Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Posts filed under: Metabolic diseases

Obesity therapeutics update

Obesity, 12th century Japan.

Obesity, 12th century Japan.

The Biopharmconsortium Blog has over the years included numerous articles about obesity, and the attempts of researchers and companies to develop treatments for this disease.

Obesity, which has historically been considered the result of “lack of willpower” or other behavioral issues, was recognized as a disease by the American Medical Association in June 2013. This followed many years of genetic, molecular biology, and physiological studies that revealed the pathobiological basis of obesity. Nevertheless, many people—including many doctors, patients, and nutritionists—persist in the believing the older view of obesity. This continues to fuel an extremely lucrative diet industry, even thought most—if not all—attempts at dieting eventually fail.

However, researchers and companies have continued in their efforts to develop approved therapies for obesity. We have followed the results of companies that had come close to obtaining FDA approval for three central nervous system (CNS)-acting antiobesity agents in 2010—only to encounter opposition due to safety concerns. However, two of their agents were approved in 2012. Now the third one was approved in September 2014.

Orexigen/Takeda’s Contrave approved by the FDA

On September 11, 2014, Orexigen Therapeutics (La Jolla, CA) and its partner, Takeda, announced that the FDA had approved their antiobesity agent, Contrave (naltrexone HCI and bupropion HCI) extended-release tablets as an adjunct to diet and exercise for chronic weight management in obese adults [body mass index (BMI) of 30 kg/m2 or greater], and in overweight adults (BMI of 27 kg/m2 or greater) who have at least one weight-related comorbid condition (e.g, high cholesterol, Type 2 diabetes, or hypertension).

However, the FDA requires Contrave’s label to carry a boxed warning of increased risk of suicidal thoughts and other psychiatric issues. The label also warns that “The effect of Contrave on cardiovascular morbidity and mortality has not been established.” Orexigen is also required to conduct several post-marketing studies, including studies in pediatric patients, and assessment of the effects of long-term treatment with Contrave on the incidence of major adverse cardiovascular (CV) events in overweight and obese subjects with CV disease or multiple CV risk factors.

The September 2014 approval of Contrave followed the February 2011 issuance by the FDA of a Complete Response Letter requiring extensive clinical studies before Contrave could be approved. In 2010 the FDA had also rejected the applications of two other preregistration antiobesity drugs—Vivus’ Qnexa and Arena Therapeutics’ lorcaserin (Lorqess). Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request.

Concern about long-term safety was the major consideration in all of these cases.

Nevertheless, lorcaserin (rebranded as Belviq) was approved in June 2012, and Qsymia (formerly known as Qnexa) was approved in July 2012.

Thus there are now three CNS-targeting weight-loss drugs on the U.S. market—all of which are “adjuncts to diet and exercise”, all of which work by suppressing appetite, and all of which have safety concerns that require post-marketing studies. Moreover, at least two of these drugs have levels of efficacy less than might be desired. For example, in one trial of Contrave, significant weight loss — defined as the loss of at least 5% of body weight — was achieved by 42% of Contrave-treated subjects, and 17% of subjects in the placebo group. The FDA says that patients taking Contrave should be evaluated after 12 weeks of treatment. Those who have failed to lose at least 5% of their body weight should discontinue Contrave.

Lorcaserin is the least efficacious of these drugs. Qsymia is the most efficacious, with 66.7% of patients on high-dose Qsymia losing at least 5% of body weight, as compared to 17.3% for placebo. The average weight loss in that trial was 10.9% of body weight with high-dose Qsymia and 1.2% with placebo.

A drop in weight of as little as 5% can have positive effects on risk of obesity’s comorbidities (e.g., insulin resistance, diabetes, high blood pressure, dyslipidemia, cardiovascular disease). Nevertheless, all three of these drugs are aids in management of obesity, rather than effective treatments. Moreover, their potential adverse effects are significant. It must be remembered that it was adverse effects that resulted in the withdrawal from the market of several antiobesity drugs (including sibutramine), and prevented the approval of any obesity drugs at all in 2010.

The FDA’s approval of these three drugs indicates that the agency is more willing to make antiobesity drugs available to patients than it has been previously, even in the face of continuing concerns about long-term safety. Rather than rejecting these drugs, the FDA is handling its concerns about safety via post-marketing studies, and restricted distribution of the drugs.

Liraglutide for treatment of obesity?

Meanwhile, Novo Nordisk is awaiting the FDA’s decision on the approval of its high-dose formulation of liraglutide (Saxenda) for treatment of obesity. An FDA advisory board recommended approval of the agent on September 11, 2014. The drug has an October 20 PDUFA date. The advisory board vote was based on Phase 3 results, which indicated that liraglutide produced an average 8% weight loss in obese subjects, when combined with diet and exercise. 69% of prediabetic obese individuals who were treated with liraglutide also showed no signs of prediabetes after 56 weeks, as compared to 33% for the placebo group.

We have discussed the potential use of liraglutide in treatment of obesity on this blog. A lower-dose formulation of this agent, under the trade name of Victoza, is already approved for treatment of type 2 diabetes. Liraglutide is a recombinant protein drug. It is a member of a class of drugs called incretin mimetics. An incretin is a gastrointestinal hormone that triggers an increase in insulin secretion by the pancreas, and also reduces gastric emptying. The latter effect slows nutrient release into the bloodstream and appears to increase satiety and thus reduce food intake. The major physiological incretin is glucagon-like peptide 1 (GLP-1), and incretin-mimetic drugs are peptides with homology to GLP-1 that have a longer half-life in the bloodstream than does GLP-1.

Although liraglutide does not act in the CNS, its major mechanisms of action in treatment of obesity appears to be—like CNS drugs—appetite control. Moreover, clinical trial results indicate that liraglutide is more of an aid in management of obesity than an effective treatment. Nevertheless, liraglutide’s antidiabetic effects and lack of CNS adverse effects constitute potential advantages over CNS-acting antiobesity drugs.

Sales of approved antiobesity drugs have been struggling

Despite the excitement over the approval of antiobesity drugs after so many roadblocks, sales of these drugs have fallen short of estimates. Estimates for Qsymia sales have fallen to $141 million in 2016 from the $1.2 billion projection for 2016 when the drug was approved in 2012. Eisai estimates that Belviq will generate $118 million in sales. Producers and marketers of these two drugs hope that the approval of Contrave will drive patient acceptance of all three CNS-targeting antiobesity drugs. At least one analyst projects that Contrave may achieve $740 million in sales in 2018.

If it is approved, Saxenda may have a sales advantage over the CNS-targeting drugs, since the low-dose formulation, Victoza for type 2 diabetes, is an established drug, with relationships with doctors and insurers already in place. Analysts project that liraglutide (branded as Saxenda) will generate $556 million in weight-loss sales in 2018, in addition to $3.2 billion for the antidiabetic low-dose formulation, Victoza.

A big factor in the level of sales of antiobesity drugs has been insurance reimbursement. It is estimated that some 50 percent of people with private insurance receive at least some coverage for diet drugs. However, insurers tend to classify Qsymia and Belviq as third-tier medications, requiring large patient co-payments. Moreover, Medicare and Medicaid do not pay for the drugs. Analysts hope that the approval of Contrave will result in expanded insurer coverage.

Obesity specialist company Zafgen continues to make progress

The vast majority of efforts to develop antiobesity drugs—over several decades—have been aimed at targeting the CNS. However, obesity is a complex metabolic disease that involves communication between numerous organs and tissues, notably adipose tissue (white, brown, and beige fat), skeletal muscle, the liver, the pancreas, the brain (especially the hypothalamus), the digestive system, and the endocrine system. The pathophysiology of obesity is also related to that of other major metabolic diseases, especially type 2 diabetes.

The mechanistic basis of obesity is not well understood, even though breakthroughs in understanding aspects of this disease have occurred in recent years. Thus there is great need for continuing basic research, and for novel programs aimed at development of breakthrough treatments for obesity based on non-CNS pathways.

One company that has been active in this area is Zafgen (Cambridge, MA), which we have been following on this blog. On June 24, 2014, Zafgen announced the closing of its Initial Public Offering. Zafgen is thus a young company pursuing an alternative approach to antiobesity drug discovery and development that has been able to go public.

In our May 23, 2012 article on this blog, we discussed Zafgen’s lead drug candidate, beloranib (ZGN-433). Beloranib is a methionine aminopeptidase 2 (MetAP2) inhibitor, which exerts an antiobesity effect by downregulating signal transduction pathways in the liver that are involved in the biosynthesis of fat. Animals or humans treated with beloranib 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.

On June 22, 2013, Zafgen announced the interim results of an ongoing double blind placebo-controlled Phase 2 study of beloranib in a group of obese men and women. These results were presented in a poster session at the American Diabetes Association’s 73rd Scientific Sessions in Chicago on June 23, 2013.

Subjects had a mean age of 40.3 years, a mean weight of 101.2 kg (223.1 lbs.), and a mean BMI of 37.9 kg/m2 at the beginning of the study. 38 subjects receiving 12 weeks of treatment in the full trial were randomized to one of three doses of subcutaneous beloranib vs. placebo. The subjects were counseled not to change their usual diet and exercise patterns—this protocol thus differed from trials of the agents discussed earlier in this article. The interim analysis was of results from the first 19 subjects who completed 12 weeks of treatment.

Beloranib appeared safe and showed dose responsive weight loss. After 12 weeks, subjects on 0.6 mg, 1.2 mg, or 2.4 mg of beloranib lost an average of 3.8, 6.1 and 9.9 kg, respectively (8.4, 13.4, and 21.8 lbs.), versus 1.8 kg (4.0 lbs.) for placebo; these results were statistically significant. In addition, beloranib treated subjects showed improvements versus placebo in CV risk factors including levels of triglycerides, LDL cholesterol and C-reactive protein. Sensation of hunger also was reduced significantly.

Subcutaneous beloranib treatment over 12 weeks was generally well-tolerated. There were no major adverse events or deaths.

If later clinical trials confirm these interim Phase 2 clinical results, beloranib may have significant advantages over the three approved CNS-targeting drugs and over Saxenda, because of beloranib’s apparent benign adverse-effect profile, and major effects on weight and fat loss, even in the absence of diet and exercise advice. However, beloranib is years away from reaching the market for treatment of severe obesity with no known genetic causation.

Zafgen is attempting to develop beloranib not only as a superior alternative to “diet drugs”, but also as an alternative to bariatric surgery. In order to obtain approval for that indication, beloranib must (in late-stage, long-term clinical trials) demonstrate both the degree of weight loss and the positive metabolic effects seen in severely obese patients treated via bariatric surgery.

