,487 adults with BMI 27–45 kg/m2 and two or more
comorbidities (hypertension, dyslipidaemia, diabetes or
prediabetes, or abdominal obesity) (CONQUER).3 Patients were
randomly assigned to receive PHEN/TPM CR 7.5/46.0 mg (n = 498),
PHEN/TPM CR 15.0/92.0 mg (n = 995) or placebo (n = 994). At 56
weeks, change in bodyweight in the 2,448 patients available for
analysis was –1.4 kg, –8.1 kg, and –10.2 kg (p<0.0001) in the
patients assigned to placebo, PHEN/TPM CR 7.5/46.0 mg, and PHEN/TPM
CR 15.0/92.0 mg, respectively. A significantly higher proportion of
patients achieved at least 5% or at least 10% weight loss in the
PHEN/TPM CR groups compared with placebo (p<0.0001) for all
comparisons. Study authors also noted significant improvements in
blood pressure, waist circumference, lipid concentrations,
glycaemia and inflammatory biomarkers (high sensitivity C-reactive
protein and adiponectin) in the PHEN/TPM CR group compared with
placebo.
- A two-year Phase 3 randomized, placebo-controlled study
(SEQUEL)4, which was a 52-week extension study of CONQUER. A total
of 866 patients from CONQUER were eligible for the extension study,
of which 676 elected to participate in SEQUEL. At week 108,
PHEN/TPM CR was associated with significant, sustained weight loss
(intent-to-treat with last observation carried forward; p <
0.0001 compared with placebo). Percentage changes from baseline in
body weight were –1.8%, –9.3%, and –10.5% for placebo, 7.5/46, and
15/92, respectively. Significantly more PHEN/TPM CR–treated
subjects at each dose achieved ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20% weight
loss compared with placebo (p < 0.001). No cardiovascular safety
signals were detected. ° A sub-analysis of SEQUEL
conducted in 475 patients with prediabetes and/or metabolic
syndrome (MetS).5 After 108 weeks, subjects with prediabetes and/or
MetS in the placebo, 7.5/46, and 15/92 groups experienced mean
percent weight loss of 2.5%, 10.9%, and 12.1%, respectively (p <
0.0001 vs. placebo). These losses were associated with reductions
of 70.5% and 78.7% in the annualized incidence rate of type 2
diabetes for those receiving 7.5/46 and 15/92, respectively (p <
0.05), versus placebo. No cardiovascular safety signals were
observed in this patient subset.
- A Phase 2 randomized, double-blind, placebo-controlled study of
PHEN/TPM CR 15/92 for the treatment of moderate to severe
obstructive sleep apnea (OSA) in obese adults.6 A total of 45
patients were randomized to placebo (n = 23) or PHEN/TPM CR (n =
22) for 28-week treatment periods in addition to
lifestyle-modification counseling. At 28 weeks, changes in the
apnea-hypopnea index (AHI), significantly favored PHEN/TPM CR over
placebo (-31.5 events/h vs. 16.6 events/h, p = 0.0084). At week 28
there was also a positive, significant (p = 0.0003) correlation
between percent change in weight and change in AHI. Authors also
noted significant improvements in overnight oxygen saturation and
reduction in blood pressure compared to placebo.
- A subset analysis of health-related quality of life (HRQOL)
conducted in 2,374 patients who had participated in EQUIP (n = 751)
or CONQUER (n = 1,623) and completed HRQOL questionnaires at weeks
28 and 56. Significant improvements in both obesity-specific
and physical HRQOL were observed at 56 weeks in both trials (p <
0.0001). Although reduction in BMI accounted for the majority
of improvements in obesity-specific and physical HRQOL, decrease in
depressive symptoms was also a significant mediator.
About Qsymia
Qsymia is approved in the United
States and is indicated as an adjunct to a reduced-calorie
diet and increased physical activity for chronic weight management
in adults with an initial body mass index (BMI) of 30 kg/m2 or
greater (obese) or 27 kg/m2 or greater (overweight) in the
presence of at least one weight-related medical condition such as
high blood pressure, type 2 diabetes, or high cholesterol.
The effect of Qsymia on cardiovascular morbidity
and mortality has not been established. The safety and
effectiveness of Qsymia in combination with other products intended
for weight loss, including prescription and over-the-counter drugs,
and herbal preparations, have not been established.
