Brown fat in humans

The CNS-targeting “Class of 2010” drugs

We have not had an article on obesity therapeutics on this blog since February 1, 2011. At that time, we had an article entitled “That’s all, folks!”, complete with the old Warner Brothers Porky Pig graphic. As of that date, all three of the obesity drug candidates that came up for FDA review in 2010-–Vivus’ Qnexa, Arena’s lorcaserin, and Orexigen’s Contrave–were rejected for approval by the FDA, and sent back for further studies. Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. All of these agents targeted the central nervous system (CNS).

Concern about long-term safety was the major consideration in the rejection of the NDAs for Qnexa, lorcaserin, and Contrave, and safety issues were also the reason for the withdrawal of sibutramine. That left only one anti-obesity drug approved by the FDA for long term use– orlistat (Roche’s Xenical), with no new drugs In sight. The outlook for obesity drugs was gloomy indeed.

However, as of May 2012, after the further studies prescribed by the FDA in 2010, two of the obesity drug Class of 2010–Qnexa and lorcaserin have received positive votes by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, and are awaiting final FDA action later this year. Contrave, after a February 6, 2012 agreement with the FDA, appears to be on track for possible NDA resubmission in 2014.

We shall continue to follow progress with the consideration of the resubmitted NDAs for Qnexa and lorcaserin in 2012.

Novel approaches based on the physiology of brown fat

Meanwhile, there is renewed interest in earlier-stage, alternative obesity therapies based on the physiology of brown fat, also known as brown adipose tissue (BAT). The May 1, 2012 issue of The Scientist has an article by the publication’s associate editor Edyta Zielinska entitled “Treating Fat with Fat: Is brown fat ready for therapeutic prime time?”  This article focuses on new discoveries in brown fat physiology, and on entrepreneurial companies that are attempting to develop these discoveries into therapeutics.

On the Biopharmconsortium Blog, we also have an article on brown fat physiology and companies attempting to develop therapeutics based on these findings. The article is dated November 17, 2010. As we state in that article, brown fat researchers and companies are seeking to develop therapeutics that work by increasing energy expenditure, rather than the usual approaches of decreasing appetite (as with the Class of 2010 CNS-targeting antiobesity drugs) or blocking absorption of fat in the gut (as with orlistat).

More specifically, these researchers and companies intend to discover and develop drugs that increase the amount and/or activity of BAT, which is a type of mitochondria-rich adipose tissue that oxidizes fat and dissipates the resulting energy as heat rather than storing it. The mitochondrial protein UCP1 (uncoupling protein 1) is the key biomolecule that makes this process possible. BAT has long been known to be central to non-shivering thermogenesis in rodents, for example to maintain body temperature when they are exposed to cold.

Until recently, researchers believed that in humans, significant populations of BAT cells were found only in infants. However, in recent years researchers found that adult humans possess reservoirs of brown fat in the neck region and other areas of the upper body as well as in skeletal muscle. Adult human BAT can be stimulated by acute exposure to cold and via the sympathetic nervous system, and by various pharmacological agents.

Energesis’ autologous brown adipose tissue transplantation program

Our November 17, 2010 article in particular focused on the Boston-based early-stage company Energesis Pharmaceuticals. Energesis was confounded by Olivier Boss, PhD (formerly of Sirtris Pharmaceuticals), Brian Freeman, MD (former Venture Partner at GreatPoint Ventures), and Jean-Paul Giacobino, MD (Professor Emeritus, University of Geneva Medical School, Switzerland). Dr. Boss serves as Energesis’ Chief Scientific Officer, and Dr. Freeman as its Chief Operating Officer.

Energesis is also mentioned in the new article in The Scientist. According to that article, Energesis is using brown fat “stem cells” (which are precursor cells found in skeletal muscle that can differentiate into either muscle or brown fat) to identify novel targets that activate brown fat. Energesis researchers then work to discover new drugs that address these targets. They are also investigating transplantation of brown fat “stem cells” as an obesity therapy.  According to the article, Energesis is planning to initiate clinical trials of their therapies within 2 to 3 years.

