Biopharmconsortium Blog

Agios Nikolaos, Crete http://bit.ly/uNaFMW

On November 17, 2011, Agios Pharmaceuticals (Cambridge, MA), arguably the leader in cancer metabolism R&D, secured $78 million in an oversubscribed Series C financing.

The company intends to use the proceeds of this financing to advance its preclinical cancer metabolism therapeutics into the clinic, and 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 conditions have a high level of unmet medical need.

Investors participating in this round included Agios’ existing strategic partner Celgene, existing investors ARCH Venture Partners, Flagship Ventures and Third Rock Ventures, and several new, undisclosed investors, including three leading large public investment funds. In conjunction with the new financing, Perry Karsen, COO of Celgene, joined Agios’ Board of Directors.

Despite being only a preclinical-stage biotech company, and despite the tough early-stage biotech venture capital market, Agios has done very well in fundraising.  In April 2010, as discussed in a Biopharmconsortium Blog article, Agios secured a $130 million upfront payment in a strategic collaboration with Celgene. In October 2011, Celgene extended its collaboration with Agios from three to four years, including making an additional $20 million payment to Agios. According to a November 11, 2011 Fierce Biotech article, Agios has secured a total of over a quarter of a billion dollars in financing, beginning with its $33 million Series A round in July 2008.

Also according to Fierce Biotech, by bringing in public investors in its new financing round, Agios has taken a financing route that has enabled other biotechs to go public. For example, Ironwood Pharmaceuticals took this route. Agios’ CEO, David Schenkein, told Fierce Biotech that his management intends to build an independent company for the long term, including securing an investor base that could support a public offering.

The Biopharmconsortium Blog has been following Agios since December 2009. See our December 31, 2009 and April 23, 2010 articles. Also see our December 22, 2010 article on the reemergence of intermediary metabolism as an important field of biology, which highlighted the role of Agios in developing applications of this field to oncology therapeutics.

Recent research at Agios

More recently, Agios researchers and academic collaborators led by Agios Scientific Advisory Board member David Sabatini M.D., Ph.D (Whitehead Institute and Massachusetts Institute of Technology, Cambridge MA) published a study in the 18 August 2011 issue of Nature. In this study, the researchers demonstrated that 70% of estrogen receptor (ER)-negative human breast cancers exhibit amplification and elevated expression of the gene for phosphoglycerate dehydrogenase (PHGDH). PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased flux through this pathway. This in turn results in increased levels of α-ketoglutarate, which is a tricarboxylic acid (TCA) cycle intermediate. (The TCA cycle, the central pathway in intermediary metabolism, was illustrated in the figure at the top of our December 22, 2010 blog post).

Suppression of PHGDH [via RNA interference (RNAi)] in breast cancer cell lines with elevated PHGDH expression, but not in those without, causes a strong reduction in cell proliferation, a reduction in serine synthesis, and a reduction in levels of α-ketoglutarate. This result indicates that most ER-negative breast cancers are dependent on deregulation of the serine synthesis pathway, and that targeting this pathway may provide a novel therapeutic strategy for this subset of breast cancers.

In the September 2011 issue of Nature Genetics, Agios founder Lewis C. Cantley, Ph.D., and Agios advisor Matthew Vander Heiden, M.D., Ph.D., (Beth Israel Deaconess Medical Center/Harvard Medical School and MIT, respectively) published a report that provides further evidence that amplification of PHGDH and deregulated activity of the serine pathway are linked to the growth and survival of certain cancers, especially melanoma and subtypes of breast cancer. This study was carried out using a novel research method called metabolic flux analysis, which is an important component of Agios’s technology platform in cancer metabolism.

These studies provide additional validation for the field of cancer metabolism as a source of novel therapeutic strategies.

Pharmaceutical industry interest in cancer metabolism

Agios is not the only company that is active in the field of cancer metabolism. For example, Forma Therapeutics (Cambridge, MA) is also conducting R&D in this field. According to an article in XConomy Boston, Forma entered into a collaboration with Genentech in cancer metabolism on June 27, 2011. Under the agreement, Genentech will receive exclusive rights to acquire one of Forma’s early preclinical-stage cancer metabolism drugs. In return, Forma will receive an upfront payment, research support, R&D milestone payments, and development funding for that drug. If Genentech decides to acquire the drug after it has met its development goals, Forma will forgo any royalty payments. Instead, Genentech will make an asset buyout payment, which will be distributed to Forma’s investors. In addition, Forma will receive milestone payments on sales of the drug.

Thus Forma’s investors will receive a return on their investments, without the need for an acquisition or an initial public offering. Forma will thus remain an independent company, free to develop its other pipeline drugs, including any other of the approximately 8-10 cancer metabolism drugs that it has already discovered.

This deal, which is made possible by the industry’s keen interest in cancer metabolism-based therapeutics, suggests that Forma, like Agios, intends to remain an independent company over the long haul. Forma has raised over $50 million in venture capital so far, and has revenue-producing alliances with Novartis, Cubist, and the Leukemia & Lymphoma Society as well as Genentech.

Conclusions

Agios is leveraging the strong biotech/pharma industry interest in cancer metabolism, and its own leadership in the field, to build and to finance its R&D programs, and also its corporate development. However, as always, all will depend on the performance of the company’s compounds in the clinic. Dr. Schenkein is providing no information on the timeline for entry of Agios’ drugs into clinical trials. However, he says that the funding secured by Agios will provide the means to get its lead drugs through proof-of-concept studies in humans.

Interestingly, Agios Pharmaceuticals’ founders and management have a particular fondness for the Greek language. At the apex of Agios’ values is arete (ἀρετή), an ancient Greek word that connotes virtue, excellence, and courage and strength in the face of adversity. CEO Schenkein also adds another meaning, “living up to ones potential”.

“Agios” itself is a Greek word (Άγιος), which means “holy” or “Saint”. This is why I chose the figure at the top of this article. It is a photo of the town of Agios Nikolaos (Άγιος Νικόλαος), Crete, which is named for Saint Nicholas.
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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.

PPARγ

This article is an update of a three-part series on insulin sensitizers for treatment of type 2 diabetes that was published on this blog in August and September of 2010.

Summary of our August/September 2010 blog articles on insulin sensitizers

In part 1 of the series (posted August 23, 2010), we focused on safety issues with the two marketed thiazolidinedione (TZD) peroxisome proliferator-activated receptor gamma (PPARγ) agonists–rosiglitazone (GlaxoSmithKline’s Avandia) and pioglitazone (Takeda’s Actos). Both of these insulin sensitizing, antidiabetic agents induce weight gain, and carry an increased risk of edema and heart failure. In addition, rosiglitazone carries an increased risk of myocardial infarction. On September 23, 2010, the FDA restricted access to Avandia, and the European Medicines Agency (EMA) recommended that the drug be pulled from the market.

In part 2 of the series (posted on August 29, 2010), we discussed a breakthrough discovery by Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues, published in the 22 July 2010 issue of Nature. It was the Spiegelman group that originally identified PPARγ as the master regulator of adipocyte biology and differentiation, which eventual led to the development of the TZD drugs.

In that research, the Spiegelman group found evidence that the insulin sensitizing and antidiabetic effects of PPARγ agonists may not be due to the agonistic effects of these compounds on PPARγ, but to their ability to inhibit phosphorylation (at Ser 273) of PPARγ by the enzyme cyclin-dependent kinase 5 (CDK5). A weak PPARγ agonist, the benzoyl 2-methyl indole (non-TZD) MRL24, inhibits CDK5 phosphorylation of PPARγ as well as rosiglitazone, and also has very good antidiabetic activity.

CDK5 phosphorylation of PPARγ does not change the ability of PPARγ to upregulate transcription of genes involved in adipocyte differentiation. However, it inhibits the ability of PPARγ to upregulate transcription of a set of genes, including the gene for the adipokine adiponectin, that induce insulin sensitivity and resistance to obesity. Although both rosiglitazone and MRL24 inhibit CDK5 phosphorylation of PPARγ, treatment with the strong agonist rosiglitazone results in upregulation of both the adipogenic and the pro-insulin resistance sets of genes, while treatment with MRL24 results only in upregulation of the pro-insulin resistance set.

Researchers hypothesize that it is the upregulation of the adipogenic gene set that is responsible for the adverse effects of strong agonists of PPARγ–weight gain, edema, and the risk of heart failure. In contrast, the upregulation of adiponectin and the other members of the pro-insulin resistance gene set is thought to be responsible for the desirable, antidiabetic effect of PPARγ agonists.