In addition to developing beloranib for severe obesity, Zafgen is developing this drug for treatment of the rare genetic disease Prader-Willi syndrome (PWS). Patients with PWS exhibit such symptoms as low muscle mass, short stature, incomplete sexual development, cognitive disabilities, and a chronic feeling of hunger that can result in life-threatening obesity. PWS is the most common genetic cause of life-threatening obesity. Many children with PWS become morbidly obese before age 5.

In January 2013, the FDA granted Zafgen orphan designation to treat PWS with beloranib. On July 10, 2014, the European Commission also granted orphan drug designation for beloranib for this indication. These regulatory actions were based on the initial results of Zafgen’s Phase 2a clinical trial of beloranib in PWS. This trial showed improvements in hunger-related behaviors and body composition, including reductions in body fat and preservation of lean body mass.

On October 1, 2014, Zafgen announced that it had begun a randomized, double-blind, placebo-controlled Phase 3 clinical trial of beloranib in obese adolescents and adults with PWS (clinical trial number NCT02179151). The company is also testing beloranib in Phase 2 trials in obesity due to hypothalamic injury, and is in preclinical studies with a second-generation MetAP2 inhibitor for treatment of general obesity.

Energesis Pharmaceuticals

The Biopharmconsortium Blog has also been following an earlier-stage company, Energesis Pharmaceuticals (Cambridge, MA), whose approach to developing antiobesity therapeutics is based on targeting brown fat. On June 19, 2014, FierceBiotech and Energesis announced that Janssen Pharmaceuticals and Johnson & Johnson Innovation had entered into a collaboration with Energesis, aimed at identifying agents that stimulate the formation of new brown fat in order to treat metabolic diseases.


The antiobesity drug field, which in 2010 was the domain of a “pall of gloom”, is now populated by three approved CNS-targeting drugs, perhaps to be soon joined by Saxenda. These drugs promise to give patients and physicians a new set of tools to aid in the management of obesity. However, the history of the CNS-targeting obesity drug field is littered with tales of the withdrawal of drug after drug due to unacceptable adverse effects. Moreover, the market—and especially payers—have not yet fully accepted the new antiobesity agents.

As readers of this blog well know, we favor approaches to treatment of obesity and its comorbidities based on targeting somatic physiological pathways that appear to be at the heart of the causation of obesity, not just the CNS. The progress of Zafgen in addressing a set of these pathways is very encouraging. However, these results must be confirmed by Phase 3 clinical trials.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Neandertals, diabetes, and drug discovery

Neanderthal Family

Neanderthal Family

In our 2010 end-of-year blog article entitled “2010: Breakthroughs, Newsmakers, And Deals Of The Year”, we proposed an alternative nominee for the life science breakthrough of the year: the determination of the sequence of approximately two-thirds of the Neandertal genome by Svante Pääbo (Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.) and his colleagues. We stated that this momentous achievement was “of great cultural significance, since it indicates that Neandertals contributed some 1-4 percent of the genome sequences of non-African present-day humans.” (This figure is now thought to be 1.5 to 2.1 percent.)

However, we also said that we had not blogged on this work “simply because it [had] nothing to do with drug discovery and development.” We then further stated that “perhaps someday, for example, some of the products of genes that are found in present-day humans but not in Neandertals could emerge as potential drug targets…researchers [had] begun studying some of these gene products in cell culture systems.”

Now, as of early 2014, one of the genes identified via sequencing Neandertal genomes has been implicated in a novel pathway involved in type 2 diabetes in present-day humans. However, rather than being a modern human gene not present in Neandertals, it is a haplotype that introgressed into modern humans via admixture with Neandertals.

The study that identified this gene initially had no connection with Neandertal genome studies at all. I was published by the SIGMA (Slim Initiative in Genomic Medicine for the Americas) Type 2 Diabetes Consortium in the 6 February 2014 issue of Nature. SIGMA is a joint U.S.-Mexico project funded by the Carlos Slim Foundation. It focuses on several important diseases that have particular relevance to public health in Mexico and Latin America, including type 2 diabetes and cancer. Type 2 diabetes has approximately twice the prevalence in Mexican and other Latin American populations, as compared to U.S. non-Hispanic whites.

The researchers performed a genome-wide association study (GWAS), in which they analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans, including 3,848 with type 2 diabetes and 4,366 non-diabetic controls. As a result of that analysis, the researchers replicated the identification of haplotypes previously associated with type 2 diabetes. They also identified a novel locus associated with type 2 diabetes at genome-wide significance.  This locus spans the genes that encode the solute carrier proteins SLC16A11 and SLC16A13. The risk haplotype carries four amino acid substitutions, all in SLC16A11.  It is present at approximately 50% frequency in Native American individuals and around 10% in East Asians, but is rare in Europeans and Africans.

Each copy of the risk newly-identified haplotype is associated with an approximately 20% increased risk of type 2 diabetes. The haplotype would thus be expected to contribute to the higher burden of type 2 diabetes in Mexican and Latin American populations. Mutations in SLC16A11 had never before been associated with type 2 diabetes. SLC16A11 thus represents a novel type 2 diabetes pathway.

The Neandertal connection

The researchers noted that the sequence of the risk haplotype is highly divergent, with an estimated time to the most recent common ancestor of both the novel haplotype and a European haplotype of 799,000 years. This is long before modern humans migrated from Africa into Eurasia. Moreover, the novel haplotype is not found in Africans and is rare in European populations. The researchers therefore hypothesized that the novel haplotype entered modern human populations via admixture with Neandertals.

At the time that this research was being conducted, the variant was not seen in published Neandertal (or Denisovan) genome sequences. However, with the help of Svante Pääbo, the researchers obtained access to a then-unpublished full-length Neandertal genome sequence from a Central Asian specimen. The Central Asian Neandertal genome sequence was homozygous across 5 killobases for the risk haplotype including all four missense SNPs in SLC16A11 . Over a span of 73 kb, the Neandertal sequence is nearly identical to that of individuals from the 1000 Genomes Project who are homozygous for the risk haplotype. The full-length Central Asian Neandertal genome has recently been published.

Moreover, the genetic length of the 73-kb risk haplotype is longer than would be expected if it had undergone recombination for the approximately 9,000 generations since the split with Neandertals. This is consistent with the hypothesis that the risk haplotype is not only similar to the Neandertal sequence, but was probably introduced into modern humans relatively recently through archaic admixture. Although this particular Neandertal-derived haplotype is common in the Americas, Native Americans and Latin Americans have the same proportion of Neandertal ancestry genome-wide as other Eurasian-derived populations. In general, although non-African populations have about the same percentage of Neandertal genes, different populations have different complements of genes derived from Neandertals.

Functional studies of SLC16A11

Although the risk haploype encodes four missense mutations in a single gene, the gene for SLC16A11, there is no formal genetic proof that SLC16A11 is responsible for increased risk of type 2 diabetes. Therefore, the researchers performed preliminary functional studies of SLC16A11.

Via immunofluorescence studies, the researchers found that SLC16A11 was expressed in the liver, the salivary glands and the thyroid. When the gene for SLC16A11 was introduced into HeLa cells, SLC16A1 was found to localize in the endoplasmic reticulum, but not in the plasma membrane, Golgi apparatus, or mitochondria. Other SLC16 family members show distinct intracellular localization pattern within the membranous structures of the cell.

SLC16A11, and other SLC16 family members, are solute carrier transporters (SLCs). We discussed SLCs and their role in transporting small-molecule nutrients and drugs across the blood-brain barrier in our 2009 book-length report, Blood-Brain Barrier: Bridging Options for Drug Discovery and Development, published by Cambridge Healthtech Institute. We also discussed SLCs in a 2009 article entitled “Strategies to Overcome Blood-Brain Barrier” in Genetic Engineering and Biotechnology News.

SLC16 family proteins are monocaboxylate transporters, which transport such compounds as lactate, pyruvate and ketone bodies, as well as thyroid hormone and aromatic amino acids, across biological membranes. As of 2008, of the 14 known members of this family, eight (including SLC16A11) had unknown functions.

The SIGMA researchers expressed SLC16A11 (or control proteins) in HeLa cells, and looked for changes in intracellular concentrations of approximately 300 polar and lipid metabolites. Expression of SLC16A11 resulted in substantial increases in intracellular triacylglycerol (triglyceride) levels, with smaller increases in intracellular diacylglycerols, and decreases in lysophosphatidylcholine, cholesteryl esters, and sphingomyelin. Since triglyceride synthesis occurs in the endoplasmic reticulum of hepatocytes, the researchers hypothesized that SLC16A11 may have a role in hepatic lipid metabolism.

Moreover, serum levels of triglycerides and accumulation of intracellular lipids are associated with insulin resistance, the metabolic syndrome, and the risk of developing type 2 diabetes. Thus, although further functional studies of SLC16A11 are needed, the researchers hypothesize that the novel risk allele for type 2 diabetes that they identified may exert its pro-diabetic effect by altering lipid metabolism in the liver.


This study, a GWAS in Mexican and other Latin American samples, is an illustration of how genetic mapping studies in understudied populations may identify previously undiscovered aspects of disease pathogenesis.

The risk gene identified in this study, SLC16A11, has not previously been associated with type 2 diabetes. It thus potentially represents a novel diabetes pathway, which might yield new targets for drug discovery. This new pathway might be important in type 2 diabetes not only in Native Americans and Latin Americans, but in other populations as well, even in those that lack mutations in SLC16A11.

The study initially had nothing to do with Neandertal genetics. However, the researchers noted unusual population genetics features of the risk haplotype that they identified, which led them to identify this haplotype as having entered modern human populations via introgression from Neandertals. Via the initial introgression, natural selection and/or genetic drift, the haplotype became fixed in Native Americans and some East Asians, but not in other Eurasian-derived populations such as Europeans and Euro-Americans.

It is extremely unlikely that either Neandertals, or Native Americans and Latin Americans in pre-modern times, had type 2 diabetes. However, modern diets, perhaps in concert with other risk genes, produced type 2 diabetes in carriers of the mutant SLC16A11 gene. The well-know case of the Pima Indians indicates that change from native diets and high levels of physical activity to processed foods and a more “Western” lifestyle is the major cause of the high levels of type 2 diabetes and obesity in this genetically-predisposed population. (It is not known, however, whether SLC16A11 is a factor in Pima Indians.)

