In the 12 November issue of Nature, there was a research article and a News and Views minireview about targeting an intracellular signaling pathway with a novel type of compound called a stapled peptide.
Signaling pathways are crucial for cellular physiology, and in the pathobiology of important diseases ranging from metabolic diseases to cancer. In many cases, signaling proteins that work by binding to other proteins in protein-protein interactions are key control points in signaling pathways. However, protein-protein interactions in all but a few cases cannot be readily addressed with small molecule drugs. These targets are therefore called “undruggable”. Some signaling pathways consist entirely of these “undruggable” targets, and can only be addressed indirectly (if at all) via targeting other pathways that interact with them.
Several small-molecule drugs that do address protein-protein interactions are natural products. The best known of these is the immunosuppressant FK506 (tacrolimus, Astellas’ Prograf). This is one reason for the new interest in natural products by some companies and researchers, as we discussed in a previous blog post.
However, the 12 November Nature article, authored by James E Bradner (Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA, and the Dana-Farber Cancer Institute, Boston, MA), Gregory Verdine (Department of Chemical Biology, Harvard University, Cambridge MA, and the Dana-Farber Cancer Institute), and their colleagues, takes a different approach. The researchers target specific intracellular protein-protein interactions by designing special types of peptides known as stapled peptides.
The signaling pathway that is the focus of this article is the Notch pathway. In normal physiology, this pathway regulates various aspects of cell-cell communication, cellular differentiation, cell proliferation, and cellular survival or death. Deregulated Notch pathway function is involved in diseases including cancers of the lung, ovary and pancreas, and in T-cell acute lymphoblastic leukemia (T-ALL), which is a cancer of immature T cells.
Notch is a cell-membrane receptor. Binding of one of its ligands (on the surface of an adjacent cell) to the extracellular domain of Notch triggers sequential cleavage of the Notch intracellular domain by a metalloproteinase known as TACE (tumor necrosis factor alpha converting enzyme) and by γ-secretase (an enzyme which is also involved in the amyloid pathway that is implicated in Alzheimer’s disease). The free intracellular domain of Notch, called ICN, migrates to the nucleus, and docks with the DNA-bound transcription factor CSL. The interaction between CSL and ICN creates a groove along the interface of the two proteins, which serves as a docking site for the mastermind-like protein MAML1. The resulting trimolecular complex initiates specific transcription of Notch-dependent target genes.
The binding domain of MAML1 that engages the elongated groove formed by the ICN-CSL complex is in the form of an α-helix. The researchers therefore designed a series of peptides derived from portions of the sequence of the MAML1 binding domain. These were stapled peptides in which hydrocarbon moieties are used to constrain, or “staple”, MAML1 binding-domain mimetic sequences into an α-helical conformation. One such stapled peptide, SAMH1, gave the highest affinity binding to ICN and CSL, and competitively inhibited binding of wild-type MAML1 to these proteins.
SAMH1 was cell-penetrant, and inhibited intracellular Notch pathway signaling in cultured T-ALL cell lines. Moreover, SAMH1 reduced the proliferation of a variety of T-ALL cell lines in vitro, but was inactive against T-cell tumor lines that were not dependent on the Notch pathway for their proliferation. In SAMH1-sensitive T-cell tumor lines, SAMH1 treatment activated caspases, which are involved in apoptosis. In a mouse model of T-ALL, intraperitoneally injected SAMH1 inhibited leukemic progression, and inhibited Notch pathway signaling in leukemic cells in vivo.
Stapled peptides are not conventional “drug-like” compounds. Their molecular weights are several times greater than the 500-dalton maximum prescribed by Lipinski’s rules (developed by the leading medicinal chemist Chris Lipinski), which are used to define “drug-like” properties of small molecule compounds. Moreover, peptides are usually subject to protease degradation in vivo, and thus have short serum half-lives. In most cases, peptides do not enter into cells efficiently, except for those peptides that have specific cell-membrane receptors.
However, stapled α-helical peptides, in addition to their improved binding activities to their specific targets, are protease-resistant, have improved serum half-lives, and are cell penetrant. Researchers attribute these properties to the constrained conformation of these molecules, and to the hydrocarbon staples themselves. For example, the hydrocarbon staples may confer lipophilic properties to these molecules, and thus render them membrane-penetrant.
In an earlier study, Dr. Verdine and researchers at the Dana-Farber Cancer Institute and Children’s Hospital in Boston designed a stapled α-helical peptide that initiated apoptosis by specifically binding to and activating a member of the Bcl-2 family, and that inhibited the grown of leukemic cells in a mouse model. The researchers have been continuing to develop and to determine the mechanisms of action of their Bcl-2 family-targeting stapled peptides.
The discovery-stage biotechnology company Aileron Therapeutics was founded in 2005 to develop and commercialize stapled peptides. The company’s scientific founders include Dr. Verdine, Loren Walensky (Dana-Farber Cancer Institute), and the late Stanley J. Korsmeyer (Dana-Farber Cancer Institute, a pioneer in the study of the Bcl-2 family and its role in apoptosis and in the biology of cancer). It has a pipeline of stapled peptides that it is developing for the treatment of solid and hematological tumors, the most advanced of which are in the preclinical stage. Aileron has managed to attract venture capital despite the current adverse conditions--in June 2009, the company closed a $40 million Series D financing.
Stapled peptides represent an exciting and innovative technology with the potential to address “undruggable” protein-protein interactions, and thus to treat diseases that represent major unmet medical needs. However, this technology is in an early stage, and the therapeutic value of stapled peptides has not yet been confirmed in the clinic.
Friday, November 27, 2009
Sunday, November 8, 2009
Anti-aging biology: new basic research, drug development, and organizational strategy
In the 2 October issue of Science (the "Ardipithecus ramidus issue”), there was a Perspective (authored by Matt Kaeberlein and Pankaj Kapahi) and a Report (authored by Colin Selman and his colleagues) on recent findings in anti-aging biology.
Since the late 1980s, researchers have found that caloric restriction (CR) (reduction in caloric intake while maintaining essential nutrients) slows aging in a variety of organisms—yeasts, nematodes, fruit flies, mice, and most recently rhesus macaques. In the recently published 20-year study in rhesus macaques, CR not only increased lifespan, but also delayed the onset of a suite of aging-related disease conditions—diabetes, cancer, cardiovascular disease, and brain atrophy. This parallels the studies with other organisms.
Researchers who have been studying the CR model have been attempting to elucidate the mechanisms by which CR works to slow the aging process and to retard aging-related disease. They hope to find targets for drugs to mimic the effects of CR in humans, since long-term CR is not practical for most people. Over the years, researchers have discovered several pathways by which CR appears to exert its effects. The Report describes new research results on one such pathway, the mammalian target of rapamycin (mTOR) pathway. The Perspective reviews this research in the context of related recent studies.
In a report published in Nature earlier this year (16 July 2009), researchers found that rapamycin administered in food increased the median and maximal lifespan of genetically heterogeneous laboratory mice, whether it was fed to middle-aged (600 days old) or young adult (270 days old) mice. Rapamycin feeding beginning at 600 days of age led to an increase in lifespan of 14% for females and 9% for males, on the basis of age at 90% mortality.
Rapamycin targets mTOR (mammalian target of rapamycin), a kinase that regulates signaling pathways that affect many cellular processes. mTOR forms two protein complexes that are active in intracellular signaling—mTORC1 and mTORC2. It is mTORC1 that is most sensitive to rapamycin. mTORC1 works to coordinate cellular growth and survival responses induced by changes in the availability of nutrients, and also responses to cellular stresses (e.g., hypoxia, DNA damage and osmotic stress). Genetic inhibition of TORC1 in yeast and invertebrates has been found to extend their lifespan. In particular, in the nematode Caenorhabditis elegans, TORC1 interacts with the insulin pathway (via raptor, a component of TORC1) to control lifespan. The role of the insulin pathway in the enhancement of lifespan by CR in C. elegans has been known for many years. The role of mTORC1 at the junction of nutrient and stress sensing pathways, together with these results in invertebrates and now mice, has led researchers to hypothesize that the mTORC1 pathway may be involved in CR-mediated enhancement of lifespan, and that drugs that modulate this pathway may substitute for CR in lifespan extension.
In other studies, inhibition of the mTOR pathway in mice was found to retard development of such aging-related conditions as cancer, metabolic disease, and cardiovascular disease. This effect has also been seen in studies of CR in mice and in nonhuman primates, as stated above.
