Company

Ticker Symbol

Product(s)

GlaxoSmithKline

GSK

AlliTM (Orlistat)

Roche Laboratories, Inc.

RO.S

XenicalÒ (Orlistat)

Amylin Pharmaceuticals, Inc.

AMLN

ByettaÒ (Exenatide)

SymlinÒ (Pramlintide)

Eli Lilly and Company

LLY

ByettaÒ (Exenatide)

Phentermine

Ortho-McNeil Neurologics, Inc

TopamaxÒ (Topiramate)

Eisai, Inc.

ESALF.PK

ZonegranÒ (Zonisamide)

Glaxo Smith Kline

GSK

Wellbutrin (Bupropion)

Merck

MRK

Taranabant

Sanofi-Aventis

SNY

Rimonabant

Shionogi & Co, Ltd

SGIOF.PK

S-2367

Inclusion Criteria

• Key opinion leader in obesity medicine
• Board-certified in area of specialty
• 2-30 years of experience post-training
• Request disclosure of past and current consulting relationships

Panelists’ Name

Hospital/academic affiliation

State

Caroline Apovian, MD

Boston University School of Medicine / Boston Medical Center

MA

Ayman Arafat, MD

Charite Campus Benjamin Franklin

Berlin, Germany

Jamy Ard, MD

University of Alabama at Birmingham

AL

Daniel Bessesen, MD

Denver Health Medical Center

CO

Anthony Hollenberg, MD

Beth Israel Deaconess Medical Center / Harvard Medical School

MA

Kenneth Storch, MD

Storch Medical Nutrition Associates

PA

Ian Yip, MD

UCLA School of Medicine / Nutrition Medical Center

CA

Question

Page

Q1. Use of medications to treat obesity

What medications are you using on a regular basis to treat obesity? Please comment on those that you are using as indicated as well as those that you are using off-label. What combinations of medications are you using on a regular basis?

6

Q2. Experience with Alli™

Please discuss your experience with Alli™ (over-the-counter Orlistat). How many of your patients are using the medication? What has been their experience with it? Among all your patients who tried Alli, what percentage stopped the medication due to side effects? How has it impacted your use of Xenical®?

8

Q3. Symlin® (Pramlintide)

Please review the attached NAASO 2007 abstract about Pramlintide. What do you think about the results of the study? Based on this information and your experience, please comment on the use of Pramlintide for weight loss and weight maintenance in patients with and without diabetes.

10

Q4. Topiramate and Phentermine

Please review the attached NAASO 2007 abstract about Topiramate and Phentermine as combination therapy. What do you think about the results of the study? Have you used these medications in combination in your clinical practice? If so, has your clinical experience matched the outcomes of this study? How promising is this combination therapy?

11

Q5. Zonisamide and Bupropion

Please review the attached NAASO 2007 abstract about the combination sustained release product of Zonisamide and Bupropion. What do you think about the results of the study? Have you used these medications in combination in your clinical practice? If so, has your clinical experience matched the outcomes of this study? How promising is Zonisamide and Bupropion as a combination treatment of obesity?

13

Q6. Naltrexone and Bupropion

Please review the attached NAASO 2007 abstract about Naltrexone and Bupropion. What do you think of the results of the study? Have you used these medications in combination in your clinical practice? If so, has your clinical experience matched the outcomes of this study? How promising is this combination therapy?

14

Q7. Taranabant

Please review the attached NAASO 2007 abstract about Taranabant. What do you think of the results of the study? What do you think is the future of this medication? In light of the situation surrounding Rimonabant, what will the studies of Taranabant need to show?

16

Q8. S-2367

Please review this press release and NAASO 2007 abstract about Shinogi’s drug S-2367, a neuropeptide-Y Y5 receptor antagonist. What do you think about this drug in terms of both its mechanism and efficacy? How significant is the adverse event of hemolysis that was described in the abstract? Should the drug proceed to phase 3 studies? Please explain why or why not.

18

Q9. Potential treatments?

There were a few peptides and drugs in early stages of development that were presented at the 2007 NAASO – The Obesity Society annual meeting including: • AM4112, a neutral CB1 receptor antagonist • GII81771X, a selective CCK-A agonist • Capsinoids, transient receptor potential vanilloid 1 agonists • Trodusquenime (MSI-1436), a protein tyrosine phosphatase 1B inhibitor • QRFP, an orexigenic peptide • AMP-12279, a combination of two molecules that regulates CB1 and other CNS and peripheral targets Which two of these do you think shows the most promise as a potential treatment of obesity? What is it that makes you think so – their mechanisms? Anything else?

18

Q10. Compelling information

What do you expect to be the most compelling information being presented at the 2007 NAASO – The Obesity Society annual meeting? Please explain why you think it is so interesting and important.

21

Appendices A-G

24

Introduction

Welcome to this discussion among specialists in Obesity Medicine in which we will review information presented at the 2007 annual meeting of NAASO -- The Obesity Society. Panel Intelligence discussions are enhanced when you, as a panelist, not only respond to the posted questions, but also reply to comments made by our moderator and your fellow panelists. We look forward to a lively and interactive discussion. Please note: In your participation on this panel, Panel Intelligence expects and requires that you comply with the terms of the Consultant Confidentiality Agreement to which you previously agreed. If you have any questions about the terms of that agreement, please review them through the link provided on your Panel Intelligence home page after you've logged in.

Instructions for reading and posting responses

Identifying Icons: Questions are marked with a . Important information is marked with a . Moderator questions are marked with . Supporting Documents are marked with .

Instructions for reviewing abstracts

During this discussion, you will be asked to review research abstracts presented at NAASO 2007. These abstracts are viewable by clicking on links marked with this symbol: . Clicking on those links opens a separate pop-up window, allowing you to view the abstracted data. You may minimize or close and re-open these windows as often as is necessary or convenient for you. However, please keep in mind that if a link appears not to open for you, it is possible that the pop-up window is already open but has been minimized to the bottom of your screen. Thank you for again for your participation.

Q1. Use of medications to treat obesity

What medications are you using on a regular basis to treat obesity? Please comment on those that you are using as indicated as well as those that you are using off-label. What combinations of medications are you using on a regular basis?

