Metabolic Disease Drug Development

Metabolic Disease Drug Development October 24-25, 2012; Boston, MA Full Commentary – Draft

Executive Highlights

We are excited to be brining you our full coverage of the Metabolic Disease Drug Development conference held during part of the World Series (October 25-26) in Boston, MA. MDDD was intimate, as all the presentations occurred in a single room at the Hyatt Regency. Despite its small size, the conference offered some very noteworthy learning. In particular, we learned that Pfizer has an SGLT-2 inhibitor, ertugliflozin, ready for phase 3 development. Our full reporting on this news and more is below. We have divided our full notes into three sections: 1) Drug Development and the Regulatory Process, 2) Drugs on the Market, and 3) Drugs in Development. Additionally we have highlighted our favorite five talks in blue and talks that did not appear in our daily conference reports in yellow.

  • Several presentations discussed new therapeutic targets and future approaches to treating diabetes. During a panel discussion, Dr. Steven Cohen (External Scientific Affairs, Cardiovascular- Metabolism, Daiichi Sankyo, Parsippany, NJ) noted that since therapies based on new targets will take five to ten years to reach the market, their efficacy and safety profiles need to be strong enough to compete with drugs such as DPP-4 inhibitors and GLP-1 agonists, which might be generic at that time. During the same panel discussion, Dr. Slava Gedulin, (VP, Research& Development, Lumena Pharmaceuticals) argued that the future of diabetes treatment lies with combination therapies, not monotherapy. In a thorough review, Dr. Guoqiang Jiang (Director of Knowledge Discovery, Worldwide Licensing, Merck, Whitehouse Station, NJ) named several promising drug targets that are currently being investigated: GPR119, GPR120, GPR40, SGLT-2, AMPK, and FGF21. Dr. Jiang also discussed the merits of peptide hormone (e.g., GLP-1, glucagon, GIP) combination therapies, as well as non-injectable insulins and GLP-1 agonist treatments. Both Dr. Eleftheria Maratos-Flier (Joslin Diabetes Center, Boston, MA) and Dr. Junming Yie (Senior Scientist, Metabolic Disorders, Amgen, Thousand Oaks, CA) gave presentations on the potential of FGF21 therapy to improve glucose homeostasis and promote weight loss. Preclinical studies show that mice lacking FGF21 have livers with higher fat content and that FGF21 reduces fasting blood glucose levels, improves glucose tolerance and insulin sensitivity, and ameliorates obesity.
  • A highlight of the conference was learning that Pfizer has an SGLT-2 inhibitor, ertugliflozin, (previously called PF-04971729 and of an unknown mechanism) ready for phase 3 development. Dr. Vincent Mascitti (Senior Director, Global R&D, Pfizer, New York, NY) presented data demonstrating that ertugliflozin provided good efficacy during a phase 2 trial: an average A1c reduction of 0.8% from an unknown baseline and an average weight loss of~2.5 kg [5.5 pounds; 3% of the body weight of the cohort]. Dr. Mascitti emphasized ertugliflozin’shigh selectivity and favorable safety profile as possible differentiating factors. Ertugliflozin’s development timeline puts it behind BMS/AZ’s dapagliflozin and J&J’s canagliflozin. As a reminder, BMS/AZ expect dapagliflozin to be approved by the European Commission by the end of 2012 and plans to resubmit dapagliflozin to the FDA in mid-2013; J&J filed canagliflozin in the US in May 2012 and in the EU in June 2012. Ertugliflozin also appears to be slightly behind Lilly/BI’s empagliflozin, since Pfizer stated that ertugliflozin is ready to begin phase 3 development while Lilly/BI is on track to complete initial phase 3 studies of empagliflozin by the end of 2012.
  • The conference featured notable commentary on the obesity market and on potential new anti-obesity drugs. During a thought-provoking panel discussion on the desired risk:benefit profile of metabolic drugs, Dr. Steven Smith (Sanford-Burnham Institute, Orlando, FL) explained that current and past anti-obesity drugs haven’t been efficacious enough to produce substantial improvements or reductions in healthcare utilization or dollars spent on drugs. Similarly, Dr. Steven Russell (Massachusetts General Hospital, Boston, MA) stated that currently, he is only seeing the needed weight loss from bariatric surgery. One pharmacotherapy that could potentially produce greater weight loss is Zafgen’s obesity medication, the MetAP2 inhibitor beloranib. During his presentation, Dr. Tom Hughes (CEO, Zafgen, Cambridge, MA) stated that Zafgen looks for the drug to produce a weight loss of at least 20%, making it competitive with lap banding.
  • The conference included three presentations during focused on incretin therapies, specifically Sanofi/Zealand Pharma’s once-daily GLP-1 agonist lixisenatide (Lyxumia) and Lilly/BI’s DPP-4 inhibitor linagliptin (Tradjenta). Dr. Riccardo Perfetti (VP, Global Medical Affairs, Diabetes, Sanofi, Paris, France) highlighted the need for better mealtime glucose control, noting that roughly half of the eight million insulin users do not meet the A1c target of 7%, despite having well-controlled fasting glucose levels. He discussed the merits of using lixisenatide as an alternative to mealtime insulin, citing evidence from three phase 3 studies investigating lixisenatide as an adjunct to insulin glargine. Dr. Michael Mark (VP, Cardiometabolic Disease Research, BI, Ingelheim am Rhein, Germany) then detailed how linagliptin differs from other DPP-4 inhibitors, emphasizing that linagliptin is the only xanthine-based DPP-4 inhibitor, that it is more potent than its competitors, and that it is the only DPP-4 inhibitor that does not require dose adjustments in patients with renal impairment. Dr. Mark also noted that linagliptin may provide cardioprotection, perhaps due to its action on several substrates. Furthermore, in his presentation, Dr. Leo Seman (US Medical Director Metabolism, BI, Ingelheim, Germany) discussed a 52-week study that demonstrated that linagliptin is safe and efficacious in people with severe renal impairment.
  • MDDD featured many informative presentations, including two notable panel discussions; throughout the report, we have highlighted our favorite five talks in light blue. One panel discussion included expert speakers Dr. Steven Russell (Massachusetts General Hospital, Boston, MA) and Dr. Steven Smith (Sanford-Burnham Institute, Orlando, FL), who highlighted the need for more effective weight loss and diabetes drugs. In the second panel discussion on promising drug targets for diabetes and/or obesity, Dr. Richard Pittner (Head of Cardiovascular & Metabolic External Innovation, Pfizer, New York, NY) shared his perspective on balancing convenience and efficacy, which he gained while working on the development of Byetta at Amylin. Arguably the most notable talk was Dr. Vincent Mascitti’s (Senior Director, Global R&D, Pfizer, New York, NY) presentation in which he revealed that Pfizer has an SGLT-2 inhibitor (ertugliflozin) ready for phase 3 development. In addition, Merck’s Dr. Guoqiang Jiang (Director of Knowledge Discovery, Merck, Whitehouse Station, NJ) gave a thorough and interesting review of the various possible new target classes and the companies that are developing candidates within each class. On the obesity front, Dr. Steven Smith (Sanford- Burnham Institute, Orlando, FL) provided thought-provoking opinions on obesity medications, the current regulatory environment, and study design.


Table of Contents 


Drug Development and the Regulatory Process

Clinical Strategies to Speed Passage to Market


Steven Russell, MD, PhD (Massachusetts General Hospital, Boston, MA); Shakun Karki, PhD (Boston University School of Medicine, Boston, MA); and Steven Smith, MD (Sanford- Burnham Institute, Orlando, FL)

Dr. Russell: I’m a clinical endocrinologist that focuses on diabetes. I’m working on the artificial pancreas automated insulin/glucose delivery – and not so much on drug development for type 2 diabetesDr. Smith: I work at the Florida Hospital Translational Research Institute. I’m a clinical endocrinologist that focuses primarily on obesity work, and I have stayed in tune with the regulatory environment through work with lorcaserin’s phase 3 program and as president elect of The Obesity Society.

Dr. Karki: I primarily work with an obese and morbidly obese population who want to go through bariatric surgery. In one study we are performing, we have followed members of this population for 12 months so we collect samples at baseline, and we are publishing data from that at the moment.

Dr. Russell: I am a little bit of a skeptic about new drugs; that might have something to do with my training – I did my training with Dr. David Nathan (Mass General), and I have heard his name cursed in some corners by people trying to develop new drugs in this space. But his point is that a lot of new drugs that have come out in this space are weak in lowering A1c. I think we only have two fantastic drugs in this space: metformin and insulin. I realize that that is a tall wall to climb, and they certainly have their disadvantages; insulin is associated with weight gain (editor’s note – also hypoglycemia) and metformin cannot be used in all patients (editor’s note – Dr. Eric Topol of Scripps suggests this is 22% of all type 2 patients). Yet, at the same time, we know we can get the A1c lowering we need from those drugs. So when a new drug comes out, we are concerned that we are going to have to use multiple drugs on top of these old ones to get the A1c we need, and we are concerned about the side effects that will result from doing so. It is interesting; in academic circles, I think we use less of the new drugs than primary care doctors and endocrinologists who work in a more clinical setting. For example, I did not have a single patient on rosiglitazone (GSK’s Avandia) when Dr. Steve Nissen’s study came out. I would like to see new drugs come out that have real efficacy, and I would like to see limited to no safety concerns, because a new drug has to pull me away from my go-to drugs, like metformin, which is associated with lower mortality risk.

Dr. Smith: Regarding obesity: essentially we have what I call “a half and a one” drug on the market because the second one hasn’t made it into prescriber’s hands yet [Dr. Smith is referring to Belviq (Arena/Eisai’s lorcaserin)]. We’re dealing with a huge treatment gap between bariatric surgery and diet plus exercise. That’s the reality that we most often see in our clinical practice. It was touched upon earlier that the risk:benefit ratio will really determine how these drugs will perform in the market, as well as their uptake by physicians (in terms of willingness to prescribe) and by payors (in terms of willingness to spend money on them). We can’t underestimate the pain and suffering that obesity patients go through independent of cardiovascular and diabetes risk. The functional capacity of obesity patients – an inability to move or walk or work or perform in society – will ultimately drive a lot of our discussion on risks and benefits, outside of the cardiovascular space. There’s evidence of an increase in the number of people willing to undergo bariatric surgery and the risk that goes along with that. That trend will continue. The epidemiology has not changed – every year, there’s a bounce in the number about obesity statistics but then the next year, they catch up. The functional aspects are important. I highlighted that the GW/FDA recommended looking at endpoints other than cardiovascular endpoints. Another big development in the field related to an assessment of functional capacity other than cardiovascular risk is the Edmonton obesity staging system. We should think about obesity in terms of cardiovascular and diabetes risk, but other facets of the obese state will also drive the risk/benefit discussion. Maybe not to an equal degree as cardiovascular risk, but they will be increasingly important to payors to make sure that we spend money to treat obesity in patients that actually need it, as opposed to people who want to look good in a bathing suit.

Dr. Karki: Coming from obesity research, I am going to have to say that I am cautiously skeptical of obesity drugs. I personally do not prescribe medicines, but I work very closely with the people who do prescribe such medicines. To explain my though process, I want to present one case: we had a morbidly obese 20-year-old female come in recently. What can you say to her? How long can she take one of these drugs for? Can she only take it for six-months? A year? Two years? The rest of her life? We do not know the long-term effect of those drugs. Changing diet and physical activity, however, is not going to be enough for fighting obesity. Bariatric surgery is on the other side, and is extreme. So what is in between? A drug would be ideal, but safety is my primary concern, and we have to look into it very closely.

Dr. Smith: I have a slightly different perspective on the risk/benefit safety issue when it comes to patients with late stage obesity and/or other clear comorbidities. There is a phrase that we use in out clinics: “not losing weight is not safe.” These are metabolic train wrecks going to metabolic and bariatric surgery, and what we don’t know is how these drugs perform in the short run to help people get off the sofa and out of their recliners and actually start moving once they achieve weight loss. Other than the Swedish Obesity Study, we don’t know about the safety of many of these surgical procedures that patients undergo. Surgery is our benchmark, not the safety of our statins. Diet and exercise don’t work for these people. They have failed multiple diets, and have tried a lot of things. There’s data that fibrosis in the hypothalamus negatively affects their metabolism. George Bray said that obesity is a chronically relapsing neurochemical disease, not a “will-power disease”. All the things we use in the clinic to motivate people don’t work. Are we going to treat them with a drug, or with surgery? Or with diets? We’re stuck in the middle of the treatment gap and we will have to do something.