In part 3 of the series (published on September 16, 2010), we discussed two essays, also published in the 22 July 2010 issue of Nature, that discuss using the new breakthrough results of the Spiegelman group to discover and develop improved insulin sensitizers. These essays recommended that researchers screen for compounds that inhibit CDK5 phosporylation of PPARγ rather than those that are strong PPARγ agonists. We also discussed the prospects for early-stage non-TZD partial or selective agonists of PPARγ, which might constitute second-generation insulin sensitizers.

New research from the Spiegelman group based on their 2010 breakthrough result

On September 4, 2011, Nature published, as an “advance online publication”, a new paper [subsequently published in Nature's 22 September 2011 print edition] by Bruce Spiegelman, Patrick R. Griffin and Theodore Kamenecka (Scripps Research Institute, Jupiter, Florida) and their colleagues on discovery of novel compounds that bind to PPARγ and block its phosphorylation by CDK5, and which completely lack PPARγ agonist activity. (These compounds are thus neither full nor partial/selective agonists of PPARγ.)

One of these compounds, SR1664, exhibited potent antidiabetic and insulin sensitizing activity in two mouse models of obesity-associated type 2 diabetes. However, unlike full agonists such as rosiglitazone, it did not cause fluid retention and weight gain in these animal models. Fluid retention and weight gain are major adverse effects of TZDs in their own right, and are also thought to be related to the even more serious cardiovascular adverse effects of TZDs. Moreover, SR1664 did not interfere with bone mineralization in cultured osteoblasts; this assay is a model for the loss of bone mineral density and increase risk of fracture seen with TZDs.

The researchers developed SR1664 by starting with a partial agonist of PPARγ developed by GlaxoSmithKline, known as compound 7b. Using compound 7b as a scaffold for chemical modification, the researchers optimized for (1) high binding affinity for PPARγ, (2) blocking of CDK5-mediated PPARγ phosphorylation and (3) lacking classical agonism. The structure of two resulting compounds, SR1664 and SR1824, are given in the new Spiegelman/Griffin paper.

Although the new study suggests that SR1664 may be as efficacious an insulin sensitizer as TZDs without inducing their major adverse effects, the safety of these compounds in humans (as opposed to the mouse models) remains unproven. Moreover, SR1664 has unfavorable pharmacokinetic properties and is thus not a good candidate for development as a drug. According to a press release, Dr. Griffin’s molecular therapeutics group and Dr. Kamenecka’s medicinal chemistry group at Scripps have been using S1664 as a molecular scaffold for the discovery of derivatives with improved pharmacokinetic properties. They are advancing such newer compounds into additional studies.

Why develop new insulin sensitizers rather than depending on current antidiabetic drugs?

In Heidi Ledford’s commentary published in the 22 July 2010 issue of Nature, the author points out that some observers believe that pharmaceutical companies will be reluctant to attempt to develop new insulin sensitizers that target PPARγ, given the checkered history of that class of drugs. And other medical authorities believe that the older, inexpensive, and well proven type 2 diabetes drugs–insulin, metformin, and sulfonylureas–are adequate for the treatment of type 2 diabetes.

However, there remain important unmet needs in the treatment of type 2 diabetes. These especially include dealing with the relentlessly progressive nature of type 2 diabetes–for example, even patients who initially succeed in reaching glycemic goals with only diet/exercise and metformin will eventually need multidrug treatment, including insulin. Progression of type 2 diabetes is mainly due to the loss of pancreatic beta-cell function, which results in increased impairment of a patient’s ability to produce insulin in response to increased blood glucose.

Despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function. It will be important to determine if nonagonist second-generation insulin sensitizer candidates, such as those being developed by the Spiegelman and Griffin groups, also have the beta-cell preserving or enhancing effects of TZDs.

The Harvard/Scripps efforts to discover safer insulin sensitizers illustrate the potential role of academia (based on breakthrough science) in areas of drug discovery and development that industry is reluctant to undertake. However, although these academic groups might potentially take the nonagonist insulin sensitizers through lead optimization and preclinical studies, eventually industry (whether a biotech company or a pharmaceutical company) will need to take the compounds through clinical trials in order for any drugs to reach the market.
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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.

Galega officinalis (Goat's Rue) From JoJan http://bit.ly/l5Ybco

Metformin (Bristol-Myers Squibb’s Glucophage, generics), an oral biguanide antidiabetic drug, is the most widely prescribed agent for treatment of type 2 diabetes. The drug mainly works by lowering glucose production by the liver, and thus lowering fasting blood glucose.

Although metformin–approved in the United States in 1994, and in Europe prior to that–has been used for many years, its mechanism of action is not well understood. In 2005, signal-transduction pioneer Lewis Cantley (Beth Israel Deaconess Cancer Center/Harvard Medical School, Boston MA), and his colleagues–including Reuben J. Shaw (now at the Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA)–published a report showing that metformin targets the adenosine monophosphate (AMP)-activated kinase (AMPK) pathway in the liver. We discussed this report and its implications in our 2007 Cambridge Healthtech Institute Insight Pharma Report, Diabetes and Its Complications.

AMPK is found in all eukaryotic organisms, and serves as a sensor of intracellular energy status. In mammals, it also is involved in maintaining whole-body energy balance, and helps regulate food intake and body weight. We  have discussed the potential role of AMPK in regulation of lifespan, and as a target in anti-aging medicine and in metabolic disease, in earlier articles on this blog. (See here and here.)

AMPK is activated by increases in the ratio of AMP to ATP, caused by energy stress. Under conditions of energy stress, AMP levels go up, and AMP binds to a specific site on the AMPK γ subunit. This induces a conformational change that exposes the activation loop of the α subunit. This allows an upstream serine/threonine kinase to phosphorylate this activation loop. In several mammalian cell types, including liver and skeletal muscle, that kinase is LKB1. Drs. Cantley and Shaw in 2005 showed that metformin targets the LKB1-AMPK pathway in the liver, and that metformin requires LKB1 to lower glucose production by the liver. However, neither LKB1 nor AMPK is the direct target of metformin, and as of 2005, that direct target was unknown.

A new genetic study that suggests that ATM kinase may affect the ability of patients to respond to metformin

Now–as of February 2011–comes a Nature Genetics paper that indicates that the serine/threonine kinase ATM (ataxia telangiectasia mutated) acts upstream of AMPK to mediate the therapeutic effects of metformin. ATM is a DNA repair protein that is recruited and activated by double-strand breaks in DNA. It initiates activation of the DNA damage checkpoint, leading to cell cycle arrest, followed by DNA repair or apoptosis. Thus the role of ATM in the AMPK pathway and in the therapeutic effects of metformin is surprising indeed.

In the study reported in the Nature Genetics paper, researchers of The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group and The Wellcome Trust Case Control Consortium 2 performed a genome-wide association study (GWAS) for glycemic response to metformin in type 2 diabetes patients in the U.K. In a population of nearly 4,000 patients, they identified a single-nucleotide polymorphism (SNP) designated rs11212617, which was associated with treatment success. This SNP occurs in a genetic locus that also contains the gene that encodes ATM. In a rat hepatoma cell line, inhibition of ATM by the specific inhibitor KU-55933 (KuDOS Pharmaceuticals, Cambridge, U.K., which was acquired by AstraZeneca in 2005) attenuated metformin-mediated phosphorylation and activation of AMPK.

The analysis by Morris Birnbaum and Reuben Shaw in the 17 February 2011 issue of Nature

The 17 February 2011 issue of Nature contained a Forum entitled “Genomics: Drugs, diabetes and cancer.” This consisted of two analyses of the implications of the Nature Genetics paper for metformin’s mechanism of action, and for understanding diabetes and the connections of the metformin-activated ATM/AMPK pathway with cancer. The first analysis was by Morris J. Birnbaum, M.D., Ph.D. (University of Pennsylvania Medical School, Philadelphia, PA), who does research on the role of AMPK and insulin in energy metabolism and in diabetes. The second analysis is by Dr. Reuben Shaw, mentioned earlier. Dr. Shaw’s research centers around LKB1 [also known as serine/threonine kinase 11 (STK11)]. LKB1, a serine/threonine kinase, is not only a regulator of hepatic glucose production via AMPK, but is also a tumor suppressor. Germline mutations in LKB1 are associated with the familial cancer Peutz-Jegher syndrome, and somatic mutations in LKB1 are present in various other cancers. In particular, the Lkb1 gene is one of the most frequently muted genes in human lung adenocarcinomas.