Panelist 4: I prescribe sibutramine, orlistat and phentermine (off label) for weight loss. If a person has other indictions I prescribe wellbutrin and topiramate, but not with obesity as a primary indication. I currently do not prescribe any combination therapy for obesiity.

Panelist 1: phentermine as Adipex Meridia Topamax xenical ALLI wellbutrin zonisamide

Panelist 6: Phentermine is usually my drug of choice followed by tenuate, both are scheduled IV medications. Sibutramine is a great medication, however, most insurance companies do not cover weight loss medication and therefore, the Cash price of buying sibutramine, will in a majority of cases, become prohibitive from a cost stand-point. I have not found Orlistat and Alli to be very effective for weight loss. I sometimes use Bontril for a short time after I exhausted other options.

Panelist 5: Currently I am not involved in the clinical treatment of obesity.

Panelist 2: For patients with BMI below 35-40 I try to center the intervention on Behavior, gradual long-term increase in fitness. For selected patients in this population, I use sibutramine, orlistat and off-label wellbutrin. Sometimes SSRI for bingers. Rarely Effexor or Cymbalta. For patients who clearly need chronic therapy, especially if BMI>40, my pharmacologic tools include: phentermine, topamax, phen-topa together, sometimes zonegran if topa not tolerated or patient already on Wellbutrin since there is data.

Panelist 7: Phentermine Sibutramine Xenical (very rarely due to side effects) Exenatide, particulalry in those with primary insulin resistance or night eating tendencies. I have combined the centrally acting agents with the peripheral agents in some instances. Metformin is often added for those in later stages of weight loss.

To panelist 7 and others

Panelist 7 noted using “Exenatide, particulalry in those with primary insulin resistance or night eating tendencies.” Please comment on the use of exenatide in patients with night eating tendencies. What is the rationale for using the medication in this subset of patients? What percent of your patients have night eating? What percent of patients with night eating receive treatment with exenatide?

Panelist 5: Many obese patients consume the majority of their calories from dinner on. Success of exanitide in promoting weight loss can thus be attributed in a subset to preventing this.

Panelist 4: The group at Penn has conducted a number of preliminary drug trials using sertaline for night eating syndrome. This would be the evidence based choice.

Panelist 1: I agree with using an SSRI to treat night eating syndrome

Panelist 8: Exenatide is effective in inducing weight reduction (may be in part due to nausea)..However, this medication should be used in patients with DM or IR. I don´t know anything about its application in patients with night eating disorders!.

Panelist 7: Our use is based on the idea that exenatide may have some effects on sensory specific satiety. We have observed that a significant number of night eaters select specific "types" of foods. They are usually higher in carbohydrates...I think the weight loss effects seen with exenatide may actually be due to effects in this area. I have no data to support this conjecture, but our clinical experience supports that research in this area could be informative.

Panelist 2: We find night eating to be a prevalent pattern. A clinically significant number of these also are diagnosed with sleep apnea. In my experience, it is helpful, but not sufficient, to treat the sleep pathology early on. We have had some success with SSRI's and off-label use of topiramide in night eaters. Have used exenatide in only 1 severe night eater (diabetic) and there was an improvement in weight and HbA1c.

Panelist 1: I have not used exenatide specifically for night eating syndrome. I do use it in patients with obesity and type II DM and find that weight loss is improved

Exenatide for weight loss

Please describe in greater detail how you are using exenatide for weight loss in patients with and without diabetes. What type of weight loss are you seeing? What about side effects? What type of patient demand has there been for this medication? Has cost been a factor, and if so, how?

Panelist 1: Yes cost is a factor so I can only prescribe to those with diabetes. The weightloss is between 5 and 10 pounds

Panelist 5: There is significant demand for this medication. I think there is alot of anticipation for the long-acting formulations.

Panelist 6: I only use it in patients with diabetes who failed to achieve glycemic goals when they have failed on oral agents. Most insurance would not pay unless it's in diabetic patients and cost definitely will become an issue.

Panelist 6: I have only used it in patients with diabetes because of the cost. Using it in patient without diabetes is an off-label use and won't be covered by insurance. Cash price of this medicine because prohibitive for many patients. Moreover, it's an injection. In patients with diabetes, I have seen a good 10 lbs weight loss. It could be due to nausea and patients did feel like eating as much. It may have anorexia effect, but don't know the mechanism of action in weight reduction for this medication.

Panelist 8: Because of the costs, it can only be prescribe to those with diabetes unless the patients with IGT/IR are willing to pay. The weightloss is between 6-8% BW.

Panelist 2: Using in obese diabetic patients after metformin, combined with active lifestyle measures, to facilitate weight loss. Most patients in my population are unaware of Byetta till I inform them. None pay out of pocket so far.

Panelist 4: I use this when they have failed other medications or have had substantial weight gain on insulin. Cost is definitely an issue, but insurance has been supportive for these very limited indications.

Panelist 7: We are typically using in non-diabetic patients who have a high preference for carbohydrates or sweets, have some type of insulin resistance or metabolic syndrome, or those who have not tolerated centrally acting agents. Any diabetic with poor control or those on sulfonylureas experiencing weight gain.

Panelist 8: Sibutramine, Xenical, Orlistat. Exenatide or Metformin in case of IR or IGT (off-label). Rimonabant

Q2. Experience with alli™

Please discuss your experience with alli™ (over-the-counter orlistat). How many of your patients are using the medication? What has been their experience with it? Among all your patients who tried alli, what percentage stopped the medication due to side effects? How has it impacted your use of Xenical®?

Panelist 4: A few of my patients have tried alli, I have not heard much either favorable or unfavorable from them. I do not suggest it as a primary therapy and so it has not impacted my use of Xenical to my knowlege.

Panelist 1: Many of my patients are using ALLI there are no side effects in these patients since half the dose of Xenical My use of Xenical hs not changed

Panelist 6: Alli 60 mg is just half of dosage of orlistat that has been approved by the FDA since ?1998. I have not found orlistat to be effective in a majority of situation. Medications that work on the CNS is more effective in my clinical experiences. Alli is approved over the counter. That's the big fuss about it because one does not need to see a doctor to get the prescription. Most of my patients get orlistat prescription from me, not Alli.

Panelist 5: again, though I do not actively use it, it does not appear to be on the top of anyones list because of side effects/efficacy.

