QSYMIA™

LisaLuna Medical Primary Care

www.qsymia.com

What is Qsymia?

Qsymia= Phentermine + Topiramate extended-release

Phentermine, Sympathomimetic amine anorectic Topiramate extended-release, Antiepileptic drug

Phentermine

• An appetite suppressant to help reduce weight in obese patients – used short-term and combined with exercise

• A psycho-stimulant drug of the phenethylamine class, with pharmacology similar to Amphetamine

Topiramate extended-release• An anticonvulsant (antiepilepsy) drug

– Topiramate was first approved by the FDA in 1996– The last patent for topiramate in the U.S. was for

pediatric use; this patent expired on February 28, 2009

• Extended-release: – allowing a twofold or greater reduction in frequency of

administration of a drug in comparison with the frequency required by a conventional dosage form.

Mechanism

Phentermine

• Target organ: Hypothalamus portion of the brain• Effect: Stimulate the adrenal glands to release

norepinephrine

• Peripheral Effect: Release epinephrine or adrenaline, causing fat cells to break down stored fat

– Epinephrine(adrenaline)& Norepinephrine: fight-or-flight response

Topiramate

• blockage of voltage-dependent sodium channels

• an augmentation of gamma-aminobutyrate (GABA) acid activity at some subtypes of the GABA- α receptors

• antagonism of AMPA/kainate subtype of the glutamate receptor

• inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV

Topiramate (continued)

• The exact mechanism of action is unknown

• Weight loss was initially seen as a side effect– effect on taste

Clinical Trials

Phase 0 study Phase I Study

Phase II Study Phase III studyPhase IV study

Phase 0 Study

• Exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals

• Pharmacodynamics and Pharmacokinetics

– Pharmacodynamics: what dose Drug do to Person?– Pharmacokinetics: what dose person do to Drugs?

Pharmacodynamics of Qysmia

Central Nervous System stimulation and elevation of blood pressure

Pharmacokinetics for Phentermine

– Approximately dose-proportional– 6 hours to reach the peak blood concentration– A high fat meal does not affect phentermine

pharmacokinetics, 17.5% plasma protein bound

Maximum concentration (Cmax) 49.1 ng/mL

time to Cmax (Tmax) 6 hr

area under the concentration curve from time zero to the last time with measureable concentration (AUC0-t)

1990 ng hr/mL⋅

Fig.1.1 Pharmacokinetics descriptive values for Phentermine

Pharmacokinetics for Topiramate

– approximately dose-proportional– 9 hours to reach the peak blood concentration– 15-41% plasma protein bound

Maximum concentration (Cmax) 1020.0 ng/mL

time to Cmax (Tmax) 9 hr

area under the concentration curve from time zero to the last time with measureable concentration (AUC0-t)

61600 ng hr/mL⋅

Fig.1.2 Pharmacokinetics descriptive values for Topiramte

Phase I Study---- Screening for safety

Studies that are usually conducted with healthy volunteers and that emphasize safety. The goal is to find out what the drug's most frequent and serious adverse events are and, often, how the drug is metabolized and excreted

• A Phase I, Open-Label, Parallel-Group, Single Dose, Non-Randomized Study To Compare The Pharmacokinetics Of Each Individual Component ( Topiramate And Phentermine) Of The Combination Product VI-0521 In Subjects With Mild, Moderate And Severe Renal Impairment To Subjects With Normal Renal Function

Reporting Groups Description

Placebo No text entered

Top Dose PHEN/TPM 15mg/92mg

Fig.1.3 Upper Level for Phen/Tpm dosage

Adverse reactions

NO serious adverse reaction found

Other adverse reaction includes paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth

Phase II Study

Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition). For example, participants receiving the drug may be compared with similar participants receiving a different treatment, usually an inactive substance (called a placebo) or a different drug. Safety continues to be evaluated, and short-term adverse events are studied

Phase II Study provided by VIVUS:

*Phentermine 3.75 mg and topiramate 23 mg daily for the 1st week; Phentermine 7.5 mg and topiramate 46 mg daily for the 2nd week; Phentermine 11.25 mg and topiramate 69 mg daily for the 3rd week; Phentermine 15 mg and topiramate 92 mg daily for the 4th week**Placebo daily for 4 weeks

Values

Enrollment number 80

Ages Eligible for Study 21 Years to 45 Years

Genders Eligible for Study Both

Condition ICMJE OverweightObesity

Intervention ICMJE Drug: VI-0521*Drug: Placebo**Other: Alcohol or fruit juice

Fig.2.1 Phase II Study of Drug VI-0521 and Placebo descriptive values

Effectiveness

For the Treatment of Obstructive Sleep Apnea Hypopnea Syndrome in Obese Adults

Study Type: Interventional

Study Design:

Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment

Condition: Sleep Apnea

Interventions: Drug: VI-0521Drug: placebo

Fig.2.2 Results for the effectiveness of VI-0521 in Phase II Study

Effectiveness(continued)

Placebo Top Dose

Number of Participants Analyzed 23 22

Change in the Apnea/Hypopnea Index Between Baseline and Week 28/Early Term**

-16.6 ± 4.15 -31.46 ± 4.25

Placebo Top Dose

Number of Participants Analyzed 23 22

Percent Change in Weight From Baseline to Week 28*

-10.26 ± 1.17 -4.21 ± 1.15

*[units: percent change] Least Squares Mean ± Standard Error**[units: events/hour] Least Squares Mean ± Standard Error

Fig.2.3 Results for the effectiveness of VI-0521 on weight change in Phase II Study

Fig.2.4 Results for the effectiveness of VI-0521 on Apnea/hypopnea Change in Phase II Study

Adverse Reaction

NO serious adverse reaction found

Other adverse reaction includes paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth

Phase III Study

Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

#1 A Safety and Efficacy Study of VI-0521 to Evaluate the Long Term Treatment of Obesity in Adults With Obesity-Related Co-Morbid Conditions.