Rapamycin is an immunosuppressant that is marketed as Wyeth’s (now Pfizer’s, since the October 2009 merger) Rapimmune, to prevent organ transplant rejection. More recently, a derivative of rapamycin, temsirolimus (Wyeth/Pfizer’s Toricel) has been approved for treatment of renal cell carcinoma. The authors of the Nature paper therefore hypothesized that rapamycin may have extended lifespan in the mice either by working via CR-related pathways that control lifespan, by postponing death from cancer, or both.
The finding that oral rapamycin can retard aging in mice, even when fed to 600-day-old mice (the equivalent of 60 years old in humans) raises hope for the development of anti-aging drugs for human use. However, rapamycin itself cannot be used for this purpose because of its immunosuppressant effects. (In the mouse rapamycin feeding studies, the mice were kept under specific pathogen-free conditions.) If researchers were to attempt to modulate the mTORC1 pathway to extend lifespan, they would therefore need to discover other drugs that modulate that pathway without rapamycin’s side effects. Learning more about specific pathway components that may be targeted to increase lifespan may help researchers discover such drugs.
In the new Selman et al. report, researchers endeavored to learn more about how the mTORC1 pathway might extend lifespan in mice. They constructed knockout mice that lacked S6 protein kinase 1 (S6K1). S6K1 is a downstream target of mTORC1, which upregulates mRNA translation and protein synthesis in response to mTORC1 signaling. The researchers found that deletion of the gene for S6K1 resulted in a 19% increase in median lifespan in female mice (as compared to wild-type females), and also increased maximum lifespan. S6K1 deletion had no effect on the lifespan of male mice. This was in contrast to the study with rapamycin feeding, which showed lifespan extension in both sexes, even though the effect in female mice was greater. However, the results of the two studies are not strictly comparable, since mice of different genetic background were used in the two studies.
Female S6K1 knockout mice also showed improvement in several biomarkers of aging (e.g., motor and neurological function, level of physical activity, insulin sensitivity, glucose tolerance, fat mass, immunological parameters). Hepatic gene expression in 600-day-old female S6K1 knockout mice resembled that of wild type mice subjected to CR. Female S6K1 knockout mice showed increased hepatic, muscle, and adipose tissue expression (as compared to wild-type mice) of genes associated with other pathways associated with longevity, including genes for sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK).
Selman et al. went on to obtain evidence that the effect of S6K1 knockout on lifespan in female mice is due to activation of AMPK. The gene expression profile of muscle tissue of long-lived female S6K1 knockout mice resembled the profile of wild-type mice treated with the AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR). Hepatocytes from S6K1 knockout mice also showed enhanced AICAR activation of AMPK as compared to hepatocytes from wild type mice. A parallel study in C. elegans showed that deletion of the aak-2 gene, which encodes a subunit of AMPK, suppresses lifespan extension in mutants that lack rsks-1, the nematode homolog of S6K1. These results suggest that S6K1 knockout may exert its pro-longevity effects via activation of AMPK.
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. AMPK has been implicated in metabolic response to CR in eukaryotic organisms from yeasts to humans, and it mediates the effects on lifespan of at least one type of CR regimen in C. elegans. Thus the hypothesis that lifespan extension via the mTORC1-S6K1 pathway works via AMPK activation is an attractive one.
However, it is not known how deletion of S6K1 (or its inhibition via mTORC1 in rapamycin-treated mice) might activate AMPK. Moreover, as pointed out by Kaeberlein and Kapahi, there are other downstream targets of S6K1 that might play a role in anti-aging effects of SK61 deletion or inhibition. Among these is hypoxia-inducible factor-1α (HIF-1α). Moreover, there are other biomolecules and pathways that have been implicated in the effects of CR on retarding aging. These especially include the sirtuins, an evolutionarily conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases.
As shown by the Perspective and Report in the 2 October issue of Science, anti-aging research is an exciting area of basic biological research, and researchers still have much to learn about pathways that mediate the effects of CR on longevity. However, this field is already being applied to drug discovery and development. A basic issue in applying anti-aging research to the development of drugs is that one clearly cannot use increased lifespan as an endpoint in clinical trials. Companies must test putative anti-aging drugs against one or more diseases of aging. The hope is that any “anti-aging” drugs approved for treatment of one disease of aging 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).
The two principal types of “anti-aging” drugs currently in company pipelines are sirtuin modulators and AMPK activators. Sirtris Pharmaceuticals (Cambridge, MA, a wholly-owned subsidiary of GlaxoSmithKline [GSK]) is developing the SIRT1 activators SRT501 (a proprietary formulation of the natural product resveratrol) and SRT2104 (a novel synthetic small-molecule SIRT1 activator that is structurally unrelated to resveratrol and is up to 1000-fold more potent). SRT501 is in Phase II clinical trials in type 2 diabetes. SRT2104 has been tested in Phase I trials in healthy volunteers, and was found to be safe and well tolerated. Elixir Pharmaceuticals (Cambridge, MA) is developing a preclinical-stage SIRT1 inhibitor for treatment of Huntington’s disease and certain cancers, and a preclinical-stage SIRT1 activator for treatment of type 2 diabetes and obesity. Elixir also has a research-stage SIRT2 inhibitor under development for treatment of type 2 diabetes and obesity.
Companies developing AMPK activators include a collaboration between Metabasis Therapeutics (La Jolla, CA; about to be acquired by Ligand Pharmaceuticals, San Diego, CA) and Merck--preclinical oral AMPK activators, for treatment of type 2 diabetes and hyperlipidemia), Mercury Therapeutics (Woburn, MA)--research and preclinical-stage oral AMPK activators for treatment of type 2 diabetes, and Betagenon (Umea, Sweden)--the preclinical-stage oral AMPK activator BG8702, for treatment of type 2 diabetes.
The relationship between sirtuin-modulator developer Sirtris and GSK represents a prime example of the attempt of large pharmaceutical companies to become more “biotech-like” in order to improve their R&D performance. We discussed this strategy in our recent report, Approaches to Reducing Phase II Attrition. GSK acquired Sirtris for $720 million in June 2008. In December 2008, GSK announced that it had appointed Christoph Westphal, the CEO and co-founder of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD). The CEEDD works to develop external alliances with biotech companies, with the goal of acquiring promising new drug candidates for GSK’s pipeline. Michelle Dipp, who was the vice president of business development at Sirtris at the time of GSK’s appointment of Dr. Wesphal, is now Vice President and the head of the US CEEDD at GSK. Dr. Westphal, who is also a former venture capitalist, remains as CEO of Sirtris, and is based at Sirtris’ Cambridge location.
Thus anti-aging research, despite the fact that it is mainly in the basic research stage, is not only beginning to produce drug candidates, but has also been having an impact on the organizational strategy of one of the major pharmaceutical companies, GSK.
Since the late 1980s, researchers have found that caloric restriction (CR) (reduction in caloric intake while maintaining essential nutrients) slows aging in a variety of organisms—yeasts, nematodes, fruit flies, mice, and most recently rhesus macaques. In the recently published 20-year study in rhesus macaques, CR not only increased lifespan, but also delayed the onset of a suite of aging-related disease conditions—diabetes, cancer, cardiovascular disease, and brain atrophy. This parallels the studies with other organisms.
Researchers who have been studying the CR model have been attempting to elucidate the mechanisms by which CR works to slow the aging process and to retard aging-related disease. They hope to find targets for drugs to mimic the effects of CR in humans, since long-term CR is not practical for most people. Over the years, researchers have discovered several pathways by which CR appears to exert its effects. The Report describes new research results on one such pathway, the mammalian target of rapamycin (mTOR) pathway. The Perspective reviews this research in the context of related recent studies.
In a report published in Nature earlier this year (16 July 2009), researchers found that rapamycin administered in food increased the median and maximal lifespan of genetically heterogeneous laboratory mice, whether it was fed to middle-aged (600 days old) or young adult (270 days old) mice. Rapamycin feeding beginning at 600 days of age led to an increase in lifespan of 14% for females and 9% for males, on the basis of age at 90% mortality.
Rapamycin targets mTOR (mammalian target of rapamycin), a kinase that regulates signaling pathways that affect many cellular processes. mTOR forms two protein complexes that are active in intracellular signaling—mTORC1 and mTORC2. It is mTORC1 that is most sensitive to rapamycin. mTORC1 works to coordinate cellular growth and survival responses induced by changes in the availability of nutrients, and also responses to cellular stresses (e.g., hypoxia, DNA damage and osmotic stress). Genetic inhibition of TORC1 in yeast and invertebrates has been found to extend their lifespan. In particular, in the nematode Caenorhabditis elegans, TORC1 interacts with the insulin pathway (via raptor, a component of TORC1) to control lifespan. The role of the insulin pathway in the enhancement of lifespan by CR in C. elegans has been known for many years. The role of mTORC1 at the junction of nutrient and stress sensing pathways, together with these results in invertebrates and now mice, has led researchers to hypothesize that the mTORC1 pathway may be involved in CR-mediated enhancement of lifespan, and that drugs that modulate this pathway may substitute for CR in lifespan extension.