Panelist 2: Don't normally initiate discussion of Alli in medically obese patients, due to minor benefit above placebo. Most frequently use it as part of LDL-lowering strategy, especially in statin-intolerant patients. I am supportive of patients who wish to try it.

Panelist 7: Most people do not want to use this medication when compared to others simple based on side effects. Many realize that if they don't take it, they won't have the treatment effects. So, they use it when it's most convenient. The addition of Alli to the market has not changed my prescribing habits for xenical.

Panelist 8: Only few of my patients used alli. The effect in the regular dose doesen´t seem to be strong. I did not see any side effects. It has not impacted my use of Xenical to my knowlege.

Marketing medications to treat obesity

What do you think about the marketing plan used by GlaxoSmithKline for alli? Was it effective? What can be learned from this product launch that should be applied to other medications approved for the treatment of obesity, both prescription and OTC?

Panelist 5: did not pay much attention to the marketing plan of gsk. not a big fan of this for the treatment of obesity.

Panelist 4: I would say the marketing plan has been successful given the sales numbers relative to other weight loss medications. I think it is true that consumers drive prescriptions.

Panelist 7: I think it was smart because it gives the consumer a "program" not just a pill. Most physicians don't have the skills or time to do weight management. It's more than prescription writing.

Panelist 8: The marketing plan must be successful, since the sales were relative high compared to other weight loss medications despite the fact that this medication is not really effective!

Panelist 2: As far as I know, it is commercially successful. I'm skeptical that it will provide long-term benefit beyond a small percentage of consumers. I am surprised that it has not been marketed more effectively to hypercholesterolemic patients with statin-intolerance.

alli™ and hyperlipidemia

Panelist 2 stated: ” I am surprised that it [alli™] has not been marketed more effectively to hypercholesterolemic patients with statin-intolerance.” What do you think about this comment? Do you use alli in this way? What changes have you seen in the lipid profiles of hypercholesterolemic patients who use alli? Should the marketing of the drug target this population? Please explain your reasoning behind your answer.

Panelist 1: I have not used ALLI or orlistat in this way although this is a good thought

Panelist 5: am not aware of how effective it would be in statin intolerant patients. is it effective?

Panelist 6: I have not used it for that population. The changes in cholesterol seen in reported studies mainly contributed by the intensive dietary therapy that was implemented during those trials. THe placebo group lost >6% of body weight. In the real world, I believe that people would try ALli for a few months and noted that it's not a miracle pill. They would then move on to find another one.

Panelist 8: I did not use it for such an indication and I don´t know about data showing weightreduction-independent effects on Hypercholesterinemia. Statin therapy is not only effective through a reduction of cholesterin, it also has CV protective effects.

Panelist 2: It is known to low LDL independently of weight loss.

Panelist 4: Effects of orlistat on lipids have been studied previously. The primary effects are to reduce triglycerides and raise HDL. Modest lowering of LDL cholesterol has been seen in some studies but not consistently. One would guess that this effect would be reduced on the OTC dose. There are other products such as plant sterols, zetia, bile acid binding resins that would be more mainstream if someone had statin intolerance.

Panelist 7: I have not used alli in this way; most people I've seen have not been convinced that the "treatment effects" are worth the weight loss achieved.

Panelist 6: Marketing by GSK was great. I saw all those ads in Magazines and that account for the great initial success of launch of Alli. But just like all other products. People will try it a couple of times and found that it's not a miracle and will stop using it after a while.

Panelist 1: GSK used a plan similar to their successful plan for OTC switch for nicotine patch The ALLI plan was also successful so far. It is a good plan for any weight loss drug - to promote the idea that there is no magic pill and that diet and exercise are key

Please review this abstract about pramlintide  (Appendix A)

Q3. Symlin® (pramlintide)

Please review the attached NAASO 2007 abstract about pramlintide. What do you think about the results of the study? Based on this information and your experience, please comment on the use of pramlintide for weight loss and weight maintenance in patients with and without diabetes.

Panelist 1: This drug should be used for obesity good weight loss results side effects are managable

Panelist 6: Good results. 360 mcg BID resulted in a 8 kg weight reduction around 7%. Results are comparable to rimonabant and meridia. Better than Orlistat.

Panelist 5: drop out rate is quite high despite being less than placebo. results of primary endpoint of weight loss do not appear to be given suggesting marginal effectiveness. at best there may be small groups who respond to pramlintide therapy.

Panelist 4: The results are encouraging. The drop out rate is a bit lower than often occurs in weight loss studies. However, the utility of defining responders versus non responders is not ideal. People (and their treating physicians) will need to know what their chance of losing weight overall is, not just in the "responders". The use for weight loss is promising, but we need more long term data published. Cost and administration remain barriers.

Panelist 7: I think the evidence is supportive of further investigation. The potential for pramlintide is that it promotes longer term weight reduction, even past the point when mose weight loss intervention reach a plateau. In my opinion, I think this is because the caloric restriction that occurs as a result of early satiety is modest, but sustainable. This is the type of research that needs to be done though. I have not used it in non-diabetics because exenatide is easier to use.

Panelist 2: Not enough data here to draw conclusion, but it appears that the effectiveness of pramlintide plus lifestyle modifications, in a subset of patients, warrants it's ongoing investigation. Likely to be a useful tool in (to be defined) clinical centers of excellence.

Panelist 8: This drug seems to be effective in treating obesity, the weight loss results are impressive and longlasting. The side effects are managable

Symlin® use now?

Based on the data presented in the abstract about Symlin, and your knowledge of the medication as a treatment for obesity, would you consider using the drug at this point? Please explain why or why not. If so, please describe the patients for whom you think this treatment would be appropriate. Would you use it in patients without diabetes?

Panelist 5: recent jcem paper using high dose pramlinitide showed some success (30% of test patients lost >5% BW), hoever placebo group receiving multiple injections showed very little weight loss making data difficult to be sure of. Cost of the amount used (240 ug) is hundreds per month. Would thus not use as a primary agent for obesity.

Panelist 4: The data is encouraging, however given past experiences I think it is risky to prescribe a medication off label without a substantial worldwide clinical experience. In addition the cost/insurance issues will be an issue for many.

Panelist 7: I would use it at this point, but because of cost and administration issues, in a limited set of patients.

Panelist 8: The data is encouraging. However, I think also that it is risky to prescribe a medication off label without a substantial worldwide clinical experience. There is need for more studies.

