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.

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.

Genetic Engineering & Biotechnology News (GEN) featured my new article, entitled “Overcoming Phase II Attrition Problem”, on the top of Page One of its August 2009 edition.

Here is an image of Page One of the August 2009 issue.

And here am I, at the IBC Drug Discovery and Development Week conference (formerly known as DDT) in Boston, on Tuesday, August 4, holding a copy of the August issue. Thanks to Keri Dostie of IBC for taking this photo.

If you were at the conference, you may have read the article in one of the advance copies of the August GEN that were available there. Or you can look for your own copy, which you should receive in the mail shortly. More immediately, you can read the article by downloading the PDF on our website:

https://biopharmconsortium.com/GEN_PIIAtt_0809.pdf

The article discusses the most important challenge facing the pharmaceutical industry today, the need to improve R&D productivity. It outlines leading-edge strategies for reducing pipeline attrition and for increasing the number of drugs that reach the market and that address unmet medical needs.

If you need a more in-depth exposition, you may have your company order a copy of our May 2009 book-length report, Approaches to Reducing Phase II Attrition, an Insight Pharma Report published by Cambridge Healthtech Institute (CHI). The GEN article is based in part on that report.

You may discuss issues raised by the article or the report by leaving a comment on this blog post.

Thanks are in order to those who helped make the GEN article a success. Four industry executives were quoted in the article– Charles Gombar and Evan Loh of Wyeth, Bruce H Littman of Translational Medicine Associates, and Peter Lassota of Caliper Life Sciences. (Full transcripts of interviews with these and other executives are included in an appendix to the CHI Insight Pharma report.) Drs. Littman and Lassota also reviewed the article prior to publication.

Hearty thanks also to those who served as editors of the article—Laurie Sullivan and Al Doig at CHI and John Sterling and Tamlyn Oliver at GEN. Producing a lead article for GEN (or for other publications) requires an extra level of effort from editors as well as authors, so thanks to all who participated in this effort.

Interleukin-1 beta

Interleukin-1 beta

In a blog published by Harvard Business School, Scott Anthony discussed Novartis’ R&D strategy as an example of “disruptive innovation”.

Scott Anthony is president of Innosight, an innovation consulting, training, and investment firm. Innosight’s founder, Harvard Business School professor Clayton Christensen, is the originator of the concept of “disruptive innovation”. A disruptive innovation is an innovation that improves a product or service in ways that the market does not expect. An example is desktop publishing versus traditional publishing, or the automobile versus the horse and buggy.

In his blog post (dated June 18, 2009), Mr. Anthony cites the focus of Big Pharma on developing blockbuster drugs that target the largest disease conditions. This strategy has become increasingly ineffective, due to efficacy and safety failures despite every-larger R&D budgets. In contrast, he states that Novartis is attempting to develop the most effective drugs via an understanding of the mechanisms of a disease condition, no matter how small. These effective drugs can then be tested against larger indications, and may eventually become blockbusters.

We also discuss Novartis’ R&D strategy, in our new book-length report on improving the productivity of drug development, Approaches to Reducing Phase II Attrition, published in May by Cambridge Healthtech Institute.

Novartis’ drug discovery and development strategy is based on biochemical pathways. For example, Novartis researchers note that in many cases rare familial diseases are caused by disruptions of pathways that are also involved in more common, complex diseases. The researchers therefore develop drugs that target these pathways, and obtain proof-of-concept (POC) for these drugs by first testing them in small populations of patients with the genetic disease. Drugs that have achieved POC may later be tested in larger indications that involve the same pathway.

The first drug that Novartis has been developing using this strategy is the interleukin-1β inhibitor Ilaris (canakinumab). The company conducted its first clinical trials in patients with cryopyrin-associated periodic syndromes, (CAPS), a group of rare inherited auto-inflammatory conditions that are characterized by overproduction of IL-1β. In June 2009, the FDA approved Ilaris for treatment of CAPS. Novartis is currently testing Ilaris in more common diseases in which the IL-1β pathway is thought to play a major role, including rheumatoid arthritis.

In our report, we discuss Novartis’ strategy as part of a more general discussion of biology-driven drug discovery (i.e., drug discovery based on understanding of disease mechanisms), and of other strategies to reduce pipeline attrition.

Despite Mr. Anthony’s identification of Novartis’ strategy as an example of a novel “disruptive innovation”, biology-driven drug discovery and even pathway-based drug discovery is not a new strategy. For example, most biologics (mainly developed by biotech companies, with Genentech being the best example) have been developed via biology-driven R&D. Kinase inhibitors for treatment of cancer have been developed via pathway-based strategies, often utilizing years or decades of academic research on signaling pathways in normal and cancer cells. Novartis’ Gleevec (imatinib) is an example of such a kinase inhibitor—it was the example of Gleevec that led Novartis to adopt its pathway-based strategy in the first place.

Biology-driven drug discovery and development, whether practiced by Novartis or by other companies such as Genentech, is aimed at developing effective drugs as Mr. Anthony says. Moreover, leading biologics (e.g., Avastin, Humira, Rituxan, Enbrel, Herceptin) are now on track to be the biggest-selling drugs in 2014, according to the market research firm Evaluate Pharma.

Thus biology-driven drug discovery and development has become a commercial success for many companies, not just for Novartis.

We at Haberman Associates have been advocates of biology-driven drug R&D for over a decade, long before anyone labeled it a “disruptive strategy”. Rather than being a novel, disruptive strategy, it is a fairly old strategy that most large pharmaceutical companies bypassed in favor of industrialized drug R&D based on genomics and high-throughput screening. However, the latter strategy has been generally ineffective, and Big Pharma has had to turn increasingly to biology-driven biotech companies as sources of innovative drugs. Now Novartis’ pathway-based strategy is showing considerable success in building that company’s pipeline, and Roche is integrating itself with Genentech to become a biotech company that is a member of the Biotechnology Industry Organization (BIO) rather than the Pharmaceuticals Research and Manufacturers of America (PhRMA).

The case of biology-driven drug R&D is an example of how a largely overlooked older strategy may become disruptive, when applied in the right way. Are there overlooked strategies and technologies that might become the basis of your company’s R&D success?

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.