In other studies, inhibition of the mTOR pathway in mice was found to retard development of such aging-related conditions as cancer, metabolic disease, and cardiovascular disease. This effect has also been seen in studies of CR in mice and in nonhuman primates, as stated above.
Rapamycin is an immunosuppressant that is marketed as Wyeth’s (now Pfizer’s, since the October 2009 merger) Rapimmune, to prevent organ transplant rejection. More recently, a derivative of rapamycin, temsirolimus (Wyeth/Pfizer’s Toricel) has been approved for treatment of renal cell carcinoma. The authors of the Nature paper therefore hypothesized that rapamycin may have extended lifespan in the mice either by working via CR-related pathways that control lifespan, by postponing death from cancer, or both.
The finding that oral rapamycin can retard aging in mice, even when fed to 600-day-old mice (the equivalent of 60 years old in humans) raises hope for the development of anti-aging drugs for human use. However, rapamycin itself cannot be used for this purpose because of its immunosuppressant effects. (In the mouse rapamycin feeding studies, the mice were kept under specific pathogen-free conditions.) If researchers were to attempt to modulate the mTORC1 pathway to extend lifespan, they would therefore need to discover other drugs that modulate that pathway without rapamycin’s side effects. Learning more about specific pathway components that may be targeted to increase lifespan may help researchers discover such drugs.
In the new Selman et al. report, researchers endeavored to learn more about how the mTORC1 pathway might extend lifespan in mice. They constructed knockout mice that lacked S6 protein kinase 1 (S6K1). S6K1 is a downstream target of mTORC1, which upregulates mRNA translation and protein synthesis in response to mTORC1 signaling. The researchers found that deletion of the gene for S6K1 resulted in a 19% increase in median lifespan in female mice (as compared to wild-type females), and also increased maximum lifespan. S6K1 deletion had no effect on the lifespan of male mice. This was in contrast to the study with rapamycin feeding, which showed lifespan extension in both sexes, even though the effect in female mice was greater. However, the results of the two studies are not strictly comparable, since mice of different genetic background were used in the two studies.
Female S6K1 knockout mice also showed improvement in several biomarkers of aging (e.g., motor and neurological function, level of physical activity, insulin sensitivity, glucose tolerance, fat mass, immunological parameters). Hepatic gene expression in 600-day-old female S6K1 knockout mice resembled that of wild type mice subjected to CR. Female S6K1 knockout mice showed increased hepatic, muscle, and adipose tissue expression (as compared to wild-type mice) of genes associated with other pathways associated with longevity, including genes for sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK).
Selman et al. went on to obtain evidence that the effect of S6K1 knockout on lifespan in female mice is due to activation of AMPK. The gene expression profile of muscle tissue of long-lived female S6K1 knockout mice resembled the profile of wild-type mice treated with the AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR). Hepatocytes from S6K1 knockout mice also showed enhanced AICAR activation of AMPK as compared to hepatocytes from wild type mice. A parallel study in C. elegans showed that deletion of the aak-2 gene, which encodes a subunit of AMPK, suppresses lifespan extension in mutants that lack rsks-1, the nematode homolog of S6K1. These results suggest that S6K1 knockout may exert its pro-longevity effects via activation of AMPK.
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. AMPK has been implicated in metabolic response to CR in eukaryotic organisms from yeasts to humans, and it mediates the effects on lifespan of at least one type of CR regimen in C. elegans. Thus the hypothesis that lifespan extension via the mTORC1-S6K1 pathway works via AMPK activation is an attractive one.
However, it is not known how deletion of S6K1 (or its inhibition via mTORC1 in rapamycin-treated mice) might activate AMPK. Moreover, as pointed out by Kaeberlein and Kapahi, there are other downstream targets of S6K1 that might play a role in anti-aging effects of SK61 deletion or inhibition. Among these is hypoxia-inducible factor-1α (HIF-1α). Moreover, there are other biomolecules and pathways that have been implicated in the effects of CR on retarding aging. These especially include the sirtuins, an evolutionarily conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases.
As shown by the Perspective and Report in the 2 October issue of Science, anti-aging research is an exciting area of basic biological research, and researchers still have much to learn about pathways that mediate the effects of CR on longevity. However, this field is already being applied to drug discovery and development. A basic issue in applying anti-aging research to the development of drugs is that one clearly cannot use increased lifespan as an endpoint in clinical trials. Companies must test putative anti-aging drugs against one or more diseases of aging. The hope is that any “anti-aging” drugs approved for treatment of one disease of aging 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).
The two principal types of “anti-aging” drugs currently in company pipelines are sirtuin modulators and AMPK activators. Sirtris Pharmaceuticals (Cambridge, MA, a wholly-owned subsidiary of GlaxoSmithKline [GSK]) is developing the SIRT1 activators SRT501 (a proprietary formulation of the natural product resveratrol) and SRT2104 (a novel synthetic small-molecule SIRT1 activator that is structurally unrelated to resveratrol and is up to 1000-fold more potent). SRT501 is in Phase II clinical trials in type 2 diabetes. SRT2104 has been tested in Phase I trials in healthy volunteers, and was found to be safe and well tolerated. Elixir Pharmaceuticals (Cambridge, MA) is developing a preclinical-stage SIRT1 inhibitor for treatment of Huntington’s disease and certain cancers, and a preclinical-stage SIRT1 activator for treatment of type 2 diabetes and obesity. Elixir also has a research-stage SIRT2 inhibitor under development for treatment of type 2 diabetes and obesity.
Companies developing AMPK activators include a collaboration between Metabasis Therapeutics (La Jolla, CA; about to be acquired by Ligand Pharmaceuticals, San Diego, CA) and Merck--preclinical oral AMPK activators, for treatment of type 2 diabetes and hyperlipidemia), Mercury Therapeutics (Woburn, MA)--research and preclinical-stage oral AMPK activators for treatment of type 2 diabetes, and Betagenon (Umea, Sweden)--the preclinical-stage oral AMPK activator BG8702, for treatment of type 2 diabetes.
The relationship between sirtuin-modulator developer Sirtris and GSK represents a prime example of the attempt of large pharmaceutical companies to become more “biotech-like” in order to improve their R&D performance. We discussed this strategy in our recent report, Approaches to Reducing Phase II Attrition. GSK acquired Sirtris for $720 million in June 2008. In December 2008, GSK announced that it had appointed Christoph Westphal, the CEO and co-founder of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD). The CEEDD works to develop external alliances with biotech companies, with the goal of acquiring promising new drug candidates for GSK’s pipeline. Michelle Dipp, who was the vice president of business development at Sirtris at the time of GSK’s appointment of Dr. Wesphal, is now Vice President and the head of the US CEEDD at GSK. Dr. Westphal, who is also a former venture capitalist, remains as CEO of Sirtris, and is based at Sirtris’ Cambridge location.
Thus anti-aging research, despite the fact that it is mainly in the basic research stage, is not only beginning to produce drug candidates, but has also been having an impact on the organizational strategy of one of the major pharmaceutical companies, GSK.
Sunday, October 25, 2009
Liraglutide (Novo Nordisk’s Victoza) for treatment of obesity?
The field of obesity drugs has been a very difficult one for the pharmaceutical industry. Attempts to develop these drugs have been plagued by major safety failures, notably the notorious “Fen-Phen” case that led to market withdrawal and numerous lawsuits. More recently, rimonabant (Sanofi-Aventis’ Acomplia) failed to gain FDA approval due to psychiatric adverse effects, and the company also later withdrew the drug from the market in Europe. Currently marketed drugs have marginal efficacy and troublesome side effects. The complex physiology of weight control, and our inadequate knowledge of pathways that control energy balance, make development of effective agents difficult.
Moreover, there is a lingering perception that obesity is merely a “lifestyle issue” and a failure of “personal responsibility”. This is despite the consistent finding that weight is as heritable as height, and that there are physiological factors that militate against long-term, medically significant weight loss by overweight or obese individuals. These research results indicate that safe and efficacious obesity drugs will be necessary, in addition to diet and exercise, to ward off obesity and its comorbidities in the rapidly growing, worldwide overweight population.