As for studies of the Neandertal genome, John Hawks, Ph.D. (University of Wisconsin), an anthropologist who has been active in studies of the genetics of Neandertals and of Upper Paleolithic modern humans, believes that studies of the genomes of these ancient peoples may have relevance for the biology of present-day humans. [I took a Massive Open Online Course (MOOC) led by Dr. Hawks, entitled “Human Evolution: Past and Future” between late January and early March, 2014.]

Other researchers who study ancient genomes generally agree. As indicated by the SIGMA diabetes study, both genes for modern humans that were not present in Neandertals, and genes introgressed from Neandertals into modern humans may be relevant to modern human biology—and perhaps eventually to drug discovery.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Zafgen makes progress in development of obesity drug beloranib

Methionine aminopeptidase 2. Source: PDBbot.

Methionine aminopeptidase 2. Source: PDBbot.

On November 15, 2013 obesity specialty company Zafgen (Cambridge, MA) announced the results of its Phase 2 study of beloranib in a press release.

We discussed beloranib (ZGN-433) in our May 23, 2012 article on the Biopharmconsortium Blog. Beloranib is a methionine aminopeptidase 2 (MetAP2) inhibitor. 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.

The results of the Phase 2 study of beloranib

The Phase 2 study of beloranib (clinical trial number NCT01666691) was presented at Obesity Week 2013 in Atlanta, GA. It was a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of a range of doses of beloranib administered as twice-weekly subcutaneous injections for 12 weeks. The trial enrolled 147 subjects, of which 122 completed the study. They were mainly obese women with a mean age 48.4 years, a mean body weight of 100.9 kilograms (222.45 pounds), and a mean body mass index (BMI) of 37.6 kg/m2. (On the average, these subjects had grade 2 obesity, as measured by BMI.) The subjects in this four-armed study were treated with one of three doses of the drug, or with placebo. They were given no instructions regarding diet or exercise.

After 12 weeks of treatment, subjects lost from an average of 5.5 kilograms (12.1 pounds) (on 0.6 mg of drug twice-weekly) to 10.9 kilograms (24.03 pounds) (on 2.4 mg of drug twice-weekly), as compared to 0.4 kilograms (0.88 pounds) in the placebo group. These results were statistically significant. The study also showed that weight loss with beloranib was progressive and continuing at week 12. Subjects experienced a reduced sense of hunger, with improved cardiometabolic risk markers (e.g., lowered LDL, triglycerides, and blood pressure, and increased HDL). The drug was generally well-tolerated.

The study showed no serious adverse effects that were deemed to be related to beloranib treatment. The most common adverse effects with a higher incidence rate in those taking beloranib vs. placebo were nausea, diarrhea, headache, injection site bruising, and insomnia. These adverse effects were generally mild, transient and self-limiting.

The researchers who conducted the study concluded that the Phase 2 results suggest that beloranib has the potential to be an effective and promising treatment for severe obesity.

Zafgen secures $45 million in Series E financing

On December 4, 2013 Zafgen announced in another press release that it has secured $45 million in a Series E equity financing. New investors include RA Capital Management, Brookside Capital, Venrock, Alta Partners, an undisclosed blue chip investor, and a private investor.  These investors join the Zafgen’s previous backers, which include Atlas Venture and Third Rock Ventures. With the new financing, Zafgen has brought its total funding to date to $114 million.

Proceeds from Zafgen’s Series E financing will be used to support the continued development of beloranib.


As we have discussed earlier on this blog, despite the approvals of several antiobesity agents that work via the central nervous system, obesity treatments remain inadequate. This is especially true in the case of severe obesity. With the rapid worldwide acceleration in incidence of obesity and its complications, the need for more effective therapies 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.

The results of the Phase 2 study with beloranib are promising, but as usual must be confirmed by Phase 3 clinical studies.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Agios Pharmaceuticals becomes a clinical-stage company!

Agios Efstratios, Greece. Source: Christef

Agios Efstratios, Greece. Source: Christef

In a news release on September 23, 2013, Agios Pharmaceuticals (Cambridge, MA) announced that it had initiated its first clinical study. The company further discussed its early clinical and preclinical programs in its press release on its Third Quarter financial report, dated November 7, 2013.

Specifically, the company initiated a Phase 1 muticenter clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of orally-administered AG-221 in this patient population. The first stage of the Phase 1 study is a dose-escalation phase, which is designed  to determine the maximum tolerated dose and/or the recommended dose to be used in Phase 2 studies. After the completion of this phase, several cohorts of patients will receive AG-221 to further evaluate the safety, tolerability and clinical activity of the maximum tolerated dose.

We discussed AG-221 in our June 17, 2013 article on this blog. AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

As we summarized in our June 17, 2013 article, wild-type IDH1 and IDH2 catalyze the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant forms of IDH1 and IDH2, which are found in certain human cancers, no longer catalyze this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). Agios researchers hypothesized that 2HG is an oncometabolite. They further hypothesized that developing mutant-specific small molecule inhibitors of IDH1 and IDH2 might inhibit the growth or reverse the oncogenic phenotype of cancer cells that carry the mutant enzymes.

As we further discussed in our article, Agios researchers published two articles in the journal Science in May 2013 that support these hypotheses. The researchers showed that drugs that inhibit the mutant forms of IDH1 and IDH2 can reverse the oncogenic effects of the mutant enzymes in patient-derived tumor samples. These results constitute preclinical support for the hypothesis that the two mutant enzymes are driving disease, and that drugs that target the mutant forms of the enzymes can reverse their oncogenic effects.

In the results reported in one of these research articles, Agios researchers tested a mutant-IDH2 inhibitor in hematologic malignancies (including one model leukemia and one patient-derived leukemia), and showed that treatment with the inhibitor caused differentiation of the leukemic cells to normal blood cells. This preclinical study thus supports the initiation of Agios’ new Phase 1 study of AG-221 in patients with mutant-IDH2 bearing hematologic malignancies.

Additional pipeline news in Agios’ Third Quarter 2013 Report

In addition to the report of the initiation of Phase 1 studies of AG-221, Agios reported  that it had advanced AG-120, a mutant-IDH1 inhibitor, toward Investigational New Drug (IND) filing. The company plans to initiate Phase 1 clinical trials of AG-120 in early 2014, in  patients with advanced solid and hematological malignancies that carry an IDH1 mutation.

Agios also reported in their Third Quarter 2013 Report that the company had advanced AG-348 into IND-enabling studies. AG-348 is an activator of pyruvate kinase R (PKR). Germline mutation of PKR can result in pyruvate kinase deficiency (PK deficiency), a form of familial hemolytic anemia. Agios’ in vitro studies indicate that PKR activators can enhance the activity of most common PKR mutations, and suggest that these compounds may be potential treatments for PK deficiency.

Agios’ AG-348 program is part of its R&D aimed at development of treatments for inborn errors of metabolism (IEM). We discussed this program in our November 30, 2011 article on this blog.

Agios to present preclinical research at the ASH meeting in December 2013

In a second November 7, 2013 press release, Agios announced that it would present the results of the preclinical studies of its lead programs in cancer metabolism and in IEM at the 2013 American Society of Hematology (ASH) Annual Meeting, December 7-10, 2013 in New Orleans, LA.

Agios researchers will give one presentation on a study of AG-221 treatment in a primary human IDH2 mutant bearing acute myeloid leukemia (AML) xenograft model. They will also present two posters–one on a mutant-IDH1 inhibitor in combination with Ara-C (arabinofuranosyl cytidine) in a primary human IDH1 mutant bearing AML xenograft model, and another on the effects of a small molecule activation of pyruvate kinase on metabolic activity in red cells from patients with pyruvate kinase deficiency-associated hemolytic anemia.

Can Agios Pharmaceuticals become a new Genentech?

On October 13, 2013, XConomy published an article on Agios’ CEO, David Schenkein. The article is entitled “David Schenkein, Cancer Doc Turned CEO, Aims to Build New Genentech”.

As many industry experts point out, the business environment is much different from that in which Genentech (and Amgen, Genzyme and Biogen) were founded, and grew to become major companies. As one illustration of the difference between the two eras, neither Genentech nor Genzyme are independent companies today. Biogen exists as a merged company, Biogen Idec, which between 2007 and 2011 had to fend off attacks by shareholder activist Carl Icahn.

Moreover, this has been the era of the “virtual biotech company”. These are lean companies with only a very few employees that outsource most of their functions, and that are designed to be acquired by a Big Pharma or large biotech company. The virtual company strategy has been designed to deal with the inability of most young biotech companies to go public in the current financial environment. (However, there has been a surge in biotech IPOs in the past year, including Agios’ own IPO on June 11, 2013. So it is possible that the environment for young biotech companies going public is changing.)

Nevertheless, the XConomy article states that when Dr. Schenkein was in discussions with venture capitalist Third Rock on becoming the CEO of one of their portfolio companies, he stated that he wanted “a company with a vision, and investor support, to be a long-term, independent company”. As we have discussed in this blog, and also in an interview for Chemical & Engineering News (C&EN), Agios’ strategy is to build a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance. This strategy has been characterized (especially in the 1990s and early 2000s) as “Built to Last”, a term that I used in the interview.

Later, Agios posted a reprint of the C&EN article on its website, which it retitled “Built to Last”. This illustrates Agios’ commitment to “Built to Last”, as is more importantly shown by the company’s financial and R&D strategy.

Even if Agios cannot become the next Genentech, it–as well as a few other young platform companies mentioned in the CE&N article–might become an important biotech or pharmaceutical company like Vertex. However, all depends on the success of Agios’ products in the clinic and at regulatory agencies like the FDA, as well as the future shape of the corporate, financial and health care environment.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Obesity, sarcopenia, aging, and health


In our  June 25, 2010 article on the Biopharmconsortium Blog, we discussed the “contrarian” views of Dr. Katherine M. Flegal and her colleagues at the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC) on the epidemiology of obesity.

According to Dr. Flegal, based on epidemiological data from the National Health and Nutrition Examination Survey (NHANES), people in the overweight class have a lower risk of death than those in either the normal weight or the obese class. These weight classes are determined on the basis of the body mass index (BMI), with underweight at <18.5, normal weight at 18.5-24.9,  overweight at 25-29.9, and obesity at >30.

Dr. Flegal’s conclusions–as summarized in our 2010 article–were mainly based on work published in the 2005-207 period, as well as other analyses of her results published between 2005 and 2010. In January 2013, Dr. Flegal and her colleagues published a report in the Journal of the American Medical Association. This report was based on an analysis of a wide variety of published reports indexed in PubMed and EMBASE that reported all-cause mortality for weight categories based on standard BMI categories.

