Hello from La Jolla, CA, where our team has wrapped up the second day of the Keystone Symposia New Therapeutics for Diabetes and Obesity meeting. The small-and-powerful conference is all about the cutting-edge of diabetes and obesity treatments. Polyagonists generated a huge amount of buzz in the first two days, with Dr. Richard DiMarchi (Indiana University, Bloomington, IN) introducing the concept of “increlins” (incretin+insulin receptor agonists) and Sanofi and Lilly presenting phase 1 and phase 2 data, respectively, for their GLP-1/glucagon dual agonists. We also heard an industry perspective (from Novo Nordisk’s Dr. Alan Moses) and a patient perspective (from JDRF’s Dr. Aaron Kowalski) on therapy development in diabetes, were treated to a intensive panel on the latest and greatest controversies in diabetes, and saw a glimpse of what therapeutic targets may be on the horizon for type 1 diabetes and obesity. See below for our top 10 highlights from days #1-2 of the conference and stay tuned for our day #3 report as the conference wraps up!
1. Dr. Richard DiMarchi (Indiana University, Bloomington, IN and most recently Novo Nordisk) introduced the concept of “increlins” and offered a look at impressive preclinical data on their effects on glucose and body weight.
2. Sanofi’s Dr. Philip Larsen presented new phase 1 data for Sanofi’s GLP-1/glucagon dual agonist SAR425899 demonstrating impressive body weight, fasting plasma glucose, and A1c reductions in patients with type 2 diabetes and overweight or obesity (n=36) over 28 days.
3. Lilly’s Dr. David Moller shared phase 2 data (n=420; 24 weeks) for the most advanced GLP-1/glucagon dual agonist to date, its Transition Therapeutics-partnered LY2944876 (TT401).
4. Ms. Nancy Thornberry (Kallyope, New York, NY) moderated a 1.5-hour panel discussion featuring Drs. Philip Home (Newcastle University, Newcastle upon Tyne, UK), Robert Henry (UC San Diego, CA), Alan Moses (Novo Nordisk, Bagsværd, Denmark), and Philip Larsen (Sanofi, Frankfurt, Germany) that addressed the potential of many exciting new therapies and touched on the industry incentives for their development.
5. The dynamic Dr. Aaron Kowalski (JDRF, New York, NY) urged attendees to reframe drug and therapy development in terms of a “diabetes scorecard” that incorporates the glycemic effects, burden, and value of the therapy.
6. With characteristic candor, Dr. Philip Home (Newcastle University, Newcastle upon Tyne, UK) argued that all current type 2 diabetes drugs, including insulin, do not have enough of an effect on glucose lowering.
7. Dr. Home offered his take on the most – and least – promising targets for truly transformative type 2 diabetes therapy.
8. Dr. Alan Moses (Novo Nordisk, Bagsværd, Denmark) provided a candid insider’s view on the challenges of bring a drug from discovery through development to regulatory approval, highlighting Novo Nordisk’s experiences with the development of Tresiba (insulin degludec) and Victoza (liraglutide).
9. Dr. Matthias von Herrath (La Jolla Institute, CA) argued that a combination approach to immunotherapy will be required to slow or prevent type 1 diabetes progression.
10. Dr. Steven Smith (Florida University, Orlando, FL) offered a glimpse at the path forward for development of anti-obesity treatments.
Top Ten Highlights
1. Dr. Richard DiMarchi (Indiana University, Bloomington, IN) introduced the concept of “increlins” and offered a look at impressive preclinical data on their effects on glucose and body weight. He defined increlins as single molecule agonists of the insulin receptor and one or more incretin receptors, such as GLP-1, GIP, or glucagon. Dr. DiMarchi provided an overview of the synthetic pathway (patent application recently published) that transforms a single incretin receptor agonist into a co-agonist with full activity at both receptors. Using this method, Dr. DiMarchi’s team was able to create a GLP-1/GIP/insulin triple agonist. He showed data in pigs and monkeys demonstrating improved glucose control and body weight reductions with the increlin. Notably, the glucose reductions only occurred in the context of high glucose. The triple agonist had greater glucose-lowering and weight loss efficacy in comparison to single agonists of each receptor and dual agonists of various combinations of the three receptors. In mouse studies, the increlin was able to achieve greater and faster blood glucose lowering with <5% of the insulin dose, indicative of its high efficacy and potency. Furthermore, there was no apparent sign of hypoglycemia associated with increlin therapy. Dr. DiMarchi is a true expert at creating multiple agonist therapies (the GLP-1/GIP/glucagon triple agonist derived from his work with Dr. Matthias Tschoep [Helmholtz Zentrum Munchen, Munich, Germany] recently demonstrated promising preclinical results) and Novo Nordisk was very smart to acquire his companies Calibrium and MB2 last year. We assume that Novo Nordisk has development rights to the increlin field, considering the term is trademarked by Calibrium, and we’ll be interested to see if Novo Nordisk will add it to its pipeline in the near future. Up until this week, Novo Nordisk was the only major diabetes drug manufacturer without an incretin-based dual agonist in its early-stage pipeline, though Lilly discontinued development of its phase 2 candidate just yesterday – see our competitive landscape for an overview of other candidates in development. During Q&A, Dr. DiMarchi painted a vision of the future in which a patient taking eight or nine medications to address their diabetes and various other comorbidities could replace many of the therapies with a single polyagonist – a tantalizing vision indeed!