In October 2011, Energesis was awarded a U.S. Department of Defense Small Business Technology Transfer (STTR) grant to develop therapeutics based on autologous BAT transplantation. The project is a feasibility study to define a source and culture system for the generation of human BAT for autologous transplantation therapy. It will involve isolating and characterizing the best brown adipocyte progenitor sub-population from human muscle biopsies, expanding these cells, and establishing the optimal culture conditions for in vitro differentiation to generate approximately 50 grams of BAT cells for transplantation. This project is being conducted in collaboration with Dr. Stephen R. Farmer of the Boston University School of Medicine; Boston University is Energesis’ academic partner on the STTR grant.

According to a January 31, 2012 article in Wired magazine, the U.S. Army’s interest in Energesis’ technology is the result of the growing incidence of overweight and obesity in the Army’s recruit pool, as in young Americans in general. The Army is funding the Energesis/Boston University researchers in the hopes of using autologous BAT transplantation to boost weight loss in military personnel.

According to Brian Freeman, an autologous cell transplantation therapy might also be commercialized for treatment of severely obese individuals in lieu of bariatric surgery. Such an autologous cellular therapy would be analogous to the FDA-approved Genzyme cell transplantation therapy products Carticel and Epicel. It may be easier and faster for Energesis to gain FDA approval for an autologous BAT transplantation product than to develop and gain approval for a drug based on the company’s BAT research. Energesis will therefore pursue both drug discovery and autologous cell transplantation programs, with the strategy to gain early approval and revenues for a transplantation product while it continues to pursue drug discovery and development. Success in development of an autologous transplantation product should also boost the company’s prospects for funding, which would enable its wider R&D programs.

Other approaches to brown adipose tissue-based therapies

The May 1 2012 Edyta Zielinska article begins with a discussion of metabolic diseases start-up Ember Therapeutics. As stated in the article, Ember was founded by Third Rock Ventures partner Lou Tartaglia, a scientist by background who was formerly the Vice President of Metabolic Diseases at Millennium Pharmaceuticals. Ember was launched with $34 million in financing from Third Rock. The company plans to work both on therapeutics based on BAT biology, and on developing a new generation of safer insulin sensitizers for treatment of type 2 diabetes. The latter area of focus is based on studies by Ember scientific founders Dr. Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and Patrick R. Griffin (Scripps Research Institute, Scripps FL) We discussed that work on our blog in an August 29, 2010 article, which was followed by two additional articles on September 16, 2010 and September 21, 2011.

In the January 11 2012 issue of Nature, Dr. Spiegelman’s group reported the discovery of a myokine hormone (i.e., a cytokine produced by muscle cells), which the researchers named irisin. Irisin is named after the Greek goddess Iris, the messenger of the gods. It acts on white adipose cells in culture and in vivo to stimulate what appears to be development into brown fat-like cells. Specifically, irisin stimulates expression of UCP1 and an array of other brown fat genes. Mildly increased blood levels of irisin results in an increase in energy expenditure in mice with no changes in movement or food intake, as would be expected with an increase in brown fat levels. This results in improvements in obesity and glucose homeostasis. Exercise increases levels of blood irisin in mice and humans, leading to the hypothesis that irisin is an “exercise hormone” that mediates at least some of the beneficial metabolic effects of exercise. Irisin is therefore a potential therapeutic for metabolic diseases such as type 2 diabetes and obesity. Ember entered into an exclusive license agreement with Dana-Farber Cancer Institute for the irisin technology, and is optimizing and developing a proprietary molecule based on this technology. This molecule is designed to augment and activate the body’s brown fat. This research constitutes the company’s lead BAT biology program.

On March 28, 2012, Ember also exclusively licensed technology from the Joslin Diabetes Center (Boston, MA) covering bone morphogenetic protein 7 (BMP7), and its role in BAT development. The role of BMP7 in BAT biology was discovered by Ember scientific co-founder C Ronald Kahn, M.D. and his colleagues, who published their findings in Nature in 2008.

In addition to its lead irisin program, Ember is developing a pipeline of biologics (including those based on BMP7) and small molecules designed to increase BAT levels and to activate BAT-specific pathways. According to the article in The Scientist, among the pathways being investigated by Ember are those involving the PRDM-16 transcription factor and FoxC2.