Important Safety
Information
Qsymia (phentermine and topiramate
extended-release) capsules CIV is contraindicated in pregnancy; in
patients with glaucoma; in hyperthyroidism; in patients receiving
treatment or within 14 days following treatment with monoamine
oxidase inhibitors; or in patients with hypersensitivity to
sympathomimetic amines, topiramate, or any of the inactive
ingredients in Qsymia.
Qsymia can cause fetal harm. Females of
reproductive potential should have a negative pregnancy test before
treatment and monthly thereafter and use effective contraception
consistently during Qsymia therapy. If a patient becomes pregnant
while taking Qsymia, treatment should be discontinued immediately,
and the patient should be informed of the potential hazard to the
fetus.
The most commonly observed side effects in
controlled clinical studies, 5% or greater and at least 1.5 times
placebo, include paraesthesia, dizziness, dysgeusia, insomnia,
constipation, and dry mouth.
About VIVUS
VIVUS is a biopharmaceutical company committed
to the development and commercialization of innovative therapies
that focus on advancing treatments for patients with serious unmet
medical needs. For more information about the Company, please
visit www.vivus.com.
Forward-Looking
StatementsCertain statements in this press release are
forward-looking within the meaning of the Private Securities
Litigation Reform Act of 1995 and are subject to risks,
uncertainties and other factors, including risks and uncertainties
related to the timing of initiation and completion of the
post-approval clinical studies required as part of the approval of
Qsymia by the U.S. Food and Drug Administration, or FDA; risks and
uncertainties related to the response from FDA to any data and/or
information relating to post-approval clinical studies required for
Qsymia; risks and uncertainties related to our ability to work with
FDA to significantly reduce or remove the requirements of the
clinical post-approval cardiovascular outcomes trial, or CVOT;
risks and uncertainties related to the impact of the indicated uses
and contraindications contained in the Qsymia label and the Risk
Evaluation and Mitigation Strategy, or REMS, requirements; risks
and uncertainties related to the fact that we may be required to
provide further analysis of previously submitted clinical trial
data; and risks and uncertainties related to our discussions with
the European Medicines Agency, or EMA, relating to the resubmission
of the marketing authorization application for Qsymia, and the
assessment by the EMA of the marketing authorization application.
These risks and uncertainties could cause actual results to differ
materially from those referred to in these forward-looking
statements. The reader is cautioned not to rely on these
forward-looking statements. Investors should read the risk
factors set forth in VIVUS’ Form 10-K for the year ended December
31, 2017 as filed on March 14, 2018, and as amended by the Form
10-K/A filed on April 26, 2018, and periodic reports filed with the
Securities and Exchange Commission. VIVUS does not undertake
an obligation to update or revise any forward-looking
statements.
VIVUS,
Inc. |
Investor
Relations: Lazar Partners |
Mark Oki |
David Carey |
Chief Financial
Officer |
Managing Director |
oki@vivus.com |
dcarey@lazarpartners.com |
650-934-5200 |
212-867-1768 |
___________________________1 Ritchey ME, Harding A, Hunter S,
Peterson C, Sager PT, Kowey PR, et al. Cardiovascular safety during
and after use of phentermine and topiramate. J Clin Endocrinol
Metab 2019;104(2):513-522.2 Allison DB, Gadde KM, Garvey WT,
Peterson CA, Schwiers ML, Najarian T, et al. Controlled-release
phentermine/topiramate in severely obese adults: a randomized
controlled trial (EQUIP). Obesity 2012;20(2):330-42.3 Gadde KM,
Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers, et al.
Effects of low-dose, controlled-release, phentermine plus
topiramate combination on weight and associated comorbidities in
overweight and obese adults (CONQUER): a randomised,
placebo-controlled, phase 3 trial. Lancet 2011;37(9774):1341-52.4
Garvey TW, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA,
Schwiers M, et al. Two-year sustained weight loss and metabolic
benefits with controlled-release phentermine/topiramate in obese
and overweight adults (SEQUEL): a randomized, placebo-controlled,
phase 3 extension study. Am J Clin Nutr 2012; 95(2):297-308.5
Garvey TW, Ryan DH, Henry R, Bohannon NJV, Toplak H, Schwiers M, et
al. Prevention of Type 2 diabetes in subjects with prediabetes and
metabolic syndrome treated with phentermine and topiramate extended
release. Diabetes Care 2014;37(4):912-21.6 Winslow DH, Bowden CH,
DiDonato KP and McCullough PA. A randomized, double-blind,
placebo-controlled study of an oral, extended-release formulation
of phentermine/topiramate for the treatment of obstructive sleep
apnea in obese adults. Sleep 2012;35(11):1529-39.
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