- Dr. DiMarchi suggested that creating a “smart” insulin can involve adding incretin effects to insulin therapy rather than further optimizing the pharmacokinetics of insulin itself. He asserted that insulin “while a miraculous medicine is quite frankly a lousy drug” that requires optimization in terms of stability, time action, delivery, reproducibility, therapeutic index, and pharmacology. Pointing to the remarkably long and flat action of Novo Nordisk’s Tresiba (insulin degludec), Dr. DiMarchi suggested that we are nearing the end of the road in terms of our ability to improve the pharmacokinetics of insulin. He suggested that further optimization of insulin therapy will involve the addition of complementary pharmacology such as GLP-1 agonists, GIP, and possibly glucagon. He even stated that Nordisk’s Xultophy (insulin degludec/liraglutide) is a next step toward “smart insulin,” as it is an insulin-based therapy that decreases insulin dose with no weight gain and a sizable reduction in hypoglycemia. We’re intrigued by this approach and will be interested to see whether it will catch on with others involved in diabetes drug development – we wonder whether it will receive any mention at the upcoming JDRF meeting on glucose-responsive insulin.
2. Sanofi’s Dr. Philip Larsen presented new phase 1 data for Sanofi’s GLP-1/glucagon dual agonist SAR425899 demonstrating promising body weight, fasting plasma glucose, and A1c reductions in patients with type 2 diabetes and overweight or obesity (n=36) over 28 days. Participants on the high dose of SAR425899 experienced a mean weight loss of 5.46 kg (~12 lbs; vs. 2.37 kg [~5.2 lbs] in the placebo-treated group), a mean A1c reduction of 0.59% (vs. a 0.06% increase in the placebo-treated group; baseline A1c 7.5% in the placebo group and a very low 7.2% in the SAR425899 group), and a mean reduction in fasting plasma glucose of 3.04 mmol/l (~55 mg/dl) (vs. 1.24 mmol/l [~22.3 mg/dl] in the placebo-treated group). The trial also met its primary endpoint of safety and tolerability. This four-week, phase 1b study provides the first in-human data we’ve seen for the candidate; the results seem to demonstrate a solid efficacy and safety profile that is more impressive in terms of weight loss than glucose lowering, though we recognize that further longer lasting clinical trials are required to determine whether the impressive weight loss seen for SAR425899 will translate into additional improvement of glycemia on top of what is mediated through its incretin effect. This may be a characteristic of the class as a whole, as Lilly/Transition Therapeutics’ GLP-1/glucagon dual agonist achieved non-inferior A1c reductions and superior weight loss compared to AZ’s Bydureon (exenatide once-weekly) in a phase 2 trial (see below). Preclinical studies in in-human primates had demonstrated superior glucose and weight-lowering efficacy with a relevant surrogate to SAR425899 compared to Novo Nordisk’s market-leading GLP-1 agonist Victoza (liraglutide) and it remains to be seen how this might translate in humans. Based on this profile, we wonder if an obesity or even prediabetes indication might be possible for a GLP-1/glucagon dual agonist, though there would certainly be regulatory/commercial challenges in both cases. Sanofi has previously highlighted SAR425899 as one of its most promising early-stage pipeline candidates (particularly emphasizing its weight loss potential) and we expect that the company will advance the product into phase 2 on the basis of these promising results.