Q: For those working on drugs, we would all like to come up with drugs that are effective and are safe, and do not have to be proven safe by extremely expensive and time consuming studies. The question is how do we get drugs across the threshold of having to test them in such large populations. For some reason, maybe for a good reason, the FDA has focused on cardiovascular risk, though I think thyroid risk might be more important to look at. For obesity, we have as a one-size-fits-all treatment paradigm, and though the efficacy bar has been low, the safety bar has been very high. Do you see momentum for getting drugs out there that do not require 10,000 patient studies?

Dr. Russell: There are going to be unknown risks that come out post-marketing. So the amount of efficacy has to be great enough that the provider and patient are excited enough about the drug to make the risk worth it. So if a drug is going to cause a person to lose only a few kilograms, I just can’t prescribe that, because that is only a few drops in the bucket for what patients need. I would like companies that are only going to get modest weight loss to cut their losses early in development; nip these drugs in the bud early on. It is not worth the financial risk.

Dr. Smith: The lines have been drawn in the sand for cardiovascular risk. It’s very clear that the diabetes criteria will spill into obesity – there’s no doubt about that. Regarding broader risk, managing that in the traditional fashion through the phase 3 program is certainly possible. We can be smarter about how we adjudicate cases. There’s a fair amount to clarify around that part. The question is whether there is going to be an alternative pathway for highly efficacious drugs that is independent of the “modest weight loss” pathway that is in place for the broader patient population. We’ve seen hints, although we haven’t had any clarity around the possibility that there could be alternative approaches. There have been multiple public statements. This is independent of the GWU conversation, which is mostly around adding additional biomarkers. This is a second conversation about an alternative regulatory pathway for highly effective drugs for morbidly obese patients. I think there’s more optimism about that alternative pathway compared to the GWU conversations, which would add more burden rather than less to the regulatory pathway. They may help with payors down the road, but not with the regulatory pathway. If we have additional political pressure and multiple organizations pushing on Capitol Hill, then we can see movement in that direction.

Dr. Karki: Just looking at the drugs that are out there on the market right now; Qsymia works both peripherally and centrally [on the nervous system] compared to Orlistat, which works only peripherally. Orlistat has fewer side effects than Qsymia, so it looks like a drug that works peripherally has fewer side effects and may be possible to use more long term than one that works centrally. I am not very familiar with the regulatory environment, but I think people need to think about the pathway they are targeting.

Q: One of the concerns that we have about the potential of obesity drugs with regards to taking on the diabetes model for cardiovascular assessment is that, when we think about peripheral and central mechanisms for obesity, what are the biomarkers for cardioprotection? If we’re not seeing the profound lowering of LDL that was standard ten to 15 years ago, it creates another obstacle for pursuing that indication. If we get into a space where we how have to show cardioprotection with weight loss, what are some surrogate biomarkers that could demonstrate a potential for cardioprotection outside of LDL or cholesterol?

Dr. Karki: One of the things we do frequently is flow-mediated dilation for studying cardiovascular outcomes in the long-term.

Q: I would argue that for every study that has a positive association, there’s one with a negative association with that endpoint. And the cost is prohibitive. It’s a useful tool for targets in the early clinical stage, but is it scalable to larger trials?

Dr. Smith: I am not sure if I heard your question right. My perspective, at least at this point in time, is that we are not being asked to show cardioprotection – we are being asked to show no harm.

Q: The targets we’re selecting aren’t going to be in clinical development for another five to ten years. As the regulatory environment changes, we’ll see increasing pressure to show cardioprotection not just from a regulatory perspective, but also from payors. We’ll wonder how to get reimbursements for the drugs if they can’t be differentiated, and an obvious place for differentiation is cardioprotection. It’s unclear how you get to that place without going through an enormous outcomes trial and without having a well validated surrogate.

Dr. Russell: That may be a very hard wall to climb because a recent study, not yet published, found that even when weight loss occurs, it does not result in cardioprotection. So I agree that it should be more of an issue of not having a negative signal. Under those circumstances I can’t see how they can demand cardioprotective proof.

Dr. Smith: Let me follow up more on this. There are other ways to go after payors and cost-effectiveness independent of cardiovascular risk. I think this approach is one of the roads less traveled. It’s been a little difficult right now because we haven’t had enough efficacy to see substantial improvements or reductions in healthcare utilization or dollars spent on drugs, etc. We did some analyses way back in the day on fen- phen and it showed a very nice cost effectiveness for other medication usage with fen-phen levels of efficacy – which is double digit weight loss, but not that impressive. I think we can work on the payor side independent of reducing death, and we need to work more on this. Another place is in the economic discussion around presenteeism, absenteeism, work performance, and other outcomes that need to be explored not only from a dollar and cents standard, but also because of the increasing emphasis that companies are placing on health and performance in the workplace. This needs to be further pursued. To convince payors, we need to look more broadly than just cardiovascular death and events and need to move toward other measures in the US and European workplace. I hope this helps a little bit. In the distant future we may reach a tipping point where we have to show cardioprotection from a regulatory standpoint. I hope I’m not too starry-eyed, but I don’t see that in the timeline you just alluded to. I think there are enough other benefits from weight loss that we can make the case that as long as we show no harm, we’re in the right place.

Comment: A follow up on that, the Edmonton scale publication (Editor’s note – this is the Edmonton Obesity Staging System or EOSS) that recently came out really pointed out the utility – reduction in cardiovascular risk and death –when weight loss occurs for people in the upper tier of the Edmonton scale. If you had a way to identify those upper scale patients, the cardioprotective impact of weight loss could be a lot better. If you look at registration programs that these drugs have put out so far, you see that they really lean to having lower tier patients that are not high risk for cardiovascular risk. I think that if you have the guts, you should go for it and enroll high-risk patients.

Dr. Smith: I agree with that. I believe it’s possible that you have to have a big “gut check” before writing the check. In my mind, I’m not surprised by the Look AHEAD results. This was an ivory tower academic study where everybody in the control group had thumb screws on the doses of aspirin, statins, and other medications, and the likelihood of showing benefit in this situation is different than in the real-life setting, where the effect is likely to be less. I’m on the steering committee so I can say I’m bullish about the design being used on the naltrexone/bupropion outcomes trial, which is a real life study. I believe that the application of other cardiovascular drugs and treatments is not going to approach anything near what we saw with Look AHEAD. Real life studies and people are necessary to understand the benefits for obesity drugs in people.

Dr. Russell: I would second that. Mean glucose in people with type 2 diabetes is not where we would like to see it, and we know that there are going to be complications with that. A huge benefit would be if you got enough weight loss on these medications that you improve mean glucose or reduce the amount of insulin people. In a clinical trial study, participants’ diabetes medications are very closely monitored. In the real world, however, diabetes medication management is terrible. Ideally, it would be great for studies to be able to account for the real world reality.

Dr. Smith: In the fen-phen clinic, it gave us a 12-13% weight loss over a year. Half of our patients on insulin went off insulin and half of people on oral agents went off those. I do believe that the value of good obesity drugs to other comorbidities, not just diabetes, will become increasingly apparent. If I were a betting man, in terms of payors, it’s an easier mark to go after diabetes prevention. There is some rationale for being able to do that from a cost standpoint and a payor standpoint.

Dr. Karki: We have seen similar results in the matter of six months, plus after weight loss surgery. After losing significant weight from weight loss surgery, patients reduce diabetes medications. That is one of the first things we see, and other complications with obesity then improve.

Q: In our heavily medicated society, for studies like this where you look at the ability to discontinue a medication as a benefit endpoint, in how many of the studies was the patient’s medication carefully examined upfront to determine whether the patients should have been on the medication in the first place?

Dr. Smith: That’s an easy answer: zero for the recording. It’s just not common in phase 3 programs to do that.

Dr. Rusell: How would you really know if patients needed the medication, short of withdrawing the medication and looking for an the effect? That would be a complicated trial to run.

Q: Well I think reducing medications is a pseudo-benefit; I am not sure that the benefit is actually there.

Dr. Smith: I wasn’t arguing that from a medical standpoint, I was arguing that from an economic standpoint and a payor standpoint. Whether the medications are needed or not, someone is paying for them.

Dr. Russell: From the pharmaceutical industry standpoint, you are just cannibalizing your previous medications – though many of those are off patent. [Laughter]

Comment: I don’t think anyone minds that.

Dr. Smith: The other thing – if we actually get this right – is that there is good data showing that weight reduction is good for knee surgery and for back surgery, from a metabolic standpoint. It’s across therapeutic areas and disciplines. Modest weight loss – of 10% – improves a lot of orthopedic problems and improves fertility. The list keeps on going. Those are added medical and economic benefits that we’ve lost sight of in this cardiovascular-event-driven frenzy that we’ve been in these past five to eight years. It’s important for all of us to think about this, and we should push on the FDA and on Capitol Hill to try to get us out of this cardiovascular view. We have to start talking about this.

Dr. Russell: I think that comes back to my original point. If you can’t get to 10% weight loss, then as a diabetologist, I don’t see any real impact on their diabetes. But if you get over that, then I can start peeling off medications. From the standpoint of a provider, I am feeling good about things. But right now I am only seeing the needed weight loss with bariatric surgery.

Dr. Smith: I think we need start to think about responder analysis. I made this argument to the second lorcaserin advisory committee. The responder population is what is really important. We need doctors to not prescribe drugs to patients for whom the drug is not working. I think once we have a larger repertoire of medications, we can better tailor therapies for a person to what they respond to. That is the reason for the stopping rule for both Qsymia and lorcaserin.

Dr. Russell: That is a really good point, and something I really keep in mind with GLP-1 agonists. It would be great to have some way to determine who is going to respond. There are some people who do well with GLP-1 agonists, but there are a lot who do not. It is a pain in the neck to prescribe medications that only 30% of your patients are going to stay on and do well on.


Harvey Katzeff, MD (Global Director of Scientific Affairs for Diabetes, Merck, Whitehouse Station, NJ)

In his presentation, Dr. Harvey Katzeff described challenges in the development of diabetes and obesity drugs. After remarking that Dr. Steve Nissen’s actions has made drug approval more expensive and difficult, Dr. Katzeff emphasized that the criteria for reimbursement have also become more stringent. To Dr. Katzeff, the greatest potential lies with obesity drugs, due to the large patient population (112 million obese people) and the significant overlap between obesity and both diabetes and the metabolic syndrome. Dr. Katzeff then listed challenges to drug development, including the high expectations for a “perfect agent” and the media’s misleading portrayal of drug candidates. He also noted that since several hormones collectively regulate body weight, focusing on just one target is unlikely to produce sufficient, long-term weight loss. Multi-target approaches are likely required, and researchers should focus on quickly identifying responders to the drug. After reviewing the FDA guidance on cardiovascular risk assessment in diabetes drugs, Dr. Katzeff discussed the regulatory considerations for developing drugs for the treatment of prediabetes (details below). Turning back to obesity candidates, Dr. Katzeff stated that the FDA will likely implement cardiovascular safety requirements similar to those for diabetes drugs. He noted that the FDA has not yet defined a clear standard of safety for obesity drugs, and that the advisory committee’s view on obesity therapies appears to be influenced by external parties (and their respective views on drug safety vs. the need for more obesity therapies).