In this study, the researchers compared all-cause mortality in the normal weight class (BMI 18.5-24.9) with that in the overweight (BMI 25-<30), grade 1 obese (BMI of 30-<35) and grade 2 and 3 obese (BMI of ≥35) classes. They came to similar conclusions as in their earlier studies. Specifically, both obesity (all grades) and grades 2 and 3 obesity were associated with significantly higher all-cause mortality as compare to normal weight. Grade 1 obesity was not associated with higher all-cause mortality, and overweight was associated with significantly lower all-cause mortality.

Reactions to Dr. Flegal’s 2013 study

As usually happens when one of Dr. Flegal’s “contrarian” studies is published, other leaders of the obesity epidemiology and nutrition community who hold the “majority” view react strongly against it. This was detailed, for example, in a feature article  in the 23 May issue of Nature written by science writer Virginia Hughes. On 20 February 2013, a meeting was held at the Harvard School of Public Health “to explain why [Dr. Flegal’s new study] was absolutely wrong”. The organizer of the meeting, Dr. Walter Willett, said in an earlier radio interview, “This study is really a pile of rubbish, and no one should waste their time reading it.” At the meeting, speaker after speaker got up to criticize the Flegal study.

The major concern of Dr. Willett and the other speakers was that Dr. Flegal’s study (and the commentary on that study in the popular press) would serve as a license for the general public and for doctors to let up on weight loss programs, and to undermine public policies aimed at curbing the rate of obesity. Dr. Willett was also concerned that the Flegal studies might be “hijacked by powerful special-interest groups, such as the soft-drink and food lobbies, to influence policy-makers”.

Nevertheless, as also detailed in Ms. Hughes’ article, other researchers accept Dr. Flegal’s results, and see them as part of the evidence for what they call “the obesity paradox”. Although for the general population overweight increases one’s risk of type 2 diabetes, cardiovascular disease, and cancer, overweight in some populations may not be harmful and may even lower the risk of death. These populations especially include people over 50 and especially those over 60 or 70, as well as patients with cardiovascular disease or cancer. We also discussed the decreased association of mortality with weight in older people in our June 25, 2010 article.

Explaining the “obesity paradox”, and the need for better metrics than BMI

In the 23 August issue of Science, Rexford S. Ahima, M.D., Ph.D. and Mitchell A. Lazar, MD., Ph.D. (both metabolic disease researchers at the Perelman School of Medicine, University of Pennsylvania, Philadelphia PA) published a Perspective entitled “The Health Risk of Obesity—Better Metrics Imperative”. The goal of this essay was to enable researchers to find better means to study and to explain the “obesity paradox”, and to use the results of their studies to improve the health of patents with metabolic diseases and their complications (e.g., cardiovascular disease).

These researchers noted that although it is easily measured and widely used, BMI does not adequately measure body composition (especially the proportion of muscle and fat) and the distribution of fat in the body. These factors may be especially important for such health outcomes as development of insulin resistance and type 2 diabetes, and cardiovascular risk. Other researchers, notably Dr. José Viña and his colleagues at the University of Valencia in Spain, who wrote a critical response to Dr. Flegal’s 2013 article, came to similar conclusions. The Spanish researchers criticized Flegal’s studies because they were based on BMI. However, unlike Dr. Willett, they accept the validity of the “obesity paradox”.

Notably, the Ahima and Lazar article includes a figure that shows metabolically healthy people with  normal and obese BMIs, and contrasts them with metabolically unhealthy people with normal and obese BMIs. The main difference between metabolically healthy versus unhealthy people (whatever their BMI) is muscle mass and fitness. The unhealthy subjects exhibit muscle loss, or sarcopenia, and reduced fitness.

The authors note that skeletal muscle accounts for the majority of glucose disposal. Thus loss of muscle mass, or sarcopenia, due to aging and/or physical inactivity, can result in reduced insulin sensitivity, development of diabetes, and poor cardiovascular health. This applies people with poor metabolic health, whether they have apparently normal BMIs or are obese. Metabolically unhealthy individuals–whether of normal BMI or obese–also have excess visceral fat. Excess visceral fat is associated with the metabolic syndrome and development of type 2 diabetes and cardiovascular disease.

Drs. Ahima and Lazar call for better metrics than BMI, in order to assess a patient’s risk of metabolic disease. They cite the “body shape index”, which quantifies abdominal adiposity (and thus visceral adiposity) relative to BMI and height as potentially a better predictor of mortality than BMI. The body shape index is based on measuring waist circumference, and adjusting it for height and weight. They further call for the development of “accurate, practical, and affordable tools to assess  body composition, adipose hormones, myokines, cytokines, and other biomarkers” to use in assessing obesity and other metabolic disorders in order to determine the risk of developing diabetes and cardiovascular disease, and the risk of mortality.

Appreciating the role of muscle mass in health and disease

The analysis of Ahimsa and Lazar also suggests the hypothesis that loss of muscle mass–sarcopenia–due to aging and/or lack of exercise may be a key factor in the development of obesity-related diseases.

There are at least two other recent reports that focus on sarcopenic obesity. The first, a 2012 paper in Nutrition Reviews entitled “Sarcopenic obesity in the elderly and strategies for weight management” is authored by Zhaoping Li, M.D., Ph.D. and David Heber, M.D., Ph.D. of the Center for Human Nutrition, David Geffen School of Medicine, University of California at Los Angeles. The second paper, entitled “Sarcopenic obesity: strategies for management”, by Melissa J. Benton, PhD, MSN and her colleagues (Valdosta State University College of Nursing, Valdosta, GA) was published in 2011 in the American Journal of Nursing. The first of these reports is a scientific review article, while the second is a practically-oriented report for nurses (carrying continuing education credits); the lead author is a nurse with advanced training in education, sports medicine, and gerontology.

The Li and Heber paper covers much of the same ground as the Ahimsa and Lazar Science Perspective, with respect to the inadequacy of BMI as a metric for obesity, and the need to have better measures of body composition (especially with respect to fat versus skeletal muscle). However, it goes beyond this concern for metrics, by focusing on “sarcopenic obesity”, its relationship with a sedentary lifestyle and with aging, and how sarcopenic obesity might be treated.

Loss of muscle mass as a function of aging in sedentary individuals results in age-associated decreases in resting metabolic rate and muscle strength, and is also a major factor in decreases in activity levels.  These factors result in the decreased energy requirement in aging individuals. If (as is usual) calorie intake does not decrease to match the decreased energy requirements, obesity (i.e., accumulation of excess body fat) results. Sarcopenic obesity in aging individuals is associated not only with type 2 diabetes and other metabolic and cardiovascular diseases, but also with loss of independence and increased risk of mortality. It is a major public health challenge in the over-65 population.

Li and Heber discuss various means to measure body composition, and thus to diagnose sarcopenia and sarcopenic obesity. They then go on to discuss ways to treat this condition, via emphasizing resistance training and increased intake of protein, in order to increase muscle mass and the resting metabolic rate. The authors cite resistance training as “the most effective intervention for reversing sarcopenia in the elderly”. Based on evidence in the field, the authors also hypothesize that increased dietary protein (especially the use of protein supplements or meal replacements) is also important in building muscle mass and as a result reducing fat mass.

It is known that increased dietary protein results in maintenance of muscle mass during calorie-restricted diets, as compared to diets with “normal” or inadequate intakes of protein. However, the authors see the need for more research to determine whether a high-protein diet (up to 35% of caloric intake) will be beneficial in improving muscle anabolic responses to resistance exercise in older adults.

The Benton et al. paper also emphasizes the role of resistance training and a high-protein diet in treatment of sarcopenic obesity. However, being a practically-oriented nursing article, it gives specific recommendations for exercise, as well as sources of high-quality protein in the diet. (This article focuses on high-protein foods, not protein supplements.)

This article also states that nurses should be knowledgeable about sarcopenic obesity and its management. They should also educate older patients on utilizing resistance training and dietary protein to prevent or reverse sarcopenia and sarcopenic obesity. This education should also apply to educating now-healthy aging adults on the need to prevent these conditions, since prevention is easier than reversing sarcopenic obesity once it has developed.

It would seem that not only nurses, but also primary care physicians and other doctors need to be aware of these issues as well.

The Benton et al. paper also wisely counsels that patients contemplating diet and exercise programs such as recommended in their article should first consult with their primary care physician. We agree with this recommendation. We also once again emphasize that this blog does not exist to give diet or exercise advice, or to receive comments or guest posts that purport to give such advice.

However, you are welcome to use this article, or better yet the publications we have cited herein, to help your primarily care provider to be aware of issues involving sarcopenic obesity. Some medical facilities also include physical therapists and/or access to gyms with trainers who can help patients with exercise programs, once one’s primary care physician has been consulted.


1. Currently marketed drugs for obesity–and for such conditions as type 2 diabetes, dyslipidemia, and other metabolic diseases that are usually found in obese individuals and metabolically unhealthy individuals with normal BMI–are generally prescribed as adjuncts to diet and exercise. “Diet and exercise” generally means the types of hypocaloric diets and aerobic exercise conventionally prescribed for weight loss. Researchers and physicians may need to take sarcopenic obesity into account when prescribing these drugs for patients with this condition, and in designing and conducting clinical trials. Diet and especially exercise recommendations may be different for patients with sarcopenic obesity than the current recommendations.

2. We have discussed “alternative” (i.e., non-CNS  or gut targeting) antiobesity therapies now in development in several articles on this blog. Unlike CNS-targeting drugs [e.g., lorcaserin (Arena’s Belviq) and phentermine/topiramate (Vivus’ Qsymia)], which are aimed at curbing appetite, these novel therapeutics are designed to increase energy expenditure or to inhibit the biosynthesis of fat. These drugs, if and when they are approved, will be indicated for patients with extreme obesity, such as those who may currently be candidates for bariatric surgery.

Similarly, we have discussed Novartis’ bimagrumab, an anti-muscle wasting drug now entering Phase 3 clinical trials in patients with the rare muscle wasting disease sporadic inclusion body myositis (sIBM). Bimagrumab is also in Phase 2 clinical trials in sarcopenic older adults with mobility limitations. If and when this drug is approved, it will be at least initially indicated for patients with sIBM, and perhaps eventually for older adults with severe sarcopenia (with or without obesity) that has resulted in mobility limitations.