3. Lilly’s Dr. David Moller shared phase 2 data (n=420; 24 weeks) for its Transition Therapeutics-partnered GLP-1/glucagon dual agonist LY2944876 (TT401). The candidate – the most advanced in its class – achieved non-inferior A1c reductions compared to AZ’s Bydureon (exenatide once-weekly) (1.33%-1.44% vs. 1.42%; baseline=8.2%-8.3%). The highest 50 mg dose of the candidate produced weight loss that was significantly great – by 1.3 kg (~2.9 lbs) – than the weight loss seen with exenatide once-weekly (p=0.05) though not comparable to some other drugs already on the market. Indeed, as Dr. Moller acknowledged during Q&A, Lilly announced its decision not to advance the candidate into phase 3 earlier this week. He noted that the decision was strategic and based on the product not meeting Lilly’s specified efficacy bar for advancement and emphasized that “the molecule has a nice profile with no significant safety issues.” Overall, we think this reflects the very high bar for the field – see our take on the decision for more and check out our GLP-1 agonist/glucagon competitive landscape for an overview of the growing industry interest and investment in this area. We wonder if Lilly will pursue a different GLP-1/glucagon dual agonist or another polyagonist candidate in the future. Lilly does list “increlins” as an area of interest on its website and we wouldn’t be surprised if the company pursued a hopefully more potent polyagonist candidate.
4. Ms. Nancy Thornberry (Kallyope, New York, NY) moderated a 1.5-hour panel discussion featuring Drs. Philip Home (Newcastle University, Newcastle upon Tyne, UK), Robert Henry (UC San Diego, CA), Alan Moses (Novo Nordisk, Bagsværd, Denmark), and Philip Larsen (Sanofi, Frankfurt, Germany) that addressed the potential of many exciting new therapies and touched on the industry incentives for their development. The wide-ranging discussion touched on topics including the impact of the recent positive EMPA-REG OUTCOME and LEADER results on diabetes treatment guidelines and practice, the regulatory and payer pressures on innovation, how the artificial pancreas and glucose-responsive insulin might shape diabetes care, drug development for diabetes-related comorbidities such as diabetic nephropathy and NASH – and much, much more. Notably, the discussion often offered a valuable industry perspective on various issues. For instance, the panel suggested that the long-term, expensive studies needed for many diabetes complications pose a barrier to entry for many pharmaceutical companies, though diabetic nephropathy and NASH were highlighted as two comorbidities that were more feasible than many others (such as neuropathy). Dr. Moses noted that Novo Nordisk has taken the leap to performing a long phase 2 study investigating semaglutide for NASH, but he also acknowledged the expensive and high-risk nature of the undertaking. See below for some of the panel’s most illuminating comments.
- On the impact of EMPA-REG OUTCOME and LEADER: Dr. Moses noted that the positive results of EMPA-REG OUTCOME and LEADER demonstrating a cardioprotective benefit for Lilly/BI’s Jardiance (empagliflozin) and Novo Nordisk’s Victoza (liraglutide) will set the bar even higher for new diabetes drugs and make diabetes drug development that much more challenging. Dr. Larsen suggested that the results create an opportunity and expectation for diabetes drugs to address a much broader range of clinically meaningful outcomes beyond A1c. On the other hand, one of Dr. Home’s main takeaways from the EMPA-REG OUTCOME results is that the widely-used three-point MACE endpoint is flawed, as the components went in different directions in that trial. From a clinical perspective, Dr. Henry noted that he expects empagliflozin to eventually receive a privileged position in the diabetes treatment guidelines and shared that the VA has already switched to using empagliflozin as the preferred SGLT-2 inhibitor.
- On the impact of regulatory and payer pressure on innovation: Dr. Larsen reminded attendees that “all innovation comes with a price tag” and that recouping investment costs depends on being able to differentiate new products on the marketplace.
- On CGM and artificial pancreas: The panel was fairly negative on the utility of CGM for patients with type 2 diabetes who are not on insulin therapy. Dr. Home and Dr. Moses both suggested that use of CGM in this population can introduce too much data and actually impose an additional burden on patients without much of a clinical benefit (we wonder if comments like this reflect the latest CGM products). On the other hand, Dr. Home praised the “sense of relief and freedom” patients have reported from the use of automated insulin delivery systems. Dr. Henry echoed this sentiment, noting that patients are “looking for a break from a disease that is every minute of every day.” Boy, are we.