Currently, late-stage drugs developed by three small California companies, Vivus Pharmaceuticals, Orexigen Therapeutics, and Arena Pharmacuticals, are approaching NDA submission. This follows a long hiatus, since the FDA has approved no anti-obesity drug since 1999. The companies hope that the drugs will reach the market in late 2010 or early 2011. All three drugs work in the brain to suppress appetite, as does the currently marketed prescription drug sibutramine (Abbott’s Meridia/ Reductil). The other current agent, orlistat, is available in prescription form as Roche’s Xenical, and in a low-dose over-the-counter form, GlaxoSmithKline’s alli. Orlistat works in the gut to reduce absorption of fats.
Now comes a report in the 23 October 2009 issue of the Lancet, comparing the effects of liraglutide (Novo Nordisk’s Victoza) and orlistat on weight loss in a 20-week double-blind, placebo-controlled Phase II trial in 564 obese healthy volunteers on a hypocaloric diet and increased physical activity. (A subscription is required to see the complete article). The researchers found that in the 20-week period, subjects on liraglutide lost a significant 4.8-7.2 kilograms (10.6-15.8 pounds), depending on the dose, as compared to 4.1 kilograms (9.0 pounds) on orlistat and 2.8 kilograms (6.2 pounds) on placebo. 76% of subjects on the 3.0-milligram/day dose of liraglutide lost over 5% of their body weight, as compared to 30% of subject on placebo. All doses of liraglutide reduced blood pressure, and the 1.8 mg through 3.0 mg doses reduced the prevalence of prediabetes (e.g., fasting plasma glucose above normal, but below that which is classified as diabetes) by between 84-96%. The most common side effects of liraglutide were nausea and vomiting, which usually occurred during the first month of treatment. However, these effects were mainly transient and rarely led to subjects discontinuing treatment. No serious adverse effects were seen.
In an open-label extension of the trial, subjects on liraglutide maintained their weight loss, according to Novo Nordisk. Additional questions need to be addressed, including whether subjects on liraglutide maintain their weight loss after they stop taking the drug.
Unlike the two currently marketed obesity drugs, liraglutide is administered via subcutaneous self-injection. Liraglutide was approved in Europe earlier this year, and is currently marketed in Europe for treatment of type 2 diabetes. However, it is awaiting FDA approval for that indication. It is not yet approved for treatment of obesity in any jurisdiction.
Liraglutide 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.
The first incretin mimetic to reach the market is exenatide (Amylin/Lilly’s Byetta), which is based on a Gila monster lizard salivary peptide and was approved for treatment of type 2 diabetes in 2005. Physicians sometimes prescribe exenatide off-label for treatment of obesity. Exenatide has a relatively short half-life, and must be self-injected twice a day. Amylin and Lilly are therefore developing a longer-acting, once-weekly formulation for treatment of type 2 diabetes. Researchers working with Amylin and Lilly also reported positive results of a clinical trial of exenatide in treatment of nondiabetics for obesity at a scientific meeting earlier this year. Amylin is also developing two earlier-stage biologics, pramlintide/metreleptin and davalintide, for treatment of obesity. Neither is an incretin mimetic.
Liraglutide is a GLP-1 analogue designed to bind to human serum albumin in the bloodstream, and thus has a longer half-life than exenatide, and is self-injected only once a day. Liraglutide is thus more convenient for patients to use than exenatide. The results of a study published in the Lancet earlier this year indicate that liraglutide is more effective than exenatide in long-term reduction in blood glucose (measured as hemoglobin A1c) in patients with type 2 diabetes.
The development of liraglutide for obesity represents part of a larger trend—the development of drugs that treat both type 2 diabetes and obesity. In the case of development of obesity drugs, the regulatory pathway for diabetes is easier than for obesity. Companies therefore tend to develop dual diabetes/obesity drugs first for diabetes. As the drugs prove themselves in the clinic, with respect to safety, antidiabetic efficacy, and effects on weight loss, companies may also develop them for obesity. This is the case with liraglutide.
In the case of treatment of type 2 diabetes, reducing weight in obese diabetics undergoing drug treatment is a major unmet need. Antidiabetics that also induce weight loss are therefore of special value. We discussed this issue in our 2008 article, “Addressing unmet type 2 diabetes needs”.
There are at least several companies with early stage dual diabetes/obesity drugs. These companies generally prefer to develop these drugs 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.
Novo Nordisk is also waiting to hear from the FDA regarding regulatory approval of liraglutide for treatment of type 2 diabetes before proceeding with further development of the drug for obesity.
We have produced two additional resources for understanding drug development in type 2 diabetes and obesity. These are, Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D and Obesity Drug Pipeline Report Overview, both published by Cambridge Healthtech Institute.
Moreover, there is a lingering perception that obesity is merely a “lifestyle issue” and a failure of “personal responsibility”. This is despite the consistent finding that weight is as heritable as height, and that there are physiological factors that militate against long-term, medically significant weight loss by overweight or obese individuals. These research results indicate that safe and efficacious obesity drugs will be necessary, in addition to diet and exercise, to ward off obesity and its comorbidities in the rapidly growing, worldwide overweight population.
Currently, late-stage drugs developed by three small California companies, Vivus Pharmaceuticals, Orexigen Therapeutics, and Arena Pharmacuticals, are approaching NDA submission. This follows a long hiatus, since the FDA has approved no anti-obesity drug since 1999. The companies hope that the drugs will reach the market in late 2010 or early 2011. All three drugs work in the brain to suppress appetite, as does the currently marketed prescription drug sibutramine (Abbott’s Meridia/ Reductil). The other current agent, orlistat, is available in prescription form as Roche’s Xenical, and in a low-dose over-the-counter form, GlaxoSmithKline’s alli. Orlistat works in the gut to reduce absorption of fats.
Now comes a report in the 23 October 2009 issue of the Lancet, comparing the effects of liraglutide (Novo Nordisk’s Victoza) and orlistat on weight loss in a 20-week double-blind, placebo-controlled Phase II trial in 564 obese healthy volunteers on a hypocaloric diet and increased physical activity. (A subscription is required to see the complete article). The researchers found that in the 20-week period, subjects on liraglutide lost a significant 4.8-7.2 kilograms (10.6-15.8 pounds), depending on the dose, as compared to 4.1 kilograms (9.0 pounds) on orlistat and 2.8 kilograms (6.2 pounds) on placebo. 76% of subjects on the 3.0-milligram/day dose of liraglutide lost over 5% of their body weight, as compared to 30% of subject on placebo. All doses of liraglutide reduced blood pressure, and the 1.8 mg through 3.0 mg doses reduced the prevalence of prediabetes (e.g., fasting plasma glucose above normal, but below that which is classified as diabetes) by between 84-96%. The most common side effects of liraglutide were nausea and vomiting, which usually occurred during the first month of treatment. However, these effects were mainly transient and rarely led to subjects discontinuing treatment. No serious adverse effects were seen.
In an open-label extension of the trial, subjects on liraglutide maintained their weight loss, according to Novo Nordisk. Additional questions need to be addressed, including whether subjects on liraglutide maintain their weight loss after they stop taking the drug.
Unlike the two currently marketed obesity drugs, liraglutide is administered via subcutaneous self-injection. Liraglutide was approved in Europe earlier this year, and is currently marketed in Europe for treatment of type 2 diabetes. However, it is awaiting FDA approval for that indication. It is not yet approved for treatment of obesity in any jurisdiction.
Liraglutide 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.
The first incretin mimetic to reach the market is exenatide (Amylin/Lilly’s Byetta), which is based on a Gila monster lizard salivary peptide and was approved for treatment of type 2 diabetes in 2005. Physicians sometimes prescribe exenatide off-label for treatment of obesity. Exenatide has a relatively short half-life, and must be self-injected twice a day. Amylin and Lilly are therefore developing a longer-acting, once-weekly formulation for treatment of type 2 diabetes. Researchers working with Amylin and Lilly also reported positive results of a clinical trial of exenatide in treatment of nondiabetics for obesity at a scientific meeting earlier this year. Amylin is also developing two earlier-stage biologics, pramlintide/metreleptin and davalintide, for treatment of obesity. Neither is an incretin mimetic.
Liraglutide is a GLP-1 analogue designed to bind to human serum albumin in the bloodstream, and thus has a longer half-life than exenatide, and is self-injected only once a day. Liraglutide is thus more convenient for patients to use than exenatide. The results of a study published in the Lancet earlier this year indicate that liraglutide is more effective than exenatide in long-term reduction in blood glucose (measured as hemoglobin A1c) in patients with type 2 diabetes.
The development of liraglutide for obesity represents part of a larger trend—the development of drugs that treat both type 2 diabetes and obesity. In the case of development of obesity drugs, the regulatory pathway for diabetes is easier than for obesity. Companies therefore tend to develop dual diabetes/obesity drugs first for diabetes. As the drugs prove themselves in the clinic, with respect to safety, antidiabetic efficacy, and effects on weight loss, companies may also develop them for obesity. This is the case with liraglutide.