It will be an extremely long time–if ever–before such drugs are approved for the broader obese and obese-sarcopenic population (or those at risk for these conditions). The diet and resistance exercise approaches discussed in this article may be appropriate for many in this broader group of individuals, and are free of drug-related adverse effects. They may also prevent the development of extreme obesity and its complications, as well as loss of independence due to sarcopenia or obese sarcopenia.

3. We have also discussed the development of anti-aging therapies in various articles in this blog. This field has generated a lot of interest in the news lately, because of Google’s launch of the anti-aging company Calico. As we discussed, for example, in our August 15, 2013 aging article, no pharmaceutical company can run a clinical trial with longevity as an endpoint. Companies must test their drugs against a particular aging-related disease. Many such companies test their agents (e.g., drugs that target sirtuins) against type 2 diabetes.

Why develop an “anti-aging” drug for type 2 diabetes rather than a specific antidiabetic drug? The hope is that an “anti-aging” drug approved for treatment of, for example, type 2 diabetes, will have pleiotropic effects on multiple diseases of aging, and will ultimately be found to increase lifespan or “healthspan” (the length of a person’s life in which he/she is generally healthy and not debilitated by chronic diseases).

Given the major role of sarcopenia and sarcopenic obesity in aging-related disability and mortality, those involved in research and development of anti-aging therapeutics need to take preservation and restoration of muscle mass into account, as they study and/or target pathways involved in aging and longevity.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company,  please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

New findings on mechanism of activation of sirtuins may vindicate Sirtris founders

Sir2, the yeast homologue of SIRT1

Sir2, the yeast homologue of SIRT1

The Biopharmconsortium Blog has from time to time been following novel developments in anti-aging medicine, including attempts to develop activators of sirtuins. However, we have not had an article on sirtuins since December 1, 2010. At that time, we reported on the discontinuation by GlaxoSmithKline (GSK) of its lead sirtuin activator, SRT501, a proprietary formulation of the natural product resveratrol (which is found in red wine).

Sirtuins are nicotinamide adenine dinucleotide (NAD+)–dependent protein deacetylases, which have been implicated in control of lifespan in yeast, the nematode Caenorhabditis elegans, and the fruit fly Drosophila. Mammalian sirtuins have been implicated (via animal model studies) in protection against aging-related diseases such as metabolic and cardiovascular diseases, neurodegeneration, and cancer.

As we discussed in our December 1, 2010 article, GSK acquired the sirtuin-pathway specialty company Sirtris (Cambridge, MA) for $720 million in June 2008. This gave GSK ownership of Sirtris’ sirtuin modulator drugs. As stated in that article, although GSK discontinued development of SRT501, it was continuing  development of Sirtris’ non-resveratrol synthetic selective sirtuin 1 (SIRT1) activators, which in addition to their greater potency, had more favorably drug-like properties.

Recently, resveratrol and synthetic sirtuin activators such as those developed by Sirtris have come to be known as  “sirtuin-activating compounds” (STACs).

Sirtuin-activating compounds (STACs) under a cloud

As we discussed in our February 10, 2010 blog article, researchers at Amgen found evidence that the apparent in vitro activation of SIRT1 by resveratrol depended on the substrate used in the assay. The Amgen group found that the fluorescent SIRT1 peptide substrate used in the Sirtris assay is a substrate for SIRT1, but in the absence of the covalently linked fluorophore, the peptide is not a SIRT1 substrate. Resveratrol did not activate SIRT1 in vitro as determined by assays using two other non-fluorescently-labeled substrates.

Researchers at Pfizer also found that resveratrol and three of Sirtris’ second-generation STACs activated SIRT1 when a fluorophore-bearing peptide substrate was used, but were not SIRT1 activators in in vitro assays using native peptide or protein substrates.The Pfizer researchers also found that the Sirtris compounds interact directly with the fluorophore-conjugated peptide, but not with native peptide substrates.

Moreover, the Pfizer researchers were not able to replicate Sirtris’ in vivo studies of its compounds. Specifically, when the Pfizer researchers tested SRT1720 in a mouse model of obese diabetes, a 30 mg/kg dose of the compound failed to improve blood glucose levels, and the treated mice showed increased food intake and weight gain. A 100 mg/kg dose of SRT1720 was toxic, and resulted in the death of 3 out of 8 mice tested.

The Pfizer researchers also found that the Sirtris compounds interacted with an even greater number of cellular targets (including an assortment of receptors, enzymes, transporters, and ion channels) than resveratrol. For example, SRT1720 showed over 50% inhibition of 38 out of 100 targets tested, while resveratrol only inhibited 7 targets. Only one target, norepinephrine transporter, was inhibited by greater than 50% by all three Sirtris compounds and by resveratrol. Thus the Sirtris compounds have a different target selectivity profile than resveratrol, and all of these compounds exhibit promiscuous targeting.

Finally, as we reported in our December 1, 2010 blog article, NIH researcher Jay H. Chung and his colleagues found evidence that resveratrol works indirectly, via the energy sensor AMP-activated protein kinase (AMPK), to activate sirtuins. Since activation of AMPK increases fatty acid oxidation and upregulates mitochondrial biogenesis, this study suggested that the effect of resveratrol on AMPK may be more important than its more indirect activation of sirtuins in the regulation of insulin sensitivity.

All of these studies left Sirtris/GSK’s STACs under a cloud.

On March 13, 2013, GSK reported that it was shutting down Sirtris and its Cambridge MA facilities, just five years after its $720 million acquisition. GSK also said that it was offering transfers to the Philadelphia area for some of the 60 remaining Sirtris employees. Although GSK was closing Sirtris, it said that it remained confident in Sirtris’ drug candidates. The pharma company said that following Sirtris’ “highly successful” research on the biology of sirtuins, further development of Sirtris’ drug candidates “requires the resource and expertise available from our broader drug discovery organization.” GSK will be “exami[ing] [its] research against a variety of therapeutic conditions, with the aim of moving potential assets into the clinic within the next three to four years.”

New evidence that STACs activate SIRT1 in vitro under certain conditions

On 8 March 2013, the journal Science published a report by Sirtris founder David A. Sinclair, Ph.D. (Harvard Medical School, Boston MA) and his colleagues [from academia and from Sirtris, GSK, and from Biomol (Plymouth Meeting, PA)] that identified conditions under which STACs activate SIRT1 in vitro. This research report was accompanied by a Perspective in the same issue of Science authored by Hua Yuan, Ph.D. and Ronen Marmorstein, Ph.D. (Wistar Institute, Philadelphia, PA).

Dr. Sinclair and his colleagues hypothesized that the fluorophore tags on peptide substrates that were used in the original, successful SIRT1 activation assays might mimic hydrophobic amino acid residues of natural substrates at the same position as the fluorophore (i.e, +1 relative to the acetylated lysine that is engaged by SIRT1). Consistent with this hypothesis, the researchers found that non-fluorophore-tagged natural SIRT1 substrates with a large hydrophobic amino acid residue [i..e, tryotophan (Trp), tyrosine (Tyr), or phenylalanine (Phe)] at positions +1 and +6 or +1 were selectively activated by STACs. Examples of such substrates are peroxisome proliferator-activated receptor γ coactivator 1α acetylated on lysine at position 778 (PGC-1α–K778), and forkhead box protein O3a acetylated on lysine at position 290 (FOXO3a-K290). The PGC-1α–K778 peptide contains Tyr at the +1 position and Phe at the +6 position, and FOXO3a contains Trp at the +1 position. Substitution of these aromatic amino acids on either acetylated peptide with alanine (Ala) resulted in complete abolition of SIRT1 activity.

The researchers identified over 400 nuclear acetylated proteins that are potential SIRT1 targets that support STAC-mediated activation of SIRT1, on the basis of their structure. They tested five of these native sequences and found that three of them supported SIRT1 activation.

Kinetic analysis of SIRT1 activation by STACs in the presence of the above peptide substrates showed that the enhancement in the rate of SIRT1 deacetylation was mediated primarily through an improvement in peptide binding. This is consistent with an allosteric mechanism of activation. In allosteric regulation, an allosteric activator (in this case, a STAC) binds to a regulatory site (also known as an allosteric site) that is distinct from the catalytic site of an enzyme (in this case, SIRT1). Binding of the activator to the allosteric site results in the enhancement of the activity of the enzyme, for example by causing a conformational change in the protein that results in improved biding of the catalytic site to the substrate.

In order to investigate the nature of the hypothesized SIRT1 allosteric site, the researchers screened  for SIRT1 mutant proteins that could not be activated by STACs in the presence of an appropriate peptide substrate. As a result of these studies, the researchers identified a critical glutamate (Glu) residue at position 230 of SIRT1, which is immediately N-terminal to the catalytic core of SIRT1.  Glu230 of SIRT1 is conserved from flies to humans. Replacement of Glu230 with another amino acid, such as lysine or alanine, resulted in attenuation of SIRT1 activation by STACs, independent of the substrate used.  Structural studies identified a rigid N-terminal domain that contains Glu230, and is critical for activation by STACs.

The researchers then studied the effects of STACs on cultured cells (murine myoblasts), expressing either wild-type SIRT1 or mutant SIRT1 in which Glu230 is replaced with lysine (SIRT1-E222K, which is the murine equivalent of human SIRT1-E230K). Cells expressing the mutant SIRT1 did not respond to STACs, but cells expressing wild-type SIRT1 did. Specifically, cells expressing wild-type SIRT1 exhibited STAC-stimulated increases in ATP levels, mitochondrial mass, and mitochondrial DNA copy number, but cells expressing mutant SIRT1 did not. In STAC-treated cells, the researchers found no evidence of SIRT1-independent AMPK phosphorylation. This goes against studies discussed earlier in this article, that indicate that resveratrol works via activating AMPK. They also found no evidence for inhibition of phosphodiesterase isoforms in the STAC-treated cells. This goes against a study, published in Cell in 2012, that indicates that resveratrol ameliorates aging-related metabolic conditions by inhibiting cAMP phosphodiesterases, thus engaging a pathway that activates AMPK.

The researchers conclude that STACs act via a mechanism of direct “assisted allosteric activation” mediated by the Glu230-containing N-terminal activation domain of SIRT1. They further conclude that their findings support the hypothesis that allosteric activation of SIRT1 by STACs constitutes a viable therapeutic intervention strategy for many aging-related diseases. thus apparently vindicating the Sirtris/GSK development program.