- On innovations in insulin: Dr. Larsen characterized glucose-responsive insulin as the “holy grail” of innovation on the insulin front. Dr. Home agreed that some sort of feedback control of insulin is needed but was less certain about a specific path forward that could achieve that goal. Echoing comments from his presentation at IDF, he argued that we are nearing the end of what’s possible in terms of optimizing the PK profile of basal insulins given the remarkably long and flat action profile of the latest next-generation products. Dr. Henry hopes to see a hepatospecific insulin that better mimics natural insulin secretion, though Dr. Home argued that a peripherally-selective insulin that could increase insulin sensitivity would be more useful. He also pointed to the recent failure of Lilly’s hepatoselective basal insulin peglispro, though Dr. Moses was quick to argue that hepatoselective insulins still have a lot of potential and that research in that area should not be blocked due to the issues with peglispro.
- On obesity: Dr. Moses highlighted Novo Nordisk’s large investment in obesity pharmacotherapies with the development of Saxenda (liraglutide 3.0 mg) and noted that semaglutide is being investigated for its weight-loss properties as well (now in phase 2). Ms. Thornberry later commented that one of her main takeaways from the panel was the renewed industry interest and investment in the obesity area. We’re also glad to see giants with decades of expertise in metabolic diseases like Novo Nordisk making inroads into the long-neglected area of obesity, though we worry that the financial challenges facing companies like Vivus, Orexigen, and Arena could deter other smaller companies from entering this field. Apart from Novo Nordisk, we see little interest in obesity from larger manufacturers.
5. The dynamic Dr. Aaron Kowalski (JDRF, New York, NY) urged attendees to reframe drug and therapy development in terms of a “diabetes scorecard” that incorporates the glycemic effects, burden, and value of the therapy. He suggested that uptake of and adherence to new therapies depends on a delicate balance between “diabetes health” (new tools that treat diabetes) and “diabetes happiness” (being able to live as you did before diabetes). He framed adherence to diabetes therapies as an investment and emphasized the need to make the diabetes health to diabetes happiness ratio worth it for patients. He suggested that, currently, the goals of various stakeholders in the diabetes field (from patients to physicians to payers to manufacturers) can vary widely and that aligning these goals will be important to create transformative therapies. He also reminded attendees that the ultimate metric of success in the development of diabetes therapies is the degree of patient benefit and whether or not outcomes are improved. In order to help keep this focus at the center of the long development process, Dr. Kowalski proposed a “diabetes scorecard” that would integrate various metrics related to glycemic control, burden, and value that are important to people with diabetes (and their loved ones), clinicians, and payers. In a basic science-heavy meeting, Dr. Kowalski’s presentation put the focus squarely back on the patients who will (hopefully) ultimately benefit from the findings presented in other talks and drew attention to the importance of considering the preferences of multiple stakeholders while developing new therapies.
6. With characteristic candor, Dr. Philip Home (Newcastle University, Newcastle upon Tyne, UK) argued that all current type 2 diabetes drugs, including insulin, do not have enough of an effect on glucose lowering. Dr. Home pointed to ADOPT monotherapy data and noted that from a starting A1c of 7.3%, each of the three glucose-lowering agents (rosiglitazone, glyburide, and metformin) was only able to achieve an A1c reduction of about 0.6% and that each arm of the trial eventually returned to its baseline A1c regardless of the agent used. Dr. Home pointed out that a 0.6% A1c reduction from a baseline of 7.3% is only a quarter of the reduction needed to achieve physiologic levels. Never one to mince words, Dr. Home characterized this reduction as “pathetic.” He noted that achieving physiologic glucose levels in type 2 diabetes is rare even with insulin. Interestingly, he argued that this gap between achieved target A1c and physiologic A1c is not due to hypoglycemia concerns, as the majority of patients with type 2 diabetes don’t experience significant hypoglycemia. During Q&A, Dr. Home acknowledged that Dr. Ralph DeFronzo’s triple therapy trial has seen promising results in achieving physiologic A1c and suggested that the approach of initiating multiple drugs at the onset of type 2 diabetes makes a lot of sense in a clinical setting where physicians are often reluctant to titrate up therapy appropriately. That said, Dr. Home noted that Dr. DeFronzo is fairly “rigid” in what combination he uses and implied that the specific drugs used in the combination may not matter as much. We certainly agree with Dr. Home’s overall point that even our best monotherapy medications under the best conditions generally aren’t able to return blood glucose to physiologic conditions. This state of affairs underscores the need for further investment in innovative therapies that can achieve this milestone as well as in prevention initiatives that can reduce the number of people who progress to type 2 diabetes in the first place.