In the case of treatment of type 2 diabetes, reducing weight in obese diabetics undergoing drug treatment is a major unmet need. Antidiabetics that also induce weight loss are therefore of special value. We discussed this issue in our 2008 article, “Addressing unmet type 2 diabetes needs”.
There are at least several companies with early stage dual diabetes/obesity drugs. These companies generally prefer to develop these drugs 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.
Novo Nordisk is also waiting to hear from the FDA regarding regulatory approval of liraglutide for treatment of type 2 diabetes before proceeding with further development of the drug for obesity.
We have produced two additional resources for understanding drug development in type 2 diabetes and obesity. These are, Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D and Obesity Drug Pipeline Report Overview, both published by Cambridge Healthtech Institute.
Monday, September 28, 2009
Bristol-Myers Squibb acquires monoclonal antibody leader Medarex
I was quoted in an article entitled “Bristol-Myers Squibb swallows last of antibody pioneers”, by Malorye Allison, in the September 2009 issue of Nature Biotechnology. The article focused on the monoclonal antibody sector, especially on the acquisition of Medarex by Bristol-Myers Squibb (BMS). The acquisition was completed on September 1. To read the article, go to http://www.nature.com/nbt/journal/v27/n9/full/nbt0909-781.html (subscription required).
In January, I gave a presentation to an RNAi conference, drawing lessons for the current therapeutic RNAi field from the evolution of the monoclonal antibody (MAb) field. This was discussed in a previous blog post, which focused on technological prematurity. In this blog post, we discuss the evolution of the MAb sector, how industry leaders emerged, and the acquisition of these leaders by large pharmaceutical and biotechnology companies.
MAbs are now the fastest-growing and most successful class of biologics. The majority of the MAbs on the market are indicated for oncology and inflammatory diseases. In 2005, MAbs accounted for 75% of antitumor biologics sales ($7.3B). Fueled by expanded indications and new products, MAbs are the major growth engine of the biologics sector, now and into the foreseeable future. Moreover, as we discussed in another previous blog post, leading biologics (all of which are MAbs) are on track to be the biggest-selling drugs in 2014. Large pharmaceutical companies thus have been seeking to acquire this highly successful class of drugs (including both marketed and pipeline MAbs), in order to fill their depleted pipelines and to make up for lost revenues due to current and impending patent expiries.
However, the MAb field was not always successful. Therapeutic MAbs went through nearly 20 years of scientific/technological prematurity.
The period of technological prematurity of MAbs lasted roughly from 1975 to 1994. Georges Köhler and César Milstein published the first paper on MAb technology in 1975, and they received a Nobel Prize for their work in 1984. The first MAb drug, Johnson & Johnson’s Orthoclone OKT3 was approved in 1986 for use in transplant rejection. However, this drug can only be used once in a patient due to its immunogenicity. There were not any further approvals of MAb drugs until 1994. The “deluge” of MAb drug approvals began in 1997, and has accelerated ever since. Prior to 1994, MAb technology represented great science, and it enabled researchers to make great strides in immunology, cancer research, the biology of HIV/AIDS, and other fields. (Some of this research was eventually applied to drug discovery, including the discovery of MAb drugs.) But during this period of scientific prematurity, any MAb drugs seemed to be in the distant future.
However, beginning in the early 1980s, several companies and academic labs began to develop enabling technologies designed to move this premature technology up the development curve. Among these companies were those that became the leaders In the MAb field.
The original MAbs were made via fusion of mouse B cells with murine myeloma cells, to create hybridomas. The MAbs secreted by these hybridomas contain all mouse sequences. They are highly immunogenic in humans, and are usually rapidly cleared from the circulation. They may also trigger allergic reactions and in some cases anaphylaxis. In order to create less immunogenic MAbs with the potential for efficacy and safety in humans, researchers used recombinant DNA technology to construct MAbs with mainly human sequences, but with the specific antigen-binding site of a mouse MAb.
The progression of MAb technology resulted in the following classes of products:
Among leading fully human MAb companies, Cambridge Antibody Technology utilized phage-display technology, and Abgenix and Medarex used humanized mouse technology. The great majority of marketed MAb cancer drugs are chimeric or humanized MAbs. The first fully human MAb cancer drug was approved by the FDA in 2006.
The development of MAb enabling technologies began in the early 1980s (early within the period of technological immaturity of MAb drugs). For example, Genentech’s broad Cabilly patents (issued in 1989 and 2001) resulted from the company’s collaboration with academic researchers beginning in the early 1980s. But Genentech’s first MAb products, the antitumor agents Rituxan (codeveloped with Idec) and Herceptin, did not reach the market until 1997 and 1998, respectively. Both are highly successful drugs.
The MAb sector has been characterized by a high degree of litigation over enabling technology patents (e.g., Genentech’s Cabilly patents vs. UCB Celltech’s Boss patent), and a great degree of cross-licensing of enabling technology patents, in part to settle or prevent lawsuits. From this history of technology development, patent disputes and cross-licensing, several MAb sector leaders emerged.
Over the course of the last several years, all of the public biotechnology companies that pioneered therapeutic MAb technology and become leaders in the field have been acquired. The acquisition of Medarex by BMS brings this process to a conclusion.
Are there any MAb companies that have yet to be acquired? The Nature Biotechnology article mentions several companies developing antibody conjugates, antibody fragments or antibody mimetics. However, there are also other still-independent firms that have developed proprietary technologies to produce full-length humanized or fully human MAbs. Among these are Facet Biotech (humanized MAbs), and Xoma, MorphoSys, BioInvent, and Dyax (all of which developed fully human MAb platforms based on phage display technology). Of these companies, Dyax is currently focusing on development of its proprietary non-antibody lead product, but also has a pipeline of proprietary research-stage MAbs and partnered research-stage and Phase I MAbs. The other companies are focusing solely on MAbs, and have pipelines of proprietary and partnered MAb drug candidates.
Of these companies, MorphoSys appears to have the strongest technology platform, and has used this platform to craft a unique business model that enables the company to be profitable even though it has not yet marketed a drug. Facet Biotech was spun out of PDL BioPharma last year. PDL, formerly known as Protein Design Labs, is a pioneer in humanized antibody technology, whose technology was used in the development of Genentech’s Herceptin and Avastin. In August 2009, Biogen Idec made an unsolicited offer to acquire Facet, which Facet rejected; the attempt of Biogen Idec to acquire Facet is still ongoing. Biogen Idec has been Facet’s partner since 2005, and the two companies have been codeveloping daclizumab, an anti-IL-2 receptor agent for treatment of multiple sclerosis (currently in Phase II clinical development), and volociximab, an anti-angiogenesis agent for treatment of solid tumors (also currently in Phase II). Except for Facet, none of these companies appears to be a near-term acquisition candidate.
Nevertheless, large pharmaceutical companies are continuing to work on building franchises in biologics, with an emphasis on MAb drugs. This is, for example, a factor in the Merck-Schering Plough and Pfizer-Wyeth mergers. Schering-Plough has had MAb alliances with such companies as MorphoSys and Xoma, and acquired Dutch company Organon (which had a collaboration in MAbs with Dyax) in 2007 in part because of its capabilities in biologics. Merck also acquired GlycoFi in 2006, for its capabilities in yeast-synthesized MAbs and other biologics. The newly merged Merck plans to make biologics a major focus of the company. Similarly, Pfizer acquired Wyeth in part because of its strength in biologics.
Thus, the acquisitions of the leaders in MAb technology represent an important part of a larger picture, the growing emphasis on biologics in large pharmaceutical companies, which have traditionally relied on small-molecule drugs.
In January, I gave a presentation to an RNAi conference, drawing lessons for the current therapeutic RNAi field from the evolution of the monoclonal antibody (MAb) field. This was discussed in a previous blog post, which focused on technological prematurity. In this blog post, we discuss the evolution of the MAb sector, how industry leaders emerged, and the acquisition of these leaders by large pharmaceutical and biotechnology companies.
MAbs are now the fastest-growing and most successful class of biologics. The majority of the MAbs on the market are indicated for oncology and inflammatory diseases. In 2005, MAbs accounted for 75% of antitumor biologics sales ($7.3B). Fueled by expanded indications and new products, MAbs are the major growth engine of the biologics sector, now and into the foreseeable future. Moreover, as we discussed in another previous blog post, leading biologics (all of which are MAbs) are on track to be the biggest-selling drugs in 2014. Large pharmaceutical companies thus have been seeking to acquire this highly successful class of drugs (including both marketed and pipeline MAbs), in order to fill their depleted pipelines and to make up for lost revenues due to current and impending patent expiries.