However, the authors of the companion Perspective hypothesize that the reason that existing STACs only work with SIRT1 substrates that contain hydrophobic residues at position +1 to the acetylated lysine is because they were identified via screening with a substrate that contained a hydrophobic residue mimetic–i.e., a fluorophore tag. A new screen that is not biased in this way might possibly identify STACs that exhibit selectivity for SIRT1 substrates that contain other sequence signatures. It is possible that such STACs might be better therapeutics for certain aging-related diseases than the current STACs being investigated by Sirtris/GSK. There also remain many unknowns in the biology of SIRT1, and in the biochemistry of STACs –i.e., mechanisms by with certain STACs modulate the activity of biomolecules other than SIRT1 (e.g,, cAMP phosphodiesterases). Such issues might affect the success or failure of any program to develop STACs as therapeutic compounds.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Haberman Associates in Chemical & Engineering News (C&EN) article on Agios Pharmaceuticals


Agios Germanos, Greece. Source:

Agios Germanos, Greece. Source:

I was quoted in an article in the November 19, 2012 issue of Chemical & Engineering News (C&EN) by senior editor Lisa M Jarvis. The article is entitled “Agios Takes A Long View In Cell Metabolism.”

The article focuses on Agios Pharmaceuticals’ (Cambridge, MA) strategy for building a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance.

This contrasts with the recent trend toward “virtual biotech companies”–lean companies with only a very few employees that outsource most of their functions, and that are designed for early acquisition by a Big Pharma or large biotech company. The virtual company strategy is designed to deal with the inability of most young biotech companies to go public in the current financial environment. Without the ability to go public, young companies cannot provide early-stage venture capital investors with a profitable exit within a few years after launching the company. Virtual companies typically have a few assets, such as molecules that are ready for preclinical studies or early clinical trials. The goal is to obtain enough evidence that their compounds can become drugs to interest a Big Pharma.

In contrast, there are a few young  “platform companies” that are built on a broad technology platform, which aim to address important areas of biology and potentially to develop numerous products with the potential to address important areas of unmet medical need. One of these is Agios.

“Built to Last” in the current biotech ecosystem

In the C&EN article, I was quoted as saying that only a few platform companies have been launched in recent years. In the Boston area, in addition to Agios, such companies include Forma Therapeutics and Aileron Therapeutics. I was further quoted as saying “These companies are built to last.”

That brings up the old business paradigm from the 1990s and early 2000s–“Built to Last” versus “Built to Flip”. Those involved in building virtual biotech companies–especially venture capitalists and angel investors–do not like the use of “Built to Flip” to characterize their companies. And there are some fine virtual biotechs–some, such as Energesis and Zafgen–which we have covered in our blog.

(Plexxikon, the developer of targeted melanoma drug vemurafenib, also operated as a virtual company. However, it had a technology platform, and had the potential to become an independent biotech with marketed products. Thus Plexxikon did not fit the usual “virtual biotech model”. Nevertheless, it was acquired by Daiichi Sankyo in 2011.)

However, some industry commentators believe that “Built to Flip” is an appropriate designation for virtual biotech companies, and that the virtual model is likely to be detrimental to drug discovery and to the biotech/pharma industry as a whole.

Meanwhile, the 2012 BIO International Convention in Boston had a session entitled “Moving the Goal Posts: How to Build a Free-Standing Biotech from Scratch in Today’s Environment.” This session focused on how to build the “next Vertex or even the next Genentech” (i.e., a “Built to Last” biotech company) in today’s environment. John Evans, the Vice President of Business Development & Operations of Agios was a speaker at that session. The session was moderated by Bruce Booth of Atlas Ventures. Thus, despite the preference for lean virtual biotech companies in the current funding environment, there is an interest in the entrepreneurial and venture capital communities for how free-standing biotechs might emerge under current conditions.

How to build a young platform biotech company

The Biopharmconsortium Blog has included three articles about Agios:

These articles, as well as the November 19 2012 C&EN article, outline how Agios has been building a free-standing biotech in today’s unfavorable environment. Agios’ strategy is based on three elements:

  • A stellar group of scientific founders–Drs. Craig B. Thompson, Tak W. Mak, and Lewis C. Cantley.
  • A strong proprietary technology platform based on cancer metabolism
  • A financing strategy that includes both venture capital and partnerships with established companies. In the case of Agios, their partner is Celgene. The Agios/Celgene partnership provides Agios with $150 million, and allows Agios to maintain control over the direction of its early stage research.

As stated in the C&EN article, the financial security gained via Agios’ funding by its venture investors and by Celgene enables Agios to work on multiple potential targets, with the goal of dominating the field of cancer metabolism. Agios focuses on two types of targets: metabolic enzyme species that are found only in cancer cells, and enzyme species on which a cancer cell has become dependent. Agios researchers intend to develop drugs against targets for which their are predictive biomarkers that identify the right patients for clinical studies.

New developments outlined in the November 19, 2012 C&EN article

Both the November 19, 2012 C&EN article and our Bipharmconsortium Blog articles outline Agios’ program to target a mutated form of isocitrate dehydrogenase 1 (IDH1), which together with mutated IDH2 has been implicated in 70% of human brain cancers. As stated in the C&EN article, Agios researchers have recently reported a series of compounds that selectively inhibit the mutant form of IDH1. This research had been carried out in collaboration with researchers from Ember Therapeutics (Watertown, MA). As we stated in another Biopharmconsortium Blog article, Ember specializes in targeting beige adipocytes for treatment of metabolic diseases.

As we noted in our November 30, 2011 Biopharmconsortium Blog article, Agios had slated a portion of the $78 million that it raised in its Series C financing to expand its R&D efforts into inborn errors of metabolism (IEMs). IEMs comprise a large class of inherited disorders of metabolism, most of which are defects in single genes that code for metabolic enzymes. These rare metabolic diseases have a high level of unmet medical need.

As outlined in the C&EN article, Agios’ work with mutant IDH1 and IDH2 is serving as a bridge to the company’s programs in IEMs. IDH2 mutations have been found in a class of children with 2-hydroxyglutaric aciduria, a rare inherited neurometabolic disorder that can cause developmental delay, epilepsy, and a set of other pathologies.

According to the C&EN article, IEMs are of special strategic interest to Agios. Agios CEO David Schenkein stated that expanding the company’s R&D efforts into IEMs helps the company to manage the risk profile of its portfolio. In the case of cancer, Agios researchers must identify and validate targets involved in the pathobiology of these diseases, and then to find drugs that modulate these targets. In the case of IEMs, disease biology is already validated by genetics.

Moreover, IEMs have small patient populations. Thus only small clinical trials are needed to bring a drug to market. Agios therefore believes that it can bring drugs for these diseases to market on its own, without the need for a larger partner such as Celgene or a Big Pharma.

As we discussed in a Biopharmconsortium Blog article on improving the clinical trial system, although rare diseases only require small clinical trials, finding and recruiting patients for the trials is made more difficult because of the very small number of patients with a particular disease. One solution is to work with patient advocates and “disease organizations”, some of which have patient registries. In the case of 2-hydroxyglutaric aciduria and other organic acidemias, a “disease organization” exists–the Organic Acidemia Association (OAA). Perhaps Agios will find it fruitful to work with the OAA in its patient recruitment efforts.

Currently, Agios is focused on getting compounds into the clinic–both for IEMs and for cancer. Looking down the road, the company’s $180 million war chest should enable Agios to put several compounds through proof-of-concept studies, according to Dr. Schenkein. (This is besides any cancer drug candidates that are licensed by Celgene.) Despite Agios’ strategy of conducting small trials for IEM drug candidates, Dr. Schenkein said that the company will eventually need to go public to achieve its strategic goal of dominating the cancer metabolism field.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail.  We also welcome your comments on this or any other article on this blog

Novel hypercholesterolemia drugs move toward FDA decisions




Mid-October 2012 was a busy time for the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. On October 17, 2012, the panel voted 13-2 to recommend approval of Aegerion’s lomitapide for treatment of homozygous familial hypercholesterolemia. The next day, October 18, 2012, the same panel voted 9-6 to recommend approval of Isis/Sanofi/Genzyme’s mipomersen for the same condition.

Familial hypercholesterolemia (FH) is a rare genetic condition characterized by very high levels of low-density lipoprotein (LDL, or “bad cholesterol”), in the blood and early cardiovascular disease. Most patients with FH have mutations in either the LDL receptor (which functions to remove LDL from the circulation), or in apolipoprotein B (ApoB) (the protein moiety of LDL, which binds to the LDL receptor).

Patients who are heterozygous for an FH mutation (but have one normal copy of the affected gene) may have premature cardiovascular disease in their thirties. Patients who are homozygous for an FH mutation may have severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disease, which is inherited in an autosomal dominant pattern, and occurs in one out of 500 people. Homozygous FH, however, occurs in about 1 in a million births. Homozygous FH thus qualifies as a “rare disease”.

Physicians generally treat heterozygous FH with statins, bile acid sequestrants or other lipid-lowering agents that lower cholesterol levels. Homozygous FH often does not respond to these drugs. It may require chronic treatment via LDL apheresis (removal of LDL in a method similar to dialysis) and in some cases liver transplantation.

Aegerion (Cambridge, MA), the developer of lomitapide, is a publicly-traded biotech company that seeks to “change the way that rare, genetic lipid disorders are treated”. It is currently focused on the development of lomitapide, a small-molecule compound (pictured above).

Lomitapide inhibits the microsomal triglyceride transfer protein (MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver. A 2007 article in the New England Journal of Medicine (NEJM) concluded that inhibition of MTTP by lomitapide (then known as BMS-201038) resulted in the reduction of LDL cholesterol levels in patients with homozygous FH. BMS-201038/lomitapide was originally developed by Bristol-Myers Squibb (BMS), donated to the University of Pennsylvania in 2003 and licensed to Aegerion in 2006. BMS had abandoned development of the compound after early Phase 1 and Phase 2 trials had found increases in heptatic fat content and gastrointestinal disturbances. The NEJM study (conducted by Penn researchers in collaboration with other academic researchers and with BMS) also found that therapy with the compound was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

78-week data from Aegerion’s pivotal Phase 3 study of lomitapide in adults patients with homozygous FH were published in the online version of The Lancet on November 2, 2012.