  • Dr. Katzeff began by broadly describing the challenges of diabetes and obesity drug development. Upon entering phase 1, drug candidates have a 10% chance of reaching the market. The likelihood of commercialization rises only to 50% once a drug reaches phase 3. To Dr. Katzeff, the cost of phase 3 testing – typically hundreds of millions of dollars – represents the most significant hurdle. Thus, Merck focuses on gaining an accurate, comprehensive understanding of a drug candidate during phase 2 in order to minimize this financial risk.
  • Dr. Katzeff discussed the importance of treating obesity, noting that obesity is associated with several metabolic risk factors that place patients at a greater risk for cardiovascular (CV) disease – having three or more risk factors for the metabolic syndrome increases one’s risk of heart disease from 5% to 25%. However, he also referenced the Look AHEAD study (which was recently terminated), which found that weight loss itself does not decrease cardiovascular risk or mortality. Given that diabetes patients today are commonly treated with aspirins, statins, or other medications with CV effects, showing additional CV benefit with an obesity therapy will be difficult. Furthermore, though data show that insulin resistance promotes cardiovascular disease, studies have not decisively showed that increasing glycemic control improves CV outcomes. Dr. Katzeff then pointed to rimonabant as a warning of a drug that was efficacious, but that failed phase 3 testing due to safety concerns. He reminded the audience that given the large obese population, the FDA applies a high safety standard to obesity medications.
  • The FDA’s guidance on diabetes therapies has increased the difficulty of drug development. Trials now require large patient cohorts in order to observe the number of cardiovascular (CV) events needed to assess CV risk. As an example, Dr. Katzeff noted that sitagliptin’s CV outcomes trial (TECOS) requires 1,200 cardiac events – this far exceeds the 120- 200 events that investigators typically observe in a standard phase 3 study. Given that statins only show a hazard ratio of 0.8, and given that many diabetes patients already use such medications, it is very unlikely for a diabetes drug candidate to show additional CV benefit. Dr. Katzeff estimated that the FDA guidance has resulted in a delay of 12-18 months in drug approval, as well as an additional development cost of several hundred millions of dollars.
  • Turning to therapies for prediabetes, Dr. Katzeff stated that the FDA would require that such drugs not only lower glucose levels, but also alter the natural history of the disease – as shown by a change the progression to either microvascular or macrovascular disease. Similar to the development of diabetes drugs, assessing cardiovascular risk in therapies for prediabetes will be challenging given the low event rate. Dr. Katzeff believes the FDA’s requirements will be stringent, and reminded the audience that no drug for prediabetes as been approved (to our knowledge, the FDA has not outlined a prediabetes regulatory pathway). Of great value will be biomarkers that can predict the risk of progressing from prediabetes todiabetes. In his brief discussion of possible prediabetes medications, Dr. Katzeff cited DPP-4 inhibitors and acarbose as promising therapies, though adherence to acarbose is extremely low.

Questions and Answers:

Q: Could you elaborate on what types of biomarkers you look for to identify prediabetes patients that are likely to progress to diabetes?

A: We don’t have any at this point. We need to hone in on subgroups of people with impaired glucose tolerance and impaired fasting glucose to identify potential biomarkers. That’s an area of active research for a lot of organizations.

Q: Can you elaborate a little more on why, in the Look AHEAD trial, a 5% weight loss didn’t improve outcomes?

A: We don’t have all the data out yet. The manuscript has not been presented or published. The study was stopped early because there was going to be no difference between the two groups. The experimental group did lose weight over 11 years, but there was no difference in mortality risk between the two groups. I think the weight-loss difference was just not great enough. There was a Swedish weight loss study of people who had morbid obesity and who underwent surgery. They lost 30% of their body weight and at ten years had a decreased risk of mortality.

Q: With respect to increasing the number of events that you need to show superiority – it’s a nonlinear curve. So why would anyone try to show cardiovascular superiority with a diabetes or obesity drug, given all the issues related to background therapy and residual risk?

A: There’s an important answer: getting reimbursement. Right now, in the US, metformin is the initial therapy and sulfonylureas are by far the most used second line drug. A lot of people think that sulfonylurea as a second drug may not be helpful to the heart. In order to show managed care organizations and doctors that it’s worth the premium to use a DPP-4 inhibitor or a GLP-1 agonist, they will need to show additional value. In my mind, if I can show that I’m improving outcomes and mortality compared to a sulfonylurea, that should be enough data for the government to ask that the guidelines recommend drugs with these improvements. It’s really for comparing effectiveness for reimbursement. This is true in the EU just as much, if not more so, than in the US. It would also be good for patient care.


Richard Peterson, PhD (PreClinOmics, Indianapolis, IN)

Dr. Richard Peterson, Executive VP, Research & Development, of PreClinOmics (a Spotlight Partner for the conference) quickly presented one of his company’s type 2 diabetes animal models, the ZDSD rat. A cross between the Zucker Diabetic Fatty (ZDF) rat and the Sprague Dawley (SD) rat, the ZDSD rat was developed to have the symptomatologies of type 2 diabetes (obesity, metabolic syndrome, etc.). The ZDSD rat develops insulin resistance, elevated glucose levels, and glucose intolerance in a way that closely mirrors the development of human type 2 diabetes. Additionally, PreClinOmics has found that it responds to therapeutics (including metformin, rosiglitazone, exenatide, sitagliptin, glyburide, niacin, and rimonabant) in a similar way to humans. However, in Q&A Dr. Peterson acknowledged that they have not looked at if their model responds to drugs that have been found during clinical development to not be efficacious in humans; we hope his model does respond to treatments (both positively and negatively) in a similar way to humans, as a preclinical model that reliably predicts when a drug is and is not efficacious would save significant R&D time and money. Dr. Peterson emphasized that the ZDSD model is able to mimic all these human characteristics without leptin receptor defects that most rodent models have. This is important, he said, because a model having a defective leptin pathway could throw off preclinical research of obesity and diabetes drugs, particularly if the drug impacts the central nervous system.

Questions and Answers:

Q: Thinking of obesity and diabetes, we have put drugs in the clinic that don’t work. Have you tested any of these drugs in your model to see if they work or don’t work in your model?

A: That is the crux of the problem. We have only tested drugs that in one group of patients or another works. We have not tested any drugs that have not gone on to some kind of approval in one nation or another.

Q: You had mentioned that you tested niacin in this model. Did you see any changes in cholesterol in this model?

A: You can’t really look at cholesterol in this model.

Q: Do you know what the underlying mechanism that drives diabetes is in this model?

A: We selected the beta cell failure in the ZD rat, so I think that is probably driving the diabetes. I can’t really comment on specific genetics or markers at this point.


Brante Sampey, PhD (Study Director, US Pharma/Biotech, Metabolon, Durham, NC)

Dr. Brante Sampey described Metabolon’s ability to help pharmaceutical companies throughout the drug development process, because it has industrialized functional metabolomics. Using its metabolomics technologies, Metabolon can help companies with several R&D cases, including: identifying biomarkers for early disease states and determining candidates’ mechanisms of action. The case study he provided for Metabolon’s success was its discovery and development of Quantose, a diagnostic that, he said, can identify a spectrum of insulin resistance in people with normal glucose levels.

Replenishing the Pipeline: Novel Target Classes for Obesity and T2DM


Richard Pittner, PhD (Head of Cardiovascular & Metabolic External Innovation, Pfizer, New York, New York)

Dr. Richard Pittner began his presentation with a similar message that Dr. Steven Cohen (External Scientific Affairs, Cardiovascular – Metabolism, Daiichi Sankyo, Edison, NJ) had expressed before him: though R&D costs (particularly those associated with phase 2 and phase 3) are ballooning additional drugs are not being brought to market. He explained that one of the reasons it is becoming harder to develop new drugs is that one must thin about payer reimbursement. Referring to obesity drugs as an example, he noted that while there is clearly a need for such therapies, the question of whether the drug will be reimbursed when it reaches the market makes developing such therapies a difficult decision. Dr. Pittner went on to explain the complex incentive structure currently at play in R&D. He stated that Pfizer’s pipeline status is currently 33 compounds in phase 1, 29 compounds in phase 2, 22 compounds in phase 3, and 11 compounds at registration. He believes the company clearly has a need to get more drugs to market to increase revenue, but that phase 2 and phase 3 development are so expensive that there is pressure to decrease the number of drugs going through these programs. He thus encouraged pharmaceutical companies to largely allow early innovation to occur with external groups, like biotechs, and to then either use venture capital, research alliances, or M&As to fill their pipelines. In contrast to Dr. Cohen who said that M&As have historically not led to improved productivity, Dr. Pittner said that M&As are always going to be key, particularly because, “gone are the days that biotechs funded by venture capitalists had several shots on goal”. Dr. Pittner also referred to Pfizer’s M&A with Wyeth as being an example of a successful M&A, because Wyeth’s biologic strength complemented Pfizer’s tradition in small molecules. He also said that since the M&A Pfizer has worked to change its culture so that different research and business units have more aligned goals.

  • Dr. Pittner said that over the past 5 years he has examined about 500 opportunities for in-licensing a compound, and described his selection criteria. He said that most of the time he decides not to acquire a compound is because the science is not compelling or it is too early. He remarked that many biotechs’ phase 1 data is either too short or the lead molecule and back up molecules have not been thought through enough. He therefore stated that candidate selection state is the “sweet spot” for Pfizer to work with a biotech, because Pfizer can help select what is the right lead candidate and which molecules should be the backups. The second most common reason he turns down a drug is that it is not a strategic fit for Pfizer’s research focuses (neuroscience; oncology; cardiovascular, metabolic & endocrine disease; immunology and autoimmunity; and vaccines). The third most frequent reason is that the either the development risk or cost is too high. Together these three reasons account for more than 75% of the opportunities he turns down.

Questions and Answers:

Q: Janssen is doing very similar things with external innovation. One of the biggest challenges I see working with people from the outside is changing the culture on the inside. To have this work you really have to have the trust and transparency. I find Janssen in the past has been very secretive with the information we have.

A: We take external information and confidentiality very seriously. We are typically quite open, though obviously we cannot disclose strategies. We don’t want those on the outside to have any hesitation that Pfizer is just looking at stuff to just educate itself as to what the competition is. I think Pfizer’s mindset used to be that way, but that it is changing. The only way to generate that trust is through openness and transparency. So we really have to be very precise on what information we want to see and what information we do not want to see, and any information that comes in is discarded afterwards, we do not establish a library to refer to later.

Q: How have you worked to get the many different groups at Pfizer to work together?

A: That is a significant challenge. In an environment with so much change it is hard to get people to stick their necks out and take risks. One thing we are dealing with at Pfizer is coordinating our research development and business units. The business unit has its own strategy and needs, and does not necessarily have to take the research unit product – this creates a lot of tension. If the business unit likes a product that the research unit does not, the research unit still has to do the clinical studies to the point that the business unit can take it on. It has taken time but we are making great strides in aligning the company’s goals. It was a challenge in the past; I think it is less of a challenge now.


Steven Cohen, MD (External Scientific Affairs, Cardiovascular – Metabolism, Daiichi Sankyo, Edison, NJ)

Dr. Steven Cohen described how pharmaceutical companies are getting a decreasing number of drugs to market despite increasing R&D budgets, which he called the “pharma innovation gap”. He also described how the number of drug companies is drastically shrinking, emphasizing that pharmaceutical must begin to look outside the box. He argued that M&A has not improved productivity and specifically referenced Merck’s >$40 million purchase of Schering-Plough failure to result in the successful production of many additional drugs. He went on to remark that pharmaceutical companies, while good at producing “me too” compounds, are not particularly good at discovering new first-in-class drugs. Dr. Cohen presented data showing that while 71% of follow-up compounds are produced by pharmaceutical companies only 44% of first in class drugs are. To find new drug approvals, he said, one must look to academic institutions and small biotech companies, which produce 31% and 25% of first-in- class, respectively. He also highlighted that 32% of the pipelines of the top 10 pharmaceutical companies are in-licensed, with some variation; on the upper end, 46% of Roche’s pipeline and 43% of GSK’s are in- licensed. Biotech companies also appear to be in-licensing many of their compounds (presumably from either smaller companies or academic institutions), because Dr. Cohen said 50% of Genentech’s, 42% of Biogen’s, and 25% of Amgen’s pipelines are in-licensed. He thus, argued that companies are not discovering many of their own drugs, and should embrace partnerships with academic institutions to further their pipelines.

  • Dr. Cohen stated that partnering with academic institutions is beneficial for pharmaceutical companies, because having KOLs personally invested in the development of the company’s drugs will make them follow the drug’s progress more intensely, which should result in fewer developmental surprises. Dr. Cohen explained that currently pharmaceutical companies spend a lot of resources on advisory boards and KOL consultants for external verification that their pipeline and products are at a high level, but these groups tend to not be very critical of drugs they are not personally tied to. Developing these groups’ compounds will probably result in them following the drug’s progress more critically.
  • He went on to say that it is in the interest of academics to partner with pharmaceutical companies (particularly mid-sized companies like Daiichi Sankyo) because pharmaceutical companies are better at translational medicine and have more funding. Dr. Cohen explained that with their chemists, pharmacologists, toxicologists, and translational medicine experts, pharmaceutical companies have the expertise to bring a compound from bench to bed size. Additionally, even during periods of economic hardship, pharmaceutical companies still tend to have more money than is available to academic researchers. He went on to say that working with a mid-sized company, like Daiichi Sankyo) is particularly beneficial for an academic researcher, because they do not have to deal with as much bureaucracy when interacting with the company, and that while mid-sized companies may have fewer areas of expertise than larger companies, they may surpass larger companies in the areas they do specialize in.

