Arena Pharmaceuticals and Lorcaserin

1. Arena Pharmaceuticalsand Lorcaserin 10 /1/ 2011 Steven Vig M.D.

2. Arena Pharmaceuticals Biotechnology company in San Diego, California. Publicly traded on the Nasdaq. Ticker symbol is ARNA. CEO is Jack Lief. Web site is WWW. ARENAPHARM. COM

3. Chemical Structure Lorcaserin

4. Lorcaserin 5HT2c receptor agonist. Works in hypothalamus to decrease appetite. Not FDA approved yet. 10 mg tablet twice a day with or without food. For obese patients with BMI at or above 30. For overweight patients with BMI at or above 27 with at least one condition related to excess weight.

5. Patents and financial Lorcaserin patents will continue until at least 2023 in most jurisdictions. Arena Pharmaceuticals predicts that they will have about 60 million dollars left at the end of 2011. Arena has partnered with Eisai for sales of lorcaserin in the United States, but has not yet partnered for sales outside of the United States.

6. Serotonin Receptors 7 families 5HT1 through 5HT7. 14 subtypes of 5HT receptors. Lorcaserin is a 5HT2c receptor agonist ( it �stimulates� the 5HT2c receptor).

7. Phentermine/ dexfenfluramine �Phen-fen� was taken off the market due to heart valve and pulmonary artery hypertension problems related to stimulation of the 5HT2b receptor by dexfenfluramine. Phentermine is still available as a pill for weight loss. Lorcaserin stimulates mainly the 5HT2c receptor and has minimal effect on the 5HT2b receptor. Cardiovascular problems were not seen on echocardiograms during the lorcaserin studies in humans.

8. Lorcaserin mechanism Lorcaserin (and serotonin) stimulates 5HT2c receptors on the POMC/CART neurons (pro-opio melanocortin/cocaine and amphetamine regulated transcript neurons) in the arcuate nucleus , which causes release of alpha MSH (melanocyte stimulating hormone) which then acts on MC4R receptors in the paraventricular nucleus to decrease appetite.

9. Lorcaserin pharmacology Half life is 11 hours. T max is 2.34 hours. Usual dose is one 10mg tablet twice a day with or without food. Steady state within 3 days. Concentrates in the brain. Mild to moderate cytochrome P450 2d6 inhibitor.

10. Lorcaserin metabolism 92% is recovered in the urine Use with caution if renal impairment is moderate. Do not use if renal impairment is severe or if on dialysis. No dose change for mild to moderate liver disease. Not studied for severe liver disease.

11. 5HT2c knockout mice lack the 5HT2c receptor and overeat.

12. Belly Fat (intraabdominal fat): waist circumference often correlates with risk of diabetes and heart disease.

13. Bloom study 65.9% of patients who completed one year on lorcaserin 10mg twice a day lost 5% of body weight ( compared to 35.2% on placebo). 32.0% of patients who completed one year on lorcaserin 10mg twice a day lost 10% of body weight ( compared to 13.6% on placebo). Average weight loss was 8.2% which was around 18 pounds in one year.

14. Blossom Study 62.1 % of patients who completed one year on lorcaserin 10mg twice a day lost 5% of body weight (compared with 34.7% on placebo). 34.3% of patients who completed one year on lorcaserin 10mg twice a day lost 10% of body weight (compared with 15.5% on placebo)

15. Bloom DM (diabetes mellitis) Study 44.6% of patients who took lorcaserin 10mg twice a day for a year lost 5% of body weight (compared to 17.9% on placebo). 20.8% of patients who took lorcaserin 10mg twice a day for a year lost 10% of body weight (compared to 5.8% on placebo).

16. Bloom DM (diabetes mellitis) Study Hemoglobin aic in patients who took lorcaserin 10mg twice daily for a year fell 0.9 points, (compared to a drop in hemoglobin aic of 0.4 in placebo). Fasting blood glucose fell 27.4 points, (compared to 11.9 point drop on placebo). Waist circumference decreased on lorcaserin.

17. Main side effect-headache Main side effect of lorcaserin in the Bloom DM study was headache. Headache was in 14.5% of lorcaserin patients compared with 7.1% of control patients. Headache was usually mild, occurred early in therapy, and decreased even though lorcaserin was continued.

18. Lack of other side effects No elevation of blood pressure. No elevation of pulse rate. No depression. No heart valve problems on echocardiogram studies. No addiction problem with lorcaserin , ( in fact, lorcaserin may benefit patients with addiction problems).

19. Nicotine Article from Duke University. Journal of Pharmacology and Experimental Therapeutics June 2,2011 by Levin, E. D. �Lorcaserin, a 5HT2c agonist, decreases nicotine self administration in female rats.�

20. Decrease in Reward Pathway 5HT2c agonists decrease dopamine levels in the brain, which affects the �reward pathway�. 5HT2c agonists in rats decreases nicotine use, cocaine use, and food intake. There is a potential for 5HT2c agonists to decrease use of drugs of addiction, and to decrease excessive gambling, impulsivity, and aggression, and to treat obsessive compulsive disorder.

21. Partnership with Eisai Arena Pharmaceuticals has partnered with the Japanese pharmaceutical company Eisai for sales of lorcaserin in the United States. Arena will get 31.5 to 36.5 % of net sales of lorcaserin in the United States, plus milestone payments. Lorcaserin will be made in Arena�s manufacturing facility in Switzerland.

22. Fall of 2010 In the Fall of 2010, lorcaserin was not approved by the FDA, and Arena Pharmaceuticals was given a Complete Response Letter. One item that the FDA was concerned about was the finding of breast cancer in Sprague Dawley Rats at 82 times the dose of lorcaserin that would be used in humans. Arena has been doing studies in 2011 to be able to respond to the items listed in the Complete Response Letter.

23. Prolactin Arena hopes to show the FDA that lorcaserin produces prolactin elevation in younger rats, which would account for the elevated rates of breast cancer in the Sprague Dawley rats as they age. The occurrence of breast cancer in rats due to drugs that elevate prolactin in rats is not felt to be related to a risk of breast cancer in humans.

24. Spinal tap study in humans Arena did a spinal tap study in 9 humans in 2011 who were taking lorcaserin 10mg twice a day. Lorcaserin levels in the cerebral spinal fluid were low, which is consistent with a low risk of brain tumors in humans.

25. FDA Arena Pharmaceutical will talk with the FDA in November, 2011, and plans to resubmit lorcaserin for approval in the United States for a weight loss indication in overweight/obese patients by the end of 2011. It is possible that the FDA will approve lorcaserin in May or June of 2012. It is also possible that the FDA will not approve lorcaserin.

26. Europe Arena Pharmaceuticals plans to ask for approval of lorcaserin for sales in Europe in 2012. Arena hopes to run studies in pediatric obesity in Europe.

27. An Excellent Reference Textbook �5-HT2c Receptors in the Pathophysiology of CNS disease�. By Giuseppe Di Giovanni. Published in 2010. 557 pages. Available at www. Amazon. com

28. For more information on lorcaserin: WWW. ARENAPHARM. COM

29. Remember : Your fork is not a shovel !

30. Disclaimer This slide show was put together by Steven Vig M. D., an internist in Tucson, Arizona, and was not initiated or approved by Arena Pharmaceuticals or by Eisai. For further information on lorcaserin, , please refer to the web site, WWW. ARENAPHARM.COM