However, the MAb field was not always successful. Therapeutic MAbs went through nearly 20 years of scientific/technological prematurity.
The period of technological prematurity of MAbs lasted roughly from 1975 to 1994. Georges Köhler and César Milstein published the first paper on MAb technology in 1975, and they received a Nobel Prize for their work in 1984. The first MAb drug, Johnson & Johnson’s Orthoclone OKT3 was approved in 1986 for use in transplant rejection. However, this drug can only be used once in a patient due to its immunogenicity. There were not any further approvals of MAb drugs until 1994. The “deluge” of MAb drug approvals began in 1997, and has accelerated ever since. Prior to 1994, MAb technology represented great science, and it enabled researchers to make great strides in immunology, cancer research, the biology of HIV/AIDS, and other fields. (Some of this research was eventually applied to drug discovery, including the discovery of MAb drugs.) But during this period of scientific prematurity, any MAb drugs seemed to be in the distant future.
However, beginning in the early 1980s, several companies and academic labs began to develop enabling technologies designed to move this premature technology up the development curve. Among these companies were those that became the leaders In the MAb field.
The original MAbs were made via fusion of mouse B cells with murine myeloma cells, to create hybridomas. The MAbs secreted by these hybridomas contain all mouse sequences. They are highly immunogenic in humans, and are usually rapidly cleared from the circulation. They may also trigger allergic reactions and in some cases anaphylaxis. In order to create less immunogenic MAbs with the potential for efficacy and safety in humans, researchers used recombinant DNA technology to construct MAbs with mainly human sequences, but with the specific antigen-binding site of a mouse MAb.
The progression of MAb technology resulted in the following classes of products:
- Chimeric MAbs: mouse variable region and human constant region
- Humanized MAbs: mouse hypervariable regions and human framework regions and constant regions
- Fully human MAbs: human sequences only
Among leading fully human MAb companies, Cambridge Antibody Technology utilized phage-display technology, and Abgenix and Medarex used humanized mouse technology. The great majority of marketed MAb cancer drugs are chimeric or humanized MAbs. The first fully human MAb cancer drug was approved by the FDA in 2006.
The development of MAb enabling technologies began in the early 1980s (early within the period of technological immaturity of MAb drugs). For example, Genentech’s broad Cabilly patents (issued in 1989 and 2001) resulted from the company’s collaboration with academic researchers beginning in the early 1980s. But Genentech’s first MAb products, the antitumor agents Rituxan (codeveloped with Idec) and Herceptin, did not reach the market until 1997 and 1998, respectively. Both are highly successful drugs.
The MAb sector has been characterized by a high degree of litigation over enabling technology patents (e.g., Genentech’s Cabilly patents vs. UCB Celltech’s Boss patent), and a great degree of cross-licensing of enabling technology patents, in part to settle or prevent lawsuits. From this history of technology development, patent disputes and cross-licensing, several MAb sector leaders emerged.
Over the course of the last several years, all of the public biotechnology companies that pioneered therapeutic MAb technology and become leaders in the field have been acquired. The acquisition of Medarex by BMS brings this process to a conclusion.
Are there any MAb companies that have yet to be acquired? The Nature Biotechnology article mentions several companies developing antibody conjugates, antibody fragments or antibody mimetics. However, there are also other still-independent firms that have developed proprietary technologies to produce full-length humanized or fully human MAbs. Among these are Facet Biotech (humanized MAbs), and Xoma, MorphoSys, BioInvent, and Dyax (all of which developed fully human MAb platforms based on phage display technology). Of these companies, Dyax is currently focusing on development of its proprietary non-antibody lead product, but also has a pipeline of proprietary research-stage MAbs and partnered research-stage and Phase I MAbs. The other companies are focusing solely on MAbs, and have pipelines of proprietary and partnered MAb drug candidates.
Of these companies, MorphoSys appears to have the strongest technology platform, and has used this platform to craft a unique business model that enables the company to be profitable even though it has not yet marketed a drug. Facet Biotech was spun out of PDL BioPharma last year. PDL, formerly known as Protein Design Labs, is a pioneer in humanized antibody technology, whose technology was used in the development of Genentech’s Herceptin and Avastin. In August 2009, Biogen Idec made an unsolicited offer to acquire Facet, which Facet rejected; the attempt of Biogen Idec to acquire Facet is still ongoing. Biogen Idec has been Facet’s partner since 2005, and the two companies have been codeveloping daclizumab, an anti-IL-2 receptor agent for treatment of multiple sclerosis (currently in Phase II clinical development), and volociximab, an anti-angiogenesis agent for treatment of solid tumors (also currently in Phase II). Except for Facet, none of these companies appears to be a near-term acquisition candidate.
Nevertheless, large pharmaceutical companies are continuing to work on building franchises in biologics, with an emphasis on MAb drugs. This is, for example, a factor in the Merck-Schering Plough and Pfizer-Wyeth mergers. Schering-Plough has had MAb alliances with such companies as MorphoSys and Xoma, and acquired Dutch company Organon (which had a collaboration in MAbs with Dyax) in 2007 in part because of its capabilities in biologics. Merck also acquired GlycoFi in 2006, for its capabilities in yeast-synthesized MAbs and other biologics. The newly merged Merck plans to make biologics a major focus of the company. Similarly, Pfizer acquired Wyeth in part because of its strength in biologics.
Thus, the acquisitions of the leaders in MAb technology represent an important part of a larger picture, the growing emphasis on biologics in large pharmaceutical companies, which have traditionally relied on small-molecule drugs.
Thursday, September 17, 2009
Haberman Associates joins Innovalyst as an Affiliate
Haberman Associates has joined Innovalyst as an Affiliate.
Innovalyst is a North Carolina-based consulting consortium. It is led by four Managing Partners with over 20 years of industrial experience as executives at top-tier pharmaceutical or biotechnology companies. Innovalyst’s Intellectual Capital Advisory Network (ICAN) also includes over 75 Affiliates with an extraordinary breadth and depth of life science business skills.
Since 1997, Haberman Associates has been a member of the Biopharmaceutical Consortium (BPC), a Boston-based life science consulting network. We shall continue to maintain our membership in BPC, and our Boston-area location. However, we shall also expand our network to include Innovalyst. In addition to Haberman Associates, another BPC member, Trilogy Associates (headed by Joseph Kalinowski), is both a member of BPC and an Innovalyst Affiliate. Trilogy relocated to North Carolina in 2008.
Haberman Associates will maintain its primary focus on science and technology strategy, and on new product development via internal R&D and partnering. However, we shall be able to draw on our partners in BPC and Innovalyst to form project teams to take on larger, more complex projects requiring multiple areas of expertise, especially for large pharmaceutical and biotechnology companies. We shall also continue to serve life science clients of all sizes, from start-ups to major corporations.
If you have any questions about Haberman Associates and its expanded consulting network, or would like to discuss your company’s needs, please contact me.
Innovalyst is a North Carolina-based consulting consortium. It is led by four Managing Partners with over 20 years of industrial experience as executives at top-tier pharmaceutical or biotechnology companies. Innovalyst’s Intellectual Capital Advisory Network (ICAN) also includes over 75 Affiliates with an extraordinary breadth and depth of life science business skills.
Since 1997, Haberman Associates has been a member of the Biopharmaceutical Consortium (BPC), a Boston-based life science consulting network. We shall continue to maintain our membership in BPC, and our Boston-area location. However, we shall also expand our network to include Innovalyst. In addition to Haberman Associates, another BPC member, Trilogy Associates (headed by Joseph Kalinowski), is both a member of BPC and an Innovalyst Affiliate. Trilogy relocated to North Carolina in 2008.
Haberman Associates will maintain its primary focus on science and technology strategy, and on new product development via internal R&D and partnering. However, we shall be able to draw on our partners in BPC and Innovalyst to form project teams to take on larger, more complex projects requiring multiple areas of expertise, especially for large pharmaceutical and biotechnology companies. We shall also continue to serve life science clients of all sizes, from start-ups to major corporations.
If you have any questions about Haberman Associates and its expanded consulting network, or would like to discuss your company’s needs, please contact me.
Monday, September 7, 2009
More metabolic engineering/synthetic biology
In a previous blog post, we talked about the role of metabolic engineering and synthetic biology in facilitating a return to natural products as drug candidates in drug discovery and development. In the August 13 issue of Nature, George Church (Harvard Medical School) and his colleagues reported on their new method for accelerating the optimization of metabolic pathways to produce medically and industrially useful natural products.