Questions and Answers:

Comment: I am in academia and have my own lab. I just wanted to comment on one of the hurdles you mentioned: the IP [intellectual property] issue. In academia it is publish or perish, you have to get your stuff out. I have found that if the IP issue is defined early on that makes a huge difference. I also want to give the example of Novo Nordisk’s Innovator role; I think that it is so successful because of its transparency. Academic researchers, we dedicate time every day to find new opportunities and grants. I think that more targeted marketing of such opportunities would be beneficial.

A: I think that is an excellent point. We started our partnerships in Japan, and are now expanding it to Europe. Probably over the next year we will expand it to the US, but when we do that we have to be prepared [Laughter].

Q: How many of the Japanese partnerships were on biomarkers vs. target identification?

A: We do not work specifically in devices or biomarkers unless it is helping us with one of our drugs.

Q: What are Daiichi Sankyo’s current areas of focus?

A: Oncology and cardiovascular metabolism.


Riccardo Perfetti, MD, PhD (VP, Global Medical Affairs, Diabetes, Sanofi, Paris, France)

Dr. Riccardo Perfetti described the benefits of using GLP-1 agonists, in particular lixisenatide, with basal insulin. After briefly reviewing the ADA/EASD guidelines, Dr. Perfetti noted that despite the standard “treat-to-failure” approach to diabetes care, many physicians begin their patients on combination therapy with the rationale that using synergistic mechanisms of action may increase efficacy. He then explained that while insulin is highly effective, roughly half of the eight million people on insulin do not meet the A1c target of 7%, despite having well-controlled fasting glucose levels. This finding highlights the need to control post-prandial glucose (PPG), which can be accomplished with short acting insulins, though mealtime insulins increase the risk of hypoglycemia and lead to further weight gain. An early study with exenatide showed that adding a GLP-1 agonist to basal insulin therapy dramatically improved glycemic control in people with late-stage diabetes (not typically considered candidates for GLP-1 therapy). The result prompted Sanofi to modify lixisenatide’s phase 3 GetGOAL program to include three studies investigating lixisenatide as an adjunct to Lantus: GetGOAL-L, GetGOAL-L Asia, and GetGoal Duo1. GetGOAL-L Asia and GetGOAL-L included patients with more advanced diabetes already on insulin. In contrast, GetGoal Duo 1 enrolled only patients on oral antidiabetic therapy to examine the concurrent initiation of Lantus with lixisenatide, a scenario that Dr. Perfetti believes more closely mirrors clinical practice. The three trials showed that lixisenatide/Lantus combination therapy led to significant improvements in A1c, primarily through reducing PPG; participants also experienced greater improvements in weight, with little increased risk of hypoglycemia. Dr. Perfetti ended his talk by reviewing a 28-day study that found that lixisenatide provided greater reductions in PPG area under the curve (129%) compared to liraglutide (41% reduction).

Drugs on the Market

Mitigating CV and Systemic Risk in Cardiometabolic Drug Development


Steven Smith, MD (Sanford-Burnham Institute, Orlando, FL)

Dr. Steven Smith gave an engaging presentation on the recently approved, and late stage, obesity drugs as well as the current regulatory environment. Given the growing rates of obesity (particularly severe obesity), he said he wishes it were easier to get obesity drugs to market, but that he is not sure the FDA’s initial rejections of phentermine/topiramate ER (Vivus’s Qsymia), lorcaserin (Arena/Eisai’s Belviq), and naltrexone/bupropion (Orexigen’s Contrave) were wrong given the context – rosiglitazone and sibutramine were being withdrawn around the same time, and all three companies were less than adequately prepared to for discuss cardiovascular risk. He went on to state that the dynamics that have changed to allow Belviq and Qsymia to be approved are that 1) societal pressure to address the obesity epidemic have increased and 2) the companies provided more detailed post-marketing risk mitigation strategies. In particular, Dr. Smith argued that the stopping rule included in the package insert of Belviq and Qsymia (and the methodology of Orexigen’s Light Study) is particularly important, because not everybody responds to every drug (though he stated that MetAp2 inhibitors, like Zafgen’s beloranib, might be the exception to that rule). He hypothesized that if sibutramine’s cardiovascular outcomes trial (SCOUT) had included a stopping rule it would still be on the market. Additionally, he believes that Contrave will be found to be beneficial (in contrast to sibutramine) not because it is a better drug but because the Light Study is designed better than SCOUT. Finally, Dr. Smith said he would use Belviq as his first line medication for people with an Edmonton Obesity Staging System (EOSS) stage of 1-3. Similarly, he said that he has used high doses of liraglutide (Novo Nordisk’s Victoza) and considers it for people with an EOSS stage of 1-3. Finally, he said that given some of the nervous system adverse events associated with phentermine/topiramate he would use it in his more at risk patients, who have an EOSS stage of 2-4. The rate at which we are hearing HCPs refer to the EOSS as a tool for making prescription decisions seems to be increasing, and are glad that obesity is gradually being seen as more of a heterogeneous condition.

  • The rapidly increasing amount of severe obesity in the Untied States, Dr. Smith emphasized, is a trend he said that businessmen and -women have to be aware of. He stated that the most shocking statistic in the Robert Wood Johnson Foundation’s “F as in Fat” 2012 report is that in 2030 over 10% of American will have a BMI over 40 kg/m2.
  • Dr. Smith provided historical context for the events surrounding the FDA’s first Advisory Committee meetings for Qsymia, Belviq, and Contrave, which likely contributed to the initial negative decision. He stated that July 13, 2010 was the FDA’s Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee on rosiglitazone. Only two days later, on July 15, phentermine/topiramate had its first Ad. Comm. Similarly, news of sibutramine’s cardiovascular risk was announced on August 21, 2010; lorcaserin’s Ad. Comm. was shortly after on September 16, 2010. Finally, sibutramine was withdrawn from the US market on October 8, 2010, and the naltrexone/bupropion Ad. Comm. was held on December 7, 2010. Additionally, Dr. Smith pointed out that naltrexone/bupropion had a very similar impact on heart rate and blood pressure as sibutramine, so it must have been difficult for the Ad. Comm. to feel okay about advising for another sibutramine to be brought to market at that time. Finally he said all three of the companies were less than optimally prepared for discussion around cardiovascular risk.
  • Dr. Smith described the obesity regulatory environment as stabilizing after an earthquake. He reminded the audience that the situation could be worse; he explained that at one point in time the FDA had suggested that Orexigen’s cardiovascular outcomes trial have toenroll over 75,000 patients. Still he implored the audience to place political pressure on Capitol Hill and the FDA, so as to “inject some rationality in Washington.” In particular he emphasized the need to move regulatory focus away from cardiovascular risk as the sole-to-main focus when evaluating obesity drugs’ safety, as cardiovascular disease does not fully address the many comorbidities associated with obesity.

Questions and Answers:

Q: Would you like to comment on the impact LOOKAhead might have?

A: We have been discussing it some within The Obesity Society. Part of its problem is that it was a very ivory tower study. The control group was on the maximum amount of cardiovascular medications, because if you don’t have everyone on statins and aspirin then you get negative brownie points with the NIH. It is not a real life study; people are going to live in that environment. Also, the magnitude of weight loss that was seen in LOOKAhead on average is probably not optimal to see a change in risk. Finally, there could be changes that drugs produce other than weight loss may impact cardiovascular risk.

Q: I was interested in how you address obese patients in your clinic? Do you start them on Qsymia or a GLP-1 agonist?

A: By the time they have been sent to us they have been through diet and exercise. Its not that diet and exercise are not important, it’s just that my patients have already tried it. The first thing is to look at their drugs; people are always being referred to our clinic that are taking drugs that cause weight gain. I think we are going to end up with an algorithm associated with something like the EOSS. Given the issues with phentermine/topiramate I would feel comfortable using Belviq in a person with an EOSS stage of one. Moving up from that I would start using Qsymia. Close your ears, because I am going to talk about off- label use, but we are using high dose liraglutide to good effect. Eventually, we will have enough drugs that we can get a bunch of KOLs in the room to beat each other up and come up with an algorithm.


Leo Seman, MD, PhD (US Medical Director Metabolism, BI, Ingelheim, Germany)

Dr. Leo Seman argued that Lilly/BI’s DPP-4 inhibitor linagliptin (Tradjenta) is differentiated from other DPP-4 inhibitors because of its increased safety. In particular he focused on how most of the other DPP- 4 inhibitors are cleared renally, while linagliptin is cleared through the biliary tract. In September linagliptin’s label was updated to include information on the drug’s efficacy in people with sever chronic renal impairment. The data came from a 52-week study (n=133) that enrolled people with type 2 diabetes and severe chronic renal impairment (eGFR <30 ml/min) already on insulin monotherapy or combination therapy, sulfonylurea monotherapy, glinide monotherapy, or other antidiabetic agents excluding DPP-4 inhibitors. Doses of background antidiabetic agents were kept stable for the first 12 weeks of the study and were then adjusted for the subsequent 40 weeks if glycemic targets were not met. Participants randomized to Tradjenta (5 mg once-daily) experienced a placebo-adjusted A1c reduction of 0.6% at 12 weeks and 0.7% at 52 weeks. The incidence of severe hypoglycemia was comparable between the two groups. As a reminder, linagliptin is the only DPP-4 inhibitor that does not require dose adjustment in patients with severe renal impairment, a small but meaningful advantage given the overall lack of differentiation within this class and the extent to which HCPs lives are already complicated.

Mechanistic Insights From High Potential T2DM Drugs in the Clinic


Michael Mark, PhD (VP, Cardiometabolic Disease Research, BI, Ingelheim am Rhein, Germany )

In his presentation, Dr. Michael Mark highlighted aspects of linagliptin that differentiate the drug from other DPP-4 inhibitors and discussed linagliptin’s non-glycemic effects. Dr. Mark explained that linagliptin is the only xanthine-based DPP-4 inhibitor; the compound is 20-fold more potent for DPP-4 compared to sitagliptin (Januvia) and alogliptin (Nesina), and is 50-fold more potent than saxagliptin (Onglyza) and vildagliptin (Galvus). Furthermore, because linagliptin is primarily excreted through the bile and gut rather than through the kidneys, it is the only DPP-4 inhibitor that does not require dose adjustments in patients with all levels of renal impairment (including severe CKD and end-stage renal disease), as well as patients with severe hepatic impairment. Dr. Mark then turned to linagliptin’s non- glycemic effects, noting that DPP-4 acts on several different substrates other than GLP-1, several of which (e.g., SDF-1α and BNP) may influence renal and cardiovascular function. Dr. Mark reviewed data from experimental models suggesting that linagliptin has favorable cardiovascular effects – e.g., reduction in infarct size, attenuation of oxidative stress in vessels, and improvement in endothelial dysfunction. Dr. Mark also referenced preclinical data showing that linagliptin can improve kidney function by reducing albuminuria, improving podocyte integrity, and decreasing tubular inflammation.

  • Dr. Mark provided data showing that linagliptin dissociates from DPP-4 at a slower rate compared to vildagliptin and noted that linagliptin’s tight binding with its target results in longer-lasting DPP-4 inhibition. Linagliptin has the lowest free plasma drug concentration within its drug class – an average daily concentration of 0.35 nmol/l compared to ~10.1 nmol/l for saxagliptin (the parent compound), 219 nmol/l for sitagliptin, and >267 nmol/l for vildagliptin. Dr. Mark explained that linagliptin’s high selectivity for DPP-4, along with its tight binding to the enzyme, results in a lower risk of off-target effects.
  • While other DPP-4 inhibitors are cleared via the kidney, linagliptin is primarily excreted through the bile and gut. Only 5% of its concentration is clearly via the kidney compared to 87% for sitagliptin, 85% for vildagliptin, 75% for saxagliptin, and 60-71% for alogliptin. Dr. Mark reminded the audience that because of its unique method of excretion, linagliptin is the only DPP-4 inhibitor that does not require dose adjustments in people with renal impairment and in people with severe hepatic impairment. Though we initially believed that this advantage would make linagliptin more favorable among physicians (due to simpler prescribing), it appears to have had less commercial impact to start than we believe it could have further out. .