Dr. Birnbaum’s analysis

Dr. Birnbaum notes that the finding of a role for ATM in metformin responsiveness may be an important clue to the mechanism of action of this drug. However, it may also be a false lead, with ATM having only an indirect effect on metformin’s action. He cites recent evidence that metformin acts independently from LKB1 and AMPK and of transcriptional regulation in general. In these studies, genetic ablation of LKB1 and AMPK was used to show that these mediators are dispensable for metformin’s glucose-lowering activity. Instead, metformin appears to work by inhibiting mitochondrial production of ATP in the liver, thus reducing the level of liver glucose production via gluconeogenesis (which uses ATP). This is in apparent contradiction to the 2005 results of Dr Shaw and his colleagues. Nevertheless, metformin’s inhibition of mitochondrial ATP production increases the ratio of AMP to ATP, and thus activates AMPK. There are also other pathways by which inhibition of mitochondrial ATP production may inhibit gluconeogenesis. Thus the mechanisms by which metformin causes a decrease in glucose production by the liver appear to be very complex, and are not well understood.

Dr. Birnbaum therefore speculates that ATM may affect blood glucose levels via pathways that are parallel to, but not the same as, those modulated by metformin. However, the effects of these other pathways may be synergistic with those modulated by metformin when patients are treated with the drug. Dr. Birnbaum notes that 40 years ago, it was found that patients with ataxia telangiectasia often display a type 2-diabetes-like condition, including insulin resistance. Ataxia telangiectasia is a familial disease caused by germline mutations in ATM. This suggests that  ATM may act to counteract hyperglycemia and insulin resistance.

Dr. Birnbaum concluded that biochemical and cell biology studies should be conducted to determine the nature of the interaction of ATM and the antidiabetic effects of metformin. Key to these endeavors is to determine whether there are any biomolecules other than AMPK that both are influenced by ATM and control metabolism.

Dr. Shaw’s analysis

Dr. Shaw first discusses several animal studies that help elucidate the role in glucose regulation of the biomolecules involved in the putative ATM-LKB1-AMPK pathway. He notes notes that deletion of the Lkb1 gene in mouse liver results in loss of AMPK activity in that organ, and to the development of hyperglycemia and hepatic steatosis–two conditions that are seen in type 2 diabetes. Dr. Shaw also cites the 40-year-old finding about the connection between  ataxia telangiectasia and insulin resistance and diabetes. But as he also mentions the more recent (2006) finding that mice with defective ATM activity show increased insulin resistance and abnormal glucose regulation.

Dr. Shaw then speculates as to how ATM might work to modulate patients’ antidiabetic responses to metformin. He notes that ATM is known to phosphorylate LKB1, which is the key activator of AMPK in the liver. Alternatively, ATM might also regulate AMPK independently of LKB1, and might affect responsiveness of patients to metformin by regulating other relevant targets, independently of AMPK. In this context, ATM is known to phosphorylate other, LKB1 and AMPK-independent components of the insulin signaling pathway.

In the light of these considerations, Dr. Shaw says that it is important to determine whether the rs11212617 genetic variant results in modulation of ATM activity toward AMPK activation or toward other targets relevant to glucose regulation, or indeed whether this SNP affects ATM activity at all.

Dr. Shaw then focuses on the potential relevance of metformin to cancer therapy. Researchers have found, in retrospective studies, that diabetes patients who take metformin have a lower risk of developing cancer than those treated with other antidiabetic medications. Animal studies confirm the anticancer effects of metformin, but–as discussed in a 2010 review by Dr. Michael Pollak (McGill University, Montreal, Quebec, Canada)–they indicate that the anticancer effects of this drug are mechanistically complex. Dr. Shaw asks whether metformin is a general activator of ATM (and/or its targets) in the DNA damage-response pathway, or whether its specific effects on LKB1 and/or AMPK might be responsible for the apparent beneficial effects of metformin on cancer risk.

Dr. Shaw concludes with the statement that future studies of the relationship between metformin action, ATM, LKB1, and AMPK should shed light on the relationship between metformin’s antidiabetic effects and its apparent anticancer effects.

Our conclusions

The finding, based on a genome-wide association study, which suggests that ATM, a kinase best known for its involvement in DNA repair pathways, may also be involved in diabetics’ response to metformin is surprising and intriguing. It may eventually be important in unraveling metformin’s mechanism of action in inhibition of liver gluconeogenesis, and in other antidiabetic activities. This finding indicates a connection between pathways by which metformin exerts its antidiabetic activities, and pathways that are involved in cancer.

Nevertheless, the elucidation of metformin’s mechanism(s) of action in diabetes remains a work in progress. This situation is an example of how science works in the real world (as opposed to textbooks or much of science journalism)–generating more questions than answers.

A drug like metformin, with its complex and still poorly understood mechanism of action, could not have been discovered by modern, post-genomics drug discovery strategies. Metformin was discovered via research on natural products derived from the plant Galega officinalis (known as the French lilac, goat’s rue, and by various other names), which had been known by herbalists for centuries. It is fortunate that researchers were able to study the effects of extracts of this plant, and ultimately to develop metformin, well in advance of the modern era of drug discovery. Diabetics and their physicians now have access to metformin as an inexpensive generic drug.

The continued study of the antidiabetic mechanism(s) of action of metformin may yield additional insights into control of gluconeogenesis and other metabolic pathways. Some of the findings of these studies might be relevant to drug discovery and development, for example the development and use of AMPK activators in metabolic disease and in anti-aging medicine.

Continued study of the mechanism(s) of action of metformin may also be relevant to developing new therapies for cancer. As suggested by Dr. Pollak, although metformin is off-patent and is thus not an attractive agent for development as an oncology drug by pharmaceutical or biotechnology companies, other biguanides or related compounds might be better anticancer compounds, and would be patentable. In addition to identifying such compounds, it will be important to determine and define which groups of cancer patients could best benefit from them (perhaps via biomarkers). It will then be important to conduct personalized medicine hypothesis-testing clinical trials (as discussed in an earlier blog post) designed to obtain proof-of-concept that such compounds can indeed benefit specific groups of patients.

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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.

"That's all, folks!" http://bit.ly/gSgL6b

As we said in our December 8, 2010 blog post, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that the FDA approve Orexigen’s Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.

This followed the earlier rejections in 2010 by the Advisory Committee and the FDA 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 the rejection of Qnexa and lorcaserin, and safety issues (increased risk of cardiovascular events) were the reason for the withdrawal of sibutramine. Thus the Advisory Committee’s recommendation for approval of Contrave was surprising, to us as well as to many others.

Despite the Advisory Committee’s vote to recommend approval of Contrave, it did have safety concerns. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as sibutramine.

As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.

Yesterday–January 31, 2011–was the Prescription Drug User Fee Act (PDUFA) deadline for the FDA to act on the approval of Contrave. This morning, Orexigen and its partner for Contrave commercialization, Takeda, announced that the FDA had issued a Complete Response Letter regarding the New Drug Application for Contrave.

The FDA’s Complete Response Letter stated, “before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.”  Essentially, the FDA required Orexigen and Takeda to conduct the cardiovascular safety trial of Contrave prior to marketing approval, not post-marketing as recommended by the Advisory Committee. The safety trial required by the FDA will be neither fast nor inexpensive.

As a result of the FDA ruling, what we called “the pall of gloom” descended once again on the antiobesity drug field. Forbes’ Matthew Herper, for example, declared the antiobesity drug field “effectively dead”. Herper further said, “The clear lesson is that weight-loss medicines simply do not have enough of a benefit to justify any risk – and that this makes getting them approved just about impossible.”

If you click on the “metabolic diseases” category on the right-hand panel of this blog, you will see that we have quite a number of blog articles on obesity, usually in the more holistic context of metabolic diseases–obesity, type 2 diabetes, and metabolic syndrome (which is a major risk factor for cardiovascular disease). In these articles, you will see that we are not negative about antiobesity drug development. However, we are–and have been for some time–quite negative about developing appetite suppressant drugs that address common neurotransmitter receptors in the CNS.  Such agents might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy.