Zafgen’s beloranib (ZGN-433)

Meanwhile, the other obesity start-up founded by Brian Freeman, Zafgen (Cambridge, MA) has been making progress in developing its lead drug candidate, beloranib (ZGN-433). Beloranib, a methionine aminopeptidase 2 (MetAP2) inhibitor, was originally discovered by the Korean company CKD Pharmaceuticals, and was being developed as an angiogenesis inhibitor for treatment of solid tumors. However, the drug was poorly efficacious for this indication in animal models. At much lower concentrations, however, beloranib exerts an antlobesity effect. Zafgen therefore licensed the compound from CKD, and has been developing it as an agent to induce weight loss in severely obese patients.

Beloranib targeting of MetAP2 in vivo results in downregulation of signal transduction pathways within the liver that are involved in the biosynthesis of fat. Animals or humans treated with the drug oxidize fat to form ketone bodies, which can be used as energy or are excreted from the body. The result is breakdown of fat cells and weight loss. Obese individuals do not usually have the ability to form ketone bodies.

In January 2011, Zafgen reported top-line data from a Phase Ib multiple-ascending dose study in which 24 obese women were given 0.9 milligrams/meter(2) of beloranib twice-weekly intravenous. The subjects had a median reduction in body weight of 1 kg/week or 3.1% over 26 days. Treatment with beloranib also reduced triglycerides by 38% and LDL cholesterol (“bad cholesterol”) by 23% from baseline. These results were statistically significant  (p<0.05).

Patients (who were given no instructions regarding diet or exercise) also showed a decline in hunger, and showed no treatment-related serious adverse effects. If sustained (e.g., over a 6-9 month course of treatment in individuals requiring a 20-40 percent reduction in weight) the degree of weight loss seen in this study would be comparable to bariatric surgery.

On July 7, 2011, Zafgen secured a $33 million Series C financing, which was led by the company’s original investor syndicate, including Atlas Venture and Third Rock Ventures. Proceeds from the financing were to be used to support development of Zafgen’s pipeline and especially to advance its lead compound beloranib for the treatment of severe obesity into Phase 2 clinical studies. Zafgen, like Energesis, is operated as a lean virtual company, with only 5 employees. Thus Zafgen should have sufficient cash to advance its beloranib program to the next stage.

Inducing brown fat via modulation of TGFβ signaling

In our November 17, 2010 article, we also mentioned Acceleron Pharma (Cambridge, MA), and its R&D program aimed at brown fat induction via inhibition of signaling by members of the TGFβ (transforming growth factor beta) superfamily. Acceleron is continuing to investigate this approach, and has published a report on this research in the online version of the journal Endocrinology in May 2012. Novartis researchers also published a report on their studies in this area in the online version of the journal Molecular and Cellular Biology.

Conclusions

Despite the doom-and-gloom atmosphere of the obesity drug field in late 2010 and early 2011, with investment bank and business press analysts declaring the field to be “dead”, obesity drug R&D has shown definite signs of life in recent months. NDAs for two of the “Class of 2010” CNS-targeting antiobesity drugs, Qnexa and lorcaserin, have been resubmitted and are up for reconsideration by the FDA later this year. Meanwhile, R&D efforts aimed at producing therapeutics to increase energy expenditure via brown fat induction are progressing, mainly in small entrepreneurial biotech companies. The latter approach, if confirmed by future clinical trials, appears to have a greater likelihood of inducing the degree of weight loss needed to reverse even severe obesity.

Regulatory hurdles–especially safety concerns–were the most significant factor in the failure of the initial NDA submissions of the “Class of 2010” CNS-targeting drugs. The developers of these drugs are working to overcome these hurdles via performing the additional studies mandated by the FDA followed by NDA resubmission. We shall see how well this approach is working when the FDA rules on marketing approval of Qnexa and lorcaserin later this year. Meanwhile, developers of brown-fat targeting therapies are attempting to target severe obesity rather than the general obese population. They are positioning their therapeutics as alternatives to bariatric surgery. They expect that the regulatory hurdles to treating this population will be lower than for the general obese population.

As discussed in several articles on the Biopharmconsortium Blog, the need for antiobesity agents is great, and with the fast accelerating incidence of obesity and its complications, the need is also accelerating. Moreover, our understanding of the pathogenesis of obesity is limited. Thus both continuing basic research and development of agents with novel mechanisms are sorely needed.

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