Questions and Answers:

Q: Is there any covalent interaction between the compound and DPP-4?

A: There’s no covalent binding. It’s competitive and reversible. There is a tight binding.

Q: Your data clearly explains how your compound is different with respect to selectivity, but regarding the additional benefit to the kidney and heart, would that be different from other DPP-4 inhibitors?

A: Yes and No. I would not expect a difference in the cardiovascular effects. I could hypothesize that there is a difference with the renal effects because of the tight binding of linagliptin to DPP-4 in the podocytes. That’s a hypothesis. I couldn’t even say whether the cardiovascular effects are mediated by DPP-4 or by GLP-1, but we’re looking into that. To your question, the hypothesis is that there could be a difference.

Q: Did you say what the dose timing was? Was it daily dosing or multiple dosing?

A: For the animal studies, it was either in the food or given once-daily.

Q: In patients, do you anticipate a longer period of time between doses? You have a very long duration of action with this compound.

A: There was a clinical study called the “miss a dose” study, which showed that if the patient missed one dose, you have the same degree of DPP-4 inhibition. We know that other companies have once-weekly inhibitors, but linagliptin does not qualify for once-weekly dosing.

Novel Therapeutic Targets and Drug Candidates

Replenishing the Pipeline: Novel Target Classes for Obesity and T2DM


Richard Pittner, PhD (Head of Cardiovascular & Metabolic External Innovation, Pfizer, New York, NY); Steven Cohen, MD (External Scientific Affairs, Cardiovascular- Metabolism, Daiichi Sankyo, Parsippany, NJ); and Slava Gedulin, MD, PhD (VP, Research & Development, Lumena Pharmaceuticals)

Dr. Cohen: I’m also a clinical endocrinologist so my company allows me to continue seeing patients. Once a week, I’m at Columbia University, where I have an appointment and I teach medical students and fellows about new treatments for the metabolic syndrome and endocrinology. I guess we could approach the question in two ways: first, from what’s already approved, and second, from what will be approved in the near future. On the first question, I personally like GLP-1 agonists, so I agree with something that was mentioned yesterday – that it would be great if we knew proactively which patients would respond to weight loss and A1c lowering better than other patients. I see as a differentiator – from just another DPP- 4 inhibitor or another sulfonylurea – in that GLP-1 agonists not only approach the risk of hypoglycemia, but also the increased body weight. That’s from what is approved. From what’s not approved – and I don’t know if lipid medications fit in here – we’re closely looking at PCSK9 and CETP inhibitors, even with the recent problems. But we still see our diabetes patients dying from cardiovascular disease, not specifically from diabetes. And so even with statins, which lower LDL, and other methods that lower triglycerides and increase HDL, we still need other drugs to lower the cardiovascular risk. And so what I’m hoping is that PCSK9 inhibitors (which has been shown to lower LDL up to 70-80%) and CETP inhibitors (that increase HDL and at least lower LDL), that these may help us fight the epidemic of cardiovascular disease in people with diabetes and in other patients.

Dr. Pittner: It’s a challenging question. I look at everybody’s thoughts on the DPP-4 inhibitors when the data first started coming out and I think everyone envisioned that they would have a lot of problems. The overall efficacy that these molecules generated was not that impressive. I don’t think that there was any idea that Januvia would be such a huge hit. So trying to understand what is the key driver for the success of that molecule is important. You could argue that its overall efficacy is not that great, and that its weight neutrality we thought would make it less appealing than GLP-1 agonists. At the time everyone was favoring the GLP-1 agonists. I worked on the development of Byetta, and we called that molecule magic dust, because its glycemic benefit in preclinical studies was exceptional and it translated into the clinic. But there were issues; the nausea and AEs [adverse events] make it more of a challenge to use, even though the efficacy is better from a glycemic perspective. So it is difficult to place a bet on what molecule from the panel that we have will be a good, promising medicine. The compromise of convenience for efficacy is something that certainly, at Amylin, we did not fully appreciate; the thought was that efficacy would be the driver, but convenience, safety, and overall tolerability is more of a driver than we had thought.

In terms of new molecules, and new targets, I think GPR119 is a good example. We thought that they were going to be the next GLP-1 agonists, but, ultimately, they have been very disappointing in terms of efficacy, not differentiating at all. Their clinical data has been extremely disappointing despite the hype. The bottom line is that data talks. You have to have profound efficacy these days. We already have generic metformin, and when you are picking a new target you have to keep in mind that in the 5-10 years it takes to get it to market, DPP-4 inhibitors, GLP-1 agonists, and other classes will be generic, so you will also have compete against those. So again the bar keeps getting higher. This raises the question of whether monotherapy is really the way forward. I think that combination therapy may be the way to differentiate. Finding the right complements is key to obtaining the next level of efficacy.

Again from my personal background and bias, from being at Amylin Pharmaceuticals and working on Symlin and exendin (which became Byetta), I have a personal fondness for those molecules. I also worked pretty closely with the PYYs, which hit the headlines a few years ago but were disappointing when you looked at the efficacy and tolerability as monotherapies. What I think is exciting about the gut is the numerous signals that come out postprandially and act in concert to deliver the postprandial signal. So I have a bias towards the L cell. Anecdotally, I think you could argue that replicating bariatric surgery with a pill by stimulating the L cell would be promising. Anecdotally, FGF21 is very interesting. It is a complex compound and signal, but it has great weight loss, despite only modest glycemic benefit. So there are things out there; it’s just difficult to put money on them. You just have to wait and let the data talk.

Dr. Gedulin: There are drugs in development and in existence for metabolism and the treatment of metabolic disease, and there are combinatory approaches. Those are gaining greater attention and almost everybody – clinicians and physiologists and people who are just using new approaches – understand that monotherapy will probably not be on the horizon in the future. One approach is drugs that have dual mechanisms. It’s an absolutely incredible new approach to thinking about the treatment of metabolism and metabolic diseases and, as Richard mentioned, L cell stimulation to stimulate endocrine secretion would have some opportunities. There’s opportunity to have multiple hormonal actions in just one pill. For example, L cell secretion of incretins – GLP-1 – is known, and we have already reached some sort of plateau in the development of compounds. And we’ve already reached a plateau in the A1c reduction. But L cell secretion of PYY (a hormone that regulates appetite) has potential. We’re getting close to understanding how we can combine PYY and GLP-1 to simultaneously treat some kinds of hyperplasia. It’s a human approach – these two hormones. Another hormone is oxyntomodulin, a cross of GLP-1 and PYY. And another hormone, which is incredible misunderstood, is GLP-2. GLP-2 is a factor known to have some repair function in the intestines. Nothing else. But if you look deeply in some investigations of what the hormone is doing, the hormone is an anti-inflammatory factor. And inflammation is a factor in atherosclerosis and obesity, which involves inflammation of the fat cell. This is part of obesity. Obesity is characterized by increases in different markers that lead to inflammation. What does that mean? A stimulation of these four discovered hormones can give us the opportunity to look at the scope of all metabolic diseases, and stimulation with only one small pill could be an answer for treatment. This is the approach that I think could have some future. While we don’t have this magical pill at the moment, combination therapy already exists and is achievable with insulin and GLP-1 agonists. Or with a combination of a DPP-4 inhibitor and metformin. It’s another approach that could be considered now a days. But for the future, a magic pill is probably on the horizon, but who knows what it will be.

Q: What are your thoughts on combination therapy, Richard and Steven?

Dr. Pittner: You can’t get true differentiation and maximize efficacy with a single agent. So the question is which combinations do you use. I am not saying that I am advocating for a poly pill, but I think that the regulatory environment is challenging for combining two novel agents. Combining compounds already out there is probably the simpler way to move forward.

Dr. Cohen: From a technical point of view, when you have to give a patient new medication, you think about the adverse events, the potential adverse events, and the optimal dose based on the patient’s phenotype and other medications. It’s difficult to start with a combination pill. You may want to start with metformin, then find the optimal dose, and then after a couple of months, when the patient is stable, then you may want to include something else. You may want to add sitagliptin. After you find the optimal dose for sitagliptin, you may think that if the patient is on 100 mg of sitagliptin and 2,000 mg of metformin, then you can give him Merck’s other drug, which you take twice a day. There are challenges to combination therapy. It’s not something to start right away.

Q: Since the panel mentioned incretin secretion and gut hormones a couple times. Do you think there are a significant number of gut hormones that we have not investigated yet, that have the same type of efficacy as GLP-1?

Dr. Pittner: I certainly had that dream when I worked at Amylin. We found some interesting sequences. I think the company that has truly pushed this to an art form is NGM in the Bay Area. When you think of the number of gene sequences the mathematics are amazing; you can come up with lots of new sequences. However, after 50 years of research into the gut why haven’t they found all the key players? There may be one or two that still remain, and NGM certainly has potentially identified a few interesting sequences. In terms of key drivers in terms of metabolism, it is unlikely that there will be more than one more.

Q: Shifting back to CETP inhibitors, could you share your thoughts about the two disappointing trials with dalcetrapib and evacetrapib and how that could shift the focus of some companies away from HDL?

Dr. Cohen: Initially, there was a lot of optimism with the first CETP inhibitor, but with Pfizer’s drug, it became a little less optimistic. And people of course always say that the problem is not a class-wide effect, that it’s specific to that compound. That’s why Roche continued with its CETP inhibitor and we saw a few month ago their less-than-optimal results. So, is there something generally wrong with the class? Or is it that increasing HDL via this mechanism will not have the benefits that we think it will have? I said that maybe Merck’s compound may be the most helpful because it not only increases HDL, but also lowers LDL on top of a statin. So lowering LDL even further than a baseline statin may actually improve cardiovascular outcomes. I think that’s the way the thinking is right now. But for a CETP inhibitor that does not lower LDL or have other beneficial effects, I think people are generally less positive about that.

Dr. Pittner: I guess that CETP is a dirty word at Pfizer [laughter]. I think that there were a lot of lessons learned internally. I think that the case with Pfizer was that they chose the wrong molecule for a business decision to get there ahead of everyone else. If you look at the back-up molecules, they did not have the same AEs as the primary compound. The problem was that once this data was generated it was decided that these molecules were already too far behind. Was that the wrong decision? It was thought that it was going to be bad timing, so we pretty much dropped out. But now Roche has dropped out, so maybe the timing would not have been so bad.

Q: What about GPR40 agonists? We have Takeda’s TAK-875 in phase 3. How promising do you think it will be in diabetes care?

Dr. Pittner: I find it hard to differentiate it sufficiently from GPR119 agonists. There’s a better overall biology and efficacy with the molecule, but is it differentiated enough to make it into the marketplace? I think it’ll be a challenge but again, the data will talk. Maybe phase 3 will show good data. But I put it in the category of drugs with a lot of promise but overall disappointing magnitude of efficacy. With the GPR120 agonists, will it be any different? I guess we’ll see. With GPR119 agonists, it remains to be seen whether you’ve maximized the potential of the L cell stimulation, as opposed to stimulating insulin secretion in the pancreas. I think given the bioavailability, probably not much of the molecule made it down to the lower gut to stimulate the L cells, so the biology you see is primarily driven by the beta cells, and that may not have enough horsepower. I think the jury is still out on maximizing the true biology of GPR119 and I think it’s the same thing with GPR40 agonists.

Comment: I would agree with you on that.

Q: Can I follow up on 199 (unintelligible – may have been “119”.) Is the receptor more likely on the lumen? Is the bioavailability something we should look for?

Dr. Pittner: I think there is a strong argument for a non-absorbable 199 (unintelligible) that will have better efficacy.

Dr. Gedulin: Today, it’s known that its mechanism is going toward beta cell stimulation, not intraluminal action. It could be dual-acting, but the mechanism is more toward beta cell stimulation, so it should be systemic.

Q: I understand that for the beta cell you have to have greater bioavailability. I was wondering if you primarily have L cell targeting, do you really want to work on bioavailability, because it is expressed in the lumen?