If you read our articles, you will see that there are several companies that have strategies to develop antiobesity agents that are not appetite suppressants, and that are being–or can be–developed for diabetes and/or metabolic syndrome in addition to obesity.  A common strategy is to develop diabetes/obesity drugs first for diabetes, resulting in easier FDA approval. Such drugs may later also be developed for obesity, after they prove to be safe and to induce weight loss in diabetes trials. For example, Novo Nordisk is following this strategy with the development of liraglutide (Victoza), which is already approved for treatment of type 2 diabetes.

Other established companies are pursuing different strategies, such as Amylin/Takeda’s development of pramlintide/metreleptin for obesity. This is really a metabolic syndrome-based approach to obesity. Indeed, Amylin is developing metreleptin as a single agent for treatment of diabetes and high triglycerides in patients with lipodystrophy.

Then there are several young companies covered in this blog that are developing antiobesity treatments via innovative biology-driven strategies. Two of these companies, Energesis and Acceleron, are developing antiobesity therapies that target brown fat. Such an approach is really a metabolic syndrome-based one, and might also be applied to various diabetes and/or cardiovascular indications for easier regulatory approval.

Meanwhile, a News and Analysis article in the January 2011 issue of Nature Reviews Drug Discovery lists several agents not covered in our blog. One agent, tesamorelin (Theratechnologies/Merck KGaA’s Egrifta) was approved by the FDA in November 2010 as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy. Tesamorelin is a synthetic analogue of growth hormone–releasing factor — a hypothalamic peptide that acts on the pituitary to stimulate production and release of human growth hormone. This drug is now in a Phase 2 clinical study for treatment of human growth hormone deficiency associated with abdominal obesity. This represents a potential personalized medicine approach for treatment of a specific population of obese patients. Such an approach may be looked at more favorably by regulatory agencies than a “diet pill” for the general obese population.

As we also discussed in another article, John C. Lechleiter, Ph.D., the chairman, president and CEO of Lilly, outlined the need for “public policies that enable and reward medical innovation”, especially in the metabolic syndrome/diabetes/obesity therapeutic area. This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the PDUFA, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for negotiation between industry and the FDA to achieve these ends.

We hope that industry and the FDA can work toward a more favorable environment for the approval of safe and efficacious antiobesity drugs. And Dr. John Jenkins, director of the FDA office of new drugs, said that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.” Nevertheless, we do not see the FDA approving a minimally-efficacious CNS-acting appetite suppressor for the general obese population any time in the foreseeable future.

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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.

Naltrexone

Bupropion

As many of you know, this blog has been covering the review of preregistration antiobesity drugs by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and by the FDA itself. 2010 was supposed to be the year in which one or more new obesity drugs would be approved by the FDA and reach the market. Three new drugs developed by small California companies–Vivus Pharmaceuticals’ Qnexa, Orexigen Therapeutics’ Contrave, and Arena Therapeutics’ lorcaserin, were up for FDA review this year. This follows a long hiatus, since the FDA has approved no antiobesity drug since 1999.

So far, the Advisory Committee–and later the FDA itself–has rejected approval of two of these drugs–Qnexa and lorcaserin. At the same time, the marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request.

The third preregistration antiobesity drug, Orexigen’s Contrave, was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee in December 2010, and the review was held on December 7th. Most industry experts expected that the Advisory Committee would reject Contrave as well. But, surprisingly, the Committee recommended that the FDA approve Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.

The FDA usually follows the advice of its advisory panels, but does not always do so.

Contrave is a combination of long-acting formulations of two FDA-approved drugs–naltrexone and bupropion. Orexigen designed Contrave to have a dual effect on pathways within the hypothalamus of the brain that control energy balance–increasing anorexia and inhibiting the reward effects of food. The company also believes that Contrave may block the body’s compensation for weight loss–i.e., decreased energy use and increased feeding. For additional details, see our 2008 book-length obesity report, published by Cambridge Healthtech Institute.

The Advisory Committee, although they voted positively, did not do so with much enthusiasm, since Contrave just barely met the FDA’s criteria for efficacy. The drug enabled a majority of patients to lose about 5% of their body weight. Despite the drug’s minimal efficacy, a 5% loss in body weight can have significant health effects, such as helping patients to prevent diabetes and heart disease and to control their blood pressure. Some panelists were concerned that there is no data on the drug’s efficacy or safety beyond one year of treatment. Obesity is a long-term condition, and most patients would probably require long-term treatment with Contrave if it is approved.

However, as in the previous reviews by the Advisory Committee of Qnexa and lorcaserin, the main emphasis of the discussion was on safety. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as Meridia, which at the time of its approval was also known to cause elevated blood pressure in some patients. The reason for this year’s withdrawal of Meridia was its increased risk of cardiovascular events.

As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.

Overall, the Advisory Committee concluded that physicians and patients need additional options to treat obesity, and that the risk-to-benefit ratio for Contrave falls on the side of benefits. Although that was the general conclusion of the panel, some members did not agree.

When the FDA conducts its own review of Contrave, it not only must decide on whether to approve the drug, but also on the drug’s label and on requirements for post-marketing studies. FDA action is expected by the end of January 2011.

As we discussed in a previous blog post, Takeda is Orexigen’s commercialization partner for Contrave. Under their agreement, Orexigen granted Takeda North American (U.S, Mexico, and Canada) marketing rights for Contrave; Orexigen retains copromotion rights in the United States. Takeda paid Orexigen $50 million upfront, and will pay (upon FDA approval) tiered double-digit royalties (starting at 20% and increasing to 35%) on any net sales of Contrave. The deal is estimated to be worth a potential $1 billion. Takeda will also share the costs of further development of these drugs, presumably including any post-marketing studies.

As we also discussed in the same article, Takeda also has an agreement with Amylin to develop earlier-stage antiobesity drugs, with the potential for greater efficacy than drugs that address appetite-control pathways in the CNS that involve common neurotransmitters.

The approval of Contrave (if the FDA goes along with its Advisory Committee’s recommendations) may affect the strategy of Vivus and Arena as they work with the FDA to obtain reconsideration for approval of Qnexa and lorcaserin, respectively. And it might restart research on early-stage antiobesity drugs, which has been largely on hold as the pharmaceutical/biotechnology industry and the medical and financial communities awaited approval of one or more of the three drugs being reviewed by the FDA in 2010. And–by lifting the “pall of gloom” over the antiobesity drug field–it might improve funding and partnering prospects for such early-stage obesity specialist companies as Zafgen and Energesis, which we discussed in an earlier blog post.

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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.

Resveratrol

In statements to Fierce Biotech and to the Myeloma Beacon, GlaxoSmihtKline (GSK) said that it has stopped all development of its proprietary resveratrol formulation SRT501. Thanks also to the “In the Pipeline” blog for the information on the Myeloma Beacon statement.

As you all may recall, 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, including SRT501. GSK also appointed Christoph Westphal, then CEO of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD), and Michelle Dipp, then vice president of business development at Sirtris, as Vice President and the head of the US CEEDD at GSK.

According to the Fierce Biotech article, the precipitating factor in GSK’s decision to halt development of SRT501 was the result of a Phase 2a study of the drug in advanced multiple myeloma. The company suspended the study after several patients developed kidney failure. GSK said that in its analysis, the company concluded that SRT501 “may only offer minimal efficacy while having a potential to indirectly exacerbate a renal complication common in this patient population.” It then said that the company has “no further plans to develop SRT501.”

Instead, GSK intends to focus on development of Sirtris’ non-resveratrol synthetic selective sirtuin 1 (SIRT1) activators, which in addition to their greater potency, have more favorably drug-like properties. In its statement to the Myeloma Beacon, GSK in particular mentioned SRT2104 and SRT2379 as the focus of its continuing activity. According to the Sirtris website, SRT2104 is in Phase 2 studies in metabolic and cardiovascular disease, and SRT2379 is in Phase 1 studies in healthy volunteers. Neither compound is currently being tested in cancer.

We discussed Sirtris’ SIRT1 activators in the context of the anti-aging biology field, in a February 10, 2010 blog post. In summary, the mechanism of action of reseveratrol and of Sirtris/GSK’s sirtuin activators is unclear. They apparently activate multiple targets, and they may not be direct SIRT1 activators at all. Nevertheless, Sirtris’ studies of these compounds in mice indicate that they have efficacy in treatment of metabolic diseases. The Phase 2 clinical trials in humans are still ongoing.