7. Dr. Home offered his take on the most – and least – promising targets for truly transformative type 2 diabetes therapy. He based his picks on the hypothesis that excess caloric intake, rather than obesity in and of itself, causes type 2 diabetes. Dr. Home outlined three major promising mechanisms of action for future therapies: (i) drugs that suppress appetite, (ii) drugs that enhance metabolism, and (iii) drugs that enhance calorie loss. Within the first group, he highlighted PPY or PPY/GLP-1 agonist combinations as having especially potent potential. He was less positive about GLP-1/glucagon dual agonist combinations, suggesting that the class needs more proof of concept trials. GLP-1/glucagon dual agonists have received a significant amount of industry attention and investment in the last year, though as mentioned above, Lilly very recently declined to advance its candidate (partnered with Transition Therapeutics) into phase 3 development after modest phase 2 results. On the metabolism enhancers, Dr. Home suggested that uncoupling agents, while dangerous, could potentially be worth pursuing if it was possible to achieve only 10% of their full effect with a drug. He also highlighted mitochondrial ion pump enhancers and mitochondrial multipliers as promising options. Finally, Dr. Home touched on SGLT-1/2 dual inhibitors and fat or carbohydrate absorption inhibitors as potential targets, though he noted that tolerance may be problematic for these agents. On the flip side, Dr. Home suggested that a host of different types of therapeutic targets are unlikely to yield significant clinical benefits, including G-protein receptor drugs, insulin receptor agonists, 11-beta HSD1 inhibitors, glucokinase activators, glucose-6-phosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon antagonists, and biguanide memetics. Finally, Dr. Home suggested that a new diabetes drug might not need to differentiate itself through glucose lowering if it has another added benefit, highlighting empagliflozin’s benefits on renal outcomes as an example. In a similar presentation at IDF 2015, Dr. Home suggested that benefits like weight reduction (as with GLP-1 agonists), heart failure benefits (as with at least one SGLT-2 inhibitor), blood pressure or LDL-lowering, or anti-inflammatory or anti-thrombotic effects may improve a drug’s chances of achieving success.
8. Dr. Alan Moses (Novo Nordisk, Bagsværd, Denmark) provided a candid insider’s view on the challenges of bringing a drug from discovery through development to regulatory approval, highlighting Novo Nordisk’s experiences with the development of Tresiba (insulin degludec) and Victoza (liraglutide). Dr. Moses provided an overview of the structural improvements that took place over the course of Tresiba’s development to produce a final molecule with a remarkably long and flat profile of action. He emphasized that Tresiba achieved the scientific and clinical goals of a better insulin and that the challenges the product faced came at the regulatory level. In particular, he pointed to the lack of a hypoglycemia claim in Tresiba’s label due to disagreements with the FDA over the definition of hypoglycemia, the open label nature of the trials conducted, and the more selected patient population than the FDA would have liked. As a result, Novo Nordisk embarked on two additional clinical trials – SWITCH 1 and SWITCH 2 – to generate more convincing data in support of a hypoglycemia benefit with Tresiba compared to Sanofi’s Lantus (insulin glargine). These double-blind trials were designed specifically to overcome the issues raised by the FDA. He noted that the improvements in hypoglycemia in patients with type 1 diabetes took the company by surprise, as most hypoglycemia in that population is caused by rapid-acting insulin and Novo Nordisk had not expected an improved basal insulin to have an impact that could be measure for overall hypoglycemia. While the data are certainly encouraging, he was careful to state that the company doesn’t know at this point whether the FDA will find the new data sufficiently acceptable to be included in the label. Dr. Moses also mentioned the FDA’s concerns about a signal for adverse cardiovascular effects with Tresiba, which was the main reason its approval was delayed. He noted that Novo Nordisk was able to ease the agency’s concerns by sharing an interim analysis from the DEVOTE CVOT, but we do not see this as an ideal across-the-board solution due to all the efforts required to ensure that the interim data remains confidential – see our coverage of the FDA’s 2014 public hearing for more on this issue. While Dr. Moses clearly views Tresiba as a significant improvement over existing basal insulin options, he also emphasized that there is still room for innovation in insulins. In particular, he highlighted once-weekly, hepatoselective, and oral insulins as promising avenues of development. He also characterized glucose-responsive insulin as the “holy grail” of insulin innovation.