Panelist 2: Would consider an off-label trial in a highly motivated patient as an alternative to weight-loss surgery: the mortality/morbidity risk would (hopefully) be lower than any WLS. Subsequently, would reassess if weight-loss was not satisfactory within the first 3-6 months.

Panelist 6: Data presented are good. But considering the cost and effectiveness, it would not be my first line of treatment.

Panelist 1: Even though the data looks very good, it is not feasible to use Symlin now for obesity - too expensive

Panelist 7: Would only use for those with the means to administer and purchase the medication (ie, very few).

Please review this abstract about topiramate and phentermine  (Appendix B)

Please review the document in the new window. If you do not see the window, it may be open and hidden behind other windows, or you may need to click on the highlighted link in the left pane of this window.

Q4. Topiramate and phentermine

Please review the attached NAASO 2007 abstract about topiramate and phentermine as combination therapy. What do you think about the results of the study? Have you used these medications in combination in your clinical practice? If so, has your clinical experience matched the outcomes of this study? How promising is this combination therapy?

Panelist 1: Phentermine alone produces good results for weight loss even without Topiramate Topamax is not for everyone some patients really have some nasty side effects

Panelist 6: I need to know what dosage of phentermine and topamax that was used in the experiment. The results were great. In the original Duke's study, phentermine was 15 mg and forgot about the Topamax dosage, (probably around 100 mg). The idea of using combination is to avoid side effects of both medicine and to achieve synergistic effect. I do see many patients experiences adverse side effects when I use more than 200 mg of topirimate.

Panelist 5: side effect profile could worsen with longer treatment but combination therapy worked well. pheneramine alone also worked well. combination therapy could improve outcome. longer study clearly needed.

Panelist 4: This is the most impressive data of the group. Combination therapy is clearly the most likely to produce the kind of weight loss that patients and physicians are looking for, and this group is to be commended for pushing research forward on this. However, safety concerns with the combination will need to be addressed with large long term trials if this combination is going to be viable. I would not prescribe this combination without more safety data.

Panelist 7: This study suggests that the phentermine combined with the topiramate somehow counteracts negative effects of the topiramate. The fact that those on topiramate lost more weight, but did not have greater changes in QOL suggests that the QOL changes are more directly affected by the medication than the weight change. This is interesting, because the IWQOL is very specific for weight related effects on QOL. I have not used this combination in practice.

Panelist 2: Results are superior to currently available long-term obesity pharmacotherapy, but not dramatic. Compared to the risks and benefits of bariatric surgery, it seems likely to be an acceptable therapy(pending large, controlled, clinical trial data).

Panelist 8: Nice study with impressive results. However, I am concerned about the safety aspect especially for Topiramate!

Qnexa™

VIVUS, Inc. is studying Qnexa, a drug containing a combination of low-dose phentermine and topiramate, as a treatment for obesity. In consideration of the prior topiramate + phentermine data, and given that both medications are FDA-approved individually for different indications, what do you think the FDA approval process for this medication will be like? Do you anticipate any obstacles to FDA approval, and if so, what are they?

Panelist 5: safety data here is key. FDA will look at this very critically. even if this were approved many would wait before using until post-approval studies were complete

Panelist 4: This was the most encouraging drug data at the meeting. I suspect the FDA will be very wary about approving a combination medication without a good deal of long term data from large trials. However, this combination looks the closest to being a winner. The neuro side effects from the topiramate looks like the biggest hurdle.

Panelist 7: The safety profile will have to be clearly demonstrated. The fact that they have been approved for other uses won't lower the bar when combined for the purposes of weight loss.

Panelist 8: Again, I am concerned about the safty profile. I think that the key for FDA accreditation is undergoing of trials with longterm data about safety. The weight loss data are clear.

Panelist 2: I think the regulatory environment for medications has become challenging. It would be wise and useful to offer pharmaceutical options indicated for the the same BMI as bariatric surgery. It would also be useful, independently of FDA, to create a Centers of Excellence program for medical bariatrics. The non-surgical options for morbidly obese patients will continue to be minimal until more research is accomplished and clinical tools are developed.

Panelist 1: I am skeptical about this study - one center, homogenous population Also phentermine works well alone Topiramate was dropped by Johnson and Johnson for obesity for a good reason - if you do not need it for seizures and psychosis it is a bad drug due to side effects I think FDA will really come down hard for safety data on the combo

Please review this abstract about zonisamide and bupropion  (Appendix C)

Q5. Zonisamide and bupropion

Please review the attached NAASO 2007 abstract about the combination sustained release product of zonisamide and bupropion. What do you think about the results of the study? Have you used these medications in combination in your clinical practice? If so, has your clinical experience matched the outcomes of this study? How promising is zonisamide and bupropion as a combination treatment of obesity?

Panelist 1: My expericence is not the same as the good results seen in this study however I feel that the combo might have a place in our armamentarium

Panelist 6: Don't have much experience using this combination. But the 8% weight loss is god.

Panelist 5: this combination therapy which targets the hypothalamus appears to offer significant benefit in a short study. drop out rate was relatively low. this dual target approach has an increased biologic chance of success and appears to work clinically. longer term studies are needed.

Panelist 4: The data at the higher dose looks impressive, but it is hard to reconcile with the 5% and 10% loss numbers which look comparable to existing medications. Clearly there is a threshold that a weight loss medication needs to cross before it is widely used, this threshold may be between 10 and 15% weight loss. I certainly have seen wellbutrin produce modest weight loss in some patients, I do not prescribe zonisamide currently for weight loss either alone or in combination.

Panelist 7: This combination sounds promising. I have not used it in treatment; however, the rate of attrition due to side effects is fairly high. It would be of interest to know if the side effects are occuring in a dose dependent way.

Panelist 2: Looks like another useful pharmacologic tool, needing long term safety and effecacity data. Would like to see parallel mono-drug arms (for at least 3 month duration) in a trial as well.

Panelist 8: This combination therapy seems to be effective targeting the hypothalamus.I don´t have experience with such a therapy. What about the safty aspect?

Empatic™

Orexigen Therapeutics, Inc. is studying Empatic (formerly Excalia™) which is a combination of bupropion and zonisamide. In consideration of the prior zonisamide + bupropion data, and given that both medications are FDA-approved individually for different indications, what do you think the FDA approval process for this medication will be like? Do you anticipate any obstacles to FDA approval, and if so, what are they?