To complicate matters further, a study published in the journal Diabetes in March 2010 by NIH researcher Jay H. Chung and his colleagues indicates 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, the effect of resveratrol on AMPK may be more important than its more indirect activation of sirtuins, at least in the case of metabolic diseases.

Thus Sirtris/GSK’s “sirtuin activators” are under a cloud.

However, as we discussed in our blog posts of November 8, 2009 and February 10, 2010, basic research on anti-aging biology has yielded ample material for drug discovery which may eventually lead to novel treatments for metabolic diseases, and perhaps for other conditions such as various cancers. For example, several companies are developing AMPK activator drugs. Thus there are other avenues for harnessing basic research on anti-aging pathways to discover and develop novel drugs for multiple conditions, even if the Sirtris compounds prove to be a dead end.

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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.

Brown fat deposits in a young woman. Source: Hellerhoff. http://bit.ly/9RNG69

As we said in our November 3, 2010 blog post, “The withdrawal of Meridia from the market, coupled with the FDA rejections of lorcaserin and Qnexa, has cast a pall of gloom on the obesity drug market. Some commentators have declared the field to be dead….”

Nevertheless, a few hardy entrepreneurs and venture capitalists continue to found and fund start-ups, whose goal is to discover and develop truly innovative classes of drugs for obesity and metabolic disease.

A November 3, 2010 Xconomy article focused on the Cambridge, MA startup biotech firm Energesis Pharmaceuticals. Energesis was confounded by Olivier Boss, PhD (formerly of Sirtris Pharmaceuticals), Brian Freeman, MD (former Venture Partner at GreatPoint Ventures), and Jean-Paul Giacobino, MD (Professor Emeritus, University of Geneva Medical School, Switzerland). Dr. Boss serves as Energesis’ Chief Scientific Officer, and Dr. Freeman as its Chief Operating Officer.

Energesis focuses on the discovery and development of drugs for the treatment of obesity, diabetes, and related metabolic diseases. The company plans to develop therapeutics that work by increasing energy expenditure, rather than the usual approaches of decreasing appetite or blocking absorption of fat in the gut. Energesis researchers intend to discover and develop drugs that increase the amount and/or activity of brown adipose tissue (BAT) to combat obesity and other metabolic diseases. BAT is a type of mitochondria-rich adipose tissue that burns fat and dissipates the energy as heat rather than storing it. The mitochondrial protein UCP1 (uncoupling protein 1) is the key biomolecule that makes this process possible. BAT has long been known to be central to non-shivering thermogenesis in rodents, for example to maintain body temperature when they are exposed to cold.

Until recently, researchers believed that in humans, significant populations of BAT cells were found only in infants. However, in recent years researchers found that adult humans possess reservoirs of brown fat in the neck region and other areas of the upper body as well as in skeletal muscle. (See the figure above.) Adult human BAT can be stimulated by acute exposure to cold and via the sympathetic nervous system, and by various pharmacological agents. Energesis’ drug discovery technology is based on the use of brown fat stem cells. The company has provided few details on its technology in published sources.

In October 2010, Energesis was named as one of the winners of the 2010 MassChallenge Global Startup Competition, where it was the top life sciences company. In that competition, Energesis was also one of the top 111 entrants that were invited to participate in a 3-month accelerator program. This provided intensive mentoring, and access to such resources as office space, legal counsel, and introductions to funding sources. Energesis, which has temporary office space in the Cambridge MA incubator Dogpatch Labs (created by venture capital firm Polaris Ventures), is now seeking additional seed-stage funding.

Brian Freeman is key to Energesis’ financing strategy. As a Venture Partner at GreatPoint Ventures, Dr. Freeman cofounded another Cambridge MA company that focuses on obesity, Zafgen. Zafgen was founded in 2005. We discussed Zafgen briefly in an earlier blog post. Zafgen’s drug discovery and development profile is based on targeting the vasculature of adipose tissue, similarly to targeting tumor angiogenesis. Zafgen already has a compound, ZGN-433 (which is a methionine aminopeptidase inhibitor), in Phase I development, and is working on earlier-stage compounds. Thus, like Energesis, Zafgen targets a novel weight-control mechanism that does not involve appetite control in the CNS or fat absorption in the gut.

Zafgen has venture funding not only from GreatPoint, but also from Atlas Ventures and Third Rock Ventures. It was named as one of the “Fierce 15” leading biotechnology companies of 2009 by FierceBiotech.

Meanwhile, another Cambridge MA biotech company, Acceleron Pharma, discovered a compound, ACE-435, which targets BAT.  ACE-435 inhibits signaling of members of the TGF-beta protein superfamily. in preclinical studies in obese animals, ACE-435 increased brown fat, decreased white fat, increased skeletal muscle, and dramatically lowered serum cholesterol and triglyceride levels. Acceleron is developing ACE-435 for treatment of metabolic diseases. The company was named as one of the “Fierce 15″ biotech companies in 2010.

Acceleron, which was founded in 2004 and has three products in the clinic, has raised three rounds of venture capital, and has a major corporate alliance with Celgene. In September 2010, it also signed a $498 million agreement with Shire to develop muscular dystrophy drugs. Acceleron is thus a more mature company than Zafgen or Energesis. Unlike Zafgen and Energesis, Acceleron works in several therapeutic areas, not just obesity and metabolic diseases.

The entrepreneurs who founded obesity specialists Zafgen and Energesis–as well as the venture capitalists who funded Zafgen, and the executives and researchers at Acceleron who have been developing ACE-435–are working on obesity drug development despite the pall of gloom caused by the failures of nearly every antiobesity drug, and the increasing currency among leaders of health insurance companies and health care providers of the old idea that obesity is entirely the fault of the obese, due to “lack of personal responsibility” or “food addiction”. This is despite the abundant evidence that obesity is a complex disease with a large genetic component. Health care leaders, as well as obese people themselves, are frustrated with the lack of solutions to the growing obesity problem, and thus may be tempted to fall back on old, discredited explanations.

The entrepreneurs, researchers, and venture capitalists behind Energesis, Zafgen, and Accleron, however, see the failure of most antiobesity drugs as an opportunity. The failed drugs target common neurotransmitter receptors in the CNS, and thus would be expected to have serious adverse effects, since these receptors are involved in multiple physiological processes in the CNS and elsewhere in the body. Drugs that target physiological pathways other than appetite control in the CNS, and which are based on superior biology-driven drug discovery strategies, may avoid the safety problems of the CNS-acting drugs, as well as exhibiting much greater efficacy. Such drugs may fulfill the major unmet medical need in the obesity area, where there are currently no good solutions.

The founding of Zafgen and Energesis also flies in the face of the current negative situation in the venture capital and credit markets, and in the economy in general.  Small companies (especially including startups) continue to find it difficult to raise cash. More established biotech companies, as well as pharmaceutical companies, also feel the need to cut budgets and especially to cut their workforces to save cash. In the Boston area, Big Biotechs Genzyme (which has been facing a hostile takeover from Sanofi Aventis, and which is in discussions to sell itself to Takeda) and Biogen Idec have slashed workforces and budgets, as has contract research firm and animal model supplier Charles River Laboratories. Acceleron also cut its workforce in November 2010.

Nevertheless, both Acceleron and Zafgen (the latter under the leadership of Brian Freeman) have managed to raise significant amounts of venture capital in this tough market. In the case of Zafgen, this is despite the generally gloomy prospects for antiobesity drugs, which are its dedicated focus. We hope that Energesis, in Dr. Freeman’s capable hands, will also be able to bring in Series A venture funding.

The type of entrepreneurial innovation shown by Energesis, Zafgen, and Acceleron has implications beyond the obesity area. In a recent speech, the CEO of Lilly, John C. Lechleiter, Ph.D. outlined the components of an environment that supports medical innovation. (We citied Dr. Lechleiter’s speech in an earlier blog post on the obesity drug market.) Among these components is what Dr. Lechleiter called “a larger ‘ecosystem’ that allows innovation to flourish”.  Such an ecosystem would include an “atmosphere” that allows innovation to thrive, “nutrients” in the form of monetary investments, and the “seeds” of human talent in relevant scientific disciplines.