Mipomersen (which will be called Kynamro if and when it is commercialized) is an antisense oligonucleotide that targets the messenger RNA for apolipoprotein B. We discussed mipomersen in our August 21, 2009 blog article on oligonucleotide therapeutics. Mipomersen represents the most advanced oligonucleotide drug in development that is capable of systemic delivery. (The only two marketed oligonucleotide drugs both treat ophthalmologic diseases and are delivered locally.) Mipomersen targets the liver, without the need for a delivery vehicle. Thus mipomersen–potentially the first systemically-delivered oligonucleotide drug to reach the market–represents the “great hope” for proof-of-concept for oligonucleotide drugs, including antisense and  RNAi-based drugs.

Patients treated with mipomersen, as with lomitapide, exhibit liver-related adverse effects, especially hepatic fat accumulation and elevated liver aminotransferase levels. Moreover, unlike lomitapide, which is an orally-delivered compound, mipomersen, which is delivered via subcutaneous injection, can cause injection site reactions and flu-like symptoms. Moreoever, mipomersen has a much longer half-life than lomitapide (30 days versus 20 hours).

Industry commentators, and well as the FDA Advisory Committee, generally favor lomitapide over mipomersen, because lomitapide appears to be the more efficacious drug in lowering LDL-cholesterol, and also because lomitapide is an oral drug. However, most of the FDA panelists, as well as other industry commentators believe that not all patients with homozygous FH would be likely to benefit from only one drug. Thus having two alternative drugs may well be better in treating this disease.

Both lomitapide and mipomersen have potentially serious adverse effects. A finding of elevated liver aminotransferase levels is enough to stop development of most drugs. However, the FDA and its Advisory Panel believe that a risk evaluation and mitigation strategy (REMS) would support appropriate use of these drugs in patients with homozygous FH, because of their life threatening disease, and because they have limited therapeutic options. Both Aegerion and Genzyme are proposing that their compounds be approved with REMS programs, including an education program for physicians and active monitoring of patients. The REMS program would also include monitoring to ensure that only adult homozygous FH patients would be treated with the drugs. However, Aegerion plans to conduct clinical trials of the use of lomitapide in pediatric homozygous FH patients, as well as patients with another rare disease, familial chylomicronemia. Genzyme has already tested mipomersen in a small number of pediatric patients.

Companies developing therapeutics for rare diseases whose mechanisms are related to those of more common diseases often attempt to first get their drugs approved for the rare disease, and then perform additional clinical trials to expand the drug’s indications to larger populations. We discussed this strategy in an earlier article on this blog. Homozygous FH is mechanistically related to not only heterozygous FH, but also to cases of severe hypercholesterolemia that are poorly controlled by statins. Both companies have shown interest in treating patients with homozygous FH and severe hypercholesterolemia, since they have preformed clinical trials that included patients with these conditions. However, the adverse effects of these drugs may limit their use to homozygous FH, at least in the near future.

Aegerion intends to market lomitapide on its own, and is ramping up its marketing and sales organization in anticipation of approval. Mipomersen, if approved, would have the benefit of the Sanofi marketing organization behind it. However, industry commentators expect lomitapide to have a large advantage over mipomersen, if both are approved. That is because of the greater efficacy of lomitapide, its oral dosing, and other factors related to injection site reactions for mipomersen and the half-lives of the compounds.

We await FDA action in the next several weeks on the approval of lomitapide and mipomersen.

Meanwhile, researchers and companies are working on potential drugs for severe hypercholesterolemia that act via an entirely different mechanism–PCSK9 (proprotein convertase subtilisin/kexin 9) inhibition. These drugs are in an earlier stage of development than lomitapide and mipomersen. However, they might eventually provide strong competition to these drugs, or replace them altogether.

For oligonucleotide drug developers and enthusiasts, the case of mipomersen–considered the “great hope” for proof-of-concept for oligonucleotide drugs by many in the field–provides several lessons. 1. At the end of the day, oligonucleotide drugs must meet the same standards of safety and efficacy as other drugs. 2. Oligonucleotide drugs may encounter competition from drugs in other classes, such as small molecules or monoclonal antibodies.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Beige fat enters the obesity-therapeutics target arena


Is beige the new brown?

This is an update to our recent discussion on targeting the physiology of brown fat [or brown adipose tissue (BAT)], in developing novel antiobesity therapies. It is based on a research article published in the July 20 2012 issue of Cell by Dr. Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues.

As we discussed in our May 23, 2012 blog article, Dr. Spiegelman, a leading metabolic disease researcher, is a founder of Ember Therapeutics. Ember is working to develop novel metabolic disease therapeutics based on Dr. Spiegelman’s work on BAT physiology and on novel insulin sensitizers.

In the work described in the new Cell article, Dr. Spiegelman and his colleagues showed that the white adipose tissue (WAT)-derived “brown fat-like cells” that they had been studying are actually a new type of cells known as “beige adipocytes”.

Other researchers had previously described a class of “brite” or “beige” adipocytes, which were induced in WAT depots that have been chronically treated with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone. Brite/beige adipocytes expressed UCP1 (uncoupling protein 1) and had high levels of mitochondria as do brown adipocytes but lacked expression of certain characteristic brown fat-specific genes. UCP1 is the key mitochondrial protein that makes the process of thermogenesis (i.e., production of heat by oxidizing fat rather than storing it) possible. As shown previously by Dr. Spiegelman and his colleagues, BAT is derived from  a myf-5 muscle-like cell lineage, via the action of the transcriptional regulator PRDM16. However, beige cells are not.

Beige precursor cells in murine subcutaneous white fat depots

In the new Cell publication, Dr. Spiegelman and his colleagues carry these earlier studies further by cloning murine beige fat cells and describing their unique gene expression signature. They first isolated adipocyte precursors from mouse subcutaneous WAT (specifically, the inguinal fat depots). These precursors are found in the stromal-vascular fraction of the adipose tissue. The researchers immortalized stromal vascular fraction (SVF) cells from subcutaneous WAT of the 3T3 mouse by passaging them in culture, similar to the classic derivation of 3T3 fibroblast cell lines by Todaro and Green 49 years ago. They cloned the resulting immortalized cells via limiting dilution, and selected the 20-some odd cell lines that could be readily differentiated (via standard differentiation protocols) to adipocytes. For purposes of comparison, the researchers also derived multiple adipogenic clones from the SVF cells of the interscapular brown fat depot.

They then differentiated the WAT-derived adiopogenic clones to adipocytes, and treated them with forskolin [an agent that raises intracellular levels of cyclic AMP (cAMP)]–increases in cAMP levels activate expression of UCP1 in the mitochondria of brown fat cells. They then determined the gene expression pattern of the differentiated and forskolin-stimulated WAT derived clones. The clones clustered into two groups, one of which had a gene expression pattern more similar to BAT cells than the other group. These two groups appeared to represent beige and white adipocytes, respectively. Comparison of these two groups of cells to BAT cells revealed that the presumptive beige adipocytes had gene expression patterns that were similar, but not identical to, those of brown adipocytes.

Further characterization of the three types of cells indicated that beige cells have characteristics of both white and brown adipocytes. Both white and beige adipocytes have low basal levels of UCP1, while brown adipocytes have higher levels. Upon cAMP stimulation, however, the beige adipocyte lines responded with a very large induction of UCP1 gene expression, reaching similar UCP1 levels to that observed in the brown adipocyte lines. White adipocyte cell lines showed little UCPI induction. These characteristics of beige and white adipocyte cell lines also were seen in in vivo studies.

Still further characterization of the three types of cell lines revealed that beige and brown fat cells have related but distinct gene expression profiles. These include a set of beige-selective genes that can distinguish beige fat cells from both brown fat cells and white fat cells. Protein expression was highly concordant with mRNA expression. Since some of the beige-selective markers are cell surface proteins, and since antibodies to these proteins are commercially available, this allowed the researchers to use fluorescence-activated cell sorting (FACS) to isolate primary beige precursor cells from the SVF of mouse inguinal fat.

Murine beige fat precursors–not white fat or brown fat–are targets of the hormone irisin

In our May 23, 2012 blog article, we discussed the myokine hormone irisin, which was recently discovered by the Spiegelman group. As we discussed, irisin is produced by muscle cells and increases with exercise. It has little or no effect on classic brown fat found in the interscapular depot. However, It acts on subcutaneous 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, producing a thermogenic effect.

In the study reported in the July 20 2012 Cell paper, the researchers used FACS to sort primary inguinal precursor cells into white and beige preadipocytes, and studied the effects of two forms of recombinant irisin on these cells during adipogenic differentiation. All cells treated either with vehicle or irisin showed good adipocyte differentiation. Both forms of irisin, but not vehicle, induced the expression of brown fat-like genes such as UCP-1 in beige cells, but had little effect on white cells. This suggests that irisin works on white fat depots in vivo by inducing brown-like gene expression in the beige cell component of preadipocytes in these depots.

Adult human “brown fat” is really beige fat

As we discussed in our blog articles of November 17, 2010 and May 23, 2012, and as illustrated in the figures at the top of each of these articles, adult humans possess what appears to be reservoirs of brown fat in the neck region and other areas of the upper body as well as in skeletal muscle.

In the study reported in the July 20 2012 Cell paper, the researchers preformed BAT biopsies from two independent cohorts of human subjects, and analyzed their gene expression signatures based on the findings of the studies of mouse brown, beige, and white adipocytes. They found that the UCP1-positive “BAT” cells from the human biopsies had gene expression signatures that resembled those of murine beige adipocytes more closely than they resemble classic brown fat or white fat. As a result of this finding, several popular articles written about the new Cell paper are entitled “Beige is the New Brown”.


Although additional research is needed to fully characterize beige fat physiology, the picture that emerges from the above study is that beige fat cells exist in subcutaneous fat mainly in a basal, unstimulated state, in which their phenotype resembles that of white fat. Once stimulated, however, beige cells activate expression of a brown fat-like thermogenic program, including expression of levels of UCP1 similar to those of brown fat cells. Thermogenesis of beige fat cells is induced by such stimuli as 1. β-adrenergic activation; 2. the myokine irisin; and 3. other polypeptide hormones, such as fibroblast growth factor 21 (FGF21), and atrial natriuretic peptide (ANP). The role of FGF21 in inducing UCP1 and the thermogenic program in adipose tissues was elucidated by Dr. Spiegelman and his colleagues. This was described in a February 2012 report in Genes & Development.

The above scenario is mainly based on studies in mice. However, as discussed earlier, humans also have what appear to be beige cells, which may be amenable to induction by irisin or other agents, thus giving rise to a thermogenic program that might be utilized to combat obesity and type 2 diabetes. Classical interscapular brown fat in humans, however, although it is present in infants, disappears as humans mature. This it is likely that beige fat will be the target such agents as irisin, which are aimed at overcoming metabolic disease via increasing energy expenditure.