Panelist 5: again side effects. zonisamide alone has significant neurologic side effects (drowsiness versus agitation). COmbination could alleviate side effects or make them worse. Thus safety profile will be key. As with all anti-obesity drugs bar is much higher for treatment of a chronic issue.

Panelist 6: Same as the Phentermine and topirimate combination. FDA will not approve a combination of drug for Weight Loss Indication without some serious look at the safety data. See what happen to rimonabant. It's approved in Europe and probably won't be approved here until 2010.

Panelist 4: Same concerns as with Qnexa. This combination does not look as good at this time, but side effects may be lower.

Panelist 7: The safety profile will have to be clearly demonstrated. The fact that they have been approved for other uses won't lower the bar when combined for the purposes of weight loss.

Panelist 8: Like Onexa. Again, I am concerned about the safty profile. I think that the key for FDA accreditation is undergoing of trials with longterm data about safety. The weight loss data hier should also be presented.

Panelist 2: Not as effective as Qnexa, but could be more suitable for indiduals intolerant of, or not responding to Qnexa. Otherwise, same comments as Question 4.

Panelist 1: there will be many obstacles again just as Topamax and phentermine due to the zonisamide being a drug used for other conditions that are CNS based For a drug that potentially many more people will want to use to lose weight the FDA will be more wary about safety

Please review this abstract about naltrexone and bupropion  (Appendix D)

Q6. Naltrexone and bupropion

Please review the attached NAASO 2007 abstract about naltrexone and bupropion. What do you think of the results of the study? Have you used these medications in combination in your clinical practice? If so, has your clinical experience matched the outcomes of this study? How promising is this combination therapy?

Panelist 1: I have used the combo in my practice with good results I think this is a good combo for obesity treatment

To panelist 1 and others

Panelist 1 stated: “I have used the combo in my practice with good results I think this is a good combo for obesity treatment” To all panelists: Is there something about the combination of naltrexone and bupropion that sets it apart as a treatment for obesity as compared to the other combination therapies mentioned in this discussion (phentermine + topiramate; zonisamide + bupropion)? Why might it be a good combination for obesity treatment? To panelist 1: Please describe your experience using this combination in clinical practice. How have patients responded to the treatment? Have they had side effects? Did you use it in patients who were on opiate therapy? If so, how did these patients respond to therapy, both in terms of weight loss and pain management?

Panelist 5: these combinations have targeted the arcuate nucleus in the hypothalamus and potentially the side effect profile will be less than than phentermine combos. Psychiatric side effects again will be of interest.

Panelist 4: One would wonder about separate effects on rewarding aspects of food combined with appetite per se as the potential advantage of the combination.

Panelist 7: The interaction with the reward system is probably the key here.

Panelist 8: I wonder about separate effects on rewarding system? I don´t know any data about comb. therapy!

Panelist 2: Naltrexone, with a unique mechanism of action, is worth pursuing as a pharmacologic tool. Would want research to look for predictors of appropriate patient subpopulations.

Panelist 1: Here I think the naltrexone may be targeting reward pathway If there is any addictive behavior - it may affect that in certain patients

Panelist 6: Interesting results. I wonder what would happen to those who are have opiate dependence like many of obese patients will because of low back pain, knee pain etc.

Panelist 5: again, targeted combination therapy appears to b effective with 10% wt loss in a short study. side effects appear few. longer term study is needed but combination therpay targeting the hypothalamus looks potentially promising.

Panelist 4: Here again a wt loss of 10% would be impressive, but the data suggest a high drop out rate (not described). The ITT data is no better than existing compounds and the combination will likely face challenges with the FDA. I do not have experience prescribing this combination.

Panelist 7: I have not used this combination, but I can see where it might be particularly useful for those that have food addiction tendencies.

Panelist 2: I have not used naltrexone till now. Based on this data, it seems worth further study. Need to see more data on the "not serious" side effects that led to such an apparently high proportion on non-completers.

Panelist 8: The results are good. The safty aspect should further be studied (I can not believe that there were no side effects?). I do not have experience prescribing this combination.

Contrave™

Orexigen Therapeutics, Inc. is studying Contrave which is a combination of naltrexone and bupropion. In consideration of the prior naltrexone + bupropion data, and given that both medications are FDA-approved individually for different indications, what do you think the FDA approval process for this medication will be like? Do you anticipate any obstacles to FDA approval, and if so, what are they?

Panelist 5: again safety data especially psychiatric side effects. this is the biggest problem with Orexigen combo therapies. however I like this better than topiramate and phentermine.

Panelist 4: Same as the comments for Qnexa.

Panelist 7: The safety profile will have to be clearly demonstrated. The fact that they have been approved for other uses won't lower the bar when combined for the purposes of weight loss.

Panelist 8: Again safety data are essential

Panelist 2: Same reply as for Qnexa.

Panelist 6: I think this combination would be even more difficult to approve that the previous two combination. Naltrexone's weight loss effect may be dose dependent. I am worried about the side effects about this combination.

Panelist 1: FDA approval again will be focused on safety since efficacy seems to be there

Please review this abstract about taranabant  (Appendix E)

Q7. Taranabant

Please review the attached NAASO 2007 abstract about taranabant. What do you think of the results of the study? What do you think is the future of this medication? In light of the situation surrounding rimonabant, what will the studies of taranabant need to show?

Panelist 1: good drug for obesity needs to be seen in depressed patients however same mechanism of action as rimonabant so same side effects will occur

Panelist 6: THis is more or less a "ME too" drug with Rimonabant. 6 mg of Taranabant seems to be slightly less effective than the 20 mg of Rimonabant. I think the company should move forward with this drug since US FDA has not approved Rimonabant bacause of potential psychiatric side effects.

Panelist 5: in 12 weeks wt loss was approx 6% in the high dose range with an apparent 13% increase over placebo in psychiatric side effects. this will have to be further examined given the problems with the cb1r antagonist class.

Panelist 4: Looks like weight loss comparable to rimonabant and existing drugs. The recent review of data by the FDA on rimonabant raises questions about psychiatric side effects for this whole class. Large long term studies will be needed for this concern, Merck has been slow to release data on this compound so it is not clear yet how it will compare.