The development of Zafgen and Energesis illustrates the importance of the Boston area biotech and pharmaceutical innovation hub in fostering the initiation and growth of biotech companies with innovative strategies that are potentially game-changing, by providing such an ecosystem. This has included entrepreneurial researchers with innovative ideas and intellectual property, lead venture capitalists willing to back their ideas (and, as in the case of Brian Freeman, to leave their venture capital firms and to join with the researchers in a start-up), universities such as Harvard, MIT, Tufts, and Boston University, the large numbers of biotech companies, both large and small, in greater Boston, the presence of Big Pharma facilities including Novartis’ R&D world headquarters, incubators such as Dogpatch Labs, and entrepreneurship competitions such as the MassChallenge and the MIT Enterprise Forum’s 100K competition.

The United States has other biotech/pharma innovation hubs as well, most notably the San Francisco Bay area and greater San Diego. As shown by the example of ZymoGenetics (see our November 11, 2010 blog post), Greater Seattle has been such an innovation hub, although biotech leaders in Seattle are afraid that their hub has been eroded by acquisitions such as that of ZymoGenetics by Bristol-Myers Squibb and the earlier Amgen-Immunex merger, with the resulting substantial layoffs. Other major U.S. biotech/pharma hubs include the Research Triangle Park area of North Carolina and greater New York/New Jersey/Philadelphia. Canada and several Western European countries also have biotech/pharma innovation hubs.

Various other cities and states in the U.S., as well as cities and countries in Europe and South and East Asia, are working to build new biotech hubs to bolster their economies. Big Pharma companies, with their massive need to acquire or partner for new, innovative drugs, must also develop strategies to foster ecosystems for innovation, both within their own organizations and in seedbeds for potential partners such as existing and emerging biotech hubs. The example of the role of the greater Boston area in spawning such companies as Energesis, Zafgen, Acceleron, and several others that have been covered in this blog may provide case studies to help Big Pharmas in formulating new strategies to foster innovation.

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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. We also welcome your comments on this or any other article on this blog.

sibutramine

As we reported in several earlier blog posts, 2010 has been a very busy year for FDA review of antiobesity drugs. At the same time, as we also reported, sibutramine (Abbott’s Meridia/ Reductil), one of the only two antiobesity agents on the market, had been under review by regulatory agencies because of cardiovascular safety concerns. In January 2010, sibutramine was suspended from the market in Europe. Early in 2010, the FDA also issued a warning that sibutramine posed an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. This resulted in an additional contraindication on the drug’s label.

On October 8, 2010, at the FDA’s request, Abbott voluntarily withdrew Meridia from the U.S. market. This leaves only one approved antiobesity drug–orlistat (Roche’s Xenical–also marketed as a low-dose over the counter formulation, GlaxoSmithKline’s alli)–on the market. Orlistat’s adverse effects are unacceptable to many patients, and its efficacy is minimal.

The FDA’s request to withdraw Meridia from the market was based mainly on the results of the SCOUT (Sibutramine Cardiovascular OUTcome Trial) study. This was a 10,744 patient, 6-year study designed to evaluate cardiovascular safety of sibutramine in obese patients over age 55 with preexisting cardiovascular disease, diabetes, or both. Most of these patients had underlying cardiovascular disease, which made them ineligible to receive sibutramine under its then current labeling. The study had been requested of Abbott by European regulatory authorities as a post-marketing commitment. The SCOUT study showed that patients with a preexisting cardiovascular condition receiving long-term treatment with sibutramine had an increased risk of nonfatal myocardial infarction and nonfatal stroke, but not of cardiovascular death or death from any cause.

According to Abbott, the great majority of studies of sibutramine (46 controlled clinical trials and over 6 million patient years of use in the 13 years since the drug’s entry onto the market) in patents in the on-label population showed no such excess cardiovascular risk as in the SCOUT study. Abbott therefore believes that Meridia has a positive risk/benefit profile in the approved patient population. However, the FDA was concerned that patients with undiagnosed cardiovascular disease might be harmed by the drug, and that since the efficacy of the drug was minimal, the risk/benefit ratio was unfavorable. Therefore, the FDA requested that Meridia be withdrawn, and Abbott, despite its objections, complied.

Also in October 2010, in accord with the recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee, the FDA issued a Complete Response Letter to Arena Pharmaceuticals regarding its New Drug Application for lorcaserin (Lorqess). (See our discussion of the advisory committee’s recommendations. The FDA requested additional data from Arena regarding studies of tumor formation in rats receiving lorcaserin, and regarding final study data from a clinical study of lorcaserin in patients with type 2 diabetes.

In the same month, and also in accord with the recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee, the FDA issued a Complete Response Letter to Vivus Pharmaceuticals regarding its New Drug Application for Qnexa (phentermine/topiramate). (See our discussion of the advisory committee’s recommendations. The FDA requested additional data from Vivus regarding the results of an extension study of Qnexa in patients who had already completed a previously-reported trial, as well as an assessment of topiramate and phentermine/topiramate’s teratogenic potential. The agency also requested evidence that the elevation in heart rate associated with Qnexa does not increase the risk of major cardiovascular events.

A third preregistration-stage antiobesity drug, Contrave, (bupropion/naltrexone) is up for review by the Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.

The withdrawal of Meridia from the market, coupled with the FDA rejections of lorcaserin and Qnexa, has cast a pall of gloom on the obesity drug market. Some commentators have declared the field to be dead, and have stated that the FDA’s safety standards require antiobesity drugs to have safety profiles comparable to diet and exercise. However, John Jenkins, M.D., director of the FDA’s Office of New Drugs, Center for Drug Evaluation and Research (CDER), said in an interview that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.”

Meanwhile, on September 21, 2010, the Lasker Foundation announced that its 2010 Lasker Award for Basic Medical Research was given to Drs. Douglas Coleman (Jackson Laboratory) and Jeffrey M. Friedman (Rockefeller University) for “the discovery of leptin, a hormone that regulates appetite and body weight—a breakthrough that opened obesity research to molecular exploration.”

Mouse researcher Coleman, working with obese diabetic mouse strains in the 1960s, showed that an appetite-suppressing substance (encoded by the ob gene) circulates in the bloodstream and signals a second molecule (encoded by the db gene) to curb hunger. Molecular geneticist Friedman, in the 1990s, showed that the ob gene encoded a hormone called leptin. The db gene encodes the leptin receptor. Leptin is produced by fat cells and is released into the circulation, and signals via leptin receptors in the hypothalamus of the brain to curb appetite and control fat mass. Although obese humans have elevated levels of leptin, these high levels of leptin fail to control fat mass. Obese humans are therefore said to be leptin resistant.

Leptin resistance caused the clinical failure of Amgen’s recombinant leptin product metreleptin, although this product does help humans with a rare familial type of morbid obesity that is caused by a loss-of-function mutation in the human homologue of the mouse ob gene. So far, researchers have not been able to unravel the mechanisms of leptin resistance in humans.

The Lasker Award-winning research on leptin showed once and for all that obesity is a complex disease which results from both genetic and environmental factors. Subsequent research has abundantly confirmed this picture. Most recently, a large genome-wide association study (GWAS) of body-mass index confirmed 14 known obesity susceptibility loci, and identified 18 new loci, including one copy number variant. These results add to the picture of obesity as a complex disease, and genes in some of the new loci may provide new insights into body weight regulation in humans. This research may also provide new leads for drug discovery and development.

The development of the three preregistration drugs that have been up for review by the FDA–lorcaserin, Qnexa, and Contrave–owe very little to the basic research on the genetics of obesity begun by Drs. Coleman and Friedman. The discovery and development of these drugs has been based on the same strategy as the development of such antiobesity drugs as phentermine, dexfenfluramine, and sibutramine–target common receptors in the CNS that are involved in (or deemed to be involved In) appetite control.

The only way that this strategy benefits from the study of the genetics of obesity is that that work demonstrated that obesity is indeed a disease, not just due to a failure of willpower. Therefore, there is a rationale to develop drugs to treat obesity. Nevertheless, so far the appetite-suppressant strategy has been a failure, leading to clinical attrition or expensive postmarketing safety failures, with the resulting product withdrawals and lawsuits.

As we discussed in previous blog posts, appetite suppressant drugs that address common neurotransmitter receptors might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy, as is true for all of these drugs so far except for Qnexa.

The drug candidate that is specifically based on the Lasker Award-winning discovery of leptin by Drs. Coleman and Friedman is Amylin/Takeda’s combination product pramlintide/metreleptin. We discussed this drug in an earlier blog post. A proof-of-concept study of pramalintide/metreleptin showed that this product was well tolerated, and gave a 12.7% mean weight loss in patients treated for 24 weeks. This appears to be superior to the efficacy of any antiobesity drug that is or ever has been on the market, as well as to lorcaserin and Contrave.  Amylin and Takeda are moving to enter pramlintide/metreleptin into Phase III clinical trials.