The Church group calls its technology Multiplex Automated Genome Engineering (MAGE). MAGE is an efficient, inexpensive, automated system to simultaneously modify many targeted chromosomal locations (such as genes or regulatory elements) across a large population of cells, through the repeated introduction of synthetic oligonucleotides. A bacteriophage-mediated homologous recombination system is used to replace the targeted sequences with sequences of the introduced oligonucleotides. As the result of this process, researchers obtain a heterogeneous, highly diverse population of cells. Researchers may subject this population to selection for a desirable property, such as more efficient production of a desired product. The selected cells may then be subjected to additional rounds of MAGE, followed by additional rounds of selection. The result is the evolution of strains that efficiently produce the desired product. These strains may be scaled up to produce the product for research or commercial purposes.
The Church group chose to demonstrate their MAGE technology by optimizing a pathway in Escherichia coli for production of the carotenoid lycopene (the red pigment found in tomatoes and watermelons, which is valued as a nutraceutical). These researchers’ approach to utilizing and optimizing this pathway builds upon the work of leading metabolic engineers Jay Keasling (University of California at Berkeley) and Gregory Stephanopoulos (MIT).
Carotenoids such as lycopene are members of a larger class of compounds called isoprenoids. Another class of isoprenoids is the terpenoids. As discussed in our previous blog post, terpenoids include numerous marketed natural product drugs, and this class of compounds is also of interest to researchers interested in discovering novel drugs. Because of common pathways for biosynthesis of precursors of carotenoids and terpenoids, Church’s work on optimizing production of lycopene in E. coli is relevant to researchers interested in applying synthetic biology to the synthesis and study of terpenoid drugs.
The pathway in E. coli (and in other prokaryotes) for synthesis of isoprenoids is known as the DXP (deoxyxylulose-5-phosphate) pathway. This is in contrast to the better-known mevalonate pathway, which is found principally in eukaryotes and in archaea. We discussed Dr. Keasling’s engineering of the mevalonate pathway in yeast and in E. coli (the latter of which was engineered to express this exogenous pathway) to produce terpenoid drugs in our 2007 synthetic biology report. A review of work on metabolic engineering of both the mevalonate pathway and the DXP pathway by the Keasling group and by others can also be found in a 2007 paper by Drs. Withers and Keasling.
In order to utilize the E. coli DXP pathway to produce lycopene, researchers must engineer the bacteria to express the enzymes that catalyze the final steps in lycopene biosynthesis (i.e., the three enzymes that convert the final product of the DXP pathway to lycopene). The Church group transfected their starting E. coli strain with a plasmid containing the genes (derived from another species of bacterium) for these three enzymes. The resulting E. coli strain produced lycopene at a basal level. It was that strain that the researchers subjected to MAGE.
The researchers used the MAGE system to target each of 20 endogenous E. coli genes in the DXP pathway. For each gene, they designed 90-mer oligonucleotides that contained variants of the gene’s ribosome binding site (RBS), in order to replace the endogenous RBS with one that would give more efficient translation of mRNA into protein. They also designed oligonucleotides to knock out four endogenous genes that encode enzymes that siphon off intermediates from the DXP pathway, in order to increase the flux through the DXP pathway to improve lycopene production. The total pool of oligonucleotides was in the hundreds of thousands. The goal was to optimize 24 genes simultaneously in order to achieve maximal lycopene production.
The researchers added the cells and oligonucleotides to the MAGE system, cycling the cells through oligonucleotide delivery (via electroporation), growth, and washing cycles, yielding billions of genetic variants per day. Every 24 hours, the researchers selected the variants that produced the reddest colonies, and thus the most lycopene. After only three days, the procedure yielded variants that exhibited a fivefold greater lycopene production than the starting strain, with a greater yield (approximately 9,000 micrograms per gram dry cell weight) than previously documented.
E. coli strains with an optimized DXP pathway, as developed by the Church group, could in principle be used to produce other isoprenoid compounds, including terpenoid therapeutics. In order to do so, researchers would need to transfect specific sets of genes to carry out the final steps of the biosynthesis of their desired compounds into the strains, instead of the specific lycopene biosynthesis genes used by the Church group. They might also use methods such as the “designed divergent evolution” technology developed by the Keasling group, to develop variants of enzymes that carry out the final steps of the biosynthesis of terpenoids, in order to discover novel terpenoid drugs that are not found in nature.
MAGE, which allows researchers to simultaneously optimize the expression of large sets of genes in a metabolic pathway, contrasts with traditional metabolic engineering, which is typically a slow process in which genetic constructs are introduced into cells one at a time. It thus represents a potential advance. However, as in the above MAGE-based optimization of lycopene production, applications of MAGE to natural product drug discovery and production will build on the work of metabolic engineers who use more conventional methods.
The Church group calls its technology Multiplex Automated Genome Engineering (MAGE). MAGE is an efficient, inexpensive, automated system to simultaneously modify many targeted chromosomal locations (such as genes or regulatory elements) across a large population of cells, through the repeated introduction of synthetic oligonucleotides. A bacteriophage-mediated homologous recombination system is used to replace the targeted sequences with sequences of the introduced oligonucleotides. As the result of this process, researchers obtain a heterogeneous, highly diverse population of cells. Researchers may subject this population to selection for a desirable property, such as more efficient production of a desired product. The selected cells may then be subjected to additional rounds of MAGE, followed by additional rounds of selection. The result is the evolution of strains that efficiently produce the desired product. These strains may be scaled up to produce the product for research or commercial purposes.
The Church group chose to demonstrate their MAGE technology by optimizing a pathway in Escherichia coli for production of the carotenoid lycopene (the red pigment found in tomatoes and watermelons, which is valued as a nutraceutical). These researchers’ approach to utilizing and optimizing this pathway builds upon the work of leading metabolic engineers Jay Keasling (University of California at Berkeley) and Gregory Stephanopoulos (MIT).
Carotenoids such as lycopene are members of a larger class of compounds called isoprenoids. Another class of isoprenoids is the terpenoids. As discussed in our previous blog post, terpenoids include numerous marketed natural product drugs, and this class of compounds is also of interest to researchers interested in discovering novel drugs. Because of common pathways for biosynthesis of precursors of carotenoids and terpenoids, Church’s work on optimizing production of lycopene in E. coli is relevant to researchers interested in applying synthetic biology to the synthesis and study of terpenoid drugs.
The pathway in E. coli (and in other prokaryotes) for synthesis of isoprenoids is known as the DXP (deoxyxylulose-5-phosphate) pathway. This is in contrast to the better-known mevalonate pathway, which is found principally in eukaryotes and in archaea. We discussed Dr. Keasling’s engineering of the mevalonate pathway in yeast and in E. coli (the latter of which was engineered to express this exogenous pathway) to produce terpenoid drugs in our 2007 synthetic biology report. A review of work on metabolic engineering of both the mevalonate pathway and the DXP pathway by the Keasling group and by others can also be found in a 2007 paper by Drs. Withers and Keasling.
In order to utilize the E. coli DXP pathway to produce lycopene, researchers must engineer the bacteria to express the enzymes that catalyze the final steps in lycopene biosynthesis (i.e., the three enzymes that convert the final product of the DXP pathway to lycopene). The Church group transfected their starting E. coli strain with a plasmid containing the genes (derived from another species of bacterium) for these three enzymes. The resulting E. coli strain produced lycopene at a basal level. It was that strain that the researchers subjected to MAGE.
The researchers used the MAGE system to target each of 20 endogenous E. coli genes in the DXP pathway. For each gene, they designed 90-mer oligonucleotides that contained variants of the gene’s ribosome binding site (RBS), in order to replace the endogenous RBS with one that would give more efficient translation of mRNA into protein. They also designed oligonucleotides to knock out four endogenous genes that encode enzymes that siphon off intermediates from the DXP pathway, in order to increase the flux through the DXP pathway to improve lycopene production. The total pool of oligonucleotides was in the hundreds of thousands. The goal was to optimize 24 genes simultaneously in order to achieve maximal lycopene production.
The researchers added the cells and oligonucleotides to the MAGE system, cycling the cells through oligonucleotide delivery (via electroporation), growth, and washing cycles, yielding billions of genetic variants per day. Every 24 hours, the researchers selected the variants that produced the reddest colonies, and thus the most lycopene. After only three days, the procedure yielded variants that exhibited a fivefold greater lycopene production than the starting strain, with a greater yield (approximately 9,000 micrograms per gram dry cell weight) than previously documented.