Dr. Gedulin: From my knowledge of working in this field, intraluminal drugs – not absorbable drugs – are the future for L cell stimulation.

Dr. Pittner: Overall the elevation of endogenous GLP-1 is insufficient. I don’t think that you have enough horsepower on the GLP-1 side to drive it.

Q: Regarding the GLP-2 effect, could you elaborate more on what kind of inflammation effect you’re seeing?

Dr. Gedulin: GLP-2 has already been described as an anti-inflammatory factor. There is some company in phase 2 development of a GLP-2 agonist for the treatment of short bowel syndrome. There is some other approach using GLP-2 agonist to treat different GI disorders, such as Chron’s disease or irritable bowel syndrome. It is in development. It GLP-2 has have some incredible anti-inflammatory function to treat and regulate systemically not only intraluminally


Guoqiang Jiang, PhD (Director of Knowledge Discovery, Worldwide Licensing, Merck, Whitehouse Station, NJ)

Dr. Guoqiang Jiang gave a thorough review of the different targets for diabetes treatments and the companies he believes are developing candidates for those targets. He began his presentation by stating that unmet need for diabetes therapies remains because currently available marketed therapies have limited efficacy and/or too many adverse events. Thus, he remarked that new treatments should improve primary (glucose control) and secondary efficacy (body weight, blood pressure, etc.), compliance, and/or safety. The first therapeutic class he reviewed was insulin, which he said will remain a key therapeutic class for diabetes, as it is projected to have 45% of the total anti-diabetic therapeutic market in 2016 (vs. 60% in 2011) – though 45% is still a large percentage, we note, that a 15% drop in market share over five years is pretty dramatic. He proceeded to describe the potential advantages and challenges of different classes in development (such as glucagon receptor antagonists), as well as how existing classes like insulin could be improved. Details on his opinions of many potential therapies can be found below. He concluded by stating that combination therapy is becoming increasingly important for both companies and patients.

  • Dr. Jiang highlighted the possibility of insulin therapy potentially being advanced via an insulin receptor-activating antibody, a small molecule mimetic, alternative routes of administration, or glucose dependent insulin.
    • Insulin receptor-activating antibody: Dr. Jiang listed XOMA as a key player in this field. We presume he was referring to XMetA, which is in preclinical development. During XOMA’s 2Q12 call the company highlighted that it was in partnership discussions for this compound and XMetS (an insulin sensitizer). For more on XMetA and S, and the company’s partnership discussions see our 2Q12 report at
    • A small molecule mimetic: He remarked that no major advances have occurred in this area and did not list any companies as currently working on such a molecule.
    • Alternative routes of administration: Dr. Jiang explained that the potential advantage of a non-injectable insulin is improving patient compliance. However, he also highlighted many challenges, including that such an agent must be able to maintain biological activity after formulation, resist degradation, and cross either the tissue or cell surface. Some of the administration methods and companies developing them include:
    • Glucose-dependent insulins: The advantage of an insulin that responds to one’s glucose levels, according to Dr. Jiang, is that it would reduce the risk for hypoglycemia. A key challenge for this field however is developing a candidate that has adequate glucose- sensing capabilities. Examples of such insulins in development, according to Dr. Jiang, include: Merck’s SmartCells, Sensulin, and Biodel’s BIOD620. As we understand it, these are all in preclinical development.
  • Another set of therapeutics Dr. Jiang detailed were therapies (other than GLP-1 agonists and DPP-4 inhibitors) that promote glucose dependent secretion of insulin. These included: GPR40, GPR119, and GPR120.
    • GPR40 agonists: GPCR40 (G protein-coupled receptor 40) is enriched in pancreatic beta cells that are activated by free fatty acids. Activation of GPR40 stimulates glucose dependent insulin secretion from the beta cell. According to Dr. Jiang clinical proof-of- concept has been reported for Takeda’s GPR40 agonist, TAK-875, (now in phase 3). For more on TAK-87 please see our F4Q11 report at
    • GPR119 agonists: GPR119 is expressed largely in the pancreas and GI tract. Activation of this receptor has been associated with reductions in food intake and weight regain in rodents. It has also been implicated in the regulation of incretin and insulin hormone secretion. According to Dr. Jiang companies developing a GPR119 agonist include: Astellas Pharma, Metabolex, and Zydus Cadila.
    • GPR120 agonists: GPR120 is expressed in the gut, adipose tissues, macrophages, and other issues. Dr. Jiang explained that it is activated by fatty acids, and stimulated GLP-1 secretion from L cells in the gut. It also improves insulin sensitivity by suppressing inflammatory pathways. Dr. Jiang listed Kindex Therapeutics, Metabolex in partnership with J&J, and Novartis as companies working on this target.
  • Dr. Jiang stated that the emerging GLP-1 agonists will likely be long acting, have alternative routes of administration, and/or be hybrid peptides. Additionally, some companies are exploring GLP-1 receptor small molecule activators.
  • Alternative routes of administration: The rationales and challenges for developing alternative routes of administration, he remarked, are similar to those for insulin. Companies developing such compounds, which Dr. Jiang listed include:
    • Oral: Emisphere, Novo Nordisk, Oramed, Shanghai Biolaxy, and Vitapharm;
    • Transdermal: TransPharma Medical and Zosano Pharma.
    • Inhaled: MannKind
  • Peptide hormones that are known to play different roles in glucose homeostasis in vivo, Dr. Jiang stated, are GLP-1, GIP, glucagon and gastrin. He then listed companies that are exploring different combinations based on these peptides.
    • GLP-1/glucagon dual agonists: Pfizer, Transition Therapeutics, Zealand, MannKind, PROLOR Biotech, and Xenetic;
    • GLP-1/GIP dual agonists: Amunix.
    • GLP-1 receptor small molecule activators have the advantage of having an oral formulation, eliminating the burden of a person having to take an injection. However, Dr. Jiang, explained, that it is challenging to mimic the GLP-1/GLP-1 receptor interaction. Companies that, according to Dr. Jiang, are exploring this therapy include: TransTech and Zydus-Cadila. Similarly, Dr. Jiang listed several companies developing GLP-1 receptor positive allosteric modulators, which included: Addex Therapeutics, Domain, and Receptors.
  • Dr. Jiang then went on to list insulin-sensitizing therapies that are in development. One such therapy is the PTP1B inhibitor, a cytoplasmic protein tyrosine phosphatase that is expressed in insulin responsive tissues such as the liver, muscle, and adipose tissues. Dr. Jiang remarked that the challenge of this treatment is achieving cell permeability and selectivity. Clinical proof-of-concept, according to Dr. Jiang, has been reported for Isis’s ISIS 113715, an antisense oligonucleotide that in a phase 2 study was shown to improve glucose control and reduce LDL-C in people with type 2 diabetes. Other companies performing similar research, which Dr. Jiang mentioned, include: TransTech Pharma, Aus Bio, Ensemble Therapeutics, and Ohr Pharmaceuticals.
  • Dr. Jiang noted that several companies have pursued glucagon receptor antagonists, because glucagon is known to be deregulation in people with diabetes. Dr. Jiang noted that clinical proof-of-concept has been reported, and that glycemic control has been demonstrated for Merck’s MK0899 and MK0577, and Lilly’s phase 2 LY2409021. However, while Merck’s compounds are reported to cause LDL elevation, Dr. Jiang stated that Lilly says LY- 2409021 does not cause LDL elevation. Another company, Dr. Jiang, said is studying glucagon receptor antagonists is Isis.
  • For SGLT-2 inhibitors, Dr. Jiang stated that efficacy has been clinically proven, but that potential challenges remain. These include urinary and genital tract infections, along with a potential association with cancer. Examples of players in this field that Dr. Jiang listed include: BMS/AZ (dapagliflozin), J&J (canagliflozin), Astellas/Kotobuki, Lilly/BI (empagliflozin), Chugai, and Taisho. We note, that at the first day of MDDD, Pfizer announced that it has a phase 3 SGLT-2 inhibitor, ertugliflozin.
  • Another potential therapy Dr. Jiang reviews was AMPK activators. AMPK is expressed in the muscle, liver, heart, and other tissues. The difficulty with this area, Dr. Jiang said, is that it is difficult to determine the desired selectivity, as there are 12 possible complexes one could target with an AMPK activator. Additionally this class may results in cardiovascular adverse events, and there is no direct evidence that AMPK activation improves glycemic control in humans. Still companies exploring this target, according to Dr. Jiang include: Betagenon, Connexios, Debiopharm, Servier, and TG Biotech.
  • The final therapeutic area Dr. Jiang described was FGF21 analogs. FGF21 is a peptide secreted from the liver, pancreas, and other tissues. Augmenting its expression has been found to increase energy expenditure and preserve beta cell mass and function. Dr. Jiang noted that the key challenge for this class is that clinical proof-of-concept has not been reported yet and that it might have negative effects on bone metabolism. Companies he believes are active in this field are: Amgen, BMS/Ambrx, and Pfizer/CovX.

Questions and Answers:

Q: I appreciate you going through the different targets. Which ones do you think have the most promise for filling the pipelines, and making it to the clinic?

A: Hmmm. It’s a really good question. I think I want to take one step back, if you look at the traditional path for treating diabetes (TZDs and insulin) you have the body weight gain. If you look at the emerging therapies (GLP-1) body weight improvement is important. Where you have therapies that will increase body weight and others that decrease body weight people will go with reducing body weight. That becomes significant. I think these therapies that reduce body weight are very interesting.


Luciano Adorini, MD (Chief Scientific Officer, Intercept Pharmaceuticals, New York, New York)

Dr. Luciano Adorini, CSO of Intercept Pharmaceuticals (which just went public on October 11 at a market cap of ~$300 million, including securities in addition to outstanding primary shares that could be seen on the day of the IPO), presented on their lead candidate obeticholic acid (OCA), a bile acid analog that is a first-in-class agonist of the farnesoid X receptor (FXR). Intercept believes that OCA has broad liver-protective properties, and is conducting a phase 3 trial of OCA in primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Intercept, however, also believes that OCA regulates glucose and lipid metabolism in the adipocyte and improves insulin secretion, insulin sensitivity, glucose uptake, and triglyceride storage. The company therefore conducted a clinical study in people with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) – its pipeline ( currently lists nonalcoholic steatohepatitis (NASH), a more severe and advanced form of NAFLD, as one of the indications the company is developing the drug for. The double-blind, placebo controlled, six-week study (n=60) found that OCA significantly improved insulin sensitivity, induced weight loss, and reduced liver damage (Intercept did not follow any measures of participants’ glucose levels). The most common adverse events were constipation and headache. The NIDDK is sponsoring a phase 2 study in NASH with OCA. This trial (designated FLINT) is comparing the effects of 18 months of OCA therapy to placebo on liver histology ( Identifier: NCT01265498). The second therapy Dr. Adorini reviewed was Intercept’s preclinical TGR5 agonist for type 2 diabetes, INT-777. Intercept has found that INT-777 can induce GLP- 1 and insulin secretion, and that it improves insulin sensitivity and glucose uptake in obese, insulin resistant mice. Additionally, INT-777 attenuates weight gain and increases basal energy expenditure in DIO mice.

  • Intercept’s six-week, double-bind, placebo controlled study in people with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) study compared obeticholic acid (OCA) 25 mg and 50 mg with placebo (n=20 for each group). Overall, Intercept found that OCA improves insulin sensitivity (p=0.0278 for both doses combined). Additionally it induces weight loss. This weight loss appears to be due to its impact on FGF19, a gut hormone directly regulated by FXR that has been shown to induce energy expenditure and weight loss.