Description

Placebo Placebo

VI-0521 Mid VI-0521 7.5 mg PHEN/46 mg TPM

VI-0521 Top VI-0521 15 mg PHEN/92 mg TPM

Fig.3.1 Phase III Study of Drug VI-0521 and Placebo descriptive dosage in Experiment 1

*[units: percent weight loss] Least Squares Mean ± Standard Error**[units: percent participants]

Measured Values Placebo VI-0521 Mid VI-0521 Top

Number of Participants Analyzed 227 153 295

Percent Weight Change at End of Treatment, Week 108. -1.8 ± 0.55 -9.32 ± 0.67 -10.5 ± 0.5

Placebo VI-0521 Mid VI-0521 Top

Number of Participants Analyzed 227 153 295

Percentage of Subjects With at Least 5% Weight Loss at End of Treatment, Week 108.

30 75.2 79.3

Effectiveness

Fig.3.3 Results for the effectiveness of VI-0521 on Percentage of Subjects With at Least 5% Weight Loss in Experiment 1 of Phase III Study

Fig.3.2 Results for the effectiveness of VI-0521 on weight change in Experiment 1 of Phase III Study

Adverse Reaction

Total, serious adverse events Placebo VI-0521 Mid VI-0521 Top

# participants affected / at risk 9/227 (3.96%) 4/153 (2.61%) 13/295 (4.41%)

Serious Adverse Events

Fig.3.4 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study

#2 A Study Comparing Multiple Doses of VI-0521 With Placebo and Their Single-agent Constituents for Treatment of Obesity in Adults

Description

Placebo PlaceboPHEN 7.5 mg 7.5 mg phentermineTPM 46 mg 46 mg topiramateVI-0521 Mid 7.5 mg/46 mg phentermine/topiramatePHEN 15 mg 15 mg phentermineTPM 92 mg 92 mg topiramateVI-0521 Top 15 mg/92 mg phentermine/topiramate

Fig.3.5 Phase III Study of Drug VI-0521 and Placebo descriptive dosage in Experiment 2

*[units: participants] [units: percent weight loss]**Least Squares Mean ± Standard Error

Placebo PHEN 7.5 mg TPM 46 mg VI-0521

Mid PHEN 15 mg

TPM 92 mg VI-0521 Top

# of Participants 103 104 102 103 106 105 103

Percent Weight Loss From Baseline to Week 28

1.7 ± 0.61

5.5 ± 0.61

5.1 ± 0.61

8.5 ± 0.62

6.1 ± 0.61

6.4 ± 0.62

9.2 ± 0.61

Placebo PHEN 7.5 mg TPM 46 mg VI-0521 Mid

PHEN 15 mg TPM 92 mg VI-0521 Top

# of Participants 103 104 102 103 106 105 103

Percentage of Subjects With at Least 5% Weight Loss at Week 28

15.5 43.3 39.2 62.1 46.2 48.6 66.0

Effectiveness

Fig.3.6 Results for the effectiveness of VI-0521 on weight change in Experiment 2 of Phase III Study

Fig.3.7 Results for the effectiveness of VI-0521 on Percentage of Subjects With at Least 5% Weight Loss in Experiment 1 of Phase III Study

Adverse Reaction

Placebo PHEN 7.5 mg TPM 46 mg VI-0521 Mid

PHEN 15 mg

TPM 92 mg VI-0521 Top

# participants affected / at risk

0/109 (0.00%)

2/109 (1.83%)

0/106 (0.00%)

1/106(0.94%)

1/108 (0.93%)

1/107 (0.93%)

2/108 (1.85%)

Fig.3.8 Results for the adverse reaction of VI-0521 in Experiment 1 of Phase III Study

Phase IV Study

Studies occurring after FDA has approved a drug for marketing. These including postmarket requirement and commitment studies that are required of or agreed to by the sponsor. These studies gather additional information about a drug's safety, efficacy, or optimal use.

Phase IV Study Status: Active, not Recruiting

http://www.clinicaltrials.gov

Potential Side Effect

• Fetal Toxicity• Increase in Heart Rate• Suicidal Behavior and Ideation• Acute Myopia and Secondary Angle Closure Glaucoma• Mood and Sleep Disorders• Cognitive Impairment• Metabolic Acidosis• Elevation in Creatinine

Sources

• Phase I, II, III, IV Study http://www.clinicaltrials.gov

• Adverse Studyhttp://www.vivus.com

QSYMIA™ This Medication Guide has been approved by the U.S. Food and Drug Administration©2012, VIVUS, Inc. All rights reserved.VIVUS, Inc1172 Castro StreetMountain View, CA 94040 USAUS Patent Numbers: 7,056,890 and 7,553,818Qsymia is a trademark of VIVUS, Inc.©2012, VIVUS, Inc.Issued: July/2012

Thank you

We Appreciate Your Patience!

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