- In the story of Victoza’s development, Dr. Moses noted that the development program was designed specifically to demonstrate improvement over the many therapies that were already available at the time and was the first comprehensive phase 3 program to take this approach. He described how phase 3 trials for Victoza involved head-to-head comparisons against AZ’s Byetta (exenatide), Merck’s Januvia (sitagliptin), Sanofi’s Lantus (insulin glargine), the sulonylurea glimepiride, and the TZD rosiglitazone. In addition, the clinical advantages of Victoza became even more apparent though the use of the clinically meaningful composite endpoint of A1c <7% with no hypoglycemia or weight gain. The need to demonstrate superiority over several active comparators was a fairly new concept at the time – and, presumably, an expensive one. Even after this ambitious phase 3 program, Victoza still stumbled upon a few regulatory challenges. One of those was the FDA requirement for a post-approval cardiovascular outcomes trial to demonstrate cardiovascular safety, though Dr. Moses acknowledged that its positive results (showing cardiovascular superiority) have made it “more important than we thought originally.” Looking to the future, Dr. Moses suggested that the company’s once-weekly GLP-1 agonist semaglutide will be even more efficacious overall and suggested that its superior efficacy may be related to differences in the two peptides’ access to the central nervous system. We wonder whether this could translate into an even greater benefit on CV outcomes – the answer should arrive soon given that the SUSTAIN 6 CVOT for semaglutide completed in March.
- Dr. Moses also highlighted several changes that he believes can ease the difficult journey from drug discovery to approval. In particular, he advocated focusing on therapies that provide a clinically meaningful difference over existing therapies (we would hope this would be an obvious goal) and investing in understanding the underlying biology. He also called for greater regulatory cohesion and cohesion in how health technology assessments are conducted and emphasized the need to apply available therapies more successfully – this could likely go a long way toward improving outcomes in type 2 diabetes in particular, where many patients still struggle to achieve targets despite the availability of many relatively effective drugs.
9. Dr. Matthias von Herrath (La Jolla Institute, CA) argued that a combination approach to immunotherapy will be required to slow or prevent type 1 diabetes progression. He noted that systematic immunosuppression is unfeasible due to its negative safety and tolerability profile. Instead, he suggested that a combination of an anti-inflammatory systemic therapy and an anti-T cell or anti-B cell therapy will be needed to “reset” autoreactive T-cells and B-cells and suppress inflammation. These therapies will likely have greater side effects, but they are short term, one-time options. Following this reset, combination therapies that maintain tolerance and beta cell function (like an antigen-specific therapy and a GLP-1 agonist) should be used continuously in the longer term. He also suggested that a similar combination could be appropriate for patients early in the progression of type 1 diabetes when the goal could be maintaining beta cell function to slow or prevent progression. This talk echoed Dr. von Herrath’s presentation at an ENDO pre-conference workshop last month and is consistent with the growing consensus in the type 1 cure field that a combination approach will likely be required for truly disease-modifying therapy. Finally, Dr. von Herrath pointed out the need for a biomarker that can help differentiate slow and fast progressors from each other in order to better enroll a more heterogeneous population for clinical trials of the kind of therapies he proposed. Previous trials of promising type 1 diabetes therapies (most notably anti-CD3 therapy) have had late-stage development failures but have shown exciting results in certain subsets of responders. Being able to identify these responders from the outset would save time and money and hopefully encourage further innovation and investment in this area.
10. Dr. Steven Smith (Florida Hospital, Orlando, FL) offered a glimpse at the path forward for development of anti-obesity treatments. He framed obesity therapy in the context of a balance between energy intake, nutrient absorption/loss, and energy expenditure. Dr. Smith described four major mechanisms of action for future anti-obesity therapies: (i) increasing energy expenditure, (ii) wasting energy, (iii) decreasing energy intake, and (iv) nutrient partitioning. He suggested that thermogenic agents may have untapped potential to offset the reduction in energy expenditure associated with weight loss. Other mechanisms to increase energy expenditure included brown adipose tissue activation, mitochondrial uncoupling, substrate cycling, and increasing fatty acid oxidation. On the wasting energy approach, Dr. Smith pointed to SGLT-2 inhibitors (which cause individuals to urinate out excess glucose and calories) and gut microbiome modulators as promising. He also suggested that gut microbiome modulators hold promise to decrease energy intake, as do peptide hormones beyond GLP-1 agonists. While several new anti-obesity drugs have been approved since 2012, uptake of pharmacotherapies in the field as a whole has been extremely slow and it’s clear that more effective therapies that offer more compelling value propositions are needed to convince patients, providers, and payers to adopt them. We’re glad to see a interest in development in this area by at least one major multinational company and hope that the investment bears fruit.
--by Helen Gao, Emily Regier, and Kelly Close