Mechanistic Insights From High Potential T2DM Drugs in the Clinic


Vincent Mascitti, PhD (Senior Director, Global R&D, Pfizer, Groton, CT)

Dr. Vincent Mascitti presented the medicinal chemistry and some phase 1 and 2 results for Pfizer’s phase 3 ready SGLT-2 inhibitor, ertugliflozin (previously called PF-04971729). Up until now we had not heard PF-04971729’s mechanism, compound name, and believed it was still in phase 2 (as it is still listed on Pfizer’s website). He acknowledged that there is substantial competition in the class (as of 2008 there were over 150 published patents), but that he believes Pfizer’s ertugliflozin might be successfully differentiated from other companies’ candidates because of Pfizer’s focus on safety while developing it. He stated that all doses of the drug were found to be safe and tolerable in phase 1 and phase 2 trials – though he did not discuss urinary tract or genital infection rates (and it is too soon to look at cancer risk). The drug was designed to be administered at a low dose (based on the data he highlighted 5-10 mg once a day appears to be likely clinical dose), which Dr. Mascitti said may reduce the potential risk of post-marketing safety problems arising (such as idiosyncratic drug reactions). According to Dr. Mascitti, contrary to some SGLT-2 inhibitors in the clinic (he did not specify which) it has no phototoxicity liability, meaning it is very unlikely to become toxic when exposed to sunlight. We had not been aware that this was a problem with any SGLT-2 inhibitors in development. Finally, Dr. Mascitti said that ertugliflozin is one of the most selective SGLT-2 inhibitors currently being studied, which he argued reduces the potential risk of off target pharmacology and side effects associated with inhibition of other SGLT and SMIT transporters (carbohydrate and myoinositol [a molecule produced by the body from glucose] transporters). Though Dr. Mascitti did not focus on ertugliflozin’s efficacy he said that it has a robust effect on urinary glucose excretion, and that the dose response is apparent and well delineated. Pfizer’s phase 2 study found ertugliflozin to have “meaningful, multifaceted improvements in glycemic control”, including an average A1c reduction of 0.8% (for the 5 mg dose – it is not clear from what baseline), average weight loss of ~2.5 kg (3% in body weight reduction for this cohort of patients), and reductions in blood pressure (~4 mmHg). We were very encouraged to hear about the progress with this compound and hope to hear more of the drug’s clinical results soon.

  • Dr. Mascitti stated that the excitement surrounding SGLT-2 inhibitors is largely because, if approved, members of the class could be the first oral anti-diabetic drugs to achieves tight and durable glycemic control with improvements in body weight, blood pressure, and potentially β-cell health). He then provided a brief overview of the history of the SGLT-2 inhibitor class, reminding the audience that current SGLT-2 inhibitors are based on the natural product, phlorizin. He stated that problems with early SGLT-2 inhibitors (O- aryl glucosides, such as GSK’s sergliflozin) were elegantly fixed by BMS’s medicinal chemists who altered the compound’s structure slightly, resulting in the discovery of dapagliflozin (a C-aryl glucoside).

Questions and Answers:

Q: I am not fully convinced this one is differentiated. In terms of selectivity couldn’t it potentially be beneficial to have a SGLT2/SGLT1 mixed inhibitor?

A: That is an important question. Ultimately time will tell where the answer lies. You have different schools of thought. Some people favor dual inhibition to claim an advantage of greater A1c lowering. But from our end the risk that you take by doing so, in terms of your safety profile, is not worth taking. We feel that differentiation can occur in terms of safety. Now there are different dimensions to the safety argument.

There is safety with respect to the mechanism; is there differentiation with respect to UTI/GFI, for instance, is one. Another was brought to the attention of the scientific community at the reading of the dapagliflozin documents that the FDA issued, where the FDA brought to attention of the community that some compounds (that were in the clinic) had been reported to increase the risk for renal tubule carcinoma in rodents (dapagliflozin not being one of them). Overall safety derives from pharmacological selectivity, and from chemotype [molecular] structure and dose size (both favorable for ertugliflozin). One should never forget that a drug is a chemical; it has to be looked at, at the molecular level. A subtle modification can make a huge difference between success and failure. For instance, some compounds that have been studied in the clinic have been associated with phototoxicity. All of this boils down to that you may claim to have differentiation based on efficacy, but we may claim that you get more differentiation based on safety.


Paul Rothenberg, MD, PhD (Head of Translational Medicine, Cardiovascular and Metabolism, Janssen, Titusville, NJ)

Dr. Paul Rothenberg provided an overview of canagliflozin’s history and development (the drug was filed in the US and Europe in May and June 2012, respectively). After briefly summarizing the action of SGLT-2, Dr. Rothenberg explained that canagliflozin’s predecessor (T-1095) entered the clinic in 2001 but was soon discontinued after failing to demonstrate efficacy in a phase 2 proof-of-concept trial, despite the earlier finding that T-1095 increased urinary glucose excretion (UGE) by 21 grams/day. J&J then developed canagliflozin in 2004 and advanced the drug to phase 1 in 2006. Dr. Rothenberg remarked that management was persuaded to support the drug’s clinical testing largely due to the use of PK/PD modeling (which predicted that canagliflozin would have greater efficacy than T-1095), as well as a new biomarker strategy that allowed for quick “Go vs. No-Go” decisions early in the development process. Dr. Rothenberg then briefly summarized canagliflozin’s large phase 3 program before discussing a GI glucose absorption study which found that following ingestion, canagliflozin transiently inhibits intestinal SGLT-1 to delay oral glucose absorption. Dr. Rothenberg ended his presentation by noting that the renal threshold for glucose (RTG; the threshold after which the kidneys begin excreting glucose) may be a better PD measure than UGE.

  • In deciding whether to advance canagliflozin into phase 1, J&J used PK/PD and PB- PK modeling, which predicted that canagliflozin would have greater efficacy than its predecessor T-1095. A PK model predicted that canagliflozin would have greater PK exposure in humans compared to T-1095. Dr. Rothenberg then briefly described the Entelos model, a quantitative model of whole-body metabolism that incorporates parameters from the pancreas, muscle, adipose tissue, liver, intestines, and kidneys. The Entelos model simulated dose-response relationships for 24-hour UGE and predicted that at a given dose, canagliflozin would have greater PD efficacy compared to T-1095 thanks to its higher PK exposure and greater potency for SGLT-2. The Entelos model also predicted the amount of UGE needed to achieve a pre-specified reduction in plasma glucose; this analysis explained why the UGE observed with T-1095 (21 grams/day) was not sufficient to improve hyperglycemia.
  • Dr. Rothenberg reviewed a GI glucose absorption study conducted to better understand canagliflozin’s mechanism of action. Earlier studies had shown that high doses of canagliflozin (>200 mg) reduced postprandial glucose during the first meal after dosing, and that this effect could not be fully attributed to the increase in urinary glucose excretion. Given that canagliflozin has a small affinity for SGLT-1 (an IC50 of 663 nM for SGLT-1 vs. an IC50 of 4 nM for SGLT-2), researchers hypothesized that the drug concentration in the gut lumen following dosing may be sufficiently high to transiently inhibit intestinal SGLT-1. The study results showed that canagliflozin 300 mg delayed the absorption of oral glucose immediately after a meal, but had no meaningful effect on total glucose absorption over the total six-hour, post-meal period. For additional information on canagliflozin’s transient inhibition of SGLT-1, please see page 6 of our ADA oral therapies report at
  • Dr. Rothenberg explained that urinary glucose excretion (UGE) has limited value as a PD measurement because it depends not only on SGLT-2 action, but also on plasma glucose levels and on glomerular filtration rate (which determines the amount of glucose brought into the kidney). He explained that as plasma glucose levels rise, the kidneys reabsorb glucose until a certain threshold – called the renal threshold for glucose (RTG) – above which they begin to excrete glucose. Given that SGLT-2 inhibitors like canagliflozin lower the RTG, measuring 24-hour mean RTG levels may provide a clearer picture of canagliflozin action compared to measuring 24-hour UGE.

Questions and Answers:

Q: Besides trying to develop a first-in-class compound, what are your thoughts on developing a best-in-class compound, considering on one hand the difficulty with dapagliflozin and on the other hand, the very close follow-ups, including lexicon’s dual inhibitor and other inhibitors?

A: As with T-1095, you learn from your mistakes. In general, the lead compound isn’t the best one. There are plenty of opportunities once you’ve blazed the pathway to getting a drug approved, and I remind you that dapagliflozin was submitted to the FDA before canagliflozin. So it’s a very reasonable approach to build on the experience of others to the extent that we can do that internally, or you can do that externally.

Q: Are there any biomarkers you can use early on in the development process to compare your drug?

A: I supposed that if you had a clinical candidate, and you could do something to its PK/PD that would give you greater efficacy, that if you have an early biomarker, you might get an early view before phase 2 or 3 on whether you have benefit. The safety and tolerability would be issues you’d have to explore separately.

Q: Did you look at incretin levels in your glucose absorption study?

A: Yes, and they go in the direction that you’d anticipate. But the data hasn’t been published so I can’t comment.

Biotech Innovation Spotlights


Tom Hughes, PhD (CEO, Zafgen, Cambridge, MA)

Dr. Tom Hughes, CEO of Zafgen, presented preclinical and clinical data on the company’s obesity medication, beloranib, a MetAP2 inhibitor. Zafgen expects the drug to produce weight loss of at least 20%, making it competitive with lap banding. Zafgen has completed three clinical studies (two of which were proof of concept) and is currently running a three-month phase 2a trial in obese individuals, some of who have diabetes. Dr. Hughes stated that these double-blind, placebo controlled studies have uniformly found that people treated with 1-2 mg of beloranib (which is administered as a twice-weekly injection) lose about a kilogram per week, regardless of their baseline weight. We note that this contrasts Qsymia, Belviq, and GLP-1 agonists, which are known for having variable efficacy in different people; it will be interesting to see if beloranib continues to have such consistent efficacy in larger trials. Dr. Hughes also detailed that the drug has been found to be safe and well tolerated, with most adverse events occurring for doses above 2 mg (greater than the 1 mg, maximally effective, dose). These adverse events mainly include difficulty falling asleep and nausea. Zafgen expects to use a REMS program, including potentially limiting distribution to specialty pharmacies (which sounds similar to Qsymia’s certified home-delivery pharmacy network), and to first have the drug indicated for obese people with Prader-Willi syndrome (a rare genetic disorder often associated with obesity). Dr. Hughes explained that the FDA is more willing to accept small studies for this orphan indication, and that the revenue generated from this market could help expand the currently five-person company so that it could tackle the large studies needed for a more general obesity indication. We think this a clever (and noble) way to go about getting the drug indicated for obesity, but wish that the regulatory environment was such that innovative drugs could be more directly brought to the boarder obesity space.

  • Dr. Hughes stated that current treatment options, including those that have been recently approved (we presume he means Belviq and Qsymia), will not be able to meet the increasing need for obesity treatments. Additionally he said that the next likely wave of obesity medication, GLP-1 agonists, have little impact on body weight. Thus, he remarked that while some people may respond to these drugs, there will be many people will not be served.
  • Beloranib works by reducing ERK tone, a regulator of metabolism. Dr. Hughes detailed how when ERK is not inhibited it activates SREB-P, which leads to increased triglyceride and cholesterol synthesis. Additionally, active ERK inhibits RORα-P leading to reduced fatty acid oxidation and increased inflammation. Thus, when left uninhibited, the ERK pathway drives weight gain and resistance to weight loss. However, when ERK tone is reduced by beloranib, Dr. Hughes stated, one sees decreased expression of genes involved in triglyceride and cholesterol synthesis, reduced inflammation, increased fatty acid oxidation, and, finally, weight loss and resistance to weight gain.

Questions and Answers:

Q: Are you going for children or adults with Prader-Willi?

A: We are not completely sure yet. You might know that people with the syndrome who live in group homes can keep proper body weight, but we will target those who are obese. We are interested in children, but will probably start with adults. These people need help and it is just a horrible, horrible situation.

Q: Why not just go to the greater population that needs it?

A: We are a company of five people, so for us to go down a regulatory program that requires a 7,000 people study and a huge financial investment is not currently realistic [laughter]. However, being small, we are nimble and more able to look at these breakthrough targets. The FDA has expressed a lot of interest in this method for bringing a drug to market and is willing to see smaller studies for such indications. So once we get our product on the market for this indication we can use the revenue to then go for a larger indication. Janssen might go straight for the general obesity indication but Zafgen probably wont [laughter].

Q: You mentioned that animals lose weight until they get to a set point and that they stop there? How much information do you have on that, and what would happen if you give it to people at a normal weight?

A: In normal weight animals we found that they did not lose weight or reduce food consumption. In terms of the set point, we expect that people will stay at that lower weight as long as you keep them on the drug. We have a lot more to learn on that topic, but I think that the FDA is realizing that obesity is a chronic condition and that people may need touch-up treatments or to switch drugs.

Q: What about resetting the set point? Do you think that is possible with this drug?