Long before researchers obtained evidence for “browning” of white fat as a potential mechanism for induction of a thermogenic program, the pharmaceutical industry had a long history of attempting to develop β3-adrenergic agonists as therapies for metabolic diseases.  Many agents were entered into clinical trials by numerous companies, but all failed, either due to lack of efficacy or to averse effects due to activation of β-adrenergic receptors in other tissues. An important underlying factor in the failure of these studies was the lack of understanding of brown (or beige) fat physiology in humans, including whether brown fat existed in adult humans at all. Of course, beige fat was completely unknown.

In our May 23, 2012 blog article, we discussed several young companies that are working to develop novel approaches to treating obesity based on brown-fat physiology and/or other non-CNS pathways involved in increasing energy expenditure. Among these companies are Ember Therapeutics. As we discussed in the May 2012 article, 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 research constitutes the company’s lead BAT biology program.

More recently, Ember completed a licensing agreement with the Dana-Farber for intellectual property related to Dr. Spiegelman’s beige fat discovery. As discussed earlier, beige fat cells are specifically targeted by irisin, which induces the thermogenic program in these cells. Especially in adult humans, which appear to lack classic brown fat, beige adipocytes and/or their precursors are the true target of irisin, and any program to develop irisin-like protein drugs for metabolic disease will need to focus on the effect of such products on beige cells. Moreover, Ember’s programs to develop small molecules via screening for compounds that activate pathways specific to the “brown fat” cell lineage will need to focus specifically on pathways involved in induction of the thermogenic program in beige adipocytes.

In contrast to Ember’s R&D programs, which must focus on beige adipocytes, Energesis Pharmaceuticals’ R&D programs focus on brown fat “stem cells” from skeletal muscle. This research thus has to do with classical BAT, which is derived from a skeletal muscle-like lineage, as opposed to beige adipocytes, which are not. Thus Ember’s and Energesis’ R&D programs represent completely different approaches to developing antiobesity agents that work to increase energy expenditure. Among the other companies mentioned in our May 2012 article, Zafgen’s R&D programs represent still another completely different approach, involving targeting the liver. Acceleron Pharma’s approach, however, probably involves targeting beige fat. In fact, Dr. Spiegelman has been a collaborator in some of their research.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Vivus’ Qsymia (formerly Qnexa) approved by the FDA–the most efficacious weight-loss drug ever approved in the U.S.


Qsymia (phentermine/topiramate CR)

On July 17th, 2012, Vivus, Inc. (Mountain View, CA) announced that the FDA has approved its antiobesity drug, Qsymia (phentermine and topiramate extended-release). This is the second antiobesity drug–after lorcaserin (Arena/Eisai’s Belviq)–to be approved in 13 years. Belviq was approved just last month; this was the focus of our June 30, 2012 Biopharmconsortium Blog article.

As discussed in that article, both Belviq (formerly Lorqess) and Qsymia (formerly Qnexa) were two of the three members of what we called the “Class of 2010” of CNS-targeting antiobesity drugs. All three of these drugs (which also included Orexigen’s Contrave) had come up for review in 2010, and were rejected by the FDA, mainly due to concern about the drugs’ long-term safety. After the companies conducted the further studies prescribed by the FDA in 2010, two of these drugs, lorcaserin and Qsymia–had received positive votes by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, as of May 2012. Then lorcaserin was approved in June 2012, and Qsymia in July 2012.

The FDA approved Qsymia as an adjunct to diet and exercise for chronic weight management in adult patients who are obese [initial body mass index (BMI) of 30 kg/m2 or greater], as well as for overweight patients with a BMI of 27 kg/m2 or greater who also have at least one weight-related comorbidity, such as hypertension, dyslipidemia, or type 2 diabetes. This is the same population for which the FDA approved Belviq last month.

According to Vivus’ President, Peter Tam, Qsymia is the “first FDA-approved once daily combination treatment” for obesity. In contrast, Belviq must be taken twice a day, and is a single-agent drug.

As we discussed in our August 4, 2010 article on this blog, Qsymia (then called Qnexa) is a low-dose, controlled release (CR) formulation of two previously FDA-approved drugs: phentermine (PHEN) and topiramate (TPM). Qsymia was designed to both suppress appetite (phentermine) and promote satiety (topiramate).

Phentermine, an amphetamine, has been prescribed as a weight-loss aid that is used short-term. It was the “phen” half of the notorious “Fen-Phen” combination. The “fen” part, fenfluramine (Pondimin) or dexfenfluramine (Redux), were serotonin modulators that caused cardiovascular side-effects. Topiramate is an anticonvulsant. As separate agents, phentermine and topiramate have minimal effects on weight loss. However, according to Vivus’ studies, the two drugs appear to have a synergistic effect, even at low doses, that results in significant weight loss. Vivus’ studies also indicate that the two drugs mitigate each other’s side effects; the low does and controlled release is also designed to reduce side effects.

Adverse effects of phentermine may include increase in blood pressure and heart palpitations, as well as gastrointestinal side effects. Side effects of topirmate may include cognitive issues, lack of coordination, aggressiveness, changes in ability to taste food and loss of appetite, cardiovascular side effects, and others. As of the August 4, 2010 publication date of our initial blog article on Qnexa/Qsymia, the risk of birth defects with ether of these drugs was unknown. However, there was preliminary evidence that topiramate might cause birth defects. More recently, on March 4, 2011, the FDA warned of an increased risk of development of cleft lip and/or cleft palate (oral clefts) in infants born to women treated with topiramate during pregnancy.

Results of Phase 3 clinical trials with Qsymia

According to the July 17th, 2012, Vivus announcement, the safety and efficacy of Qsymia were evaluated in two  multicenter randomized controlled phase 3 trials. These included the EQUIP study with severely obese patients, and the CONQUER study with overweight or obese patients with at least two weight-related comorbidities (e.g., hypertension, hypertriglyceridemia, type 2 diabetes, or central adiposity) that are related to the metabolic syndrome.

In the 56-week EQUIP study, adult male and female patients with a BMI ≥ 35 kg/m2 were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg; all patients were also on a reduced-calorie diet. The average weight loss was 10.9% of body weight for the high-dose Qsymia (PHEN/TPM CR 15/92) group and 1.2% for placebo. 66.7% of patients on high-dose Qsymia lost at least 5% of body weight, as compared to 17.3% for placebo. The difference between the Qsymia and the placebo groups were statistically significant. The high-dose Qsymia group also has significantly greater changes relative to placebo for waist circumference, blood pressure, and fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).

In the 56-week CONQUER study, adult male and female patients with a BMI of 27-45 kg/m2 and two or more obesity-related comorbidities were randomized to receive either placebo, PHEN/TPM CR (7.5/46 mg), or PHEN/TPM CR (15/92 mg). The average weight loss was 9.8% on PHEN/TPM CR (15/92 mg) {“high-dose Qsymia”), and 1.2% for placebo. The differences in weight loss between the treatment arms and the placebo arms of these studies were statistically significant.

21% of patients lost at least 5% of body weight with placebo, and 70% of patients patients lost at least 5% of body weight with high-dose Qsymia. For percentages of patients who lost over 10% of body weight, the corresponding numbers were 7% and 48%. These differences were also statistically significant.

The most common adverse reactions for patients treated with Qsymia included tingling sensation of hands and feet, dizziness, altered taste, insomnia, constipation and dry mouth.

Risk Evaluation and Mitigation Strategy for Qsymia

The FDA approved Qsymia with a Risk Evaluation and Mitigation Strategy (REMS). The goal of the strategy is to inform prescribers and women patients of reproductive potential about an increased risk of orofacial clefts in infants exposed to Qsymia during the first trimester of pregnancy, the importance of pregnancy prevention for females of reproductive potential receiving Qsymia and the need to discontinue Qsymia immediately if pregnancy occurs. The Qsymia REMS program includes a Medication Guide, Healthcare Provider training, distribution through certified pharmacies, implementation system and a time table for assessments.

As part of the approval of Qsymia, Vivus must also conduct post-marketing studies. One study will assess the long-term treatment effect of Qsymia on the incidence of major adverse cardiovascular events in overweight and obese subjects with confirmed cardiovascular disease. The company will also conduct studies to assess the safety and efficacy of Qsymia for weight management in obese pediatric and adolescent subjects, studies to assess drug utilization and pregnancy exposure, a study to assess renal function, and animal and in vitro studies.

Implications of the approval of Belviq and Qsymia

The FDA’s approval of Belviq and Qsymia indicates that the FDA is more willing to make antiobesity drugs available to patients than it has been previously, even in the face of continuing concerns about long-term safety. Rather than rejecting these drugs, the FDA is handling its concerns about safety via post-marketing studies, and restricting distribution of the drugs. (Restricted distribution of the drugs may also help prevent their unregulated use for cosmetic weight-loss, as occurred with “Fen-Phen”.)  Given the recent findings about the risk of birth defects with topiramate, the FDA is also employing a REMS designed to prevent the use of the drug by pregnant women.

Phase 2 and 3 studies of Belviq and Qsymia (although the two drugs were not compared head-to-head) indicate that Qsymia is much more efficacious than Belviq. At least some medical experts consider Qsymia to be the most effective oral antiobesity drug ever approved in the U.S.

Stock analysts forecast that the apparent greater efficacy of Qsymia is likely to give it a strong sales advantage over Belviq. Some analysts project that Qsymia’s annual worldwide sales may reach $2 billion by 2017. However, Arena has a Big Pharma marketing partner for Belviq, Eisai, while Vivus currently must market Qsymia on its own. This gives an advantage to Beviq. However, it is possible that Vivus might find a Big Pharma partner for Qsymia and its erectile dysfunction drug avanafil (Stendra), or the company might be acquired outright.

The long history of postmarking safety issues in the CNS-acting drug field, exemplified by fenfluramine/dexfenfluramine may be expected to discourage use of both Belviq and Qsymia by many physicians and patients, at least until one or both of these drugs shows a strong track record of safety. Third-party payers will also be expected not to cover either drug.


The approval of Qsymia by the FDA–just one month after the approval of lorcaserin–adds new impetus to the revival of the antiobesity drug market–including drug discovery and development, and the marketing of antiobesity agents. This includes approaches that work by increasing energy expenditure, rather than the usual approach of decreasing appetite by targeting the CNS. We discussed some of these novel approaches in our May 23, 2012 article on this 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.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.