Panelist 7: The results are reasonable. The bar will be high regarding safety for other medications that have a similar mechanism of action as rimonabant. If it has a great safety profile, it could do well.

Panelist 2: Well designed trial. Similar to rimonabant- how will FDA embrace this one? Perhaps a model for monitoring the patients on CB-1 agents for clinically significant psychiatric adversity will need to be designed and tested before this gets through. I'd be cautious with use in adolescents.

Panelist 8: This is a good drug for obesity. I have good experience with Rimonabant. Must show to be safer than Rimonabant concerning the incidence of depression.

Rimonabant

What has been happening with rimonabant since its approval was denied by the FDA? Do you think there is any hope for this drug? In your answer, please do not comment on experiences or observations derived from ongoing clinical trials.

Panelist 5: More safety data-central side effects depression etx. Not sure of the success of the drug in Europe where it is approved. I think there is little hope for this drug until there is a better understanding of the safety profile. If psychiatric side effects continue to be an issue then i believe there will be little hope.

Panelist 4: The company appears to be "full speed ahead". The investment by Sanofi in this compound is surprising given the relatively negative reception by the FDA. But, it is a crowded class and they may not want to lose momentum.

Panelist 7: Haven't followed it closely

Panelist 8: The drug is approved in Europe..we have gut experience with it

Panelist 2: Don't have much inside info. Would be interested in seeing a multi-drug trial with/without an appropriate antidepressant, such as buproprion.

Panelist 6: FDA again is very conservative about dealing with a weight loss drugs now. Have seen patients use it. Bought it from the internet. It does make you feel down initially according to my patients.

Panelist 1: The trials are still in the process of being approved by IRBs etc There is at least 5 years of data to collect in order to be eligible to go before the FDA in the US

Experience with rimonabant

For those of you who have treated patients who have taken rimonabant, please describe in detail their experience with it. What type of weight loss did patients achieve with the drug? What type of side effects did they have? For ALL panelists: Do you think the benefits of this medication outweigh the risks? Should efforts continue for this drug to receive FDA approval? Is there a subset of patients who might experience a greater benefit from this drug, and if so, who are they?

Panelist 1: I do not use rimonabant but I do think the benefits outweigh the risks as long as we develop a new system to separate those with uncomplicated overweight and obesity such that only those with obesity and complications receive such as drug. The subset of patients who would experience benefit from the drug and not the side effect of depression and anxiety we would have to define

Panelist 5: have not used rimonobant. while it is easy in a clinical trial setting to effectively exclude those who would be prone from side-effects it is much more difficult once the medication is approved. while there are those that will benefit unclear if the side-effects will allow widespread acceptance and use of this drug.

Panelist 6: I have several patients who purchased rimonabant in Europe. No great significant weight loss. But they do seem to feel more tired, fatique in the first months of taking it.

Panelist 8: I have a lot of patients who had rimonabant in Europe. Wonderful longterm weight loss results up to 10%. But some of them become depressive.

Panelist 2: I have not participated in rimonabant trials. My feeling is that it would be a valuable tool but our it should be used as part of a mult-disciplinary program with safeguards. Some sort of standard monitoring of side effects, including dysphoria should be built-in. Unfortunately, weight-loss meds tend to be used independently of other measures known to be important for weight-loss/maintenance. There should be a medical center-of-excellence certification, in parallel with the surgical coe program. Then the use of meds could be regulated by third party reimbursement policies.

Panelist 4: I have not been part of RIO trials and have not seen patients who have gotten the medication overseas. It seems like the studies need to be done to see if the risk of serious depression related AEs such as suicidal ideation can be minimized by excluding subjects with a history of previous bouts of depression.

Panelist 7: I think if screening criteria were available to help identify people who have the highest risk of adverse events, this medication could be approved.

Please review this press release about S-2367  (Appendix F)

Please review this abstract about S-2367  (Appendix G)

Q8. S-2367

Please review this press release and NAASO 2007 abstract about Shinogi’s drug S-2367, a neuropeptide-Y Y5 receptor antagonist. What do you think about this drug in terms of both its mechanism and efficacy? How significant is the adverse event of hemolysis that was described in the abstract? Should the drug proceed to phase 3 studies? Please explain why or why not.

Panelist 1: Unfortuately despite the efficacy of the drug hemolysis is a potentially deleterious side effect and I do not have high hopes for NPY antag

Panelist 6: Am I missing something? They did not report the weight changes! The mechanism of action is unique. Without knowing the efficacy, there are some safety concerns. I'll give it a thumb down. Public these days are very worried about adverse side effects especially when it was publicized by the news media.

Panelist 5: did not see the weight loss in the POC study or the OLE extension. there are hematligic side effects. not to high on this drug given that there are other NPY recetor isoforms that play a role in body weight regulation.

Panelist 4: This is the weakest of the group. The drop out rate was quite high even for a weight loss trial. The weight loss itself was quite minimal. Merck had an NPY antagonist that was withdrawn from trials because of lack of efficacy. 5% is the minimum benchmark and this drug does not look to cross that mark. This is a bigger concern than the hemolysis, if efficacy is too low there is no product.

Panelist 7: The results are not very impressive. If you consider, the group in the delayed weight reduction arm lost about 3.1 kg in 4 weeks with the fixed LCD while the immediate weight reduction group lost 3.6 kg in 12 weeks with medication. The hematologic effects sound concerning. I would want more safety information regarding mechanism of the hemolysis before determining if proceeding to phase 3 is appropriate.

Panelist 2: As mentioned by the previous panelists, high rate of adverse effects and drop outs. Next please.

Panelist 8: First, the WL findings were not unique as compared to other available medications. The hemolysis is a potentially deleterious side effect. Although the mechanism is very interesting, I do not thing that NPY-Antag. will take place in the obesity treatment without adequate safty studies.

Q9. Potential treatments?

There were a few peptides and drugs in early stages of development that were presented at the 2007 NAASO – The Obesity Society annual meeting including: • AM4112, a neutral CB1 receptor antagonist • GII81771X, a selective CCK-A agonist • Capsinoids, transient receptor potential vanilloid 1 agonists • Trodusquenime (MSI-1436), a protein tyrosine phosphatase 1B inhibitor • QRFP, an orexigenic peptide • AMP-12279, a combination of two molecules that regulates CB1 and other CNS and peripheral targets Which two of these do you think shows the most promise as a potential treatment of obesity? What is it that makes you think so – their mechanisms? Anything else?