We also discussed other drug discovery and development programs that are based on alternative strategies to CNS-targeting appetite suppressants in an earlier blog post.

The recent Advisory Panel and FDA reviews of antiobesity drugs in 2010 not only highlight the inadequacy of the CNS-targeting appetite suppressant strategy, but also the importance of regulatory policy in fostering development of innovative drugs that address unmet medical needs. In a  Nov. 3, 2010 speech at the Cleveland Clinic Medical Innovation Summit, John C. Lechleiter, Ph.D., the chairman, president and CEO Lilly outlined the need for new, innovative drugs to address the epidemic of type 2 diabetes, in the United States and in the world. Dr. Lechleiter considers diabetes to be part of a network of complex conditions, including not only diabetes, but also obesity and metabolic syndrome.

In addition to the development of novel research and clinical trial strategies in academia, biotech companies, and pharmaceutical companies, Dr. Lechleiter sees the need for “public policies that enable and reward medical innovation.” Dr. Lechleiter said, “To sustain progress against diabetes, public policies – including benefit/risk assessments, reimbursement decisions, and prescribing guidelines – must enable and foster true medical innovation.”

This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the Prescription Drug User Fee Act, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for a “real victory for innovation and for patients.”

In the area of obesity–which is a major risk factor for type 2 diabetes and cardiovascular disease (CVD)–there is a need for both innovative strategies to develop a new generation of safe and efficacious drugs (especially for obese patients who have–or are at high risk of developing–diabetes and/or CVD), and a regulatory environment that fosters successful development and marketing of such innovative drugs. This will require negotiation between industry and the FDA, as well as other stakeholders involved in policy decisions that affect the development, approval, reimbursement, and market acceptance of innovative drugs for obesity and its complications.

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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. We also welcome your comments on this or any other article on this blog.

FDA logo for illustration purposes only.

On September 23, 2010, the FDA made its decision on  what to do about the antidiabetic drug rosiglitazone (GlaxoSmithKline’s [GSK's] Avandia), based largely on the July 15, 2010 recommendations of the agency’s Endocrinologic and Metabolic Drugs Advisory Committee. That committee had voted to keep Avandia on the market with some new restrictions, because of cardiovascular safety concerns with the drug. But the committee was deeply divided with respect to the specifics of these restrictions, and whether Avandia should remain on the market at all.

The FDA decided to restrict access to Avandia by requiring GSK to submit a Risk Evaluation and Mitigation Strategy (REMS). After implementation of the REMS, Avandia will be available to patients not already taking it only if they are unable to achieve glycemic control using other drugs and, who decide not to take pioglitazone (Takeda’s Actos) for medical reasons in consultation with their physician. Patients now on Avandia will be able to continue using the drug if they appear to be benefiting from it and they acknowledge that they understand the drug’s risks. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns. These new restrictions should significantly limit the use of Avandia, whose use has already declined precipitously.

FDA officials Drs. Janet Woodcock, Joshua Sharfstein, and Margaret Hamburg (who is the FDA Commissioner) published the reasoning behind their decision in the New England Journal of Medicine.

On September 23, 2010, the European Medicines Agency (EMA) also took regulatory action on rosiglitazone. This agency recommended that the drug, marketed as Avandia, Avandamet and Avaglim in Europe, be taken off the market. These drugs will no longer be available in Europe within the next few months. The EMA published a question and answer document on its action.

During August and September 2010, we published a series of three articles on this blog on the safety issues with rosiglitazone and the other marketed drug of the insulin sensitizing thiazolidinedione (TZD) class pioglitazone, as well as how the biotechnology/pharmaceutical industry might develop improved, safer, and more efficacious insulin sensitizers. These articles are:

• “Avandia squeaks through an FDA Advisory Panel. But can the pharmaceutical/biotechnology industry develop better insulin sensitizers?”

• “Can the pharmaceutical/biotechnology industry develop better insulin sensitizers? A breakthrough result in the biochemistry of PPARγ.”

• “How might the pharmaceutical/biotechnology industry develop better insulin sensitizers?”

Please read these articles if you have not already done so.

Because of the key importance of insulin resistance in the pathogenesis of type 2 diabetes, and because of the major unmet needs in treatment of this disease, we believe that it is important to work to develop novel, innovative insulin sensitizers that can overcome the deficiencies of the TZDs and hopefully fill at least some of these unmet needs. These articles outline ways in which the industry might be able to accomplish this objective.

Lorcaserin

As we stated in our August 4, 2010 blog post, 2010 was supposed to be the year in which one or more new obesity drugs would be approved by the FDA and reach the market. Three new drugs developed by small California companies–Vivus Pharmaceuticals’ Qnexa, Orexigen Therapeutics’ Contrave, and Arena Therapeutics’ lorcaserin, were up for review by the FDA. This followed a long hiatus, since the FDA has approved no anti-obesity drug since 1999.

On July 15, 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted against FDA approval of the first of these three drugs to be reviewed, Vivus’ Qnexa (phentermine/topiramate). On September 16, 2010, the same Advisory Committee voted 9 to 5 against approval of the second drug up for review, lorcaserin (expected trade name, Lorqess).

The FDA usually follows the advice of its advisory panels, but does not always do so.

Lorcaserin is a selective serotonin receptor agonist, which is specific for the 5-HT2C serotonin receptor. This contrasts with the nonselective serotonin reuptake inhibitor and serotonin-releasing agents, fenfluramine and dexfenfluramine, which are notorious for their association with heart valve abnormalities. Lorcaserin is designed to be a more selective agent that works by a similar mechanism to dexfenfluramine or fenfluramine. The anorectic effect of fenfluramine/dexfenfluramine is due to their activity on 5-HT2C, but the adverse effects of these agents appears to be due to their activity on 5-HT2B. Therefore, lorcaserin is expected to be a safer agent that fenfluramine/dexfenfluramine.

However, like fenfluramine and dexfenfluramine, the efficacy of lorcaserin appears to be minimal. Pivotal Phase III clinical trials showed an average weight loss of 5.8% among subjects taking lorcaserin, as compared to 2.5% for the placebo group.

A Phase III clinical trial published in the New England Journal of Medicine (NEJM) in July 2010 showed that the drug caused significant weight loss and improved maintenance of weight loss as compared to placebo,  in a generally healthy obese population. Lorcaserin also improved values for such biomarkers as lipid levels, insulin resistance, inflammatory markers and blood pressure. A commentary by Arne Astrup, M.D. (University of Copenhagen, Denmark) published in the same issue of the NEJM concluded that lorcaserin appeared to have efficacy that was less than or equivalent to that of the two marketed antiobesity drugs, orlistat (Roche’s Xenical) and sibutramine (Abbott’s Meridia/Reductil). However, lorcaserin appeared to be safer than either of the two marketed drugs. (The clinical trials did not compare the drugs directly.) This it appeared to Dr. Astrup that lorcaserin might have a place in the management of obesity. However, he said that where the drug would fit in obesity management remained to be seen, and that it will be necessary to be “doubly sure” about the safety of lorcaserin, given the history of the obesity drug field.

The Advisory Committee noted that lorcaserin, although its efficacy was not great, met FDA efficacy criteria for approvable antiobesity drugs. However, some panelists thought that the study population consisted mainly of healthy obese individuals, and that in populations containing more patients with comorbidities (e.g., diabetes, cardiovascular disease) there might be a lesser degree of efficacy and/or additional safety issues. There is an ongoing study of lorcaserin in obese diabetics, which is expected to be reported by the end of 2010. However, some panelists thought that the trial population (600 patients) is too small to give meaningful results. This could mean that Arena–a company with limited resources–might need to rerun its Phase III trials in a patient population that includes more people with comorbidities.

Advisory Committee members also had various safety concerns. Animal studies indicated the potential for an increased risk of cancer, especially brain and breast tumors. A few panel members were concerned about the potential of lorcaserin to cause valvular heart disease, despite Arena’s efforts to avoid that problem via the design of the drug. Most panelists, however, saw no evidence of such a risk.

The induction of cancer in animals by a drug does not necessarily mean that the drug will cause tumors in humans. However, the animal results left many panelists uneasy. Some said that if the drug were approved, there would need to be an active surveillance program to look for possible brain and breast cancer in patients taking lorcaserin. Other panelists thought that there would need to be follow-up echocardiograms to check for valvular disease if the drug was marketed.