A: I think that would be fantastic if you could do it. But there is evidence that people with obesity have lesions in their hypothalamus and/or genetic predispositions to be obese, which may make resetting the set point difficult. In order to look at that in more detail we will need to do longer studies.

Q: It looks like you have not performed long follow-ups with study participants. Is that true?

A: That is true. As of right now, we have done ten-day follow up, and people do not gain weight back that fast. In the conversations we are having with study centers we are hearing that people do gain weight back, which is hardly a surprise.


Eleftheria Maratos-Flier, MD (Joslin Diabetes Center, Boston, MA)

Dr. Eleftheria Maratos-Flier found that obesity is associated with resistance in FGF21, a growth factor shown it preclinical studies to promote glucose homeostasis and weight loss. Dr. Maratos-Flier presented compelling data showing that mice with FGF21 expression knocked out have heavier, fattier livers, but that if you provide them with exogenous FGF21 this is reversed and their livers tend to look better than that of even wild type mice. She also presented preclinical data showing that FGF21 can induce the browning of white fat (resulting in it being more metabolically active). Dr. Maratos-Flier stated that FGF21 research has been more limited in humans, and that it has been more difficult to find and ascribe a role to FGF21 in humans. She did, however, detail some research demonstrating that FGF21 resistance is likely in obese humans, as people who are obese have higher levels of FGF21, and that people with non-alcoholic fatty liver disease (NAFLD) have higher levels of FGF21 mRNA expression than controls. Thus, in Q&A she hypothesized that if one gave obese humans additional FGF21 it might help overcome their FGF21 resistance, similar to how giving exogenous insulin to people with insulin resistance is beneficial for glucose levels.

Questions and Answers:

Q: Given that you are hypothesizing that humans have FGF21 resistance, do you expect giving them FGF21 will result in the same benefits you get in mice?

A: That is a good question. I have been asking to get FGF21 from companies to test this, but I guess nobody is there yet. Insulin works well for getting over insulin resistance. But until somebody does the experiment in humans we are not really going to know. Still, it works in mice, and we see a dose response.

Q: Thinking of the potential use of this as a therapeutic, I saw a recent paper suggesting FGF21 has a negative impact on bones, which has me concerned, can you comment on its possible effect on bones?

A: That phenomenon has not been seen in species other than the mouse. There might be some osteoporosis in the rat. Nobody has done it for a year. It may be a species effect. I must say that in that paper it looks like the bones are dissolving. There was no report that the mice die early because their bones dissolve; they actually live longer than a normal mouse. I don’t think the authors commented on if the osteoporosis plateaus. It may be that pictures were more dramatic than it really is; it may be that there is some osteoporosis, but that it is not that bad.


Junming Yie, PhD (Senior Scientist, Metabolic Disorders, Amgen, Thousand Oaks, CA)

FGF21 is a member of the fibroblast growth factor family that is highly expressed in metabolic tissues such as the liver, pancreas, adipose tissue, and muscle. Dr. Yie gave a brief introduction to FGF21 signaling, explaining that FGF21 dimerizes to bind to two receptors (beta-Klotho and the FGF receptor) and induces downstream effects in adipose tissue (increases glucose uptake and suppresses lipolysis), in the liver (decreases glucose output and increases lipid beta-oxidation and ketogenesis), and in the pancreas (improves beta cell function and survival). Dr. Yie then turned to preclinical data, noting that acute and chronic studies in multiple mouse models have shown that FGF21 reduces fasting blood glucose levels, decreases fasting insulin levels, improves glucose tolerance and insulin sensitivity, ameliorates obesity and hepatosteatosis, and improves lipid profiles. Dr. Yie ended his presentation by discussing biochemical data on FGF21 cell surface signaling.

Developing the Clinical Impact of Novel Obesity and Dyslipidemia


Margery Connelly, PhD (Scientific Director, Cardiovascular and Metabolic Diseases, Janssen, Titusville, NJ)

Dr. Margery Connelly discussed whether CETP inhibition could provide additional cardiovascular (CV) benefit when used with statins and the current standard of care. She began by noting that data indicate an inverse relationship between plasma HDL-C levels and the risk for coronary artery disease, suggesting that HDL may be cardioprotective – a 1 mg/dl increase in HDL has been associated with a 2%-3% decrease in the risk of heart disease. After the failure of niacin and omega-3 fatty acids to convincingly demonstrate CV benefit, the inhibition of the cholesteryl ester transfer protein (CETP) has emerged as a different mechanism to raise HDL levels. For background, CETP transfers natural lipids between lipoprotein classes and plays a key role in HDL metabolism. While CETP inhibition has been shown to raise HDL levels in preclinical and clinical studies, its CV effects have not been firmly established. Dr. Connelly then discussed clinical studies evaluating CETP inhibition – a phase 2 trial investigating torcetrapib (Pfizer) was halted in 2006 due to the drug’s off-target effects (e.g., increased blood pressure) and an imbalanced rate of CV events and all-cause mortality. While the nonspecific effects were not observed in trials evaluating anacetrapib (Merck) and dalcetrapib (Roche), a CV outcomes study of dalcetrapib was stopped early due to a lack of clinically meaningful efficacy. Dr. Connelly ended her presentation by listing four points that scientists have learned from previous clinical trials (details below).

  • To conclude her presentation, Dr. Connelly cited four insights gained from previous clinical trials investigating CETP inhibition: 1) there is no evidence that CETP inhibition results in abnormally large HDL particles; 2) data show that torcetrapib increases blood pressure;3) rather than enrolling a large study cohort, trials need a better way to predict a drug’s CV effects; and 4) companies may need to be more selective in choosing patients for their clinical trials. Dr. Connelly noted that CETP inhibitors still in development include Merck’s anacetrapib (phase 3), Lilly’s evacetrapib (phase 2), and Dr. Reddy’s DRL17822 (phase 2).

Questions and Answers:

Q: There’s a recent paper showing that endothelial lipase consistently raises HDL, but didn’t provide any cardiovascular benefit. Can you comment on this?

A: The paper that I think you’re referring to is the genetics paper in which patients that had mutations in their endothelial lipase and had higher HDL levels didn’t necessarily show cardioprotection. Personalized medicine would have helped there. Endothelial lipase is upregulated in humans under conditions of inflammation and similar to hepatic lipase, it does effect levels of HDL and apolipoprotein B. The best population to look would be patients with high endothelial lipase levels and high endothelial lipase activity. I don’t think you’ll see an effect of endothelial lipase on CV events unless you looked at that population. In the genetics study, they looked at the overall population of people with a mutation in endothelial lipase – and my argument would be that to see CV benefit, you would have to look at people with obesity, high inflammation levels, and high endothelial lipase levels. Just by looking at the genetics in the whole populations, you probably won’t see an effect.


Bill Washburn, PhD (Senior Research Fellow, BMS, Princeton, NJ)

Dr. Bill Washburn detailed the disappointing development of BMS-830216, an orally bioavailable, phosphate prodrug of the melanin concentrating hormone receptor (MCHR) antagonist BMS-819881. He began with a brief biological overview of the melanin concentrating hormone (MCH), a centrally- acting peptide that regulates feeding homeostasis. Dr. Washburn emphasized that a challenge in drug discovery is not creating potent MCHR antagonists (which is easily done) but creating potent antagonists that are safe enough for clinical studies – he knows of only six compounds that have advanced into the clinic. Dr. Washburn explained that BMS’ first novel MCHR1 antagonist substituted a hydroxyl group for the amine moiety that led to safety concerns (due to hERG inhibition) in other companies’ compounds. After detailing the molecular structure of this first compound, he stated that the agent was discontinued because a toxic metabolite led to the formation of biliary bile duct lesions. Modifying this initial compound to block formation of the metabolite resulted in an improved MCHR antagonist, BMS-819881 and its prodrug BMS-830216. BMS-830216 provided weight loss in rodent models and, in phase 1 trials, was found to be generally safe and tolerable. However, BMS-830216 failed to provide weight loss in phase 1, leading BMS to conclude that MCH is likely not a good target in humans. Dr. Washburn ended his presentation by listing the limitations to studying MCHR antagonists, including the inability to confirm target engagement in humans and the possible redundancy of MCHRs in humans.

Questions and Answers:

Q: Did they see any other changes in the human studies? Was there anything else measured that might have spoken do the pharmacology?

A: We did double labeling studies. It only revealed that this compound increased sensitivity to sunlight. In our in vitro model, it acted as a sensitizer, transferring energy to oxygen. We assume that’s the reason why some individuals showed a slight sensitivity to sun and had a higher propensity for sunburn. But other than that, there was nothing else.

Q: What’s the difference in the receptor structure between rats and humans? Do you have the configuration for that?

A: The homology is pretty high. We don’t think there’s any obvious explanation there. We don’t have a structure of it, so we can’t say that for certain, but based on the conserved sequence, you wouldn’t think that.


Jay Edelberg, MD, PhD (Head, PCSK9 Development and Launch Unit, Sanofi, Paris, France)

Dr. Jay Edelberg opened his presentation by discussing the role of LDL as a specific target and as a risk factor of cardiovascular (CV) disease, noting that numerous studies have shown that lowering LDL with statins reduces the risk of CV disease. However, nearly half the patients in those trials did not reach their LDL goal with statin therapy; furthermore, roughly 5-10% of patients are “statin intolerant” and cannot take statins or intensify treatment sufficiently. Thus, additional LDL-lowering therapies are needed. Dr. Edelberg then discussed the physiologic function of PCSK9 and the rationale for PCSK9 inhibition (details below). He followed with a brief summary of phase 2 results for Sanofi’s PCSK9 monoclonal antibody SAR236553/REGN727 (in partnership with Regeneron), which recently entered phase 3. In the phase 2 trials, SAR236553/REGN727 150 mg was given every two weeks via injection. Pooled phase 2 data showed that the agent lowered LDL by 70% (compared to 6% for the comparator therapy) in patients with hypercholesterolemia (with LDL-C ≥100 mg/dl) already on lipid-lowering therapies. In addition, 98-100% of patients reached a predefined LDL target goal of 100 mg/dl and 90- 97% of patients reached a target of 70 mg/dl (compared to 17% of people on statins). Dr. Edelberg announced that that the phase 3 ODYSSEY program is currently underway and will include 11 global trials with roughly 23,000 patients.

  • Dr. Edelberg briefly reviewed the physiologic role of PCSK9. LDL is cleared from circulation via binding to its receptor, which triggers the internalization of LDL. Once within the cell, LDL receptors are recycled back to the cell surface. PCSK9 binds to the LDL receptor and is internalized along with the LDL particle and once within the cell, triggers the degradation of the LDL receptor. Thus, inhibiting the action of PCSK9 would accelerate LDL clearance from the blood.
  • Dr. Edelberg touched upon the rationale for PCSK9 inhibition. Less than ten years ago, genetic studies found that people with a mutation in a PCSK9 gene exhibited markedly decreased LDL levels and a lower risk of cardiovascular disease. Based on these and other data, Sanofi developed a monoclonal antibody SAR236553/REGN727, which binds PCSK9 and prevents its interaction with the LDL receptor, thus allowing for normal receptor function and LDL clearance.

Questions and Answers:

Q: One of the big things that we got asked at Janssen was about having an injectable for lowering LDL and how patients could handle that. What are your thoughts on patient compliance and how the drug’s delivery would affect that?

A: Without specifically talking about PCSK9 drugs, we’ve seen that injectable therapies have had tremendous benefit in other therapeutic areas, particularly in diabetes with GLP-1 agonists. In rheumatoid arthritis, injectables have also transformed therapy. That is in addition to the unmet medical need and tremendous potential of PCSK9 to decrease LDL and get patients to goal – that’s really where the promise is.

Q: I agree. There’s a much larger patient population not at goal and who can’t use statins. Have you thought about testing for PCSK9 levels in patients as a diagnostic tool?

A: The answer to that lies in the pooled phase 2 data results. In a patient population with hypercholesterolemia, you see up to a 73% reduction in LDL and a large number of patients who can achieve their target goal values. When you look at those percentages, it clearly states that we have the potential to actually deliver that type of benefit to patients, so the answer is really right there.

Comment: It’s incredible, the role of PCSK9 in metabolism.

A: It’s very exciting, and it has been less than 10 year from target discovery to a full phase 3 program underway. I’m just proud to be part of this modern medicine.

-- by Hannah Deming, Nina Ran, and Kelly Close