Panelist 1: NOt really excited about any of these I am more excited about treatments that include Leptin as an agent that will keep weight off Pram-leptin-PYY for example

Panelist 6: Guts are slave to the brain. So I believe that compounds that alter CNS, e.g. orexigenic peptide, CB1 and other agents will most likely work better that the gut hormones modulator.

Panelist 5: PTP1B inhibitor would be my first choice in this group. I am not a big fan of CB!R antagonists. Glaxo study of CCK agonists have shown no effects. Studies on vanilloid receptor seem beneficial in mice, not sure about safety profile in humans. in summary, PTP1B and potentially the nove anorexic ppeptide.

Panelist 7: I think the peripherally acting peptides hold a lot of promise as you are less likely to experience CNS side effects and lower chances for interactions if you do need combination therapy.

Panelist 2: I am familiarizing myself with some of these next week. I believe the AMP-12279 has the most upside in weight-loss potential.

Panelist 8: I believe in the role of gut in modulating the brain affected energy expenditure.The peripherally acting peptides hold therefore a lot of promise as you are less likely to experience CNS side effects and lower chances for interactions if you do need combination therapy.

Potential treatments again

Please reconsider the same list of potential treatments for obesity: • AM4112, a neutral CB1 receptor antagonist • GII81771X, a selective CCK-A agonist • Capsinoids, transient receptor potential vanilloid 1 agonists • Trodusquenime (MSI-1436), a protein tyrosine phosphatase 1B inhibitor • QRFP, an orexigenic peptide • AMP-12279, a combination of two molecules that regulates CB1 and other CNS and peripheral targets Did you learn anything at this year’s NAASO meeting that would make you change your mind about the potential of any of these agents? If so, please discuss what it was and how it impacted your impression of the agent.

Panelist 5: views have not changed since my previous post.

Panelist 4: I think that the ultimate success of an agent will not be known untill moderate sized human randomized trials are done. I suspect the first successful therapy will be a combination of existing compounds where there is already some information in humans. examples were sibutramine plus rimonabant, exenatide plus wellbutrin etc. combining symlin or exenatide with exisiting marketed compounds that have safety data in humans and some weight loss effects would seem like a useful next move.

Panelist 7: I did not see anything that changed my views.

Panelist 8: I did not change my views.

Panelist 2: Found no info to modify views at NAASO 2007.

Panelist 1: I did not change my views am still excited about Leptin pram and PYY combo

Leptin?

Panelist 1 expressed interest in treatments involving leptin. What is the status of leptin as a treatment for obesity? Is it being studied as monotherapy or in combination? Are you hopeful for this medication? Please explain your reasoning behind your answer. In your answer, please do not comment on experiences or observations derived from ongoing clinical trials.

Panelist 5: Because of leptin resistance in the vast majority of obese patients monotherapy with leptin has generally not worked. However, there could be a subset of obese patients (who are not ob humans) with normal leptin levels who could respond. based on insulin resistance, there is ongoing work looking at the addition of other therapies in combination with leptin that could lessen leptin resistance. there is significant research in the understanding of leptin resistance going on around the country.

Panelist 4: It certainly would seem to be conceptually useful as part of a combination. However, the weakness is the lack of clinical experience in a large number of humans, something exenatide, symlin, topiramate, sibutramine, xenical, phentermine, wellbutrin, rimonabant have.

Panelist 7: I have little hope that leptin will be a significant treatment for the common obesity profile.

Panelist 8: The problem is that the majority of obese patients demonstrate leptin resistance (like in DM and IR, they have higher levels of leptin). However, obese patients without leptin resistance would benifit in my opinion. A comb. therapy with drugs that are able to lower leptin resistance is the key for success hier.

Panelist 2: Usefulness seems to be more as a plateau-sustainer/enhancer. Ultimately, or oral Leptin agonist would be more likely to be acceptable.

Panelist 6: Leptin will never made it until they have an oral form. When I tested it many years ago, it is a subcutaneous injection and it has many cutaneous side effects.

Panelist 1: leptin will not be used alone for generic obesity but I see it as a drug for weight maintenance

Leptin for weight maintenance

Panelists 1 and 2 suggest that leptin might be more effective for weight maintenance rather than weight loss. Why is this the case? How might this theory impact the development of the drug? Panelist 1 had also mentioned the combination therapy of pram-leptin-PYY. Without commenting on experiences or observations derived from ongoing clinical trials, please describe the status of research on leptin used as weight maintenance either in this combination or in a different formulation.

Panelist 1: As patients lose weight, the secretion of leptin from the adipose cell decreases and thus the theory would be to restore the leptin level by giving leptin for weight maintenance since many researchers feel that the reason weight gain is almost a given is that eventually through appetite and decrease in RMR patients who lose weight gain it back The data for weight maintenance for leptin combinations is not available or hasn't been gathered yet as far as I can tell

Panelist 5: for weight maintenance leptin could work if leptin levles are lowered with weight loss and resistance is diminished. still remains to be seen if it would work in this situation. ideal combination for leptin would be combination with another drug that would lower cellular resistance. Many combinations are being tried. No ideal molecule identified that lowers leptin reisistance.

Panelist 6: Talk about weight maintenance, obese patients will never happy about there weight no matter how successful they are. They always want to lose more. For example if a woman lose 50 lbs and currently weighed 180lbs, they want to lose 30 lbs!! Obese patients therefore will spend their whole life trying to lose weight to a goal that would never be achievable. The bad part from my experience is that you cannot convince them that they should try to go on to weight maintenance.

Panelist 8: I don´t know any data about leptin therapy for weight maintenance?? The idea is nice

Panelist 2: Leptin levels decline with weight-loss, even in Leptin-resistent individuals. In theory, Leptin could be used to offset hunger and decline in energy expenditure at plateau.

Panelist 4: The hypothesized mechanism has been described by others: that the fall in leptin associated with weight loss may predispose to weight regain, and that by giving leptin this might be minimized. I think that Amgen started a weight maintenance study with leptin before it was sold to Amylin, but I am not sure. If they did, and didn't publish it, makes you think it didn't work very well.

