DSI: Joseph Saponaro

Arena-II Obese

A 12-week Dose Ranging, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Safety and Efficacy of APD356 in Obese Patients.

Sponsor: Arena Pharmaceuticals, Inc
Sponsor Contact: David Donahue BS 858-453-7200 x1733 DDonahue@ArenaPham.com
Study Drug: APD356 -> is a selective Serotonin 5HT2c Receptor Agonist; these receptors are concentrated the Hypothalamus Protocol: APD356-004
Phase IIa
CRO: PPD Study Monitor: Elena Matthews, MD
CRA: Julie.Cox@Wilm.PPDi.com
SAE Hotline ? Elena Matthews, MD, PPD Development, Fax: 888-529-3580, Phone: 888-483-7729 Elena.Matthews@RTP.PPDI.com
Project Manager: Rekha.Sathyanarayana@Menlo.ppdi.com
Central Cardio: BMS (Biomedical Systems, Inc.) Echo ? BGregory@BioMedSys.com 800-877-6334
Site #: 022
Central Lab: Quintiles
Last day to enroll subjects:
Central IRB: RCRC
400 Subjects/40 Sites = 10 pts per site; equally divided into 4 treatment arms: 5mgm; 10mgm; 15mgm or Placebo
Study Duration: ~ 17 wks (3 wks screening + 12 wks Treatment + 2 wks f/u assessment off study medication)
All Visits between 7AM – 10AM
Take Med in Office and in the Morning

IC
Age: 18 - 65
BMI ? 30 - 45
Healthy
Never Depressed/Always Happy
Waist Circumference Men: ?40 Women: ?34.5

EC
Smoker within 90 days V1 (Neg. Cotinine Test); except low dose ASA once a day if on it > 2 yrs; Hepatitis B or C
Any change in Diet or Exercise within the past Month; Tubal Ligation < 2 yrs still requires double barrier method
Anxiety or Depression, h/o Depression, h/o taking a Depression Drug for any reason, no matter how long ago! Any Psych Hx.
QTc Interval ? 450 msec.; Gastric Banding or Bypass; Any Yes answer on the A-DIS; Abnormal TSH; LFTs >1.5x
B-Blocker; More than 2g/day Tylenol; BP meds, 30 days; Statins < 90 days; ASA < 14 days
Fenfluramine, dexfenfluramine; Triptans, ETOH; St. Johns Wort
HIV POS

V1 D -21 to 0 Screening, Lab, ICF, EKG, PE including Neuro-Exam Try to make the Echo the last test of the Visit; Needs Anxiety & Depression Symptom Assessment Score < 12
V2 D 1 Lab, EKG, Wait 2H in Office for APD356 Blood Level +/- 15 min.
V3 D 15 Lab, Dosing Period, EKG, Visit Window +/- 1D
V4 D 29 Lab, Dosing Period, EKG, Visit Window +/- 1D
V5 D 43 Dosing Period, Visit Window +/- 1D
V6 D 57 Lab, EKG, OK +7D
V7 D 71 F/U Period, Visit Window +/- 1D
V8 D 85 Lab, EKG, Early Term, Echo, PE& Neuro
V9 D 91 F/U Period
V10 D 98 F/U Period

Arena VIPSs

Warren A. Prosser, MBA, BS, CCRA, Director, Clinical Operations
William Shanahan, MD, VP & Chief Medical Officer
David Donahue, BS, Associate Director, Clinical Operations, 858-483-7700 x 1733, Fax: 858-677-0222 DDonahue@ArenaPharm.com

PPD VIPSs

Elena Matthews, MD, Associate Director, Clinical Operations, SAE Hotline: 888-483-7729, Fax: 888-529-3580

Medical Theory
Serotonin (5-HT) and agonists that activate 5-HT2c receptors are known to increase feelings of satiety. It is postulated that activation of the 5HT2c receptor with an agonist like APD356 may increase satiety in overweight people and cause weight loss with concomitant comorbid risk factor reductions.

APD356 is a highly selective agonist for the 5HT2c receptor. Redux and Fenfluramine were removed from the market in 1997 due to increased incidence of VHD (18%) and pulmonary HTN. The Phen-Fen combination had Phentermine (which is still available) and Fenfluramine. These are non-selective 5-HT receptor agonists. They also agonize the 5- HT2b receptor which is highly expressed in heart valves. So, it is possible that APD356 being a selective 5HT2c receptor agonist will be a safe alternative to Redux or Phen-Fen for weight loss by failure to stimulate the 5HT2b receptor which is found on heart valves.

Another potential reason APD356 is safer than Redux or Phen-Fen is that it works centrally on the brain (in the hypothalamus, an area of the brain believed to play an important role in regulating food intake & metabolism) only at the 5-HT2c receptor whereas its older competitors worked centrally (5-HT2b & 5-HT2c) and peripherally by activation of the 5-HTtransporter.

APD356 has no affinity for the 5-HT transporter nor does it cause central or peripheral release of 5-HT. This selectivity for the 5-HT2c receptor should minimize the potential for side effects.

Other studies with their AEs include:

APD356-001: Single dose study up to 20mgm; AEs: HA, dizzy, blurred vision N/V, Abd. Pain.
AEs at 40mgm: euphoria, disorientation, hallucination
APD356-002: Repeat dose study up to 20mgm; AEs were same CNS & GI

Questions

Prior use of: Redux, Phen-Fen, Dexatrim, Metabolife, Sudafed, etc....is there ever any reason that we can enroll a subject who tool one of these meds in the past? How about is they only took one pill many decades ago? Or, is it if they admit ever consuming any diet drug that has an upper property to it that they are disqualified.
Is V2 blood fasting?