Many panelists felt that lorcaserin was a promising drug, but that the evidence that this drug’s benefits outweigh its risk was not there yet. Thus, as with Qnexa, lorcaserin might eventually be approved, if Arena can present additional data that can overcome Advisory Committee and FDA doubts.

The third preregistration antiobesity drug, Contrave (bupropion/naltrexone) is up for review by the same Advisory Committee in December 2010.

On September 15, 2010 (the day before it recommended against approval of lorcaserin), the Endocrinologic and Metabolic Drugs Advisory Committee voted 8 to 8 on whether sibutramine  should be allowed to remain on the market. This reflects the continuing controversies with sibutramine–the drug’s modest efficacy coupled with an increased risk of cardiovascular adverse effects, as discussed in our August 4 blog post. The eight panelists who recommended that sibutramine remain on the market stipulated that the drug’s label should carry additional warnings, and restrictions on who can prescribe the drug.

Sibutramine has already been withdraw from the market in Europe as of January 2010. The Advisory Panel recommendations on sibutamine not only put the drug’s future in doubt, but constitute an additional blow to the antiobesity drug market as a whole. The loss of sibutramine from the market–in the absence of any new antiobesity drug approvals–would leave only orlistat (Roche’s Xenical), a modestly efficacious drug with adverse effects that are unacceptable to many if not most patients.

Meanwhile, Gil Van Bokkelen, Ph.D., the Chairman and CEO of the biotech company Athersys (Cleveland, OH), told Fierce Biotech that the advisory panel’s rejection of lorcaserin should not affect the prospects for Athersys’ development of an antiobesity drug that is also a selective 5-HT2C receptor agonist. Dr. Van Bokkelen stated that he believes that the advisory panel decision was the result of some compound-specific issues with lorcaserin, and the approach that Arena took in developing that drug. He believes that these issues should not apply to Athersys’ preclinical 5-HT2C receptor agonist, which has shown more selectivity for the receptor. Moreover, he says that preclinical studies suggest that the Athersys drug may be more efficacious than lorcaserin.

An interesting strategic issue in the development and commercialization of late-stage antiobesty drugs is the role of Big Pharma. Both Arena’s lorcaserin and Orexigen’s Contrave have attracted Big Pharma commercialization partners–Eisai for lorcaserin and Takeda for Contrave. The two deals are similar. Arena granted Eisai exclusive rights to commercialize lorcaserin in the United States. Eisai paid Arena $50 million upfront, and is to pay Arena up to an additional $90 million in milestone payments, depending on FDA approval and sales of the drug. Similarly, Orexigen granted Takeda North American (U.S, Mexico, and Canada) marketing rights for Contrave; Orexigen retains copromotion rights in the United States. Takeda paid Orexigen $50 million upfront, and will pay (upon FDA approval) tiered double-digit royalties (starting at 20% and increasing to 35%) on any net sales of Contrave. The deal is estimated to be worth a potential $1 billion. In both cases, the Big Pharma partner will also share the costs of further development of these drugs.

In both agreements, the Japanese Big Pharma companies pay their biotech partners a relatively small upfront fee, and in turn receive U.S. (in the case of Contrave, North American) marketing rights. Substantial payments to the biotechs depend on FDA approval and on the drugs doing well in the market. Eisai and Takeda are thus making small initial payments for the right to market products with a high risk of failing to gain approval, but a high prospect of reward in terms of sales should they gain approval. The biotech partners gain financial support for further development of the drug, the credibility of having a Big Pharma partner, and upon approval, the strength of a partner with the resources necessary to market a primary care drug in the U.S./North America.

The Contrave deal is not Takeda’s only obesity partnership. In November 2009, Takeda entered into a worldwide agreement to codevelop and commercialize antiobesity drugs with Amylin (San Diego, CA). The agreement included Amylin’s Phase II agents, pramlintide/metreleptin and davalintide, as well as other, earlier-stage compounds from both companies’ obesity programs. Amylin received an upfront payment of $75 million, and is eligible to receive development, commercialization, and sales-based milestone payments that could exceed $1 billion. Amylin may also receive tiered, double-digit royalties on any future sales. Under the agreement, Amylin will be responsible for leading development through Phase II in the U.S., and Takeda will lead later-stage U.S. development and all development outside of the U.S. The companies will share the costs of development according to an agreed-upon formula.

In February 2010, Amylin and Takeda decided to halt development of davalintide, a second-generation amylin mimetic. In a Phase II study, the weight loss efficacy and tolerability profile of davalintide was not improved over pramlintide, Amylin’s first-generation amylin mimetic that is marketed as Symlin for treatment of diabetes. Amylin is a natural pancreatic peptide hormone that slows gastric emptying and promotes satiety. (Amylin the company was named after amylin the hormone.) Symlin is indicated to help diabetics who take insulin to improve their post-meal glycemic control; it can also help these patients to lose weight.

Also in February 2010, Amylin and Takeda announced that they had selected pramlintide/metreleptin for advancement toward Phase III development. This is a combination product containing pramlintide and metreleptin. Metreleptin is the recombinant methionine human leptin originally developed by Amgen as an antiobesity treatment. However, Amgen’s metreleptin program failed in Phase II trials because of leptin resistance. In 2006, Amgen licensed its leptin franchise to Amylin.

In 2008, Amylin researchers published a report containing evidence that administration of amylin to leptin-resistant diet-induced obese rats can restore leptin responsiveness to these leptin-resistant animals. Co-administration of amylin and metreleptin resulted in decreased feeding and increased weight loss, and that the combination treatment reduced feeding and weight to a greater extent than amylin treatment alone. The combination of amylin and leptin also resulted in increased energy expenditure.

In the same publication, the researchers also reported the results of a proof-of-concept study of pramlintide/metreleptin. In this 24-week randomized, double-blind, clinical trial in overweight/obese subjects, administration of the combination of metreleptin and pramlintide resulted in 12.7% mean weight loss (an average loss of 25 pounds), significantly more than was seen with either drug administered as a single agent.

Amylin later reported (on its website) the results of a 28-week Phase IIb study completed in late 2009 followed by a extension study to 52 weeks. Patients who continued treatment with pramlintide/metreleptin for the full 52 weeks exhibited sustained weight loss, whereas those who received placebo during the extension study regained almost all of their weight. The combination therapy appeared to be generally well tolerated.

Takeda’s obesity strategy thus combines a short-term “bet” on the approval of Orexigen’s Contrave, with the longer-term development of potentially more effective agents in collaboration with Amylin.

Now the immediate focus in the obesity drug area will be on the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting on Contrave in December, as well as what the FDA will do with the panel’s recommendations on sibutramine.

Meanwhile, as we stated in earlier blog posts, many companies have adopted the strategy of developing drugs that treat both diabetes and obesity, and developing the drugs for diabetes first. As the drugs prove themselves in the clinic, with respect to safety, antidiabetic efficacy, and effects on weight loss, companies may later develop them for obesity. Liraglutide (Novo Nordisk’s Victoza) is one such drug that has been approved for treatment of type 2 diabetes in both the United States and Europe. Novo Nordisk is now also developing the drug for obesity. However, most dual diabetes/obesity drugs are in early-stage development for diabetes. Early stage obesity drug development is mainly on hold, awaiting the regulatory approval of the three late-stage drugs now nearing NDA submission.

The apparent lack of regulatory success of Qnexa and lorcaserin will therefore be expected to keep development of most early-stage drugs for obesity on hold.

A notable exception is Zafgen’s ZGN-433, a methionine aminopeptidase inhibitor now in Phase I development, which targets the vasculature of adipose tissue. Zafgen (Cambridge, MA) goes against the conventional wisdom by dedicating itself to the development of novel antiobesity medicines, in the face of all the negativity surrounding that field. However, as we implied in our blog post on Qnexa, this negativity is mainly due to the relatively poor prospects for drugs that address appetite-control pathways in the CNS that involve common neurotransmitters. Such drugs often have unacceptable adverse effects, and may also have a low degree of efficacy due to the complex and redundant nature of CNS weight control pathways. Instead, we believe that drugs that address metabolic pathways involved in both obesity and diabetes may have a better chance of success. Zafgen’s R&D strategy involves targeting adipose tissue directly, rather than CNS appetite-control pathways.