Panelist 7: Theoretically, it sounds good, just as leptin for weight loss. However, I have doubts that leptin replacement at any phase will ever be effective (particularly as a solo treatment modality).

Panelist 4: I think it is just too early to say.

Q10. Compelling information

What do you expect to be the most compelling information being presented at the 2007 NAASO – The Obesity Society annual meeting? Please explain why you think it is so interesting and important.

Panelist 1: The most compelling info will be on regulatio of adipose cell metabolism cytokine release, lipolysis etc This is how the fat cell stores fat instead of burning it Potential for future drugs is high

Panelist 5: mechanisms by which the brain controls blood glucose independently of body weight. novel pathways that regulate body weight. mechanisms by which diets influence physiolgy.

Panelist 6: More information on the energy balance equation. For calorie in = regulation of appeitite, hunger and satiety. For metabolism, more information on regulation of lipolysis.

Panelist 7: Long term weight loss maintenance strategies and studies of diet composition that promote long-term adherence.

Panelist 2: So many fields are active, it's hard to generalize. I am looking forward to hearing about how the clinical infrastructure is advancing to combine behavior, meds and the surgical options for individualized, long-term safety and increasing efficacity in parallel with drug development.

Panelist 8: The most compelling info that will be presented is: obesity is the biggest challenge facing us..we need to understand the mechanisms underlying the increasing shift in energy regulation towerds higher assumption, the adipose cell metabolism and the gut-brain axis in order to finde an effecive treatment. Potential for future drugs is high

Future drugs

One of the themes within the panelists’ answers was an interest in learning more about the mechanisms about body weight regulation including the gut-brain axis and adipose cell metabolism. Please share your thoughts regarding how a better understanding of these physiologic mechanisms, or others not mentioned, might help drive the development of future pharmacotherapies to treat obesity.

Panelist 5: Identification of new pathways that allow the periphery (ie gut and or adipocyte) to signal to the hypothalamus could allow for the identification of new targets for obesity therapy. Similarly, modulation of adipocyte function could influence adipokine production and improve weight loss and impact incidence o diabetes. it is also becoming increasingly clear that they hypothalamic centers that regulate body weight also regulate blood glucose levels. Thus, new target identification could allow for new therapies for both obesity and diabetes.

Panelist 7: to be successful in pharmacologically controlling body weight, there will likely need to be action at multiple sites, centrally and peripherally. Understanding the interplay for synergy and coverage of redundant systems will be key for limiting side effects and maximizing weight loss-- the holy grail.

Panelist 8: Identification of new pathways that allow the development of drugs with dual effects (the periphery: gut and or adipocyte and the hypothalamus) with lower side effects profile and longstanding effects on weight

Panelist 2: Ultimately need to find combinations that safely break through the current meds which don't commonly get beyond a total 10-15% weight loss (including placebo and lifestyle program effectiveness). The key breakthroughs would be to match Bariatric surgery which can usually get a weight loss of 25-45%, possibly to identify a master regulatory site that gets beyond the redundent pathways that require combination treatments.

Panelist 1: we need to study bariatric surgery carefully and try to mimic the kind of weight loss you see with surgery in medication Gut hormones, brain gut axis

Panelist 4: I was struck by the growing gap between the stratospheric basic science and the clinical interventions. It is almost like the basic scientists and the clinical science people are on different planets. There needs to be better real "translation".

Panelist 6: What do you think? Obesity is a complicated disease while most scientists spend their whole life studying one hormone and one genetic defects. It's like 6 blinds touching an elephant!!

Drug development

In the answers to this question, many panelists comment on the need to develop pharmacotherapy that working at both central (CNS/hypothalamus) and peripheral (gut, adipocyte) targets. Yet, in the prior discussion about Qnexa™, Empatic™, and Contrave™, many panelists expressed concerns about the CNS effects of these drugs. How will researchers be able to reconcile this conflict of wanting drugs that act on the CNS but don’t cause neurologic side effects? Will it only be achieved with the discovery of new drugs? How likely do you think it will be that researchers will be able to find a drug with the right balance? Please explain your reasoning behind your answer.

Panelist 1: I think combination drugs may be the way to go here and developing drugs with a smaller side effect profile

Panelist 5: Key problem. Answer is increased specificty of targets that affect hypothalamic targets that control appeite and energy expenditure but not hedonistic or pleasurable behavior. Alternatively, controlling peripheral petides or signals that effect hypothalamic function may be preferred strategies given lack of central side effects.

Panelist 6: Just like treating hypertension where you could use a combination of diuretics, ACE inhibitors, ARB, beta-blockers, etc, obesity shall in the future be treated with a combination of medication who does not have overlapping mechanisms of action, e.g. work on CNS, on guts, on fat cells, etc.

Panelist 8: I agree with Panelist 5. Specificty of targets must be increased, and adequate safty studies must be done. Some drugs therapy controlling peripheral petides or signals may affect hypothalamic targets controlling appetite and offer, therefore, a better strategy with low central side effects.

Panelist 2: New CNS-regulatory sites are still being discovered. We still have a primitive understanding of how this all works. For the near-future, medical treatment will need to include multiple agents with additive positive effect and minimal overlap of side-effects. Ultimately, I believe that more specific regulatory mechanisms will be uncovered and an age of effective treatments with acceptable side effects will emerge. Some genetic profiling will likely be necessary to individualize treatments unless a "master switch" is eventually found.

Panelist 4: I agree, the target would ideally be quite specific, and by using combinations, the side effects of each single agent could be minimized.

Panelist 7: Primarily, if you intervene on two targets, you might be able to use lower doses of each medication, leading to a better side effect profile.

Pbo

(N=105)

Taranabant

0.5 mg

(N=106)

2 mg

(N=109)

4 mg

(N=105)

6 mg

(N=108)

Body weight (BW; kg)

-1.3 (-1.9, 0.6)

-2.8 (-3.5, -2.2)***

-3.7 (-4.3, -3.0)***

-4.2 (-4.8, -3.6)***

-5.3 (-5.9, -4.6)***

Waist circumference (WC; cm)

-2.4 (-3.6, -1.3)

-4.2 (-5.4, -3.1)*

-4.2 (-5.4, -3.0)*

-4.8 (-5.9, -3.7)**

-5.0 (-6.1, -3.9)**