E. coli strains with an optimized DXP pathway, as developed by the Church group, could in principle be used to produce other isoprenoid compounds, including terpenoid therapeutics. In order to do so, researchers would need to transfect specific sets of genes to carry out the final steps of the biosynthesis of their desired compounds into the strains, instead of the specific lycopene biosynthesis genes used by the Church group. They might also use methods such as the “designed divergent evolution” technology developed by the Keasling group, to develop variants of enzymes that carry out the final steps of the biosynthesis of terpenoids, in order to discover novel terpenoid drugs that are not found in nature.
MAGE, which allows researchers to simultaneously optimize the expression of large sets of genes in a metabolic pathway, contrasts with traditional metabolic engineering, which is typically a slow process in which genetic constructs are introduced into cells one at a time. It thus represents a potential advance. However, as in the above MAGE-based optimization of lycopene production, applications of MAGE to natural product drug discovery and production will build on the work of metabolic engineers who use more conventional methods.
Friday, August 21, 2009
Oligonucleotide Therapeutics at IBC Drug Discovery and Development Week
IBC’s Drug Discovery and Development Week was held in Boston on the first week of August, from August 3-6, 2009. This annual event, a highlight of the summer for the Boston biotech community, had always been called “DDT”, for “Drug Discovery Technology” conference. More recently, the name was changed to “Drug Discovery & Development of Innovative Therapeutics World Congress,” but the acronym “DDT” still stuck.
This year, IBC changed the format of the conference, hence the name change. The new format no longer was as technology focused, but emphasized drug discovery and the translation of discovery into clinical studies and onto the market. With our consulting group’s focus on science and technology strategy, biology-driven drug discovery and development, and improving the effectiveness of pharmaceutical and biotechnology R&D, I naturally liked the change in format. IBC also intended the conference to focus on networking and discussion of real drug discovery, scientific research, translational medicine, and business issues. As far as I’m concerned, the conference fulfilled that purpose as well. It was good to meet with friends and colleagues old and new, and to have substantive discussions. Even the booths in the exhibit hall were populated with company executives and researchers, as well as salespeople. It seems that the exhibitors got the point of the new conference format.
A highlight of the conference was the session on oligonucleotide therapeutics, focused on RNAi. At the conference, the RNAi biotech company RXi Pharmaceuticals (Worcester, MA) presented animal study data on its proprietary self-delivered rxRNA (sd-rxRNA) compounds, which are chemically modified RNAi molecules with self-delivering moieties. sd-rxRNAs are designed to be delivered to cells and tissues without a delivery vehicle. In vivo administration resulted in systemic delivery of sd-rxRNAs to the liver. There are many disease indications that could be potentially treated by specifically targeting disease pathways in the liver using oligonucleotide therapeutics such as sd-rxRNAs. sd-rxRNAs are compatible with subcutaneous administration, and thus might be self-administered by patients. The lack of the need for a delivery vehicle also potentially allows for lower manufacturing costs.
I attended the Industry Leadership Forum on RNA therapeutics on August 4. It was like “old home week”, since many of the panelists and attendees had attended (or spoken at) the RNAi conference in Cambridge MA in January at which I had also been a speaker. When I got up to ask a question at the end of the session, panel moderator Jim Thompson of Quark Pharmaceuticals recognized me and asked me a question in return.
One of the key discussions in the Leadership Forum concerned assessing progress in the therapeutic oligonucleotide field. Proof of principle has been achieved for aptamer drugs [pegaptanib (OSI/Eyetech/Pfizer’s Macugen) for treatment of age-related macular degeneration], and for antisense agents [fomivirsen (Isis/ Novartis Ophthalmics’ Vitravene), for treatment of cytomegalovirus retinitis in AIDS patients]. These are the two first oliogonucleotide drugs to reach the market, and both treat ophthalmologic diseases and are delivered locally. Another antisense drug, Isis/Genzyme’s mipomersen is a first-in-class apolipoprotein B (apoB) synthesis inhibitor currently in Phase III trials for treatment of homozygous familial hypercholesterolemia (FH). Miopomersen is one of Isis’ second-generation chemically modified antisense therapeutics. These compounds preferentially traffic to the liver when injected intravenously, without the need for a delivery vehicle.
The panel at the Leadership Forum predicted that an approved oligonucleotide blockbuster drug, which is likely to be a locally delivered or a liver-targeting drug, is about 2-3 years away. The approval of Quark’s systemically delivered kidney-targeting RNAi drug QPI-1002 (for acute kidney injury) may occur soon thereafter. The first microRNA drugs may be approved a year or two after that. Other systemically delivered oligonucleotide drugs that target organs and tissues other than liver or kidney are “a long way off”, and the timing of their appearance is difficult to predict. This is typical of a technologically premature field, as discussed in our earlier blog post. Early formulations of oligonucleotide drugs may also fail in Phase III, thus thwarting the panel’s predictions.
The panelists agreed that it is important to target the “low-hanging fruit” (i.e., products that are locally delivered or target the liver or kidney) first in order to get the momentum of the field going. However, researchers and companies should also look at other targets, especially if they are developing novel enabling technologies in drug delivery and/or in design of therapeutic oligonucleotides with enhanced potency and specificity.
This year, IBC changed the format of the conference, hence the name change. The new format no longer was as technology focused, but emphasized drug discovery and the translation of discovery into clinical studies and onto the market. With our consulting group’s focus on science and technology strategy, biology-driven drug discovery and development, and improving the effectiveness of pharmaceutical and biotechnology R&D, I naturally liked the change in format. IBC also intended the conference to focus on networking and discussion of real drug discovery, scientific research, translational medicine, and business issues. As far as I’m concerned, the conference fulfilled that purpose as well. It was good to meet with friends and colleagues old and new, and to have substantive discussions. Even the booths in the exhibit hall were populated with company executives and researchers, as well as salespeople. It seems that the exhibitors got the point of the new conference format.
A highlight of the conference was the session on oligonucleotide therapeutics, focused on RNAi. At the conference, the RNAi biotech company RXi Pharmaceuticals (Worcester, MA) presented animal study data on its proprietary self-delivered rxRNA (sd-rxRNA) compounds, which are chemically modified RNAi molecules with self-delivering moieties. sd-rxRNAs are designed to be delivered to cells and tissues without a delivery vehicle. In vivo administration resulted in systemic delivery of sd-rxRNAs to the liver. There are many disease indications that could be potentially treated by specifically targeting disease pathways in the liver using oligonucleotide therapeutics such as sd-rxRNAs. sd-rxRNAs are compatible with subcutaneous administration, and thus might be self-administered by patients. The lack of the need for a delivery vehicle also potentially allows for lower manufacturing costs.
I attended the Industry Leadership Forum on RNA therapeutics on August 4. It was like “old home week”, since many of the panelists and attendees had attended (or spoken at) the RNAi conference in Cambridge MA in January at which I had also been a speaker. When I got up to ask a question at the end of the session, panel moderator Jim Thompson of Quark Pharmaceuticals recognized me and asked me a question in return.
One of the key discussions in the Leadership Forum concerned assessing progress in the therapeutic oligonucleotide field. Proof of principle has been achieved for aptamer drugs [pegaptanib (OSI/Eyetech/Pfizer’s Macugen) for treatment of age-related macular degeneration], and for antisense agents [fomivirsen (Isis/ Novartis Ophthalmics’ Vitravene), for treatment of cytomegalovirus retinitis in AIDS patients]. These are the two first oliogonucleotide drugs to reach the market, and both treat ophthalmologic diseases and are delivered locally. Another antisense drug, Isis/Genzyme’s mipomersen is a first-in-class apolipoprotein B (apoB) synthesis inhibitor currently in Phase III trials for treatment of homozygous familial hypercholesterolemia (FH). Miopomersen is one of Isis’ second-generation chemically modified antisense therapeutics. These compounds preferentially traffic to the liver when injected intravenously, without the need for a delivery vehicle.
The panel at the Leadership Forum predicted that an approved oligonucleotide blockbuster drug, which is likely to be a locally delivered or a liver-targeting drug, is about 2-3 years away. The approval of Quark’s systemically delivered kidney-targeting RNAi drug QPI-1002 (for acute kidney injury) may occur soon thereafter. The first microRNA drugs may be approved a year or two after that. Other systemically delivered oligonucleotide drugs that target organs and tissues other than liver or kidney are “a long way off”, and the timing of their appearance is difficult to predict. This is typical of a technologically premature field, as discussed in our earlier blog post. Early formulations of oligonucleotide drugs may also fail in Phase III, thus thwarting the panel’s predictions.
The panelists agreed that it is important to target the “low-hanging fruit” (i.e., products that are locally delivered or target the liver or kidney) first in order to get the momentum of the field going. However, researchers and companies should also look at other targets, especially if they are developing novel enabling technologies in drug delivery and/or in design of therapeutic oligonucleotides with enhanced potency and specificity.
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